Granules and tablets

Abstract

To provide granules with better uniformity of drug content by particle size than conventional granules, and to provide tablets containing the granules.SOLUTION: The granules of the present invention contain a drug (A), sugar alcohols (B), cellulose (C) having an angle of repose of less than 57°, and a binder (D). The content of the drug (A) preferably exceeds 1 mass% based on the total mass of the granules. The sugar alcohols (B) preferably have an average particle size D50 of less than 40 μm and an angle of repose of less than 65°. The loose bulk density of the cellulose (D) preferably exceeds 0.12 g / cm3. The tablet of the present invention contains the granules.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to granules and tablets containing said granules. [Background technology]

[0002] Conventionally, tablets are produced by compressing a mixture obtained by uniformly mixing raw ingredients including a drug, excipients, and other additives using a tablet press. Furthermore, in order to improve the physical properties of tablets or to improve the properties of difficult-to-handle powders and improve handling, tablets may be produced by tableting granules obtained by pre-granulating the raw ingredients, or by tableting a mixture obtained by mixing pre-granulated excipients and other ingredients with a drug.

[0003] Until now, pharmaceutical manufacturing has mainly been carried out in a batch process, where raw materials are fed in whole or in portions into a process, and after the operation is completed, the product is removed and fed into the next process, resulting in discontinuous production. However, currently, continuous production methods are being introduced, where a fixed amount of raw materials is continuously fed into a process and the product is sequentially removed, and this continuous production method is also required to produce products that maintain the same or higher quality as the previous batch method.

[0004] Tablets are required to have various properties, such as uniformity of drug content, drug dissolution, disintegration, and hardness. To improve these properties, improvements to excipients have been widely undertaken. For example, Patent Document 1 discloses granules containing a drug, sugars, starch, cellulose with a predetermined amount of water absorption, and a binder. By using these granules, tablets can be obtained that exhibit sufficient hardness at lower impact pressure than conventional tablets and have excellent disintegration and dissolution properties. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2022-139962 Summary of the Invention [Problem to be solved by the invention]

[0006] In tablets produced by compressing granules obtained by granulating a drug and excipients, the uniformity of drug content is generally evaluated by measuring the drug content of a fixed amount of granules or tablets and using the variation as an index. However, even if the variation in drug content per fixed amount of granules is small, if the drug content segregates significantly among particle sizes, the drug content of tablets prepared from the granules will vary greatly.

[0007] The present invention has been made in view of the above circumstances, and provides granules having a more uniform drug content by particle size than conventional granules, and tablets containing the granules. [Means for solving the problem]

[0008] That is, the present invention includes the following aspects. [1] Drug (A), Sugar alcohols (B), Cellulose (C) having an angle of repose of less than 57°, and Binder (D), Granules containing [2] The granules of [1], wherein the content of the drug (A) is more than 1% by mass relative to the total mass of the granules. [3] The sugar alcohol (B) has an average particle diameter D 50 The granules according to [1] or [2], wherein the particle size is less than 40 μm and the angle of repose is less than 65°. [4] The loose bulk density of the cellulose (D) is 0.12 g / cm 3 The granules according to any one of [1] to [3], wherein the granules are greater than 100%. [5] A tablet comprising the granules of any one of [1] to [4]. [Effects of the Invention]

[0009] According to the above-mentioned embodiment, it is possible to provide granules having a more uniform drug content by particle size than conventional granules, and a tablet containing the granules. DETAILED DESCRIPTION OF THE INVENTION

[0010] Hereinafter, a mode 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 example for explaining the present invention, and is not intended to limit the present invention to the following content. The present invention can be carried out by appropriately modifying it within the scope of its gist.

[0011] <Granules> The granules of this embodiment contain a drug (A), sugar alcohols (B), a cellulose (C) having an angle of repose of less than 57°, and a binder (D). The granules of this embodiment use sugar alcohols (B), a cellulose (C) having an angle of repose of less than 57°, and a binder (D) as raw materials in addition to the drug (A), thereby reducing the variation in drug content by particle size. While the reason why the granules of this embodiment have such excellent uniformity in drug content by particle size is unclear, it is presumed that the use of a combination of cellulose, which has an angle of repose of less than 57° and excellent fluidity, and sugar alcohols minimizes segregation of the drug (A) in the granulation raw material powder.

[0012] The various constituent components of the granules of this embodiment will be described in detail below.

[0013] In the present invention and the present specification, the average particle size of powders such as cellulose and sugar alcohols refers to the average particle size D measured with a laser diffraction / scattering particle size distribution analyzer (LA-950 V2 (trade name), manufactured by Horiba, Ltd.). 50 is.

[0014] In the present invention and the present specification, the angle of repose (°) of powders such as cellulose and sugar alcohols is a value measured using a Sugihara-type angle of repose measuring device.

[0015] [Drug (A)] In this specification, a drug refers to a substance added to a mixed powder, a molded product, a processed product, etc. in order to exert a desired function or effect in the fields of medicine, health foods, food, industry, etc. For example, in the field of medicine, this corresponds to an active pharmaceutical ingredient.

[0016] Examples of suitable drugs (A) contained in the tablet of this embodiment are listed below. The active pharmaceutical ingredient is preferably an active ingredient of an orally administered pharmaceutical. Examples of orally administered pharmaceuticals include antipyretic analgesic anti-inflammatory drugs, hypnotics, sedatives, anti-drowsiness drugs, antivertigo drugs, pediatric analgesics, stomachics, antacids, digestives, cardiac stimulants, antiarrhythmic drugs, antihypertensive drugs, vasodilators, diuretics, antiulcer drugs, intestinal regulators, osteoporosis drugs, antitussives and expectorants, antiasthmatics, antibacterial agents, agents for improving frequent urination, tonics, vitamins, etc. The active pharmaceutical ingredient may be used alone or in combination of two or more.

[0017] Specific examples include aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, isothibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teoclate, and mebhydrolyzed napadisilate. , promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, difeterol phosphate, alloclamide hydrochloride, cloperastine hydrochloride, pentoxyverine citrate (carbetapentane citrate), tipepidine citrate, dibunate sodium, dextromethorphan hydrobromide, dextromethorphan phenolphthalic acid, tipepidine hibenzate, cloperastine fendizoate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl- Methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guaiacolsulfonate, guaifenesin, sodium benzoate, caffeine, caffeine anhydrous, 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, aluminum hydroxide and magnesium carbonate mixed dried gel, aluminum hydroxide and sodium bicarbonate coprecipitation product, aluminum hydroxide, calcium carbonate and magnesium carbonate coprecipitation product, magnesium hydroxide and aluminum potassium sulfate coprecipitation product, magnesium carbonate, magnesium aluminum metasilicate, ranitidine hydrochloride, cimetidine,Famotidine, naproxen, diclofenac sodium, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, difenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, promethazine hydrochloride, meclizine hydrochloride, dimenhydrinate, diphenhydramine tannate, fenethazine tannate, diphenylpyraline teoclate, diphenhydramine fumarate, promethazine methylenedisalicylate, scopolamine hydrobromide Methylphencyclamine hydrochloride, oxyphencyclamine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, atropine methyl bromide, anisotropine methyl bromide, scopolamine methyl bromide, 1-hyoscyamine methyl bromide, benactidium methyl bromide, belladonna extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, papaverine hydrochloride, aminobenzoic acid, cesium oxalate, ethyl piperidylacetylaminobenzoate, aminophylline, diprophylline, theof cephalexin, ampicillin, sulfixazole, sucralfate, allylisopropylacetylurea, bromvalerylurea, etc., ephedra, nandina, chervil, onion, licorice, bellflower, scutellaria, scutellaria, senega, fritillaria, fennel, Phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including yuutan), schisandra, Examples of medicinal ingredients include ginger, atractylodes rhizome, clove, tangerine root, atractylodes rhizome, earth dragon, ginseng, ginseng, valerian, moutan pea, Japanese pepper, and extracts thereof, as well as insulin, vasopressin, interferon, urokinase, serratiopeptidase, somatostatin, and other medicinal ingredients listed in the Japanese Pharmacopoeia, the United States Pharmacopoeia (USP), the National Formulary (NF), and the European Pharmacopoeia (EP). One selected from these medicinal ingredients may be used, or two or more may be used in combination.

[0018] Drugs for health foods are not limited as long as they are ingredients formulated for the purpose of improving health, and examples thereof 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, etc. , serine, etc.), alginic acid, ginkgo leaf extract, sardine peptide, turmeric, uronic acid, echinacea, Eleuthero, oligosaccharide, oleic acid, nucleoprotein, bonito flake peptide, catechin, potassium, calcium, carotenoid, garcinia, L-carnitine, chitosan, conjugated linoleic acid, aloe vera, gymnema sylvestre extract, citric acid, kumiscutin, glyceride, glycerol, glucagon, curcumin, glucosamine, N-acetylglucosamine Samin, L-glutamine, chlorella, cranberry extract, cat's claw, germanium, enzymes, ginseng extract, coenzyme Q10, collagen, collagen peptides, coleus forskolin, 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. Joe's Menthol extract, soy isoflavones, soy saponin, soy peptides, soy lecithin, monosaccharides, protein, 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 extract, barley extract, pantothenic acid, hyaluronic acid, biotin, chromium picolinate, vitamin A, vitamin A2Vitamin 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, Melilot Extract Powder, Molybdenum, Vegetable Powder, Folic Acid, Lactose, Lycopene, Linoleic Acid, Lipoic Acid, Phosphorus, Lutein, Lecithin, Rosmarinic Acid, Royal Jelly, DHA, EPA, etc.

[0019] A drug may be water-soluble or sparingly soluble. According to the 18th edition of the Japanese Pharmacopoeia, "sparingly soluble" means that 30 mL or more of solvent is required to dissolve 1 g of solute.

[0020] Examples of poorly water-soluble solid drugs include antipyretics and analgesics such as acetaminophen, ibuprofen, benzoic acid, ethenzamide, caffeine, camphor, quinine, calcium gluconate, dimethylcaprol, sulfamine, theophylline, theopromine, riboflavin, mephenesin, phenobarbital, aminophylline, thioacetazone, quercetin, rutin, salicylic acid, theophylline sodium salt, pyrapital, quinine hydrochloride, irgapyrin, digitoxin, griseofulvin, and phenacetin, nervous system drugs, sedatives and hypnotics, muscle relaxants, blood pressure sclerosing agents, and antihistamines; acetylspiramycin, ampicillin, erythromycin, xatamycin, chloramphenicol, and triacetin. Examples of pharmaceutical active ingredients include antibiotics such as fluorandomycin, nystatin, and colistin sulfate; steroid hormones such as methyltestosterone, methylandrosterone diol, progesterone, estradiol benzoate, ethinylestradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, and prednisolone; nonsteroidal yolk hormones such as dienstrol, hexastrol, diethylstilbesterol, diethylstilbesterol dibromohydratate, and chlorotrianisene; and other fat-soluble vitamins. These active pharmaceutical ingredients may be used alone or in combination.

[0021] The drug may be in a poorly water-soluble oily or liquid form. Examples of poorly water-soluble 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, all of which are listed in the Japanese Pharmacopoeia, USP, NF, and EP. Vitamin E includes various homologs and derivatives, and is not particularly limited as long as it is liquid at room temperature. Examples include dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, and d-α-tocopherol acetate. One or more of these drugs may be used alone or in combination.

[0022] The drug may be a semi-solid active ingredient that is poorly soluble in water. Examples of poorly water-soluble semi-solid pharmaceutical substances include Chinese herbal or crude drug extracts such as earth dragon root, licorice, cinnamon bark, peony root, moutan pea, valerian, Japanese pepper, ginger, tangerine peel, ephedra, nandina fruit, scutellaria, onion root, platycodon, rhododendron, rhododendron bark, garlic, seneca, fritillary root, fennel, Phellodendron bark, coptis, zedoary, chamomile, gentian, bezoar, animal gall, siberian rhizome, ginger, soju, clove, tangerine peel, byakujutsu, chikusetsuninjin, ginseng, kakkonto, keishito, kososan, shikhokeishito, shosaikoto, shoseiryuto, bakumondoto, hangehoubokuto, and maoto; oyster meat extract, propolis and propolis extract, and coenzyme Q. One of these drugs may be used, or two or more of them may be used in combination.

[0023] The drug may be sublimable. Examples of sublimable drugs include sublimable pharmaceutical active ingredients listed in the Japanese Pharmacopoeia, the USP, the NF, and the EP, such as benzoic acid, ethenzamide, caffeine, camphor, salicylic acid, phenacetin, and ibuprofen. One drug selected from these drugs may be used, or two or more drugs may be used in combination. The sublimable drug referred to in this specification is not particularly limited as long as it has sublimability, and may be in any state, such as solid, liquid, or semi-solid, at room temperature.

[0024] These drugs may be blended in a finely pulverized state with the granules of this embodiment. For example, the drugs used in this specification may be blended in a finely pulverized state with an average particle diameter D 50 is preferably 1 μm or more and 100 μm or less, more preferably 5 μm or more and 50 μm or less, and even more preferably 10 μm or more and 20 μm or less.

[0025] The content of drug (A) is generally more than 1% by mass, 1.5% by mass or more and 99% by mass or less, preferably 2% by mass or more and 90% by mass or less, more preferably 5% by mass or more and 50% by mass or less, even more preferably 10% by mass or more and 50% by mass or less, even more preferably 20% by mass or more and 50% by mass or less, and particularly preferably 25% by mass or more and 50% by mass or less, based on the total mass of the granules.

[0026] [Sugar alcohols (B)] The sugar alcohol (B) contained in the granules of this embodiment is not particularly limited as long as it is an edible sugar alcohol, and can be, for example, various sugar alcohols used as additives for pharmaceuticals and foods, such as mannitol, xylitol, maltitol, erythritol, sorbitol, lactitol, etc. The sugar alcohol (B) contained in the granules of this embodiment may be one type, or two or more types may be used in combination.

[0027] The angle of repose of the sugar alcohol (B) contained in the granules of this embodiment is not particularly limited, but is preferably less than 65°, and more preferably 62° or less. Furthermore, the angle of repose of the sugar alcohol (B) contained in the granules of this embodiment is preferably 25° or more, more preferably 28° or more, even more preferably 30° or more, and even more preferably 33° or more. By keeping the angle of repose of the sugar alcohol (B) within the above range, segregation of the drug (A) in the granulation raw material powder can be minimized, resulting in a more uniform drug content by particle size in the granules.

[0028] The average particle diameter D of the sugar alcohol (B) contained in the granules of this embodiment 50 is not particularly limited, but is preferably less than 40 μm, more preferably 5 μm or more and less than 40 μm, even more preferably 10 μm or more and 38 μm or less, even more preferably 10 μm or more and 36 μm or less, and particularly preferably 20 μm or more and 36 μm or less. 50 By keeping the above range, segregation of drug (A) in the granulation raw material powder can be minimized, and the drug content by particle size of the granules becomes more uniform.

[0029] The content of sugar alcohol (B) is generally preferably 1% by mass or more and 80% by mass or less, more preferably 10% by mass or more and 70% by mass or less, and even more preferably 10% by mass or more and 60% by mass or less, based on the total mass of the granules. By keeping the content of sugar alcohol (B) within the above range, it is possible to incorporate sufficient amounts of other ingredients such as drug (A).

[0030] [Cellulose (C)] Cellulose is a naturally occurring, water-insoluble fibrous material that contains cellulose. In the granules of this embodiment, the cellulose (C) can be cellulose obtained by hydrolysis or the like from a cellulose raw material such as wood pulp, non-wood pulp, wheat straw, rice straw, cotton, cotton linter, hemp, ramie, bagasse, kenaf, beet, sea squirt, or bacterial cellulose. The cellulose raw material is preferably wood pulp or non-wood pulp, and more preferably wood pulp. One of these may be used as the cellulose raw material, or a mixture of two or more may also be used.

[0031] Among these, cellulose (C) contained in the granules of this embodiment is preferably cellulose powder. Generally, "cellulose powder" refers to crystalline cellulose, powdered cellulose, etc., and is suitable for use as a pharmaceutical additive or food additive. It may also be cellulose that has been treated with an additive, such as silicic acid-treated crystalline cellulose (SMCC) described in the Pharmaceutical Additives Standards 2018.

[0032] Among them, crystalline cellulose is preferred as the cellulose powder. As the crystalline cellulose, at least one that satisfies the identification test for microcrystalline cellulose described in the 10th edition of the Official Standards of Food Additives, and more preferably one that satisfies the identification test for crystalline cellulose described in the Japanese Pharmacopoeia (18th edition), may also be used. Microcrystalline cellulose described in the United States Pharmacopoeia, the European Pharmacopoeia, etc.

[0033] The angle of repose of the cellulose (C) contained in the granules of this embodiment is not particularly limited as long as it is less than 57°, but is preferably 55° or less, more preferably 52° or less, and even more preferably 50° or less. Furthermore, the angle of repose of the cellulose (C) contained in the granules of this embodiment is preferably 25° or more, more preferably 28° or more, even more preferably 30° or more, and even more preferably 33° or more. By ensuring that the angle of repose of the cellulose (C) is equal to or less than the upper limit, segregation of the drug (A) in the granulation raw material powder can be minimized, resulting in a more uniform drug content by particle size in the granules. On the other hand, by ensuring that the angle of repose of the cellulose (C) is equal to or greater than the lower limit, tablets with excellent abrasion resistance, disintegration properties, and dissolution properties can be obtained.

[0034] The loose bulk density of the cellulose (C) contained in the granules of this embodiment is 0.12 g / cm 3 More than 0.13 g / cm is preferred. 3 More than 0.50g / cm 3 Less than 0.13 g / cm is more preferable. 3 More than 0.40g / cm 3 More preferably, 0.13 g / cm 3 More than 0.38g / cm 3 Even more preferably, 0.13 g / cm 3 More than 0.35g / cm 3 The following is particularly preferred. When the loose bulk density is within the above range, the balance between weight uniformity and moldability of the tablets is better. The loose bulk density of the cellulose powder can be measured using the method described in the Examples below.

[0035] The content of cellulose (C) in the granules of this embodiment is preferably 1% by mass or more and 50% by mass or less, more preferably 5% by mass or more and 40% by mass or less, and even more preferably 5% by mass or more and 30% by mass or less, relative to the total mass of the granules. When the content of cellulose (C) is equal to or more than the above-mentioned lower limit, the tablet moldability is superior. On the other hand, when the content of cellulose (C) is equal to or less than the above-mentioned upper limit, the disintegration property and dissolution property when formed into a tablet tend to be superior.

[0036] [Binder (D)] Examples of binders include polyvinylpyrrolidone, pregelatinized starch, gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and macrogol. These binders may be used alone or in combination. Among them, hydroxypropyl cellulose, polyvinylpyrrolidone, and pregelatinized starch are preferred.

[0037] The binder content is typically 1% by mass or more and 20% by mass or less, preferably 1% by mass or more and 10% by mass or less, and more preferably 1% by mass or more and 5% by mass or less, based on the total mass of the components in the granules excluding the binder.

[0038] [Other ingredients] The granules of this embodiment may further contain an excipient other than cellulose (C) for the purpose of improving the handleability of the drug contained in the granules.

[0039] Examples of excipients other than cellulose (C) include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, powdered gum arabic, alginic acid, sodium alginate, partially pregelatinized starch, pregelatinized starch, corn starch, pumice granules, inositol, ethyl cellulose, ethylene vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrated silicon dioxide, dry yeast, and dried aluminum hydroxide gel. Ingredients: le, dried sodium sulfate, dried magnesium sulfate, agar, agar powder, 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, Genmai Koji, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ flour, rice flour, Starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, calcined gypsum, sucrose fatty acid ester, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitate, magnesium hydroxide, squalane, stearyl alcohol, stearic acid, stearyl Calcium phosphate, polyoxyl stearate, magnesium stearate, hardened soybean oil, refined gelatin, refined shellac, refined white sugar, refined white sugar spherical granules, cetostearyl alcohol, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, tricalcium phosphate, soybean oil, soybean unsaponifiables, soybean lecithin, skim milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate,Tragacanth powder, silicon dioxide, calcium lactate, Perfiller 101, white shellac, white petrolatum, hakudo, white sugar, white sugar and starch spherical granules, naked barley leaf extract powder, naked malt leaf green juice dried powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose syrup, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, poly Examples of excipients include sodium styrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltose, starch syrup, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium aluminometasilicate, methylcellulose, cottonseed flour, cottonseed oil, Japan wax, aluminum monostearate, glycerin monostearate, sorbitan monostearate, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular cornstarch starch, liquid paraffin, dl-malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate, which are classified as excipients in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha). These may be used alone or in combination of two or more.

[0040] The content of all excipients including cellulose is generally 10% by mass or more and 98% by mass or less, and preferably 50% by mass or more and 90% by mass or less, based on the total mass of the granules.

[0041] <Granule manufacturing method> The granules of this embodiment can be produced by various methods commonly used as granule production methods, for example, wet granulation or dry granulation.

[0042] The granules of this embodiment are preferably produced by a wet granulation method or a method using a continuous production system utilizing the same. Generally, wet granulation is a granulation method in which granules are formed using a liquid containing water or a binder while flowing or extruding, and can produce granules that are nearly spherical and have excellent handleability. Furthermore, wet granulation can improve the dissolution rate of poorly soluble drugs. In these respects, wet granulation is superior to dry granulation, in which granules are formed by directly compressing and pulverizing powder raw materials.

[0043] A continuous manufacturing system is a continuous manufacturing technology that consistently carries out all processes from raw material supply and granulation to drying in the solid dosage production process, including a wet granulation process in which raw materials (mixed powder) containing drugs, excipients such as cellulose (C), and other additives are granulated using water or a binding liquid to obtain wet granules, and a drying process in which the obtained wet granules are dried to obtain granules for tableting.

[0044] In the wet granulation process, granule raw materials (mixed powder) thoroughly mixed in a mixer are introduced, and water is added appropriately to granulate the raw materials. At this time, the amount of water added relative to the mass of the mixed powder is preferably 10% by mass or more but less than 40% by mass, more preferably 15% by mass or more but less than 35% by mass, and even more preferably 20% by mass or more but less than 32.5% by mass. By keeping the amount of water added within the above numerical range, granulation can be carried out more stably, and granules of the desired particle size can be obtained.

[0045] In the drying step, the wet granules obtained in the granulation step are dried to obtain granules for tableting. There are no particular limitations on the drying device as long as it can dry the wet granules with hot air.

[0046] <Tablets> The tablet of this embodiment contains the granules of this embodiment. The tablet of this embodiment contains the granules of this embodiment, which have excellent uniformity of drug content by granule size, and therefore has excellent uniformity of drug content.

[0047] The amount of the granules of this embodiment contained in the tablet of this embodiment is not particularly limited, but a practically preferable range is 99.5% by mass or less relative to the mass of the entire tablet.

[0048] [Other additives] The tablet of this embodiment may further contain other additives as needed, such as excipients, disintegrants, binders, flow agents, and lubricants.

[0049] Examples of the excipient include those exemplified as cellulose and excipients other than cellulose in the above "granules."

[0050] 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, potato starch, corn starch, pregelatinized 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" (published by Yakuji Nipposha). One type selected from these disintegrants may be used, or two or more types may be used in combination.

[0051] Examples of binders include those exemplified above for "granules." In addition to the above-mentioned binders, other binders include those classified as binders in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha), such as sugars (sucrose, fructose, lactose or lactose hydrate, fructooligosaccharides, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered candy, isomerized lactose, and honey sugar); sugar alcohols (mannitol, xylitol, maltitol, erythritol, sorbitol, and lactitol); water-soluble polysaccharides (carrageenan, locust bean gum, agar, glucomannan, xanthan gum, and tamarind gum); celluloses (crystalline cellulose, powdered cellulose, and other); starches (corn starch, potato starch, rice starch, partially pregelatinized starch, and starch paste); and inorganic compounds (calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminosilicate). One of these binders may be used, or two or more of them may be used in combination.

[0052] Examples of the fluidizing agent include those classified as fluidizing agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha), such as silicon compounds such as hydrous silicon dioxide and light anhydrous silicic acid. One type selected from these fluidizing agents may be used, or two or more types may be used in combination.

[0053] Examples of lubricants include those classified as lubricants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha), such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, talc, sodium stearyl fumarate, etc. One type selected from these lubricants may be used, or two or more types may be used in combination.

[0054] <Tablet manufacturing method> Below, a method for producing tablets using the above-mentioned granules as raw materials will be described, but this is just one example, and the method for producing tablets in this embodiment is not limited to the following method.

[0055] The tablet of this embodiment can be produced, for example, by compressing a raw material obtained by mixing the granules of this embodiment with other additives as needed. Examples of other additives include the above-mentioned excipients, disintegrants, binders, flow agents, lubricants, flavoring agents, flavorings, colorants, sweeteners, and solubilizers. One type of other additive may be blended, or two or more types may be blended in combination.

[0056] There is no particular limitation on the order in which the components are added, and there is also no particular limitation 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 transport device, a pneumatic transport device, a bucket conveyor, a pressure-feed transport device, a vacuum conveyor, a vibrating metering feeder, a spray, a funnel, or the like, or they may be added all at once.

[0057] The mixing method is not particularly limited as long as it is a commonly used method, and examples thereof include container rotation mixers such as V-type, W-type, double cone-type, and container tuck-type mixers; stirring mixers such as high-speed stirring, universal stirring, ribbon-type, Pug-type, and Nauta-type mixers; high-speed fluid mixers, drum mixers, and fluidized bed mixers. Container shaking mixers such as shakers can also be used.

[0058] The method for compression molding of tablets is not particularly limited as long as it is a commonly used method, and examples thereof include a method of compression molding into a desired shape using a mortar and pestle, a method of compression molding into a sheet in advance and then cutting into the desired shape, etc. Examples of compression molding machines include roller presses such as hydrostatic presses, briquetting roller presses, and smooth roller presses, single punch tablet presses, and rotary tablet presses.

[0059] 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 Nipposha). These coating agents may be used alone or in combination of two or more. [Example]

[0060] The present embodiment will be described in detail below with reference to examples and comparative examples, but the present embodiment is not limited thereto. The methods for measuring the various physical properties in the examples and comparative examples are as follows.

[0061] <Methods for measuring physical properties> The physical properties of the cellulose powder and granules were measured using the methods shown below.

[0062] [Physical Properties 1] (Angle of repose) Using a Sugihara-type angle of repose measuring device (slit size: 10mm deep x 50mm wide x 140mm high, with a protractor placed at the 50mm width), the dynamic free flow properties were measured when cellulose powder was dropped into the slit using a constant feeder at a rate of 50cc / min. The angle between the bottom of the device and the layer of cellulose powder formed was taken as the angle of repose (°) of the cellulose powder.

[0063] [Physical Properties 2] (loose bulk density) A Scott volume meter (model ASTM B-329-85, manufactured by Tsutsui Scientific Instruments) was used to measure the loose bulk density of the cellulose powder. First, each sample was passed through a sieve (1 mm mesh size) and filled into a 25 cc cylindrical metal container. Each sample in the 25 cc cylindrical metal container was leveled, and the mass (g) of each sample in the container was divided by 25 cc to determine the loose bulk density. Measurements were performed three times, and the average value was calculated.

[0064] [Physical Properties 3] (Average particle size of granules D 50 ) 10 g of granules were sieved for 10 minutes using a rotary sieve shaker (Sieve Shaker Type A, manufactured by Hirako Seisakusho) and JIS standard sieve mesh sizes of 500 μm, 300 μm, 250 μm, 212 μm, 150 μm, 106 μm, 75 μm, and 45 μm. The mass percentages (%) of the powder remaining on each sieve and passing through the 45 μm sieve were determined and expressed as the particle size when the cumulative mass percentage was 50%.

[0065] <Evaluation method> [Tablet manufacturing] Tablets were manufactured using each wet granule. 99.5% by mass of the wet granules and 0.5% by mass of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) were mixed by hand in a polyethylene bag for 30 seconds to obtain a mixture. The resulting mixture was compressed using a rotary tablet press to obtain tablets (tablet diameter 8 mmφ-12R, mass 180 mg). The compression pressure was appropriately set to between 4 kN and 18 kN.

[0066] [Rating 1] (Granule size ratio) Five grams of granules were fractionated by size using four sieves with different mesh sizes (φ710 μm, φ500 μm, φ150 μm, and φ75 μm). Specifically, the granules that passed through the φ710 μm sieve were classified as the "710 μm-on fraction," the granules that passed through the φ500 μm sieve as the "500 μm-on fraction," the granules that passed through the φ150 μm sieve as the "150 μm-on fraction," the granules that passed through the φ75 μm sieve as the "75 μm-on fraction," and the granules that passed through the φ75 μm sieve as the "75 μm-pass fraction." The total weight of the granules in each fraction was measured, and the percentage of the total granules was calculated to determine the particle size ratio of each fraction ([total weight of granules in each fraction] / [total weight of all granules (5 g)] × 100%).

[0067] (Relative drug content by granule size) The drug (ethenzamide) content of the granules of each fraction was measured using a spectrophotometer (calibration curve method), and the drug content (g) contained in the granules of each fraction was calculated as the "drug content (g) by granule size," and the content ratio (relative content: %) to the theoretical content (g) was also calculated. Specifically, a calibration curve for ethenzamide was first prepared. The absorption spectrum of ethenzamide was measured using a spectrophotometer, and a calibration curve was prepared based on the peak-top wavelength (ethenzamide wavelength: 292 nm). Next, each fraction granule was dissolved in pure water to prepare an aqueous solution. The aqueous solution was filtered through a resin filter to remove insoluble matter, and the ethenzamide content relative to the fraction granule mass was quantified by absorbance. In addition, for each particle size fraction, [particle size ratio (%)] x [drug content by granule particle size (g)] was calculated, and the total value of all fractions was taken as the "drug content of the entire granule (g)." Furthermore, the content ratio (relative content: %) to the theoretical content (g) was calculated.

[0068] The closer the relative content is to 100%, the closer the actual drug content in the granules is to the theoretical content. The smaller the difference in relative content between each fraction, the smaller the variation in drug content in granules by particle size, indicating excellent uniformity of drug content by particle size.

[0069] [Example 1] (Production of Granule G-a1) A mixed powder was obtained by mixing 30% by mass of ethenzamide (manufactured by Yamamoto Chemical Co., Ltd.) as the drug (A), 50% by mass of mannitol (manufactured by Mitsubishi Corporation) as the sugar alcohol (B), 20% by mass of crystalline cellulose powder (manufactured by Asahi Kasei Corporation, CEOLUS PH-101), and 1.5% by mass of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-L) as the binder (D) for 3 minutes.

[0070] The obtained mixed powder was wet granulated using a continuous granulator with 25% water added to obtain a wet granulated product. 3 The granules were dried using a fluidized bed dryer operating at 1000 kJ / min and an inlet air temperature of 85° C. to obtain dried granules (G-a1). The average particle size of the granules was 135 μm.

[0071] [Example 2] (Production of Granule G-a2) Granules (G-a2) were obtained in the same manner as in Example 1, except that crystalline cellulose powder (Ceolas UF-702, manufactured by Asahi Kasei Corporation) was used as the cellulose powder and the amount of water added to the continuous granulation device was 30% by mass. The average particle size of the granules was 126 μm.

[0072] [Example 3] (Production of Granule G-a3) Granules (G-a3) were obtained in the same manner as in Example 1, except that crystalline cellulose powder (manufactured by Asahi Kasei Corporation, CEOLUS UF-711) was used as the cellulose powder. The average particle size of the granules was 96 μm.

[0073] [Example 4] (Production of Granule G-a4) Granules (G-a4) were obtained in the same manner as in Example 1, except that crystalline cellulose powder (manufactured by Asahi Kasei Corporation, CEOLUS KG-802) was used as the cellulose powder. The average particle size of the granules was 95 μm.

[0074] [Comparative Example 1] (Manufacturing of Granule G-a5) Granules (G-a5) were obtained in the same manner as in Example 1, except that crystalline cellulose powder (manufactured by Asahi Kasei Corporation, CEOLUS KG-1000) was used as the cellulose powder and the amount of water added to the continuous granulation device was 15% by mass. The average particle size of the granules was 53 μm.

[0075] The average particle size (μm) and loose bulk density (g / cm) of the crystalline cellulose powder used as raw material 3 ) and angle of repose (°) are shown in Table 1.

[0076] [Table 1]

[0077] The particle size ratio (%) of each fraction of each granule obtained is shown in Table 2, and the drug content by particle size and the drug content of the entire granule (relative value: %) are shown in Table 3.

[0078] [Table 2]

[0079] [Table 3]

[0080] For granules to be compressed for tablet production, the smaller the variation in drug content by particle size, the better. It is preferable that the variation be at least within 100±10% of the theoretical content, and more preferably within 100±5%. As shown in Table 3, for all granules in Examples 1 to 4, which were made from crystalline cellulose powder with an angle of repose of less than 57°, the drug content by granule size was within the range of 95-105% for all but the 75 μm-pass fraction, and the variation in drug content by particle size was small. Furthermore, the drug content of the entire granule was 99-100%, nearly the theoretical content. In particular, the drug content by granule size of the 75 μm-pass fraction of the granules in Examples 2 to 4 was within the range of 100±10%, demonstrating excellent uniformity of drug content by particle size. In contrast, the granules of Comparative Example 1, which were made from crystalline cellulose powder with an angle of repose of 57° or more, had granule size content outside the range of 100±5% for both the 75 μm-pass fraction and the 500 μm-on fraction, and the drug content of the entire granule was 97%, resulting in a greater variation in drug content than the granules of Examples 1 to 4. [Industrial Applicability]

[0081] The granules of this embodiment have excellent uniformity of drug content by particle size. Therefore, by using these granules as a raw material, it is possible to provide tablets with much better uniformity of drug content than conventional tablets.

Claims

1. Drug (A), Sugar alcohols (B), Cellulose (C) having an angle of repose of less than 57°, and Binder (D), Granules containing

2. The granule according to claim 1, wherein the content of the drug (A) is more than 1% by mass relative to the total mass of the granule.

3. The sugar alcohol (B) has an average particle diameter D ５０ 2. The granules of claim 1, wherein the particle size is less than 40 μm and the angle of repose is less than 65°.

4. The loose bulk density of the cellulose (D) is 0.12 g / cm ３ The granules of claim 1, wherein the granules are greater than 10 ...

5. A tablet comprising the granules according to any one of claims 1 to 4.

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