Composition, method for manufacturing the composition, molded article, and method for manufacturing the molded article.

Abstract

The present invention provides a method for obtaining a granular composition by wet granulation of a raw material powder composition containing a drug and crystalline cellulose, the method for producing the composition having good productivity and excellent uniformity, the composition produced by the said method, and a method for producing a molded article from the said composition. [Solution] The present invention relates to a method for producing a composition comprising a drug (A) and crystalline cellulose (B), comprising a granulation step of wet granulating a raw material powder composition comprising the drug (A) and the crystalline cellulose (B), wherein the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, and the wet granulation is performed with a ratio of the amount of material added to the airflow (amount of material added / airflow) of 4.0 g / (m 3 / h) or more 65.0g / (m 3 This is a method for producing a composition, which is carried out by fluidized bed granulation under granulation conditions of less than or equal to / h.

Description

[Technical Field]

[0001] The present invention relates to a composition comprising a drug and crystalline cellulose, a method for producing a composition comprising a drug and crystalline cellulose by wet granulation, and a method for producing a molded article from the composition. [Background technology]

[0002] Conventionally, tablets are manufactured by uniformly mixing a raw material powder composition containing a drug, excipients, and other additives, and then compressing the mixture using a tablet press. Furthermore, to improve the physical properties of tablets, or to improve the handling characteristics of difficult-to-handle powders, tablets may be manufactured by pre-granulating the drug together with excipients and other additives, compressing the resulting granules, or by further mixing the granules with other components to obtain a mixture, and then compressing the resulting mixture. Dry granulation and wet granulation methods are used for granulating the raw material powder composition.

[0003] Tablets are required to possess various properties, including uniformity of drug content, drug dissolution, disintegration, and hardness. To improve these properties, various modifications are being made to excipients and other additives. For example, Patent Document 1 describes how using cellulose powder with an average particle size and bulk density within a specific range as an excipient can yield tablets with excellent hardness, abrasion resistance, and disintegration. Patent Document 2 also describes how using cellulose powder with a high proportion of mannose and xylose in its sugar composition as an excipient can yield tablets with good disintegration while maintaining excellent active pharmaceutical ingredient recovery. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2020-180083 [Patent Document 2] International Publication No. 2020 / 202598 [Overview of the project] [Problems that the invention aims to solve]

[0005] In the pharmaceutical industry, there are increasing opportunities to improve productivity while ensuring quality in order to compensate for shortages in the supply of medicines. For example, in the granulation process of turning raw material powder compositions into granules, productivity can be expected to improve by increasing the amount of raw material powder composition used in a single granulation operation (the amount of material used in a single granulation operation). In addition, the amount of drug used in a single granulation operation can be adjusted by increasing the amount of material used in a single granulation operation or by increasing the proportion of drug in the raw material powder composition. However, in the case of fluidized bed granulation, increasing the amount of material used in a fluidized bed granulator worsens the fluidity of the raw material powder, making it difficult to granulate uniformly, so improvements have been needed.

[0006] The present invention has been made in view of the above circumstances, and provides a method for producing a granular composition by wet granulation of a raw material powder composition containing a drug and crystalline cellulose, the method being able to produce a composition with good productivity and excellent uniformity, a composition produced by the said method, and a method for producing a molded article from the said composition. [Means for solving the problem]

[0007] In other words, the present invention includes the following embodiments. [1] A method for producing a composition comprising a drug (A) and crystalline cellulose (B), The process includes a granulation step of wet granulating a raw material powder composition containing the drug (A) and the crystalline cellulose (B), The crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less. The aforementioned wet granulation process is performed when the ratio of the amount of material to the airflow (amount of material / airflow) is 4.0 g / (m 3 / h) or more 65.0g / (m 3 Granulation is performed by fluidized bed granulation under granulation conditions of less than or equal to / h. A method for producing a composition. [2] A method for producing the composition of [1], wherein the wet granulation is carried out under granulation conditions in which the ratio of the amount charged to the liquid velocity per spray gun (amount charged / (liquid velocity / number of spray guns)) is 3 min· units or more and 800 min· units or less. [3] A method for producing the composition according to [1] or [2], wherein the wet granulation is carried out under granulation conditions in which the spray pressure is 0.15 MPa or more and 0.60 MPa or less. [4] A method for producing any of the compositions described in [1] to [3] above, wherein the wet granulation is carried out under granulation conditions in which the inlet temperature is 50°C or higher and 90°C or lower. [5] A method for producing any of the compositions described in [1] to [4] above, wherein the wet granulation is carried out by fluid bed granulation using a column having a tapered cylindrical shape. [6] A method for producing any of the compositions described in [1] to [5] above, wherein the content ratio of drug (A) to the total amount of the raw material powder composition is 40% by mass or more. [7] A method for producing any of the compositions described in [1] to [6] above, wherein the content ratio of crystalline cellulose (B) to the total amount of the raw material powder composition is 5% by mass or more. [8] A method for producing any of the compositions described in [1] to [7] above, wherein the wet granulation is carried out under granulation conditions in which the amount of charge relative to the maximum processing capacity in a single granulation operation in a fluidized bed granulator (amount of charge / maximum processing capacity) is 0.20 or more and 1.00 or less. [9] A method for producing any of the compositions described in [1] to [8] above, wherein the wet granulation is carried out under granulation conditions in which the amount of input is 300 g or more and 1500 g or less.

[10] A method for producing a molded article, comprising producing a composition containing the drug (A) and the crystalline cellulose (B) by a method for producing any of the compositions described in [1] to [9] above, and molding the obtained composition to produce a molded article.

[11] The method for producing the

[10] , wherein the molded body is a tablet.

[12] A composition comprising a drug (A) and crystalline cellulose (B), wherein the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, and the proportion of particles (+2 mm) remaining on a sieve with a mesh size of 2 mm is 0.3% or less.

[13] A composition comprising a drug (A) and crystalline cellulose (B), wherein the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, and the content ratio of the drug (A) with respect to the total amount of the composition is 40% by mass or more, and which is a wet granulated product.

[14] A molded body comprising a wet granulated product containing a drug (A) and crystalline cellulose (B), wherein the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, a mass CV of 1% or less, and the number of molded bodies having white matter among 100 molded bodies is 5 or less.

[15] A composition comprising a drug (A) and crystalline cellulose (B), wherein the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, and which is a wet granulated product produced by the production method of any one of the compositions [1] to [9]. [Advantages of the Invention]

[0008] According to the above aspect, the raw material powder composition can be uniformly flowed in wet granulation. Therefore, according to the above aspect, even when the charged amount of the raw material powder composition is set larger than before, a composition excellent in uniformity can be provided. Further, a molded body including the composition and excellent in mass uniformity can also be provided. [Embodiments for Carrying Out the Invention]

[0009] Hereinafter, embodiments for carrying out the present invention (hereinafter simply referred to as "the present embodiment") will be described in detail. The following present embodiment is an exemplification for explaining the present invention and is not intended to limit the present invention to the following contents. The present invention can be appropriately modified and implemented within the scope of its gist.

[0010] [Production Method of Composition] The method for producing the composition according to this embodiment is a method for producing a composition comprising a drug (A) and crystalline cellulose (B), and includes a granulation step of wet granulating a raw material powder composition comprising the drug (A) and the crystalline cellulose (B). In the method for producing the composition according to this embodiment, the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, and the wet granulation is performed with a ratio of the amount of charge to the airflow (amount of charge / airflow) of 4.0 g / (m 3 / h) or more 65.0g / (m 3 Granulation is carried out by fluidized bed granulation under granulation conditions of less than or equal to / h. In the method for producing the composition according to this embodiment, by using crystalline cellulose (B) having a bulk density and compressibility within a specific range as an excipient, even when fluidized bed granulation is performed under granulation conditions with a relatively large input volume / airflow rate, the fluidity (intra-bed fluidity) of the raw material powder composition in the fluidized bed granulator is good, and uniform granulation can be achieved.

[0011] The various components of the method for manufacturing the composition according to this embodiment will be described in detail below.

[0012] [Drugs (A)] In this specification, "drug" refers to a substance added to a mixed powder, molded product, processed product, etc., to exert a desired function or effect in the fields of pharmaceuticals, health foods, food products, industrial applications, etc. For example, in the pharmaceutical field, this refers to the active pharmaceutical ingredient.

[0013] The following are examples of suitable drugs (A) used in the method for producing the composition according to this embodiment. The active ingredient in the drug is preferably the active ingredient of an orally administered drug. Examples of orally administered drugs include antipyretics, analgesics, and anti-inflammatory drugs, hypnotics and sedatives, anti-drowsiness drugs, anti-vertigo drugs, pediatric analgesics, stomachic drugs, antacids, digestive drugs, cardiac drugs, antiarrhythmic drugs, antihypertensive drugs, vasodilators, diuretics, anti-ulcer drugs, intestinal regulators, osteoporosis treatment drugs, antitussives and expectorants, anti-asthmatic drugs, antibacterial agents, frequent urination improvers, tonics, vitamins, etc. The active ingredient may be used alone or in combination of two or more.

[0014] Specifically, for example, aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapyrin, salicylamide, lactylphenetidine, isotibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimazine tartrate, diphenhydramine tannate, diphenylpyraline theoclate, mebhydrolyzed napadisylate Promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, dipheterol phosphate, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyverine citrate (carbetapentane citrate), tipepidine citrate, sodium dibnate, dextromethorphan hydrobromide, dextromethorphan phenolphthalic acid, tipepidine hibenzate, cloperastine fendisotate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl- Methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt, potassium guaiacolsulfonate, guaifenesin, sodium caffeine benzoate, caffeine, anhydrous caffeine, vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts, vitamin B6 and its derivatives and their salts, nicotinamide, calcium pantothenate, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel (as dried aluminum hydroxide gel), dried aluminum hydroxide gel, mixed dried aluminum hydroxide / magnesium carbonate gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, magnesium aluminometasilicate, ranitidine hydrochloride, cimetidine,Famotidine, naproxen, diclofenac sodium, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, promethazine hydrochloride, meclizine hydrochloride, dimenhydrinate, diphenhydramine tannate, phenetazine tannate, diphenylpyraline theoclate, diphenhydramine fumarate, promethazine methylenedisalicylate, spocola hydrobromide Min, oxyphencycline hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methylatropine bromide, methylanisotropine bromide, methylspocolamine bromide, methyl-1-hyoscyamine bromide, methylbenactidium bromide, belladonna extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, papaverine hydrochloride, aminobenzoic acid, cesium oxalate, ethyl piperidylacetylaminobenzoate, aminophylline, diprophylline, theof Fulin, sodium bicarbonate, fursultiamine, isosorbide dinitrate, ephedrine, cephalexin, ampicillin, sulfixazole, sucralfate, allyl isopropylacetylurea, bromovalerylurea, etc., Ephedra, Nandina, Parmesan, Polygala, Licorice, Platycodon, Plantago, Plantago asiatica, Senega, Fritillaria, Fennel, Phellodendron bark, Coptis japonica, Curcuma longa, Chamomile, Cinnamon, Gentian, Ox gall, Animal bile (including bear bile), Adenophora, Examples include ginger, atractylodes rhizome, clove, citrus peel, atractylodes rhizome, earthworm, bamboo shoot ginseng, ginseng, valerian, peony root bark, Japanese pepper and their extracts, as well as medicinal active ingredients listed in the "Japanese Pharmacopoeia," "Standards for Non-Pharmacopoeial Drugs (Non-Pharmacopoeial Standards)," "United States Pharmacopeia (USP)," "National Pharmaceutical Collection (NF)," and "European Pharmacopoeia (EP)," such as insulin, vasopressin, interferon, urokinase, serrathiopeptidase, and somatostatin. One of these medicinal active ingredients may be used, or two or more may be used in combination.

[0015] As a drug for health foods, it is not limited to any ingredient formulated for the purpose of enhancing health, but examples include: green juice powder, aglycone, agaricus, ashwagandha, astaxanthin, acerola, amino acids (valine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid), seaweed powder, glutamine, glutamic acid, glycine, proline (Serine, etc.), alginic acid, ginkgo leaf extract, sardine peptide, turmeric, uronic acid, echinacea, Eleutherococcus senticosus, oligosaccharides, oleic acid, nucleoprotein, bonito peptide, catechin, potassium, calcium, carotenoids, garcinia, L-carnitine, chitosan, conjugated linoleic acid, aloe vera, Gymnema sylvestre extract, citric acid, Orthosiphon erythrostictus, glycerides, glycerol, glucagon, curcumin, glucosamine, N-acetylglucoyl Samine, L-Glutamine, Chlorella, Cranberry Extract, Cat's Claw, Germanium, Enzymes, Korean Ginseng Extract, Coenzyme Q10, Collagen, Collagen Peptide, Coleus Forskohlii, Chondroitin, Psyllium Husk Powder, Hawthorn Extract, Saponin, Lipids, L-Cystine, Perilla Extract, Citrimax, Fatty Acids, Plant Sterols, Seed Extract, Spirulina, Squalene, White Willow, Ceramide, Selenium, St. John's Wort Soybean extract, soy isoflavones, soybean saponins, soybean peptides, soybean lecithin, monosaccharides, proteins, chaste tree extract, iron, copper, docosahexaenoic acid, tocotrienols, nattokinase, natto bacteria culture extract, sodium niacin, nicotinic acid, disaccharides, lactic acid bacteria, garlic, saw palmetto, germinated rice, Job's tears extract, herb extracts, valerian extract, pantothenic acid, hyaluronic acid, biotin, chromium picolinate, vitamin A, vitamin A2Examples of ingredients include vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, hydroxytyrosol, bifidobacteria, brewer's yeast, fructooligosaccharides, flavonoids, butcher's broom extract, black cohosh, blueberry, prune extract, proanthocyanidins, protein, propolis, bromelain, probiotics, phosphatidylcholine, phosphatidylserine, beta-carotene, peptides, safflower extract, maitake mushroom extract, maca extract, magnesium, milk thistle, manganese, mitochondria, minerals, mucopolysaccharides, melatonin, Phellinus linteus, sweet clover extract powder, molybdenum, vegetable powder, folic acid, lactose, lycopene, linoleic acid, lipoic acid, phosphorus, lutein, lecithin, rosmarinic acid, royal jelly, DHA, EPA, etc.

[0016] Drugs may be water-soluble or sparingly soluble. "Sparingly soluble" in the 18th edition of the Japanese Pharmacopoeia means that 30 mL or more of water is required to dissolve 1 g of solute.

[0017] Examples of water-insoluble, solid drugs include acetaminophen, ibuprofen, benzoic acid, ethenzamide, caffeine, camphor, quinine, calcium gluconate, dimethylcaprol, sulfamine, theophylline, theobromine, riboflavin, mephenesin, phenobervital, aminophylline, thioacetazone, quercetin, rutin, salicylic acid, sodium theophylline, pyrapital, quinine hydrochloride, irgapyrin, digitoxin, griseofulvin, phenacetin, and other antipyretic analgesics, neurological drugs, sedatives and hypnotics, muscle relaxants, antihypertensives, antihistamines, etc.; acetylspiramycin, ampicillin, erythromycin, xatamycin, chloramphenicol, triacetin Examples of medicinal active ingredients listed in the "Japanese Pharmacopoeia," "External Pharmacopoeia," "USP," "NF," and "EP" include: antibiotics such as ruoreandomycin, nystatin, and colistin sulfate; steroid hormones such as methyltestosterone, methylandrostetronidol, progesterone, estradiol benzoate, ethinirestradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, and prednisolone; nonsteroidal yolk hormones such as dienstrol, hexasastrol, diethylstilbesterol, diethylstilbesterol dibrohyonate, and chlorotrianicene; and other fat-soluble vitamins. One of these medicinal active ingredients may be used, or two or more may be used in combination.

[0018] The drug may be a water-insoluble oily or liquid. Examples of water-insoluble oily or liquid active ingredients in the drug include vitamins such as teprenone, indomethacin farnesyl, menatetrenone, phytonadione, vitamin A oil, phenipentol, vitamin D, and vitamin E; higher unsaturated fatty acids such as DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), and liver oil; coenzyme Q; and oil-soluble flavorings such as orange oil, lemon oil, and peppermint oil, as listed in the "Japanese Pharmacopoeia," "External Pharmacopoeia," "USP," "NF," and "EP." Vitamin E has various congeners and derivatives, and is not particularly limited as long as it is liquid at room temperature, but examples include dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, and d-α-tocopherol acetate. One of these drugs may be used, or two or more may be used in combination.

[0019] The drug may be a semi-solid active ingredient that is poorly soluble in water. Examples of water-insoluble, semi-solid substances in drugs include, for example, earthworm, licorice, cinnamon, peony, peony bark, valerian, Japanese pepper, ginger, citrus peel, ephedra, nandina fruit, oyster shell, galangal, balloon flower, plantago asiatica, plantago radish, seneca, fritillary, fennel, phellodendron bark, cow's roe, turmeric, chamomile, gentian, ox gall, animal bile, ginseng, ginger, lanceolata, clove, citrus peel, atractylodes, ginseng, ginseng, kakkonto, keishito, kososan, shihokukeito, shoshihoto, shoseiryuto, maimondoto, hankoto, hankoto, maoto, etc., as well as herbal medicines or herbal extracts such as oyster meat extract, propolis and propolis extract, and coenzyme Q. You may use one of these drugs, or you may use two or more in combination.

[0020] The drug may be sublimable. Examples of sublimable drugs include sublimable pharmaceutical active ingredients listed in the "Japanese Pharmacopoeia," "External Pharmacopoeia," "USP," "NF," and "EP," such as benzoic acid, ethenzamide, caffeine, camphor, salicylic acid, phenacetin, and ibuprofen. One of these drugs may be used, or two or more may be used in combination. In this specification, a sublimable drug is not particularly limited as long as it is sublimable, and it may be in any state, whether solid, liquid, or semi-solid at room temperature.

[0021] These drugs may be incorporated into the composition of this embodiment in a finely ground state. For example, the drugs used herein may have an average particle size D for purposes such as improving the dispersibility of the drug or improving the uniformity of the mixture of drugs that are effective in trace amounts. 50 Preferably, the particle size is 1 μm or more and 40 μm or less, more preferably 1 μm or more and 30 μm or less, and even more preferably 1 μm or more and 25 μm or less.

[0022] In the method for producing the composition according to this embodiment, the content of drug (A) in the raw material powder composition subjected to fluid bed granulation is preferably 10% by mass or more, more preferably 20% by mass or more and 95% by mass or less, even more preferably 30% by mass or more and 90% by mass or less, even more preferably 40% by mass or more and 85% by mass or less, and particularly preferably 40% by mass or more and 80% by mass or less.

[0023] In the method for producing the composition according to this embodiment, it is also preferable that the raw material powder composition contains a high amount of drug (A) from the viewpoint of improving productivity. For example, the content of drug (A) in the raw material powder composition is preferably 50% by mass or more, more preferably 60% by mass or more, even more preferably 65% ​​by mass or more, and even more preferably 70% by mass or more, based on the total amount of the composition. When the content of drug (A) in the raw material powder composition is high, the fluidity of the raw material powder composition deteriorates, and the intra-layer fluidity in fluidized bed granulation tends to deteriorate. In contrast, in the method for producing the composition according to this embodiment, since the intra-layer fluidity is improved, a uniform composition can be obtained by fluidized bed granulation even when the content of drug (A) in the raw material powder composition is high.

[0024] [Crystalline Cellulose (B)] Cellulose is a naturally occurring, water-insoluble fibrous substance that contains cellulose. In the method for producing the composition according to this embodiment, the crystalline cellulose (B) used can be crystalline cellulose obtained by hydrolysis treatment or the like from cellulose raw materials such as wood pulp, non-wood pulp, wheat straw, rice straw, cotton, cotton linter, hemp, ramie, bagasse, kenaf, beet, sea squirt, and bacterial cellulose. The cellulose raw material is preferably wood pulp or non-wood pulp, more preferably bleached wood pulp (BP), wood-dissolved pulp (DP), or cotton linter pulp, and more preferably bleached wood kraft pulp (BKP) or wood-dissolved kraft pulp (DKP). One of these may be used as the cellulose raw material, or a mixture of two or more may be used.

[0025] "Crystalline cellulose," also known as powdered cellulose, is suitably used as a pharmaceutical or food additive. The crystalline cellulose (B) used in the method for producing the composition according to this embodiment must at least meet the confirmation test for microcrystalline cellulose described in the 9th edition of the Japanese Food Additives Standards, and more preferably meet the confirmation test for crystalline cellulose described in the Japanese Pharmacopoeia (18th edition). It may also be crystalline cellulose described in the United States Pharmacopeia, the European Pharmacopoeia, etc. Furthermore, it may be crystalline cellulose treated with additives, such as silicic acid-treated crystalline cellulose (SMCC) described in the Japanese Pharmaceutical Additives Standards 2018.

[0026] The bulk density of the crystalline cellulose (B) used in the method for producing the composition according to this embodiment is 0.30 g / mL or less, preferably 0.10 g / mL or more and 0.30 g / mL or less, more preferably 0.15 g / mL or more and 0.30 g / mL or less, even more preferably 0.20 g / mL or more and 0.29 g / mL or less, and even more preferably 0.22 g / mL or more and 0.29 g / mL or less. In the method for producing the composition according to this embodiment, by having a bulk density of crystalline cellulose (B) contained in the raw material powder composition within the above range, the fluidity within the layer is good, and the powder layer can be flowed uniformly during fluid bed granulation. The bulk density of the crystalline cellulose can be measured using the method described in the examples below.

[0027] In the method for producing the composition according to this embodiment, the compressibility of the crystalline cellulose (B) used is 45.0% or less, preferably 20.0% to 45.0%, more preferably 22.0% to 42.5%, even more preferably 24.0% to 40.0%, and even more preferably 25.0% to 40.0%. In the method for producing the composition according to this embodiment, by having the compressibility of the crystalline cellulose (B) contained in the raw material powder composition within the above range, the fluidity within the layer is good, and the powder layer can be flowed uniformly during fluid bed granulation. The compressibility of the crystalline cellulose can be measured using the method described in the examples below.

[0028] In the method for producing the composition according to this embodiment, the content of crystalline cellulose (B) in the raw material powder composition used for fluid bed granulation is not particularly limited, but from the viewpoint of obtaining a higher effect of improving fluidity within the bed, it is preferably 5% by mass or more, more preferably 5% by mass or more and 60% by mass or less, even more preferably 10% by mass or more and 60% by mass or less, and even more preferably 15% by mass or more and 60% by mass or less, based on the total amount of the raw material powder composition. The content of crystalline cellulose (B) in the raw material powder composition is also preferably 20% by mass or more and 50% by mass or less, more preferably 25% by mass or more and 50% by mass or less, even more preferably 25% by mass or more and 40% by mass or less, and even more preferably 25% by mass or more and 35% by mass or less, based on the total amount of the composition.

[0029] (Method for producing crystalline cellulose (B)) Crystalline cellulose (B) can be produced, for example, by the method described in International Publication No. 2004 / 106416 (Reference 1). Specifically, crystalline cellulose (B) can be obtained, for example, by drying a cellulose dispersion obtained by dispersing a hydrolyzed natural cellulosic substance in a suitable medium. In this case, the solid component containing the hydrolyzed cellulosic substance may be isolated from the reaction solution obtained by the hydrolysis treatment, and the dispersion prepared by dispersing this separately in a suitable medium may be dried. Alternatively, if the hydrolysis solution already forms a cellulose dispersion, this dispersion may be dried directly.

[0030] Natural cellulosic substances can be plant-based or animal-based, and are fibrous materials derived from natural products containing cellulose, such as wood, bamboo, cotton, ramie, sea squirt, bagasse, kenaf, and bacterial cellulose, preferably having a cellulose type I crystalline structure. One of the above natural cellulosic substances may be used as a raw material, or a mixture of two or more may be used. Furthermore, it is preferable to use it in the form of refined pulp, but there are no particular restrictions on the method of refining the pulp, and any type of pulp such as dissolved pulp, kraft pulp, or NBKP pulp may be used.

[0031] The hydrolysis method may be acid hydrolysis, alkaline oxidative decomposition, hydrothermal decomposition, steam explosion, etc., and it is also possible to use one method alone or two methods in combination.

[0032] In the above manufacturing method, when the solid component containing the hydrolyzed cellulosic substance is dispersed in a suitable medium, there are no particular restrictions on the medium used as long as it is used industrially, but for example, water and / or an organic solvent may be used. Examples of organic solvents include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; and ketones such as acetone and ethyl methyl ketone. In particular, organic solvents used in pharmaceuticals are preferred, and those classified as solvents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nippo Co., Ltd.) are examples. Water and organic solvents may be used alone or in combination of two or more, and after dispersion in one medium, that medium may be removed and the mixture dispersed in a different medium.

[0033] The average particle size D of the cellulose dispersed particles present in the cellulose dispersion obtained in this manner. 50 The average particle size is preferably 10 μm or larger. Having an average particle size of 10 μm or larger allows for the production of cellulose powder (crystalline cellulose) with desirable properties by drying the cellulose dispersion. In particular, cellulose dispersions with an average particle size of less than 10 μm contain a relatively large amount of cellulose-dispersed fine particle components. These fine particle components undergo excessive impact on their surface during atomization, altering their surface structure. Therefore, drying a dispersion containing a large amount of these fine particle components may result in cellulose powder that lacks the desired properties. Thus, having an average particle size of 10 μm or larger prevents the inclusion of a relatively large amount of cellulose-dispersed fine particle components.

[0034] Alternatively, cellulose dispersion particles selected by sieving, or a dispersion containing these particles, may be dispersed separately in a suitable solvent. Furthermore, either method may be used alone or in combination. There are no particular restrictions on the drying method, but for example, freeze-drying, spray drying, drum drying, shelf drying, airflow drying, vacuum drying, and drying with an organic solvent are also acceptable.

[0035] [Other ingredients] In the method for producing the composition according to this embodiment, the raw material powder composition subjected to fluid bed granulation may contain other additives in addition to drug (A) and crystalline cellulose (B), as long as the effects of the present invention are not impaired. Examples of other additives include excipients, disintegrants, binders, fluidizers, lubricants, and flavoring agents.

[0036] Excipients other than crystalline cellulose (B) include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, pumice granules, inositol, ethylcellulose, ethylene vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrated silicon dioxide, dried yeast, dried aluminum hydroxide gel, dried sodium sulfate, dried magnesium sulfate. Agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, crospovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (granules), Aspergillus oryzae, synthetic aluminum silicate, synthetic hydrotalcite Sesame oil, wheat flour, wheat starch, wheat germ flour, rice flour, rice starch, potassium acetate, calcium acetate, cellulose phthalate acetate, safflower oil, bleached beeswax, zinc oxide, titanium dioxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium bitartrate, calcined gypsum, sucrose fatty acid ester, aluminum magnesium hydroxide, aluminum hydroxide gel, aluminum hydroxide sodium bicarbonate coprecipitate, hydroxide Magnesium, squalane, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, hydrogenated soybean oil, refined gelatin, refined shellac, refined sucrose, refined sucrose spherical granules, cetostearyl alcohol, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, unsaponifiable soybean, soybean lecithin, skim milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate,Low-substituted hydroxypropylcellulose, dextran, dextrin, natural aluminum silicate, corn starch, tragacanth powder, silicon dioxide, calcium lactate, lactose, lactose granules, Perfiller 101, white shellac, white petrolatum, white barley, sucrose, sucrose / starch spherical granules, hulless barley green leaf extract powder, hulless barley leaf green juice dried powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, phytic acid, glucose, glucose monohydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxy Examples of substances classified as excipients in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.) include polyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltitol, maltose, D-mannitol, corn syrup, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium aluminometasilicate, methylcellulose, cottonseed flour, cottonseed oil, Japan wax, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular corn starch, liquid paraffin, dl-malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate. These can be used individually or in combination of two or more types.

[0037] Examples of disintegrants include celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose; starches such as carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, and partially pregelatinized starch; and synthetic polymers such as crospovidone and crospovidone copolymer, which are classified as disintegrants in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.). One of the above may be used alone, or two or more may be used in combination.

[0038] Examples of binders include sugars such as sucrose, glucose, lactose, and fructose; sugar alcohols such as mannitol, xylitol, maltitol, erythritol, and sorbitol; water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin, sodium alginate, and gum arabic; celluloses such as crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, and methylcellulose; starches such as pregelatinized starch and starch paste; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and polyvinyl alcohol; and inorganic compounds such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminosilicate, which are classified as binders in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.). One of the above may be used alone, or two or more may be used in combination.

[0039] Examples of fluidizing agents include silicon compounds such as hydrated silicon dioxide and light anhydrous silicic acid, which are classified as fluidizing agents in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.). One of the above may be used alone, or two or more may be used in combination.

[0040] Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, and talc, which are classified as lubricants in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.). One of the above may be used alone, or two or more may be used in combination.

[0041] Examples of flavoring agents include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, and 1-menthol, which are classified as flavoring agents in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.). One of the above may be used alone, or two or more may be used in combination.

[0042] Examples of fragrances include those classified as flavorings or fragrances in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.), such as orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, peppermint oil, and green tea powder. One of the above may be used alone, or two or more may be used in combination.

[0043] Examples of coloring agents include food colorings such as Food Red No. 3, Food Yellow No. 5, and Food Blue No. 1, as well as substances classified as coloring agents in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.), such as sodium copper chlorophyll, titanium dioxide, and riboflavin. One of the above may be used alone, or two or more may be used in combination.

[0044] Examples of sweeteners include aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and amacha powder, which are classified as sweeteners in the "Dictionary of Pharmaceutical Additives 2016" (published by Yakuji Nippo Co., Ltd.). One of the above may be used alone, or two or more may be used in combination.

[0045] In the method for producing the composition according to this embodiment, the total content ratio of components other than the drug (A) and crystalline cellulose (B) in the raw material powder composition subjected to fluid bed granulation is not particularly limited, but is preferably 0% by mass or more and 45% by mass or less, more preferably 1% by mass or more and 40% by mass or less, even more preferably 1% by mass or more and 30% by mass or less, and even more preferably 1% by mass or more and 20% by mass or less, relative to the total amount of the raw material powder composition.

[0046] <Preparation of raw material powder composition> The raw material powder composition used in the method for producing the composition according to this embodiment is prepared by mixing drug (A), crystalline cellulose (B), and other components as needed. There are no particular restrictions on the order in which the components are added, and either i) a method of mixing drug (A), crystalline cellulose (B), and other additives as needed all at once, or ii) a method of pre-mixing drug (A) with additives such as fluidizers, and then mixing crystalline cellulose (B) and other additives as needed is acceptable. Due to the simplicity of the operation, i) is preferred.

[0047] There are no particular restrictions on the method of adding each component, as long as it is done using a commonly practiced method. However, the components may be added continuously using a small suction conveying device, pneumatic conveying device, bucket conveyor, pressure-feed conveying device, vacuum conveyor, vibrating metering feeder, spray, funnel, etc., or added all at once. There are no particular restrictions on the mixing method as long as it is a commonly used method, but container-rotating mixers such as V-type, W-type, double-cone type, and container-tuck type mixers; agitation type mixers such as high-speed agitation type, universal agitation type, ribbon type, pug type, and Nauter type mixers; high-speed fluidized mixers, drum type mixers, and fluidized bed mixers may also be used. Container-shaking mixers such as shakers may also be used.

[0048] <Wet granulation> The method for producing the composition according to this embodiment includes a granulation step of wet granulation of a raw material powder composition containing a drug (A) and crystalline cellulose (B). This granulation step yields a composition consisting of granules containing granules containing the drug (A) and crystalline cellulose (B).

[0049] In the method for producing the composition according to this embodiment, wet granulation is performed by a fluidized bed granulation method. The fluidized bed granulation method is a granulation method in which hot air is sent from the bottom of the granulation chamber (column), and a binder solution is sprayed from a spray nozzle into the fluidized bed where the powder (raw material powder composition) is flowing, causing the powder particles to adhere to each other and grow into a granular composition.

[0050] The binder solution is a solution obtained by dissolving one or more binders in a suitable solvent such as water or ethanol. The binders can be appropriately selected from those listed above. Furthermore, the binder solution may contain additives other than binders, such as colorants.

[0051] Fluidized bed granulation in the granulation process can be carried out using known fluidized bed granulators or improved devices thereof. For example, the granulation process in the composition manufacturing method according to this embodiment can be carried out using a fluidized bed granulator equipped with a cylindrical or substantially cylindrical column, a gas supply port for blowing gas into the column, an exhaust port for exhausting gas from the column, a raw material supply port for supplying the raw material powder composition to the column, and a spray nozzle for supplying a binder solution to the column. The raw material powder composition supplied to the column flows due to the gas supplied from the gas supply port. The binder solution sprayed from the spray nozzle adheres to the layer (fluidized bed) in which the raw material powder composition is flowing, forming a granular composition. The gas supply port is preferably located at the bottom of the column. The exhaust port can be located anywhere in the column, as long as it does not exhaust the powder in the column or the liquid supplied from the spray nozzle. There may be one spray nozzle or two or more.

[0052] It is preferable to use a column with a tapered cylindrical shape (a shape in which the lower part of the cylinder is narrowed). A layer in which the raw material powder composition flows (fluidized bed) is formed in the tapered portion, which allows for more efficient flow of the raw material powder composition by the gas supplied from the gas supply port at the bottom of the column.

[0053] In fluidized bed granulation, when the fluidity within the layer of the raw material powder composition is low, the raw material powder composition may stay in the column (a state where the flow of particles stagnates), or channeling may occur in the powder layer (a state where gas preferentially flows through locally generated passages inside the layer, and the dispersion of gas becomes extremely non-uniform). Due to the staying or channeling, the production efficiency of the granulated product deteriorates, and the uniformity of the obtained granulated product also decreases. Generally, the fluidity within the layer of the raw material powder composition tends to be improved when the amount of gas supplied to the column is increased, but it tends to deteriorate when the charged amount (the amount of the raw material powder composition supplied into the column in one granulation operation) increases.

[0054] In the method for producing the composition according to the present embodiment, wet granulation is carried out by fluidized bed granulation under granulation conditions where the ratio of the charged amount to the air volume (charged amount / air volume) is 4.0 g / (m 3 / h) or more and 65.0 g / (m 3 / h) or less. In the method for producing the composition according to the present embodiment, by using crystalline cellulose (B), the fluidity within the layer of the raw material powder composition is improved. Therefore, even under conditions where the charged amount with respect to the air volume of the gas is large, that is, when granulating a larger charged amount under the conventional air volume conditions, the powder layer can be uniformly fluidized during fluidized bed granulation, and fluidized bed granulation can be efficiently carried out. As the charged amount / air volume, 10.0 g / (m 3 / h) or more and 60.0 g / (m 3 / h) or less is preferable, 12.0 g / (m 3 / h) or more and 50.0 g / (m 3 / h) or less is more preferable, 12.0 g / (m 3 / h) or more and 40.0 g / (m 3 / h) or less is further preferable, and 12.0 g / (m 3 / h) or more and 30.0 g / (m 3 / h) or less is even more preferable.

[0055] In the method for producing the composition according to this embodiment, in addition to performing fluid bed granulation within a specific range for the amount of material added / airflow, the amount of material added relative to the maximum processing capacity in one granulation operation in the fluid bed granulator (amount of material added / maximum processing capacity) is preferably 0.20 or more, more preferably 0.23 or more, even more preferably 0.3 or more, and particularly preferably 0.4 or more. Furthermore, the amount of material added relative to the maximum processing capacity in one granulation operation in the fluid bed granulator (amount of material added / maximum processing capacity) is preferably 1.00 or less, more preferably 0.90 or less, even more preferably 0.85 or less, even more preferably 0.80 or less, and particularly preferably 0.70 or less. The amount of material added relative to the maximum processing capacity in one granulation operation in the fluid bed granulator (amount of material added / maximum processing capacity) is also preferably, for example, 0.20 to 1.00, 0.20 to 0.90, 0.30 to 0.85, or 0.40 to 0.80. Specifically, when the maximum processing capacity in a single granulation operation according to the specifications of the fluidized bed granulator is 1500g, it is preferable to perform granulation under conditions where the input amount is 300g or more. By performing the granulation under conditions where the input amount is within the above range, production efficiency can be further increased. Since channeling is less likely to occur, the input amount is more preferably 350g or more, even more preferably 450g or more, even more preferably 500g or more, and particularly preferably 600g or more. When the maximum processing capacity in a single granulation operation according to the specifications of the fluidized bed granulator is 1500g, the occurrence of stagnation and channeling is further suppressed, so the input amount is preferably 1500g or less, more preferably 1300g or less, even more preferably 1200g or less, and even more preferably 1000g or less. In the specifications of the fluidized bed granulator, when the maximum processing capacity in a single granulation operation is 1500g, the input amounts are preferably 300g to 1500g, 300g to 1300g, 500g to 1200g, or 600g to 1000g.

[0056] In the method for producing the composition according to this embodiment, in addition to performing fluid bed granulation within a specific range of charge / airflow, it is even more preferable to perform the granulation under conditions where the airflow relative to the maximum airflow specified in the specifications of the fluid bed granulator is preferably 0.25 to 1.00, more preferably 0.27 to 0.60, even more preferably 0.27 to 0.55, and even more preferably 0.30 to 0.55. Specifically, the maximum airflow specified in the specifications of the fluid bed granulator is 120 m³. 3 In the case of / h, the airflow is 30m 3 It is preferable to carry out granulation under conditions where the airflow rate is 30 m / h or higher. By flowing the raw material powder composition under conditions where the airflow rate is within the above range, the in-layer fluidity can be improved. More preferably, the airflow rate is 30 m 3 / h or more 120m 3 Preferably less than / h, and 35m 3 / h or more 70m 3 / h or less is more preferable, 35m 3 / h or more 65m 3 / h or less is even more preferable, and 40m 3 / h or more 65m 3 / h or less is even more preferable.

[0057] In the method for producing the composition according to this embodiment, in addition to performing fluid bed granulation within a specific range of charge / airflow, it is preferable to perform granulation under granulation conditions where the ratio of charge to liquid velocity per spray gun (charge amount / (liquid velocity / number of spray guns)) is 3 min· units or more and 800 min· units or less. By spraying the binder solution under conditions where charge amount / (liquid velocity / number of spray guns) is within the above range, the fluidity within the bed can be further improved. More preferably, charge amount / (liquid velocity / number of spray guns) is 20 min· units or more and 400 min· units or less, more preferably 40 min· units or more and 200 min· units or less, even more preferably 60 min· units or more and 100 min· units or less, and even more preferably 70 min· units or more and 90 min· units or less.

[0058] In the method for producing the composition according to this embodiment, it is preferable to perform fluid bed granulation within a specific range of charge / airflow, and furthermore, to perform granulation under conditions where the spray pressure is 0.15 MPa or more and 0.60 MPa or less. By spraying the binder solution under conditions where the spray pressure is within the above range, the fluidity within the bed can be improved. More preferably, the spray pressure is 0.10 MPa or more and 0.50 MPa or less, more preferably 0.15 MPa or more and 0.40 MPa or less, even more preferably 0.15 MPa or more and 0.30 MPa or less, and even more preferably 0.15 MPa or more and 0.20 MPa or less.

[0059] In the method for producing the composition according to this embodiment, it is preferable to perform fluid bed granulation within a specific range for the charge amount / airflow, and furthermore, to perform the granulation under conditions where the inlet temperature is 50°C or higher and 90°C or lower. By supplying gas to the column under conditions where the inlet temperature is within the above range, a wet granule with more uniform size and composition can be obtained. More preferably, the inlet temperature is 60°C or higher and 80°C or lower, and more preferably 70°C or higher and 80°C or lower.

[0060] The method for producing the composition according to this embodiment may further include a drying step after the granulation step to dry the wet granules obtained in the granulation step. The drying method for the wet granules is not particularly limited, and any of the following methods can be used: hot air heating type (shelf drying, vacuum drying, fluidized bed drying, etc.), conductive heat transfer type (flat pan type, shelf box type, drum type, etc.), or freeze drying. In the method for producing the composition according to this embodiment, it is preferable to use a hot air heating type drying apparatus that dries the wet granules with hot air, and fluidized bed drying is more preferable.

[0061] In the method for producing the composition according to this embodiment, the granulation and drying processes may be carried out using a continuous production system. A continuous production system is a continuous production technology that consistently carries out the processes from supplying the raw material powder composition to granulation and drying in a solid dosage form production process, which includes a wet granulation process in which a raw material powder composition containing a drug (A), crystalline cellulose (B), and other additives is granulated using water or a binder solution to obtain wet granules, and a drying process in which the obtained wet granules are dried to obtain tablet granules.

[0062] In the method for producing the composition according to this embodiment, fluid bed granulation is performed under conditions of good fluidity within the bed, allowing for uniform granulation. The resulting composition consists of wet granules with excellent uniformity in composition and size. Furthermore, the method for producing the composition according to this embodiment suppresses the formation of coarse particles, resulting in wet granules with a low coarse particle content. Moreover, when granulation is performed from a raw material powder composition with a high drug (A) content, the composition obtained by the method for producing the composition according to this embodiment consists of wet granules with a high drug (A) content.

[0063] <Composition> The composition according to this embodiment is a wet-process granule containing a drug (A) and crystalline cellulose (B), wherein the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less. The drug (A) and crystalline cellulose (B) used as raw materials in the method for producing the composition according to this embodiment can be used.

[0064] The composition according to this embodiment is a granule obtained by wet granulation. The composition according to this embodiment can be manufactured, for example, by the manufacturing method of the composition according to this embodiment.

[0065] In the composition according to this embodiment, the content of drug (A) relative to the total amount of the composition is preferably 40% by mass or more, more preferably 40% by mass or more and 85% by mass or less, and even more preferably 40% by mass or more and 80% by mass or less. Due to the high content of drug (A), the composition according to this embodiment is suitable as a raw material for molded articles with a high content of drug (A).

[0066] In this embodiment, the composition preferably has a percentage of particles (+2 mm) remaining on a sieve with a mesh opening of 2 mm of 0.3% or less, more preferably 0.2% or less, and even more preferably 0.1% or less. The composition in this embodiment has a small percentage of +2 mm particles and a low proportion of coarse particles. Therefore, by using the composition in this embodiment as a raw material, it is possible to manufacture a molded article with superior compositional uniformity.

[0067] <Method for manufacturing molded articles> The method for manufacturing a molded article according to this embodiment involves producing a raw material powder composition containing drug (A) and crystalline cellulose (B) using the composition manufacturing method according to this embodiment, and then molding the obtained composition to produce a molded article. Since the composition is made of granules with excellent uniformity of composition and size, a molded article with excellent uniformity of composition and mass can be obtained. In particular, when granulation is performed from a raw material powder composition with a high content of drug (A), a molded article can be obtained that is not only highly uniform but also has a high content of drug (A).

[0068] In the method for manufacturing a molded article according to this embodiment, the method for manufacturing the composition according to this embodiment is carried out, the obtained composition is mixed with other additives as necessary, and then molded to produce a molded article. Examples of other additives include excipients, disintegrants, binders, fluidizers, lubricants, etc. Examples of these include those listed as components that can be included in the raw material powder composition.

[0069] When other additives are also used as raw materials for the molded article, the proportion of the composition obtained from the method for producing the composition according to this embodiment is not particularly limited, but a practically preferable range is 99.5% by mass or less relative to the total mass of the molded article.

[0070] There are no particular restrictions on the order in which each component is added, nor are there any particular restrictions on the method of addition as long as it is a commonly used method. For example, the components may be added continuously using a small suction conveying device, pneumatic conveying device, bucket conveyor, pressure-feeding conveying device, vacuum conveyor, vibrating metering feeder, spray, funnel, etc., or they may be added all at once.

[0071] There are no particular restrictions on the mixing method as long as it is a commonly used method, but for example, container-rotating mixers such as V-type, W-type, double-cone type, and container-tuck type mixers; agitation type mixers such as high-speed agitation type, universal agitation type, ribbon type, pug type, and Nauter type mixers; high-speed fluidized mixers, drum type mixers, and fluidized bed mixers may be used. Container-shaking mixers such as shakers may also be used.

[0072] The molded article produced by the method for manufacturing a molded article according to this embodiment is not particularly limited and may be in any dosage form, such as granules, tablets, capsules, suspensions, or sprays.

[0073] Tablets are particularly preferred as molded articles produced by the manufacturing method of the molded article according to this embodiment. Since the composition obtained by the manufacturing method of the composition according to this embodiment is used as a raw material, tablets with excellent uniformity and a small coefficient of variation (mass CV) of mass can be obtained. In particular, because the composition has a small proportion of coarse particles, tablets with a small proportion of white material in the tablet can be obtained. Furthermore, by increasing the content of drug (A) in the raw material powder composition, a molded article with excellent uniformity and a high content of drug (A) can be obtained.

[0074] For example, tablets can be manufactured by mixing the composition obtained from the method for manufacturing the composition according to this embodiment with other additives as needed, and then compress-molding it. The compression molding method is not particularly limited as long as it is a commonly used method, but examples include a method of compressing and molding into a desired shape using a die and pestle, or a method of compressing into a sheet beforehand and then cutting into a desired shape. Examples of compression molding machines include roller-type presses such as static pressure presses, briquetting roller type presses, and smooth roller type presses, as well as single-punch tablet presses and rotary tablet presses.

[0075] The compressed tablets may be further coated. Examples of coating agents used in this case include those listed in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nippo Co., Ltd.). These coating agents may be used individually or in combination of two or more.

[0076] <Molded body> The molded article according to this embodiment is a molded article comprising a wet granule containing a drug (A) and crystalline cellulose (B), wherein the crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less. The molded article according to this embodiment can be manufactured, for example, by the manufacturing method of the molded article according to this embodiment, and it is more preferable to manufacture it using the composition according to this embodiment as a raw material.

[0077] The molded article according to this embodiment is not particularly limited and may be any dosage form, such as granules, tablets, capsules, suspensions, or sprays. Tablets are particularly preferred as the molded article according to this embodiment.

[0078] In this embodiment, it is preferable that the molded article has a mass CV of 1% or less and that the number of molded articles containing white material out of 100 articles is 5 or less. It is even more preferable that the mass CV is 1% or less and the number of molded articles containing white material out of 100 articles is 4 or less. By molding the composition of this embodiment, which has excellent compositional uniformity, it is possible to produce a molded article with excellent compositional uniformity. [Examples]

[0079] The embodiment will be described in detail below with reference to examples and comparative examples, but this embodiment is not limited thereto. The methods for measuring each physical property and evaluating the tablets in the examples and comparative examples are as follows.

[0080] <Method for measuring physical properties> The physical properties of the cellulose powder were measured using the method described below.

[0081] [Physical Properties 1] (Bulk density) The "loose bulk density" was measured using a powder properties evaluation device (powder tester, manufactured by Hosokawa Micron). The sieve opening was set to 710 μm.

[0082] [Physical Properties 2] (Degree of compression) The "loose bulk density" and "firm bulk density" were measured using a powder properties evaluation device (powder tester, manufactured by Hosokawa Micron), and the degree of compression was measured using the following formula. The sieve opening was 710 μm.

[0083] [Compression (%)] = ([Bulk density of firm material (g / mL)] - [Bulk density of loose material (g / mL)]) / [Bulk density of firm material (g / mL)] × 100

[0084] [Physical Properties 3] (Intra-layer liquidity) Using a fluidized bed granulator (Multiplex, MP-01, manufactured by Powrec), the airflow was set to 45 m³ during empty operation (no raw material powder composition was loaded, load amount was 0 g). 3 The airflow scale was set to a value of / h. Furthermore, the raw material powder composition was cellulose powder, and under the condition of a input amount of 800g, the flow state of the cellulose powder in the column was observed, and the in-column fluidity was evaluated according to the following criteria. The maximum processing capacity in a single granulation operation of this fluidized bed granulator was 1500g.

[0085] <Evaluation of intra-strand liquidity> ◎: It flowed. ○: There was some stagnation, but it flowed. ×: There was a problem (it wasn't flowing, or there was channeling or stagnation).

[0086] [Manufacturing Example 1] (Manufacturing of Cellulose Powder A) 2.0 kg of commercially available pulp (average degree of polymerization 1030) was shredded and placed in 30 L of 4N hydrochloric acid aqueous solution. Hydrolysis was carried out at 40°C for 35 hours while stirring with a low-speed stirrer to obtain an acid-insoluble residue. The obtained acid-insoluble residue was filtered using a Nutsche filter, neutralized with ammonia water, placed in a 90 L plastic bucket, and pure water was added. A cellulose dispersion with a solid content of 20% by mass was prepared by stirring with a 3-One motor (type 1200G, 8M / M, blade diameter approximately 5 cm: HEIDON) at a stirring speed of 100 rpm. This cellulose dispersion was spray-dried (liquid supply rate 6 L / hour, inlet temperature 180°C to 220°C, outlet temperature 50°C to 70°C) to obtain cellulose powder A.

[0087] [Manufacturing Example 2] (Manufacturing of Cellulose Powder B) 2.0 kg of commercially available pulp (degree of polymerization 710) was shredded and placed in 30 L of 0.11 N hydrochloric acid aqueous solution. Hydrolysis was carried out at 150°C for 60 minutes while stirring with a low-speed stirrer to obtain an acid-insoluble residue. The obtained acid-insoluble residue was filtered using a Nutsche filter, neutralized with ammonia water, placed in a 90 L poly bucket, and pure water was added. A cellulose dispersion with a solid content of 5% by mass was prepared by stirring with a 3-One motor (type 1200G, 8M / M, blade diameter approximately 5 cm: manufactured by HEIDON) at a stirring speed of 500 rpm. This cellulose dispersion was spray-dried (liquid supply speed 6 L / hour, inlet temperature 180°C to 220°C, outlet temperature 50°C to 70°C) to obtain cellulose powder B.

[0088] [Manufacturing Example 3] (Manufacturing of Cellulose Powder C) 2.0 kg of commercially available pulp (degree of polymerization 790) was shredded and placed in 30 L of 4N hydrochloric acid aqueous solution. Hydrolysis was carried out at 40°C for 45 hours while stirring with a low-speed stirrer to obtain an acid-insoluble residue. The obtained acid-insoluble residue was filtered using a Nutsche filter, neutralized with ammonia water, placed in a 90 L plastic bucket, and pure water was added. A cellulose dispersion with a solid content of 10% by mass was prepared by stirring with a 3-One motor (type 1200G, 8M / M, blade diameter approximately 5 cm: HEIDON) at a stirring speed of 100 rpm. This cellulose dispersion was spray-dried (liquid supply speed 6 L / hour, inlet temperature 180°C to 220°C, outlet temperature 50°C to 70°C) to obtain cellulose powder C.

[0089] [Manufacturing Example 4] (Manufacturing of Cellulose Powder D) 2.0 kg of commercially available pulp (degree of polymerization 1030) was shredded and placed in 30 L of 0.14 N hydrochloric acid aqueous solution. Hydrolysis was carried out at 123°C for 1 hour while stirring with a low-speed stirrer to obtain an acid-insoluble residue. The obtained acid-insoluble residue was filtered using a Nutsche filter, neutralized with ammonia water, placed in a 90 L plastic bucket, and pure water was added. A cellulose dispersion with a solid content of 17% by mass was prepared by stirring with a 3-One motor (type 1200G, 8M / M, blade diameter approximately 5 cm: HEIDON) at a stirring speed of 500 rpm. This cellulose dispersion was spray-dried (liquid supply speed 6 L / hour, inlet temperature 180°C to 220°C, outlet temperature 50°C to 70°C) to obtain cellulose powder D.

[0090] [Manufacturing Example 5] (Manufacturing of Cellulose Powder E) 2.0 kg of commercially available pulp (degree of polymerization 790) was shredded and placed in 30 L of 4N hydrochloric acid aqueous solution. Hydrolysis was carried out at 40°C for 24 hours while stirring with a low-speed stirrer to obtain an acid-insoluble residue. The obtained acid-insoluble residue was filtered using a Nutsche filter, neutralized with ammonia water, placed in a 90 L plastic bucket, and pure water was added. A cellulose dispersion with a solid content of 10% by mass was prepared while stirring with a three-one motor (stirring speed 5 rpm). This cellulose dispersion was spray-dried (liquid supply speed 6 L / hour, inlet temperature 180°C to 220°C, outlet temperature 50°C to 70°C) to obtain cellulose powder E.

[0091] The bulk density, compressibility, and intralayer fluidity of each crystalline cellulose were measured. The results are shown in Table 1.

[0092] [Table 1]

[0093] [Example 1] to [Example 5], [Comparative Example 1] to [Comparative Example 4] The fluidity within a fluidized bed granulator was investigated for a raw material powder composition containing ethenzamide, a poorly soluble drug, and crystalline cellulose.

[0094] As ethenzamide, we used Grade A (hereinafter sometimes referred to as "Etz-A") and Grade P (hereinafter sometimes referred to as "Etz-P") manufactured by Yamamoto Chemical Industry Co., Ltd. As the crystalline cellulose powder, the cellulose powder obtained in Production Examples 1 to 5 was used.

[0095] Raw material powder compositions with the compositions and quantities listed in Tables 2 and 3 were prepared. Next, a fluidized bed granulator (Multiplex, MP-01, manufactured by Powrec) was used, with the airflow rates set to those listed in Tables 2 and 3. The fluidity of the raw material powder composition in the column was observed, and the intra-column fluidity was evaluated using the same criteria as in the <Evaluation of Intra-Column Fluidity> section above. The maximum processing capacity in a single granulation operation of this fluidized bed granulator was 1500g.

[0096] [Table 2]

[0097] [Table 3]

[0098] The raw material powder compositions of Examples 1 to 5, which used crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, exhibited good intra-column fluidity, allowing for uniform flow within the column. The raw material powder compositions of Comparative Examples 1 to 4, which used crystalline cellulose with a bulk density of 0.31 g / mL, resulted in channeling and stagnation.

[0099] [Example 6] to [Example 7], [Comparative Example 5] to [Comparative Example 6] A powder composition was prepared by mixing ethenzamide and cellulose powder according to the composition shown in Table 4, and this was used as the raw material powder composition. As a binder solution, an aqueous solution consisting of 6% by mass of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and 0.5% by mass of food coloring (blue) was prepared. The raw material powder composition was sprayed with the binder solution in an amount corresponding to the composition shown in Table 4, and fluidized bed granulation and fluidized bed drying were performed under the conditions shown in Table 5 to obtain the composition. Furthermore, the fluidity within the column was evaluated by observing the flow state of the composition in the column during fluidized bed granulation and fluidized bed drying, using the same criteria as in the <Evaluation of Intra-Layer Fluidity> section above. The evaluation results are shown in Table 5.

[0100] [Table 4]

[0101] [Table 5]

[0102] <+2mm ratio> The obtained composition was passed through a sieve with a mesh size of 2 mm, and the proportion of particles remaining on the sieve (+2 mm) was evaluated as ([Total mass of particles remaining on the sieve (g)] / [Total mass of particles sieved (g)] × 100%). The results are shown in Table 5.

[0103] The raw material powder compositions of Examples 6 and 7, which used crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, exhibited good intralayer fluidity, and the binder solution coated with food coloring (blue) was uniformly sprayed onto the raw material powder composition, allowing for granulation without problems. Furthermore, the proportion of +2 mm was small at 0.1%. On the other hand, the raw material powder compositions of Comparative Examples 5 and 6, which used crystalline cellulose with a bulk density of 0.31 g / mL, experienced channeling and stagnation, and the binder solution coated with food coloring (blue) could not be uniformly sprayed onto the raw material powder composition.

[0104] The obtained composition was mixed with light anhydrous silicic acid (Aerosil, manufactured by Nippon Aerosil) and magnesium stearate to the composition shown in Table 4. This was used as the raw material composition for molding, and this was compressed into tablets under the conditions shown in Table 6 to obtain molded tablets.

[0105] [Table 6]

[0106] <Tablet Mass CV> The mass of 10 tablets was measured, and the average mass and standard deviation of the mass were determined. The coefficient of variation (CV), defined as (standard deviation / average mass) × 100 (%), was calculated as the mass CV. A smaller mass CV indicates less variation in the mass of the tablets. A mass CV of 1% or less is considered a good mass CV. The evaluation results are shown in Table 6.

[0107] <Evaluation of white matter in tablets> Visual inspection was used to determine the number of tablets containing white material out of 100 tablets. A lower number of tablets containing white material indicates that the binder solution applied to the food coloring (blue) was uniformly sprayed onto the raw material powder composition, resulting in a more uniform composition and molded product. The evaluation results are shown in Table 6.

[0108] The tablets of Examples 6 and 7, obtained from crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, had a lower mass CV value and fewer tablets containing white matter than the tablets of Comparative Examples 5 and 6, obtained from crystalline cellulose with a bulk density of 0.31 g / mL. These results indicate that using crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less as an excipient allows for the production of high-quality tablets with less white matter and smaller mass variability.

[0109] Furthermore, the tablets of Examples 6 and 7, obtained from crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, were able to contain 66% or more of ethenzamide per tablet, which is prone to retention (a state where particle flow is stagnant) or channeling (a state in which gas preferentially flows through locally formed channels within the layer, resulting in extremely uneven gas dispersion) in the column during fluid bed granulation. Thus, by using crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less as an excipient, the drug content in the composition can be increased. Therefore, when producing tablets with the same drug content, it was possible to reduce the size of the tablets by reducing the amount of composition per tablet.

[0110] [Examples 8] to [Examples 9], [Comparative Example 7] A powder composition was prepared by mixing ethenzamide and cellulose powder according to the composition shown in Table 7, and this was used as the raw material powder composition. As a binder solution, an aqueous solution consisting of 6% by mass of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and 0.5% by mass of food coloring (blue) was prepared. The raw material powder composition was sprayed with the binder solution in an amount corresponding to the composition shown in Table 7, and fluidized bed granulation and fluidized bed drying were performed under the conditions shown in Table 8 to obtain the composition. Furthermore, the fluidity within the column was evaluated by observing the flow state of the composition in the column during fluidized bed granulation and fluidized bed drying, using the same criteria as in the <Evaluation of Intra-Layer Fluidity> section above. The percentage of +2mm was also evaluated using the same criteria as in the evaluation of Example 6. The evaluation results are shown in Table 8.

[0111] [Table 7]

[0112] [Table 8]

[0113] The raw material powder compositions of Examples 8-9, which used crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, exhibited good intralayer fluidity, and the binder solution coated with food coloring (blue) was uniformly sprayed onto the raw material powder composition, allowing for granulation without problems. Furthermore, the proportion of +2mm granules was small at 0.01%. On the other hand, the raw material powder composition of Comparative Example 7, which used crystalline cellulose with a bulk density of 0.31 g / mL, experienced stagnation, and the binder solution coated with food coloring (blue) could not be uniformly sprayed onto the powder composition.

[0114] [Example 10] to [Example 13], [Comparative Example 8] to [Comparative Example 9] The fluidity within a fluidized bed granulator was investigated for a raw material powder composition containing ethenzamide, a poorly soluble drug, and crystalline cellulose.

[0115] For ethenzamide, we used Grade A (sometimes referred to as "Etz-A") manufactured by Yamamoto Chemical Industry Co., Ltd. For crystalline cellulose powder, we used the cellulose powder obtained in Production Examples 1 to 5.

[0116] The raw material powder compositions with the compositions and quantities listed in Table 9 were prepared. Next, a fluidized bed granulator (Multiplex, MP-01, manufactured by Powrec) was used, set to the airflow rate listed in Table 9, and the fluidity of the raw material powder composition in the column was observed to evaluate the intra-column fluidity using the same criteria as in the <Evaluation of Intra-Column Fluidity> section above. The maximum processing capacity in a single granulation operation of this fluidized bed granulator was 1500g.

[0117] [Table 9]

[0118] The raw material powder compositions of Examples 10 to 13, which used crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, exhibited good intra-column fluidity, allowing for uniform flow of the raw material powder compositions within the column. On the other hand, even when using crystalline cellulose with a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less, the amount of raw material powder composition charged is small at 300 g, and the ratio of the amount charged to the airflow (amount charged / airflow) is 3.8 g / (m³). 3 Under the granulation conditions of Comparative Example 8, which were approximately 300g / h, channeling occurred. Even when using crystalline cellulose (cellulose powder D) with a bulk density of 0.31 g / mL as the raw material powder composition, the amount of raw material powder composition charged was small at 300g, and the ratio of the amount charged to the airflow (amount charged / airflow) was 3.8 g / (m 3 Under the granulation conditions of Comparative Example 9, which were approximately ( / h), channeling occurred. [Industrial applicability]

[0119] The method for manufacturing the composition of this embodiment yields a composition consisting of granules with excellent uniformity. Therefore, the composition obtained from the method for manufacturing the composition of this embodiment and the method for manufacturing a molded article using it as a raw material can provide a molded article with excellent uniformity in composition and mass.

Claims

1. A method for producing a composition containing a drug (A) and crystalline cellulose (B), The process includes a granulation step of wet granulating a raw material powder composition containing the drug (A) and the crystalline cellulose (B), The crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less. The aforementioned wet granulation process is performed when the ratio of the amount of material to the airflow (amount of material / airflow) is 4.0 g / m ３ / h) or more 65.0g / (m ３ Granulation is performed by fluidized bed granulation under granulation conditions of less than or equal to / h. A method for producing a composition.

2. A method for producing the composition according to claim 1, wherein the wet granulation is carried out under granulation conditions in which the ratio of the amount charged to the liquid velocity per spray gun (amount charged / (liquid velocity / number of spray guns)) is 3 min·granules or more and 800 min·granules or less.

3. A method for producing the composition according to claim 1, wherein the wet granulation is carried out under granulation conditions where the spray pressure is 0.15 MPa or more and 0.60 MPa or less.

4. A method for producing the composition according to claim 1, wherein the wet granulation is carried out under granulation conditions in which the inlet temperature is 50°C or higher and 90°C or lower.

5. The method for producing the composition according to claim 1, wherein the wet granulation is carried out by fluidized bed granulation using a column having a tapered cylindrical shape.

6. A method for producing the composition according to claim 1, wherein the content ratio of the drug (A) to the total amount of the raw material powder composition is 40% by mass or more.

7. A method for producing the composition according to claim 1, wherein the content ratio of the crystalline cellulose (B) to the total amount of the raw material powder composition is 5% by mass or more.

8. A method for producing the composition according to claim 1, wherein the wet granulation is carried out under granulation conditions in which the amount of material added relative to the maximum processing capacity in a single granulation operation in a fluidized bed granulator (amount of material added / maximum processing capacity) is 0.20 or more and 1.00 or less.

9. A method for producing the composition according to claim 1, wherein the wet granulation is carried out under granulation conditions in which the amount of input is 300 g or more and 1500 g or less.

10. A method for producing a molded article, comprising producing a composition containing the drug (A) and the crystalline cellulose (B) by a method for producing a composition according to any one of claims 1 to 9, and molding the obtained composition to produce a molded article.

11. The manufacturing method according to claim 10, wherein the molded body is a tablet.

12. The product contains drug (A) and crystalline cellulose (B), The crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less. The percentage of particles (+2 mm) remaining on a sieve with a mesh size of 2 mm is 0.3% or less. composition.

13. The product contains drug (A) and crystalline cellulose (B), The crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less. The proportion of drug (A) in the total amount of the composition is 40% by mass or more. A composition that is a wet-process granulated material.

14. A molded article comprising a wet-process granule containing a drug (A) and crystalline cellulose (B), The crystalline cellulose (B) has a bulk density of 0.30 g / mL or less and a compressibility of 45.0% or less. The mass CV is 1% or less, and the number of molded bodies containing white material out of 100 is 5 or less. Molded body.

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