JP2020180083A - Cellulose powders, tablets, and methods for producing tablets - Google Patents

Abstract

To provide cellulose powders providing tablets with excellent hardness, abrasion and disintegration, to provide tablets containing the cellulose powders, and to provide production methods thereof.SOLUTION: The cellulose powder has an average particle size of 10 μm or more and 40 μm or less, and the ratio of the mass of the powder passed through a sieve having a mesh size of 32 μm to the total mass of the powder provided to the sieve having the mesh size of 32 μm is more than 60 mass% based on the total mass of the powder. The tablet contains the cellulose powder. The method for producing the tablet is a method using the cellulose powder.SELECTED DRAWING: None

Description

The present invention relates to cellulose powders, tablets, and methods for producing tablets.

Conventionally, in the fields of medicine, health food, food, and industry, it has been widely practiced to prepare a composition in which an active ingredient and other additives are mixed. In particular, since many active ingredients used in the fields of pharmaceuticals and health foods have low moldability, excipients are used as other additives when preparing compositions such as tablets, granules, and fine granules. It is common to use it. Among them, crystalline cellulose is widely used as an excipient for tablets because it has both high moldability and quick disintegration property at the same time.

Tablets are required to have various performances such as hardness, disintegration, abrasion resistance, elution, content and mass uniformity, and these performances depend on the excipient used, the type of active ingredient and the compounding ratio. , Fluctuates greatly. For example, in general, when the content of the active ingredient in a tablet is high, the tablet tends to have a low hardness and a high abrasion property, reflecting the physical properties of the active ingredient. In this case, the moldability is insufficient. When various excipients are used, sufficient hardness and abrasion resistance may not be obtained.

On the other hand, tablets having high hardness tend to have a delay in disintegration time, and tablets having an excellent balance of hardness, abrasion resistance and disintegration property are required.

For example, Patent Document 1 describes a method for producing a high-dose preparation in which elution of minodronic acid, tablet hardness, pestle adhesion and the like are improved by blending cellulose powder.

Patent Document 2 describes a method for producing a tablet using cellulose powder, which does not cause compression molding disorders such as attachment of branched chain amino acids and reduced palatinose to a punch, capping, and sticking.

Patent Document 3 describes 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl)] using cellulose powder, which has both appropriate hardness and rapid disintegration in the oral cavity. ) -2-Morphorinyl] Methyl] The method for producing an orally disintegrating tablet of benzamide is described.

Japanese Unexamined Patent Publication No. 2013-0285994 International Publication No. 2005/099681 International Publication No. 2009/102038

As described above, in the prior art, although various studies have been made for the purpose of improving the performance required for tablets, tablets having an excellent balance of hardness, wearability and disintegration of tablets have not been obtained.

The present invention has been made in view of the above circumstances, and provides a cellulose powder capable of obtaining a tablet having excellent hardness, abrasion resistance and disintegration property, a tablet containing the cellulose powder, and a method for producing the same.

That is, the present invention includes the following aspects.
The cellulose powder according to the first aspect of the present invention has an average particle size of 10 μm or more and 40 μm or less, and the ratio of the mass of the powder passed through the sieve having a mesh size of 32 μm to the total mass of the powder provided to the sieve having a mesh size of 32 μm is It is more than 60% by mass with respect to the total mass of the powder.
The bulk density may be 0.1 g / mL or more and 0.4 g / mL or less.
The specific surface area may be 1.0 m ² / g or more and 2.6 m ² / g or less.
The degree of compression may be 35 or more and 60 or less.
The tablet plastic deformation rate when a tablet made of only the cellulose powder is prepared may be 87% or more.

The tablet according to the second aspect of the present invention contains the cellulose powder according to the first aspect.

The method for producing a tablet according to the third aspect of the present invention is a method using the cellulose powder according to the first aspect.
The method for producing a tablet according to the third aspect is a step of granulating a mixture containing an active ingredient to obtain a granulated product, and adding an additive containing the cellulose powder to the granulated product for compression molding. And the steps to be performed may be included.

According to the cellulose powder of the above aspect, it is possible to provide a cellulose powder capable of obtaining a tablet having excellent hardness, abrasion resistance and disintegration property. According to the tablet of the above aspect and the method for producing the same, a tablet having excellent hardness, abrasion resistance and disintegration property can be obtained.

Hereinafter, embodiments for carrying out the present invention (hereinafter, simply referred to as “the present embodiment”) will be described in detail. The present invention is not limited to the following embodiments, and can be variously modified and implemented within the scope of the gist thereof.

≪Cellulose powder≫
Cellulose powder is generally referred to as crystalline cellulose, powdered cellulose, or the like, and is preferably used as a pharmaceutical additive or a food additive. Crystalline cellulose is preferable as the cellulose powder. The crystalline cellulose conforms to at least the confirmation test of microcrystalline cellulose described in the 8th edition of the Food Additives Official Regulations, and preferably conforms to the confirmation test of crystalline cellulose described in the 17th revised Japanese Pharmacopoeia. To do.

The cellulose powder of this embodiment is preferably type I crystals. Known crystal forms of cellulose are type I, type II, type III, type IV, etc., but type I has the same crystal structure as natural cellulose such as ramie, cotton linter, and wood pulp, so it can be used as a natural resource. It does not require any special treatment just by using it, and is excellent in terms of cost and environmental impact.

The cellulose powder of the present embodiment has an average particle diameter of 40 μm or less, preferably 30 μm or less, and more preferably 20 μm or less. When the average particle size is not more than the above upper limit value, moldability is more likely to be exhibited when added to the powder containing the active ingredient. The lower limit of the average particle size is not particularly limited, but can be 10 μm or more in consideration of handleability.

The average particle size of the cellulose powder is a particle size of 50% of the cumulative volume measured by a laser diffraction type particle size distribution meter (LA-950 V2 type (trade name), manufactured by HORIBA, Ltd.).

In the cellulose powder of the present embodiment, the ratio of the mass of the powder passed through the sieve having a mesh size of 32 μm to the total mass of the powder provided to the sieve having a mesh size of 32 μm is more than 60% by mass with respect to the total mass of the powder, which is 70. By mass or more is preferable, 80% by mass or more is more preferable, 85% by mass or more is further preferable, and 90% by mass or more is particularly preferable. When the proportion of particles having a particle diameter of 32 μm or less is not more than the above lower limit, the hardness of the obtained tablet tends to be better.

The ratio (mass%) of the mass of the powder that passed through the sieve with a mesh size of 32 μm to the total mass of the powder used for the sieve with a mesh size of 32 μm is a sieve with a mesh size of 32 μm (made of stainless steel specified by JIS standard). (Made by ALPINE), and can be calculated by dividing the mass of the powder that has passed 32 μm (outer diameter 200φ) by the total mass of the powder used for the measurement.

The cellulose powder of the present embodiment preferably has a bulk density of 0.4 g / mL or less, more preferably 0.3 g / mL or less, and even more preferably 0.2 g / mL or less. When the bulk density is not more than the above upper limit value, moldability is more likely to be exhibited even at a low impact pressure during tablet molding, and a tablet having a higher hardness can be obtained. The lower limit of the bulk density is not particularly limited, but from the viewpoint of handleability, it can be 0.1 g / mL or more.

The bulk density of the cellulose powder can be measured by using the method described in Examples described later.

Cellulose powder of the present embodiment, the ratio is preferably at least 1.0 m ² / g surface area, more preferably at least 1.5 m ² / g, more preferably not less than 2.0 m ² / g. When the specific surface area is at least the above lower limit value, the contact area at the time of tablet molding increases, the moldability tends to be further improved, and a tablet having a higher hardness can be obtained. The upper limit of the specific surface area is not particularly limited, but can be set to 2.6 m ² / g or less from the viewpoint of handleability.

The specific surface area of the cellulose powder can be measured by using the method described in Examples described later.

The cellulose powder of the present embodiment preferably has a degree of compression of 35 or more, more preferably 40 or more, and even more preferably 50 or more. When the degree of compression is at least the above lower limit value, there is a tendency that the cellulose powder can be better crushed and arranged during tablet molding while maintaining good fluidity. The upper limit of the degree of compression is not particularly limited, but can be 60 or less from the viewpoint of handleability.

The degree of compression of the cellulose powder can be measured by using the method described in Examples described later.

When a tablet made of only the cellulose powder of the present embodiment is prepared, the tablet plastic deformation rate is preferably 87% or more, more preferably 89% or more, still more preferably 90% or more. Due to moisture absorption, the thickness of the tablet increases from the time of tablet molding to 24 hours later. Cellulose powder having a large increase has a low tablet plastic deformation rate and cannot maintain compression moldability, so that the hardness tends to decrease. Therefore, when the tablet plastic deformation rate is at least the above lower limit value, the compression moldability can be maintained, and the decrease in hardness with time after tablet molding can be more effectively suppressed.

The tablet plastic deformation rate when a tablet made of only cellulose powder is produced can be measured by using the method described in Examples described later.

<Manufacturing method of cellulose powder>
The method for producing the cellulose powder of the present embodiment will be described below.
The cellulose powder of the present embodiment can be obtained, for example, by including a step of dispersing a hydrolyzed natural cellulose-based substance in an appropriate medium to obtain a cellulose aqueous dispersion, and a step of drying the aqueous dispersion. The solid content concentration of the aqueous cellulose dispersion is not particularly limited, and can be, for example, 1% by mass or more and 20% by mass or less. In this case, even if the solid content containing the hydrolyzed cellulosic substance is isolated from the hydrolysis reaction solution obtained by the hydrolysis treatment, and the dispersion prepared by separately dispersing this in an appropriate medium is dried. Good. Further, when the cellulose dispersion liquid is formed in the same state as the hydrolyzed solution, the dispersion liquid can be directly dried.

The natural cellulosic substance may be of vegetable or animal origin, and is a fibrous substance derived from a natural substance containing cellulose such as wood, bamboo, cotton, ramie, sea squirt, bagasse, kenaf, and bacterial cellulose. It preferably has an I-type crystal structure. As the raw material, one of the above natural cellulosic substances may be used, or a mixture of two or more of them may be used. Further, it is preferably used in the form of refined pulp, but the method for refining the pulp is not particularly limited, and any pulp such as dissolved pulp, kraft pulp, and NBKP pulp may be used.

In the above-mentioned production method, water is preferable as the medium used when the solid content containing the natural cellulosic substance is dispersed in an appropriate medium, but there is no particular limitation as long as it is used industrially, for example. An organic solvent may be used. Examples of the organic solvent 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 acetone and ethyl methyl ketone. Examples include ketones. In particular, organic solvents are preferably used in pharmaceutical products, and such organic solvents are classified as solvents in "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.). Water and the organic solvent may be used alone or in combination of two or more, or may be dispersed once in one medium, then the medium may be removed and dispersed in different media. ..

The average particle size of the cellulose-dispersed particles can be controlled within a desired range by adjusting the degree of polymerization of the raw material cellulose by hydrolysis and the stirring force in at least one of the hydrolysis and dispersion steps of cellulose. it can. In general, when the acid, alkali concentration, and reaction temperature of the hydrolyzed solution are increased, the degree of polymerization of cellulose tends to decrease, the average particle size of cellulose in the dispersion tends to decrease, and even if the stirring power of the solution is strengthened, The average particle size of the cellulose-dispersed particles tends to be small. The method for hydrolyzing the natural cellulosic substance may be acid hydrolysis, alkali oxidative decomposition, hot water decomposition, steam explosion or the like. Further, these methods may be used alone or in combination of two or more.

Acids or alkalis can be used to hydrolyze natural cellulosic substances, but industrially, acids are often used. The acid concentration at the time of hydrolysis is preferably 0.1% by mass or more and 1.0% by mass or less. When the acid concentration is at least the above lower limit value, the hydrolysis reaction of the natural cellulosic substance can be promoted more efficiently, and the average particle size of the cellulose-dispersed particles can be 40 μm or less. On the other hand, when the acid concentration is not more than the above upper limit value, it is more effective to suppress the hydrolysis of the natural cellulosic substance from progressing too much, and it is more effective that the average particle size of the cellulosic dispersed particles is less than 10 μm. Can be suppressed.

For example, pulp fibers having an average width of 2 μm or more and 30 μm or less and an average thickness of 0.5 μm or more and 5 μm or less are subjected to a temperature of 110 ° C. or more and 140 ° C. or less in hydrochloric acid of 0.1% by mass or more and 1.0% by mass or less under pressure. Hydrolyze while turning the stirrer. The progress of hydrolysis can be controlled by adjusting the motor power (P: unit W) and the stirring capacity (L: unit L) of the stirrer. For example, by adjusting the P / V represented by the following formula to a range of 0.2 W / L or more and 6.0 W / L or less, the average particle size of the finally obtained cellulose particles is controlled to 40 μm or less. Is possible.

P / V (W / L) = [actual power of agitator motor (W)] / [stirring capacity (L)]

In producing the cellulose powder of the present embodiment, the P / V when the average particle size is controlled by the hydrolysis reaction (there is no crushing step of the cellulose powder obtained after the drying step) is 0.2 W / L or more. It is preferably 0 W / L or less, more preferably 0.2 W / L or more and 4.0 W / L or less, and further preferably 0.2 W / L or more and 3.0 W / L or less. When the P / V is at least the above lower limit, the hydrolysis reaction of the natural cellulosic substance can be promoted more efficiently, the average particle size of the cellulosic dispersed particles can be 40 μm or less, and further, drying can be performed. The average particle size of the subsequent cellulose powder can also be 40 μm or less.

In addition, when disc-type spray drying is performed when the average particle size is controlled by the hydrolysis reaction, it is also necessary to control the disc-type turntable speed and the solid content concentration of the cellulose aqueous dispersion to be spray-dried. The solid content concentration of the aqueous cellulose dispersion is preferably in the range of 1% by mass or more and 7% by mass or less, and the peripheral speed of the spray-dried disc is preferably 130 m / sec or more and 220 m / sec or less. When the solid content concentration is at least the above lower limit value, the productivity can be kept good. On the other hand, when the solid content concentration is equal to or less than the above upper limit value, the generation of coarse secondary agglomerates is more effectively suppressed at a peripheral speed of 130 m / sec, and the average particle size of the obtained cellulose powder is 40 μm. It can be as follows. Tablets obtained by blending the cellulose powder thus obtained tend to have higher hardness and faster disintegration. Further, when the solid content concentration is not more than the above upper limit value, the peripheral speed can be increased and the average particle diameter can be controlled to 40 μm or less even at 220 m / sec.

The drying method for drying the cellulose aqueous dispersion to obtain the cellulose powder is not particularly limited. For example, any of freeze-drying, spray-drying, drum-drying, shelf-drying, air-flow drying, and vacuum-drying may be used, one type may be used alone, or two or more types may be used in combination. The spraying method for spray drying may be any of a disc type, a pressurized nozzle, a pressurized two-fluid nozzle, a pressurized four-fluid nozzle, or the like, and one type may be used alone, or two or more types may be used. May be used together.
At the time of the spray drying, a trace amount of water-soluble polymer and surfactant may be added for the purpose of lowering the surface tension of the dispersion liquid, and a foaming agent may be added to the dispersion liquid for the purpose of accelerating the vaporization rate of the medium. Alternatively, gas may be added.

Even when the average particle size of the dried cellulose powder is larger than 40 μm, the average particle size can be adjusted to 10 μm or more and 40 μm or less by subjecting it to a pulverization step described later.

In the crushing process, the dried cellulose powder is pulverized by an ultracentrifugal crusher (ZM-200, manufactured by Resch), a jet mill (STJ-200, manufactured by Seishin Enterprise), a hammer mill (H-12, manufactured by Hosokawa Micron), and a bantam mill (AP). -B, Hosokawa Micron, Pin Mill (160Z, Paulec), Feza Mill (FM, Hosokawa Micron), Hammermill (HM-600, Nara Kikai Seisakusho), Flash Mill (FL-250N, Dalton), Ball Mill (Emax) , Retsch), vibrating ball mill (2C, TRU), screen mill (U30, Paulek), etc. that allows the screen to pass through. In particular, a jet mill crusher (STJ-200, manufactured by Seishin Enterprise Co., Ltd.) is a flow-type crusher that crushes particles while colliding with each other at a high air pressure, and is preferable because secondary particles are easily crushed into primary particles.

≪Tablet≫
By blending the cellulose powder into a composition containing an active ingredient, tablets having excellent hardness, abrasion resistance and disintegration property can be obtained. That is, in one embodiment, the present invention provides a tablet containing the above-mentioned cellulose powder.

Hereinafter, a composition for tableting, which comprises one or more active ingredients and the above-mentioned cellulose powder, is referred to as "the composition of the present embodiment".

<Active ingredient>
In the present specification, the active ingredient is an ingredient added to a mixed powder, a molded product, a processed product, etc. in order to exert a desired function or effect in a pharmaceutical product, a health food, a food product, an industrial field, or the like. Say. For example, an active ingredient in the pharmaceutical field is a pharmaceutical medicinal ingredient.

Hereinafter, suitable active ingredients contained in the composition of the present embodiment will be illustrated.
As the medicinal active ingredient, the active ingredient of the orally administered drug is preferable. Orally administered drugs include, for example, antipyretic analgesics, antihypertensive drugs, anti-drowsiness drugs, expectorants, pediatric analgesics, stomachic drugs, antacids, digestive drugs, cardiotonics, arrhythmia drugs, antihypertensive drugs, etc. Examples thereof include vasodilators, diuretics, anti-ulcer drugs, intestinal regulators, osteoporosis remedies, antitussive expectorants, anti-asthmatic drugs, antibacterial agents, frequent urine improving agents, nourishing tonics, vitamins and the like. The active ingredient may be used alone or in combination of two or more.

Specifically, for example, aspirin, aspirin aluminum, acetaminophen, ethenzamid, sazapyrin, salicylamide, lactylphenetidine, isotibenzyl hydrochloride, diphenylpyrrine hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolysine hydrochloride, tryperenamine hydrochloride, tonsylamine hydrochloride. , Fenetazine hydrochloride, methodilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebuhydrolin napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-malein -Chlorpheniramine maleate, diferrol phosphate, alocramide hydrochloride, cloperastine hydrochloride, pentoxiberin citrate (carbetapentane citrate), tipepidin citrate, dibunato sodium, dextrometholphan hydrobromide, dextrometholphan Phenolphthalic acid, tipepidin hibenzate, cloperastine fendyzoate, codeine phosphate, dihydrocodein phosphate, noscapine hydrochloride, noscapin, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guayacol sulfonate, guayphenesin, sodium benzoate cafe Inn, 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 their derivatives and their salts, nicotinic acid amide, calcium pantothenate, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), hydroxide Aluminum gel (as dry aluminum hydroxide gel), dry aluminum hydroxide gel, mixed dry gel of aluminum hydroxide / magnesium carbonate, co-precipitated product of aluminum hydroxide / sodium hydrogen carbonate, aluminum hydroxide / calcium carbonate / magnesium carbonate Co-precipitate product, co-precipitate product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, magnesium aluminometasilicate, lanitidine hydrochloride, simethidine, famo Tidin, naproxene, diclophenac sodium, pyroxicum, azulene, indomethacin, ketoprofen, ibprofen, diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, promethazine hydrochloride, mecrydin hydrochloride, dimenhydrinate, diphenhydramine tannate, diphenhydramine tannate, diphenyltinate Diphenhydramine fumarate, promethazine methylene disalicylate, spocoramine hydrobromide, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methylatropin bromide, methylanisotropin bromide, methylspocoramine bromide, methyl-1 bromide -Hyostiamine, methylbenactidium bromide, veradonna extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, papaverin hydrochloride, aminobenzoic acid, cesium oxalate, piperidylacetylaminobenzoate ethyl, aminophyllin, diprofillin, theophylline , Sodium hydrogen carbonate, flusultiamine, isosorbide nitrate, ephedrine, cephalexin, ampicillin, sulfixazole, scralfate, allylisopropylacetylurea, bromvalerylurea, maou, nantenjitsu, ohi, onji, kanzo, kikyo, shazenshi, shazensou, senega , Baimo, Uikyo, Oubaku, Ouren, Gajutsu, Kamitsure, Keihi, Gentiana, Goou, Beast (including Yutan), Shajin, Shokyo, Sojutsu, Chouji, Chimpi, Byakujutsu, Earth Dragon, Chikusetsu Carrot, Carrot, Kanokosou , Buttonpi, Sansho and their extracts, insulin, bazopressin, interferon, urokinase, seratiopeptidase, somatostatin, etc. "Japanese Pharmacopoeia", "Japanese Pharmacopoeia Non-Pharmaceutical Standards (External Group)", "US Pharmacopoeia" The pharmaceutical and medicinal ingredients described in "Promethazine (USP)", "National Drug Collection (NF)", and "European Pharmacopoeia (EP)" can be mentioned. One type selected from the above may be used alone, or two or more types may be used in combination.

The active ingredient for health foods is not limited as long as it is an ingredient blended for the purpose of enhancing health, but for example, green juice powder, aglycon, agarix, ashwaganda, astaxanthin, acerola, amino acids (valine, leucine, isoleucine, etc. Lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid, seaweed powder, glutamine, glutamic acid, glycine, proline, serine, etc.), alginic acid, strawberry leaf extract, sardine peptide, corn, uron Acid, echinacea, eleuthero, oligosaccharide, oleic acid, nuclear protein, cutlet obsipeptide, catechin, potassium, calcium, carotinoid, garcinia, L-carnitine, chitosan, conjugated linoleic acid, kidati aloe, gymnema sylvestre extract, citric acid, kumiskutin, glyceride , Glysenol, Glucagon, Curcumin, Glucosamine, L-Glutamine, Chlorella, Cranberry extract, Cat's claw, Germanium, Enzyme, Koryo ginseng extract, Coenzyme Q10, Collagen, Collagen peptide, Corius forskolin, Chondroitin, Psyllium husk powder, Sanzashi extract, Saponin, lipid, L-cystine, perilla extract, citrimax, fatty acid, plant sterol, seed extract, spirulina, squalane, citrus white yanagi, ceramide, selenium, St. Jones wort extract, soy isoflavone, soy saponin, soy peptide, soy lecithin, monosaccharide , Protein, chest tree extract, iron, copper, docosahexaenoic acid, tocotrienol, natto kinase, natto fungus culture extract, niacin sodium, nicotinic acid, disaccharide, lactic acid bacterium, garlic, sawtooth palm, sprouted rice, honeybee extract, herb extract, valeryan Extract, pantothenic acid, hyaluronic acid, biotin, chromium picolinate, vitamin A, vitamin A2 vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, hydroxytyrosole, bifidus, Beer yeast, fructo-oligosaccharide, flavonoid, butcher's bloom extract, black kohosh, blueberry, prune extract, proanthocyanidin, protein, propolis, bromeline, probiotics, phosphatidylcholine, phosphatidylserine, β-carotene, peptide, Benibana extract, Maitake extract, Maca extract, Magnesium, Milk thistle, Manganese, Mitochondria, Minerals, Mucopolysaccharide, Melatonin, Meshimakobu, Merilot extract powder, Molybdenum, Vegetable powder, Folic acid, Lactose, Lecithin, Linoleic acid, Lipoic acid, Phosphorus (phosphorus) ), Lutein, lecithin, rosmarinic acid, royal jelly, DHA, EPA and the like.

The active ingredient may be poorly soluble as well as water-soluble. "Slightly soluble" means that the amount of water required to dissolve 1 g of solute is 30 mL or more in the 17th revised Japanese Pharmacopoeia.
Water-soluble, solid active ingredients include, for example, acetaminophen, ibuprofen, benzoic acid, etenzamid, caffeine, camphor, quinine, calcium gluconate, dimethylcaprol, sulfamine, theophylline, theopromine, riboflavin, mephenesin, pheno. Antipyretic analgesics such as barbital, aminophyllin, thioacetazone, quercetin, rutin, salicylic acid, theophylline sodium salt, pyrapital, quinine hydrochloride, irgapiline, dichitoxin, glyceofrubin, phenacetin, nervous system drugs, sedative hypnotics, muscle relaxants, blood pressure sclerosing agents , Antihistamines, etc .; Antibiotics such as acetylspiramycin, ampicillin, erythromycin, xatamycin, chloramphenicol, triacetyloleandomycin, nystatin, colistin sulfate; methyltestosterone, methylandrostetrondiol, progesterone, estradiolbenzoate, etini Steroid hormones such as estradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, bledonizolone; dienstrol, hexatrol, diethylstilvesterol, diethylstilvesterol dibrohionate, chlorotrianisen Non-steroidal egg yolk hormones such as; other fat-soluble vitamins, etc., such as pharmaceutical medicinal ingredients described in "Japanese Pharmacy", "External Group", "USP", "NF", "EP", etc. .. One type selected from the above may be used alone, or two or more types may be used in combination. If it is poorly soluble in water, the effect of the present invention can be obtained by blending it as an active ingredient in the composition of the present embodiment regardless of the degree of sublimation and surface polarity.

The active ingredient may be a poorly water-soluble oil or liquid. Examples of the poorly water-soluble oily and liquid active ingredients in the active ingredient include vitamins such as teprenone, indomethacin farnesyl, menatetrenone, phytonadione, vitamin A oil, phenipentol, vitamin D and vitamin E, and DHA (docosahexaenoic acid). , EPA (Eikosapentaenoic acid), higher unsaturated fatty acids such as cod liver oil, coenzyme Qs, oil-soluble flavors such as orange oil, lemon oil, peppermint oil, etc. "Japanese Pharmacy", "External Group", Examples thereof include pharmaceutical and medicinal ingredients described in "USP", "NF" and "EP". Vitamin E has various homologues and derivatives, but is not particularly limited as long as it is liquid at room temperature. For example, dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, d-α-tocopherol acetate and the like can be mentioned. One type selected from the above may be used alone, or two or more types may be used in combination.

The active ingredient may be a semi-solid active ingredient that is sparingly soluble in water. The sparingly water-soluble semi-solid form in the active ingredient includes, for example, earth dragon, kanzo, keihi, shakuyaku, buttonpi, kanokosou, sansho, ginger, chimpi, maou, nantenjitsu, ouhi, onji, kikyo, shazenshi, shazensou, stone.蒜, Seneca, Baimo, Uikyo, Oubaku, Ouren, Gajutsu, Kamitsure, Gentiana, Goou, Beast, Shajin, Ginger, Sojutsu, Chouji, Chinhi, Byakujutsu, Chikusetsu carrot, Carrot, Kakkonto, Keishito, Kaori Chinese herbal or crude drug extracts such as Susan, Shikou Keishito, Koushikoto, Shoseiryuto, Bakumondoto, Hangekobokuto, Mahoto; oyster meat extract, propolis and propolis extract, coenzyme Q And so on. One type selected from the above may be used alone, or two or more types may be used in combination.

The active ingredient may be sublimable. Examples of sublimable active ingredients include "Japanese Pharmacopeia", "US Pharmacopeia", "USP", "NF", and "EP" such as benzoic acid, ethenzamide, caffeine, camphor, salicylic acid, phenacetin, and ibuprofen. Examples thereof include sublimable pharmaceutical medicinal ingredients described in. One type selected from the above may be used alone, or two or more types may be used in combination. The sublimable active ingredient referred to in the present specification is not particularly limited as long as it has sublimation properties, and is semi-solid regardless of whether it is solid or liquid at room temperature. It may be in any state.

These active ingredients may be blended with the cellulose powder in the composition of the present embodiment in a finely pulverized state. For example, the active ingredient used in the present specification has an average particle size of 1 μm or more and 40 μm or less for the purpose of improving the dispersibility of the active ingredient or improving the mixing uniformity of the active ingredient having a medicinal effect in a small amount. It may be finely pulverized. The average particle size of the active ingredient is more preferably 1 μm or more and 20 μm or less, and further preferably 1 μm or more and 10 μm or less.

<Other additives>
The composition of the present embodiment may further contain other additives in addition to the above-mentioned active ingredient. Examples of other additives include excipients, disintegrants, binders, fluidizers, lubricants, flavoring agents and the like.

Examines other than cellulose powder include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, rubber arabic powder, alginic acid, sodium citrate, pregelatinized starch, and pebble grains. , Inositol, ethyl cellulose, ethylene vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pebbles, carmellose, carmellose sodium, hydrous silicon dioxide, dried yeast, dried aluminum hydroxide gel, dried sodium sulfate, Dried magnesium sulfate, canten, powdered canten, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, cloth Povidone, magnesium aluminate silicate, calcium silicate, magnesium silicate, light anhydrous citric acid, light liquid paraffin, kei powder, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (grains), genmai koji, synthetic silicic acid Aluminum, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ flour, rice, rice starch, potassium acetate, calcium acetate, cellulose phthalate, safflower oil, sala shimitsuro, zinc oxide, titanium oxide, magnesium oxide, β-Cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, citric acid, potassium hydrogen tartrate, roasted citric acid, sucrose fatty acid ester, alumina magnesium hydroxide, aluminum hydroxide Gel, aluminum hydroxide / sodium hydrogen carbonate coprecipitate, magnesium hydroxide, scrawan, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, soybean hardening oil, refined gelatin, purified cellac, purified sucrose, purified Spheroidal granules of sucrose, cetostearyl alcohol, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, D-sorbitol, calcium tertiary phosphate, soybean oil, soybean unkenide, soybean lecithin, skim milk powder, talc, ammonium carbonate, calcium carbonate , Magnesium carbonate, Neutral anhydrous sodium citrate, Low substitution hydroxypropyl cellulose , Dextran, dextrin, natural aluminum silicate, corn starch, tragant powder, silicon dioxide, calcium lactate, lactose, lactose granules, perfiller 101, white celac, white vaseline, hakudo, sucrose, sucrose / starch spherical granules, hadakamugi Green leaf extract powder, bare malt leaf green juice dry powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, Phytic acid, dextrose, glucose hydrate, partially pregelatinized starch, purulan, propylene glycol, powdered reduced malt sugar candy, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, Polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltitol, Maltose, D-mannitol, water candy, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium aluminometasilicate, methyl cellulose, cotton starch, cotton starch, mokurou, aluminum monostearate, mono Glycerin stearate, sorbitan monostearate, medicated charcoal, lacquer oil, aluminum sulfate, calcium sulfate, granular starch, liquid paraffin, dl-apple acid, calcium phosphate-hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate Classified as an excipient in "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nihonsha Co., Ltd.) such as granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, etc. There are things. These may be used alone or in combination of two or more.

Disintegrants include celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low substitution hydroxypropyl cellulose; carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato. Starches such as starch and partially pregelatinized starch; those classified as disintegrants in the "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nihonsha Co., Ltd.) such as synthetic polymers such as crospovidone and crospovidone copolymer are listed. Be done. One type selected from the above may be used alone, or two or more types may be used in combination.

As binders, sugars such as sucrose, glucose, lactose, and fructose; sugar alcohols such as mannitol, xylitol, martitol, erythritol, and sorbitol; gelatin, purulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, and tamarind. Water-soluble polysaccharides such as gum, pectin, sodium alginate, and arabic gum; celluloses such as crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, and methyl cellulose; starches such as pregelatinized starch and starch paste; polyvinylpyrrolidone, carboxyvinyl polymer, Synthetic polymers such as polyvinyl alcohol; "Pharmaceutical Additives Dictionary 2016" (published by Pharmaceutical Affairs Daily Co., Ltd.) such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, inorganic compounds such as magnesium silicate aluminate. Examples of those classified as binders. One type selected from the above may be used alone, or two or more types may be used in combination.

Examples of the fluidizing agent include those classified as fluidizing agents in "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.) such as silicon compounds such as hydrous silicon dioxide and light anhydrous silicic acid. One type selected from the above may be used alone, or two or more types may be used in combination.

Examples of the lubricant include those classified as a lubricant in the "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.) such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, and talc. One type selected from the above may be used alone, or two or more types may be used in combination.

As a flavoring agent, "Pharmaceutical Additives Dictionary 2016" such as glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, etc. (Yakuji Nihonsha Co., Ltd.) Issuance) includes those classified as flavoring agents. One type selected from the above may be used alone, or two or more types may be used in combination.

As fragrances, oils such as orange, vanilla, strawberry, yogurt, menthol, sardine oil, cinnamon oil, peppermint oil, peppermint oil, etc., and "Pharmaceutical Additives Dictionary 2016" (published by Pharmaceutical Affairs Daily) such as green tea powder Examples include those classified as agents and fragrances. One type selected from the above may be used alone, or two or more types may be used in combination.

Coloring agents include edible pigments such as edible red No. 3, edible yellow No. 5, edible blue No. 1, and "Pharmaceutical Additives Dictionary 2016" (published by Pharmaceutical Affairs Daily) such as copper chlorofin sodium, titanium oxide, and riboflavin. Examples include those classified as agents. One type selected from the above may be used alone, or two or more types may be used in combination.

Examples of sweeteners include those classified as sweeteners in the "Pharmaceutical Additives Dictionary 2016" (published by Pharmaceutical Affairs Daily) such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and amacha powder. Be done. One type selected from the above may be used alone, or two or more types may be used in combination.

<Tablet manufacturing method>
The method for producing a tablet by tableting a composition containing one or more active ingredients and the cellulose powder of the present embodiment (the method for producing a tablet of the present embodiment) will be described below, but this is an example. Therefore, the effect of this embodiment is not limited to the following methods.

As a method for producing tablets, a method of mixing the active ingredient with the cellulose powder of the present embodiment and then compression molding can be adopted. At this time, in addition to the active ingredient, other additives may be added, if necessary. Other additives are selected from, for example, the above-mentioned excipients, disintegrants, binders, fluidizers, lubricants, flavoring agents, flavors, colorants, sweeteners, solubilizing agents and the like. One or more types can be mentioned.

The order of addition of each component is not particularly limited, and i) a method of collectively mixing the active component, the cellulose powder of the present embodiment, and other additives as necessary and compression molding, ii) the active component, and flow. Any method may be used in which at least one of the agent and the lubricant is pretreated and mixed, the cellulose powder of the present embodiment is mixed with another additive if necessary, and then compression molding is performed. .. I) is preferable because of the ease of operation. It is also possible to add a lubricant to the compression molding mixed powders obtained in i) and ii), further mix them, and then perform compression molding. The method of adding each component is not particularly limited as long as it is a usual method, but a small suction transport device, an air transport device, a bucket conveyor, a pumping type transport device, a vacuum conveyor, a vibrating metering feeder, a spray, and a funnel. It may be added continuously using or the like, or it may be added all at once. As the spraying method, a method of spraying the active ingredient solution / dispersion liquid using a pressure nozzle, a two-fluid nozzle, a four-fluid nozzle, a rotating disk, an ultrasonic nozzle, etc., and a method of dropping the active ingredient solution / dispersion liquid from a tubular nozzle. It may be any of.

The mixing method is not particularly limited as long as it is a commonly used method, but is a container rotary mixer such as a V-type, W-type, double-cone type, or container tack type mixer; high-speed stirring type, universal stirring type, Stirring mixers such as ribbon type, pug type, and Nauter type mixers; high speed flow type mixers, drum type mixers, and fluidized bed type mixers may be used. It is also possible to use a container shaking type mixer such as a shaker.

The compression molding method of the composition is not particularly limited as long as it is a usual method, but a method of compression molding into a desired shape using a mortar and a pestle, or a method of compression molding into a sheet in advance to obtain a desired shape. It may be a method of dividing. As the compression molding machine, for example, a static pressure press machine, a briquetting roller type press machine, a roller type press machine such as a smoothing roller type press machine, a single punch tableting machine, a compressor such as a rotary tableting machine can be used. ..

The method for dissolving or dispersing the active ingredient in the medium is not particularly limited as long as it is a usual dissolution and dispersion method, but it is a unidirectional rotary type, a multi-axis rotary type, a reciprocating type such as a portable mixer, a three-dimensional mixer, and a side mixer. Stirring and mixing method using agitating blades such as reversing type, vertical movement type, rotary + vertical movement type, pipeline type, jet type stirring and mixing method such as line mixer, gas blowing type stirring and mixing method, high shear homogenizer, high pressure A mixing method using a homogenizer, an ultrasonic homogenizer, or the like, or a container shaking type mixing method using a shaker may be used.

The solvent used in the above-mentioned production method is not particularly limited as long as it is used for pharmaceutical products, and for example, at least one of water and an organic solvent may be used. Examples of the organic solvent 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. Etc., "Pharmaceutical Additives Dictionary 2016" (published by Pharmaceutical Affairs Daily) includes those classified as solvents. It may be used alone or in combination of two or more, and may be dispersed once in one medium, then the medium may be removed and dispersed in different media.

When dissolving the active ingredient in the medium, a water-soluble polymer, fat or oil, a surfactant or the like may be used as a dissolution aid. As the water-soluble polymer, oil and fat, and surfactant used as the dissolution aid, those described in "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.) can be appropriately used. These may be used alone or in combination of two or more.

The molded article in the present specification has a form of granules, fine granules, slugs, tablets, etc., and contains the cellulose powder of the present embodiment, one or more active ingredients, and if necessary, other additives. It is a thing.

As a method for molding into tablets, for example, a mixture of the active ingredient and the cellulose powder of the present embodiment, or one or more active ingredients and the cellulose powder of the present embodiment are mixed with other additives as necessary. An example is a direct tableting method (direct driving method) in which the product is compression-molded as it is. In addition, a manufacturing method such as a polynuclear tablet having a pre-compressed tablet as an inner core, or a multi-layer tablet in which a plurality of pre-compressed compacts are stacked and recompressed may be used. The direct locking method is preferable from the viewpoint of productivity and ease of process control.

The compression-molded tablet (molded article) may be further coated. Examples of the coating agent used in this case include the coating agents described in "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.). These may be used alone or in combination of two or more.

Further, in the method for producing a tablet of the present embodiment, it is preferable to pre-granulate a mixture containing an active ingredient before compression molding. When the active ingredient is pre-granulated, the cellulose powder may be added to the active ingredient and used together for granulation (referred to as "intra-granular addition method"), or may be added after the granulation active ingredient is granulated. Good (referred to as "post-end addition method"), but the post-end addition method is preferred. By the terminal addition method, the hardness of the obtained tablet can be made better as shown in Examples described later.

That is, in one embodiment, the present invention provides a method for producing a tablet, which comprises the following steps.
Step of granulating a mixture containing an active ingredient to obtain a granulated product;
A step of adding an additive containing the cellulose powder to the granulated product and compression molding the product.

Granulation methods include dry granulation, wet granulation, heat granulation, spray granulation, and microencapsulation. Specifically, as the wet granulation method, the fluidized bed granulation method, the stirring granulation method, the extrusion granulation method, the crushing granulation method, and the rolling granulation method are effective. In the fluidized bed granulation method, the fluidized bed granulation method is effective. In the granulator, the fluidized powder is sprayed with a binding liquid to granulate. In the stirring granulation method, powders are mixed, kneaded, and granulated at the same time in a closed structure by rotating the stirring blades in the mixing tank while adding the bonding liquid. In the extrusion granulation method, a wet mass kneaded by adding a binding liquid is forcibly extruded from a screen of an appropriate size by a method such as a screw type or a basket type to granulate. In the crushing and granulating method, a wet mass kneaded by adding a binding liquid is sheared and crushed by a rotary blade of a granulator, and the centrifugal force of the wet mass is ejected from the outer screen to granulate. In the rolling granulation method, the granules are rolled by the centrifugal force of the rotating rotor, and at this time, the binding liquid sprayed from the spray gun is used to grow spherical granules having a uniform particle size in a snowball manner. .. Among them, as the granulation method, a wet granulation method is preferable from the viewpoint of hardness, abrasion resistance and disintegration of the obtained tablet.

The method for drying the granules is one of hot air heating type (shelf drying, vacuum drying, fluidized bed drying), conduction heat transfer type (flat pan type, shelf box type, drum type), and freeze drying. Can also be used. In the hot air heating type, the hot air is brought into direct contact with the additive, and at the same time, the evaporated water is removed. In the conduction heat transfer type, the additive is indirectly heated through the heat transfer wall. In freeze-drying, the additive is frozen at -10 ° C or higher and 40 ° C or lower, and then heated under high vacuum (1.3 x ^10-5 MPa or higher and 2.6 x 10 ^-4 MPa or lower). Sublimates and removes water.

The method for adding one or more active ingredients, the above-mentioned cellulose powder, other additives, or granules is not particularly limited as long as it is a usual method, but a small suction transport device, an air transport device, a bucket conveyor, etc. It may be added continuously using a pumping type transport device, a vacuum conveyor, a vibrating metering feeder, a spray, a funnel, or the like, or may be added all at once.

The content of the cellulose powder is 0.1% by mass or more and 50% by mass or less with respect to the total mass of the composition or the molded product, and the content of the active ingredient is 0. In the composition and the molded product of the present embodiment, which are 1% by mass or more and 20% by mass or less, the content CV value of the active ingredient in the composition and the molded body is preferably 5% by mass or less, preferably 2% by mass or less. More preferably, 1.5% by mass or less is further preferable. The "active ingredient content CV value" referred to here can be calculated by the following equation using the average value and standard deviation of the active ingredient content in the composition or the molded product.

Active ingredient content CV value (%) = ([standard deviation] / [average active ingredient content]) x 100

The content of the active ingredient in the composition and the molded product of the present embodiment can be determined by preparing a calibration curve for each active ingredient and using a quantification method by an absorptiometry, depending on the circumstances of each active ingredient. , An appropriate quantification method may be selected. For example, when the active ingredient is poorly soluble, a quantification method using gas chromatography is appropriate, and when a plurality of active ingredients are contained, a quantification method using liquid chromatography is appropriate. For the method of quantifying the active ingredient, the description of the general test method of the 17th revised Japanese Pharmacopoeia can be referred to.

The present embodiment will be described in detail with reference to Examples and Comparative Examples, but the present embodiment is not limited thereto. The physical properties of Examples and Comparative Examples and their measurement methods are as follows.

<Measurement method of physical properties>
[Physical properties 1] Average particle size Using a laser diffraction type particle size distribution meter (LA-950 V2 (trade name), manufactured by HORIBA, Ltd.), compressed air pressure 0.10 MPa, feeder speed 160, feeder initial speed coefficient in dry measurement mode. It was measured at 1.2 and a refractive index of 1.51. The cumulative volume of 50% particles obtained by the measurement was taken as the average particle size (μm) of the cellulose powder.

[Physical properties 2] Ratio of the mass of the powder passed through the sieve with a mesh size of 32 μm to the total mass of the powder used for the sieve with a mesh size of 32 μm (ratio of particles having a particle size of 32 μm or less)
Aspirate 5.0 g of cellulose powder with an air jet sheave (A200LS: manufactured by ALPINE) for 5 minutes (-2.0 Pa or more), and divide the mass of the powder that has passed through a sieve with a mesh opening of 32 μm by the mass of the original powder. The ratio (mass%) of particles having a particle diameter of 32 μm or less was calculated. The sieve used was made of stainless steel (made by ALPINE) specified by JIS standard, and 32 μm (outer diameter 200φ) was selected.

[Physical Properties 3] Bulk Density Cellulose powder was adjusted to a rate of 50 mL / min with a quantitative feeder and dropped onto a Scott volume meter (ASTM-B-329-98, manufactured by Tsutsui Rikagaku Kikai). When the powder was filled in the 25 mL sample container, it was scraped off and the mass of the powder was divided by the volume (25 mL) to calculate the bulk density (g / mL).

[Physical properties 4] The specific surface area was measured by the BET method using TriSTAR (manufactured by Micromeritics) and nitrogen as an adsorbed gas. About 1 g of each cellulose powder was charged into a cell and measured. As each cellulose powder used for the measurement, one which was dried under reduced pressure at 110 ° C. for 3 hours was used.

[Physical Properties 5] Compressibility The "loose apparent specific gravity" and "hard apparent specific gravity" were measured with a powder physical property measuring machine (PT-R, manufactured by Hosokawa Micron), and the compressibility was measured by the following formula. The sieve used had a mesh opening of 710 μm, and the funnel was made of metal (coated with antistatic spray) and had an inner diameter of 0.8 cm. The VIBRATION was performed at 2.0 (60 Hz).

Degree of compression (%) = ([Hard apparent specific gravity]-[Loose apparent specific gravity]) / [Hard apparent specific gravity] x 100

[Physical properties 6] Tablet plastic deformation rate Using 0.5 g of cellulose powder in a tableting data recording device (TK-TB20KN, manufactured by Special Measurement), tableting speed 0.5 mm / sec, maximum tableting pressure 5 kN, tablet diameter Tablets were prepared under the condition of 11.3 mmφ. A graph was created with the vertical punching gap (mm) as the horizontal axis and the lower punching load (MPa) as the vertical axis. Areas S1 and S1 + S2 were calculated from the values on the horizontal axis and the vertical axis, and the tablet plastic deformation rate was calculated from the following formula. In the following formula, "S1 + S2" represents the maximum area using the minimum vertical punch gap, and "S1" represents the restored area 24 hours after the preparation of the tablet.

Tablet plastic deformation rate (%) = 100-S1 / (S1 + S2) x 100

<Tablet evaluation method>
[Evaluation 1] Hardness The hardness of tablets was measured. Specifically, the hardness was measured with a hardness tester (Tablet Tester 8M, manufactured by DR.SCHLEUNIGER) after about 20 hours or more and 48 hours or less had elapsed immediately after the tableting. The tablets were placed in Lamizip to prevent moisture absorption, sealed, and stored at room temperature until the hardness was measured. The average value of 10 tablets with each pressing force was taken as the hardness of the tablets.

[Evaluation 2] The mass (Wa) of 37 wearable tablets was measured, and these were placed in a tablet wearability tester (PTFR-A, manufactured by PHARMA TEST) and rotated at 25 rpm for 4 minutes. Then, the fine powder adhering to the tablet was removed, the mass was measured again (Wb), and the degree of abrasion was calculated from the following formula.

Abrasion = (Wa-Wb) / Wa × 100

Those having a wearability of 0.3% or less were evaluated as having good wearability.

[Evaluation 3] For disintegrating tablets, the disintegration time (seconds) in pure water at 37 ° C. was determined using a disintegration tester (NT-40HS type, manufactured by Toyama Sangyo). The average value of each of the 6 tablets was taken as the disintegration time of the tablets.

<Manufacturing of cellulose powder>
[Example 1] Production of cellulose powder A 2.0 kg of commercially available pulp (degree of polymerization 830) is shredded, placed in 30 L of a 5N hydrochloric acid aqueous solution, and stirred with a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). Hydrolysis was carried out at 40 ° C. for 20 hours while (stirring speed: 30 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 18% by mass was prepared while stirring (stirring speed: 500 rpm) with (manufactured by HEIDON). After spray-drying this cellulose dispersion (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower), an airflow type crusher (single track jet mill STJ-200 type, Using Seishin Enterprise Co., Ltd.), pulverization was performed at a pulverization pressure of 0.7 MPa and a powder supply rate of 10 kg / hour to obtain cellulose powder A.

[Example 2] Production of cellulose powder B 2.0 kg of commercially available pulp (degree of polymerization 1100) is shredded and placed in 30 L of a 0.14 N hydrochloric acid aqueous solution, and a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). Hydrolyzed at 121 ° C. for 1 hour with stirring (stirring speed 30 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 17% by mass was prepared while stirring (stirring speed: 500 rpm) with (manufactured by HEIDON). After spray-drying this cellulose dispersion (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower), an airflow type crusher (single track jet mill STJ-200 type, Using Seishin Enterprise Co., Ltd.), pulverization was performed at a pulverization pressure of 0.7 MPa and a powder supply rate of 10 kg / hour to obtain cellulose powder B.

[Example 3] Production of cellulose powder C 2.0 kg of commercially available pulp (degree of polymerization 710) is shredded and placed in 30 L of a 0.11 N hydrochloric acid aqueous solution, and a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). Hydrolyzed at 150 ° C. for 60 minutes with stirring (stirring speed 180 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 5% by mass was prepared while stirring (stirring speed: 500 rpm) with (manufactured by HEIDON). This cellulose dispersion was spray-dried (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower) to obtain cellulose powder C.

[Example 4] Production of cellulose powder D 2.0 kg of commercially available pulp (degree of polymerization 830) is shredded, placed in 30 L of a 5N hydrochloric acid aqueous solution, and stirred with a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). Hydrolysis was carried out at 40 ° C. for 20 hours while (stirring speed: 30 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 18% by mass was prepared while stirring (stirring speed: 500 rpm) with (manufactured by HEIDON). After spray-drying this cellulose dispersion (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower), an airflow type crusher (single track jet mill STJ-200 type, Using Seishin Enterprise Co., Ltd.), pulverization was performed at a pulverization pressure of 0.6 MPa and a powder supply rate of 10 kg / hour to obtain cellulose powder D.

[Example 5] Production of cellulose powder E 2.0 kg of commercially available pulp (degree of polymerization 1100) is shredded and placed in 30 L of a 0.14 N hydrochloric acid aqueous solution, and a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). Hydrolyzed at 121 ° C. for 1 hour with stirring (stirring speed 30 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 17% by mass was prepared while stirring (stirring speed: 500 rpm) with (manufactured by HEIDON). After spray-drying this cellulose dispersion (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower), an airflow type crusher (single track jet mill STJ-200 type, Using Seishin Enterprise Co., Ltd.), pulverization was performed at a pulverization pressure of 0.6 MPa and a powder supply rate of 10 kg / hour to obtain cellulose powder E.

[Example 6] Production of Cellulose Powder F 2.0 kg of commercially available pulp (degree of polymerization 710) is shredded and placed in 30 L of a 0.11 N hydrochloric acid aqueous solution, and a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). Hydrolyzed at 150 ° C. for 60 minutes with stirring (stirring speed 180 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 8% by mass was prepared while stirring (stirring speed: 500 rpm) with (manufactured by HEIDON). This cellulose dispersion was spray-dried (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower) to obtain cellulose powder F.

[Comparative Example 1] Production of Cellulose Powder G 5.0 g of cellulose powder F is sucked (-2.0 Pa or more) with an air jet sheave (A200LS: manufactured by ALPINE) for 5 minutes, and the powder and eyes on a sieve having an opening of 32 μm 50% by mass of each powder under the sieve having an opening of 32 μm was placed in a polyethylene plastic bag and manually mixed for 3 minutes to obtain cellulose powder G.

[Comparative Example 2] Production of Cellulose Powder H 2.0 kg of commercially available pulp (degree of polymerization 790) is shredded, placed in 30 L of a 4N hydrochloric acid aqueous solution, and stirred with a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). While hydrolyzing at 40 ° C. for 24 hours, an acid-insoluble residue was obtained. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 10% by mass was prepared while stirring (stirring speed: 5 rpm) with (manufactured by HEIDON). This cellulose dispersion was spray-dried (disk peripheral speed 170 m / sec, liquid supply speed 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower) to obtain cellulose powder H.

[Comparative Example 3] Production of Cellulose Powder I 2.0 kg of commercially available pulp (degree of polymerization 790) is shredded, placed in 30 L of a 4N hydrochloric acid aqueous solution, and stirred with a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). While hydrolyzing at 40 ° C. for 48 hours, an acid-insoluble residue was obtained. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 10% by mass was prepared while stirring (stirring speed: 100 rpm) with (manufactured by HEIDON). This cellulose dispersion was spray-dried (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower) to obtain cellulose powder I.

[Comparative Example 4] Production of Cellulose Powder J 2.0 kg of commercially available pulp (degree of polymerization 1030) is shredded and placed in 30 L of a 0.14 N hydrochloric acid aqueous solution, and a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Ryo Kogyo). Hydrolyzed at 121 ° C. for 1 hour with stirring (stirring speed 30 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue is filtered using Nutche, neutralized with aqueous ammonia, placed in a 90 L poly bucket and pure water is added, and three-one motor (type 1200 G, 8 M / M, blade diameter about 5 cm: A cellulose dispersion having a solid content concentration of 17% by mass was prepared while stirring (stirring speed: 500 rpm) with (manufactured by HEIDON). This cellulose dispersion was spray-dried (liquid supply rate 6 L / hour, inlet temperature 180 ° C. or higher and 220 ° C. or lower, outlet temperature 50 ° C. or higher and 70 ° C. or lower) to obtain cellulose powder J.

Table 1 shows the physical properties of the cellulose powders A to J.

<Manufacturing of tablets>
Tablets having various formulations were produced using cellulose powders A to J.

[Example 7]
37.5% by mass of etenzamid (manufactured by Iwaki Pharmaceutical Co., Ltd.) and 62.5% by mass of 200M lactose (manufactured by DFE phama) were charged into a fluidized bed granulator (MP-01, manufactured by Paulec), and HPC-SL (manufactured by Nippon Soda) After spraying 200 g of the binding liquid prepared to be a 6 mass% aqueous solution (spray rate: 15 g / min, spray pressure: 1 kg / cm ² ), granulating and drying (granulation temperature: 65 ° C., drying temperature: 75 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less), the obtained granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. Next, 80% by mass of the active ingredient-containing granules, 20% by mass of the cellulose powder A obtained in Example 1, and 1% by mass of croscarmellose sodium (Kiccolate (trade name), ND-2HS, manufactured by Asahi Kasei) (outside split). Was placed in a polyethylene plastic bag and mixed by hand for 3 minutes. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The mixed powder is charged into a rotary tableting machine (Clean Press 12HUK Collect, manufactured by Kikusui Seisakusho) and tableted (tablet conditions: tablet mass: 180 mg, tablet diameter: 8 mmΦ, 12R, rotor speed: 54 rpm, feeder type. : Open feeder, tableting pressure: 4 kN or more and 10 kN or less, number of mortars: 12), tablets were obtained.

[Example 8]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder B obtained in Example 2 was used instead of the cellulose powder A obtained in Example 1.

[Example 9]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder C obtained in Example 3 was used instead of the cellulose powder A obtained in Example 1.

[Example 10]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder D obtained in Example 4 was used instead of the cellulose powder A obtained in Example 1.

[Example 11]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder E obtained in Example 5 was used instead of the cellulose powder A obtained in Example 1.

[Example 12]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder F obtained in Example 6 was used instead of the cellulose powder A obtained in Example 1.

[Comparative Example 5]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder G obtained in Comparative Example 1 was used instead of the cellulose powder A obtained in Example 1.

[Comparative Example 6]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder H obtained in Comparative Example 2 was used instead of the cellulose powder A obtained in Example 1.

[Comparative Example 7]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder I obtained in Comparative Example 3 was used instead of the cellulose powder A obtained in Example 1.

[Comparative Example 8]
Tablets were obtained by the same method as in Example 7 except that the cellulose powder J obtained in Comparative Example 4 was used instead of the cellulose powder A obtained in Example 1.

[Comparative Example 9]
37.5% by mass of etenzamid (manufactured by Iwaki Pharmaceutical Co., Ltd.) and 62.5% by mass of 200M lactose (manufactured by DFE phama) were charged into a fluidized bed granulator (MP-01, manufactured by Paulec), and HPC-SL (manufactured by Nippon Soda) After spraying 200 g of the binding liquid prepared to be a 6 mass% aqueous solution (spray rate: 15 g / min, spray pressure: 1 kg / cm ² ), granulating and drying (granulation temperature: 65 ° C., drying temperature: 75 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less), the obtained granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. Next, 100% by mass of active ingredient-containing granules and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, Asahi Kasei) were placed in a polyethylene plastic bag and mixed by hand for 3 minutes. did. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

Table 2 shows the evaluation results of the tablets obtained in Examples 7 to 12 and Comparative Examples 5 to 9.

From Table 2, the tablets using the cellulose powders A to F (Examples 7 to 12) had good hardness, abrasion resistance, and disintegration property.
Further, in the tablets using the cellulose powders A to F (Examples 7 to 12), the hardness tends to be improved as the bulk density of the cellulose powder decreases and the specific surface area and the degree of compression increase. It was.
Further, in tablets using cellulose powders A to F (Examples 7 to 12), the disintegration property becomes better as the proportion of particles having a particle size of 32 μm or less and the average particle size decrease. There was a tendency.

On the other hand, none of the tablets using the cellulose powders G to J (Comparative Examples 5 to 8) had good hardness, abrasion resistance and disintegration property. In addition, the tablets (Comparative Example 9) that did not use cellulose powder were significantly inferior in hardness, abrasion resistance, and disintegration property.

[Example 13]
Etensamide (manufactured by Iwaki Pharmaceutical Co., Ltd.) 37.5% by mass and 200M lactose (manufactured by DFE phama) 62.5% by mass were charged into a stirring granulator (VG-10, manufactured by Paulec), and HPC-SL (manufactured by Nippon Soda) was 6 138 g of a binding solution prepared to be a mass% aqueous solution was added all at once in 30 seconds and granulated for 3 minutes (blade: 280 rpm, cloth: 1500 rpm). Then, the resulting granules were dried by a fluidized bed granulator (MP-01, manufactured by Paulec) (drying temperature: 70 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less). The dried granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. 80% by mass of active ingredient-containing granules, 20% by mass of cellulose powder A, and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, Asahi Kasei) were placed in a polyethylene plastic bag. Hand mixed for 3 minutes. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

[Example 14]
Tablets were obtained using the same method as in Example 13 except that cellulose powder B was used instead of cellulose powder A.

[Example 15]
Tablets were obtained using the same method as in Example 13 except that cellulose powder C was used instead of cellulose powder A.

[Comparative Example 10]
Tablets were obtained by using the same method as in Example 13 except that cellulose powder J was used instead of cellulose powder A.

[Comparative Example 11]
Etensamide (manufactured by Iwaki Pharmaceutical Co., Ltd.) 37.5% by mass and 200M lactose (manufactured by DFE phama) 62.5% by mass were charged into a stirring granulator (VG-10, manufactured by Paulec), and HPC-SL (manufactured by Nippon Soda) was 6 138 g of a binding solution prepared to be a mass% aqueous solution was added all at once in 30 seconds and granulated for 3 minutes (blade: 280 rpm, cloth: 1500 rpm). Then, the resulting granules were dried by a fluidized bed granulator (MP-01, manufactured by Paulec) (drying temperature: 70 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less). The dried granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. 100% by mass of active ingredient-containing granules and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, manufactured by Asahi Kasei) were placed in a polyethylene plastic bag and mixed by hand for 3 minutes. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

The evaluation results of the tablets obtained in Examples 13 to 15 and Comparative Examples 10 to 11 are shown in Table 3.

From Table 3, the tablets using the cellulose powders A to C (Examples 13 to 15) had good hardness, abrasion resistance and disintegration property.
Further, in the tablets using the cellulose powders A to C (Examples 13 to 15), the hardness tends to be improved as the bulk density of the cellulose powder decreases and the specific surface area and the degree of compression increase. It was.

On the other hand, the tablets using the cellulose powder J (Comparative Example 10) and the tablets not using the cellulose powder (Comparative Example 11) were inferior in hardness, abrasion resistance and disintegration property.

[Example 16]
Ibuprofen (manufactured by Yonezawa Hamari Chemical Co., Ltd.) 37.5% by mass and 200M lactose (manufactured by DFE phama) 62.5% by mass were charged into a stirring granulator (VG-10, manufactured by Paulec), and HPC-SL (manufactured by Nippon Soda). 138 g of a binder solution prepared to form a 6 mass% aqueous solution was added all at once in 30 seconds, and granulation was performed for 3 minutes (blade: 280 rpm, cloth: 1500 rpm). Then, the resulting granules were dried by a fluidized bed granulator (MP-01, manufactured by Paulec) (drying temperature: 70 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less). The dried granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. 80% by mass of active ingredient-containing granules, 20% by mass of cellulose powder A, and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, Asahi Kasei) were placed in a polyethylene plastic bag. Hand mixed for 3 minutes. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

[Example 17]
Tablets were obtained using the same method as in Example 16 except that cellulose powder B was used instead of cellulose powder A.

[Example 18]
Tablets were obtained using the same method as in Example 16 except that cellulose powder C was used instead of cellulose powder A.

[Comparative Example 12]
Tablets were obtained by the same method as in Example 16 except that cellulose powder J was used instead of cellulose powder A.

The evaluation results of the tablets obtained in Examples 16 to 18 and Comparative Example 12 are shown in Table 4.

From Table 4, the tablets using the cellulose powders A to C (Examples 16 to 18) had good hardness, abrasion resistance and disintegration property.

On the other hand, the tablets using the cellulose powder J (Comparative Example 12) were inferior in hardness, abrasion resistance and disintegration property.

[Example 19]
37.5% by mass of ascorbic acid (manufactured by Watanabe Chemical) and 62.5% by mass of 200M lactose (manufactured by DFE phama) were charged into a stirring granulator (VG-10, manufactured by Paulek), and HPC-SL (manufactured by Nippon Soda) 138 g of a binder solution prepared to be a 6 mass% aqueous solution was added all at once in 30 seconds, and granulation was performed for 3 minutes (blade: 280 rpm, cloth: 1500 rpm). Then, the resulting granules were dried by a fluidized bed granulator (MP-01, manufactured by Paulec) (drying temperature: 70 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less). The dried granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. 80% by mass of active ingredient-containing granules, 20% by mass of cellulose powder A, and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, Asahi Kasei) were placed in a polyethylene plastic bag. Hand mixed for 3 minutes. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

[Example 20]
Tablets were obtained using the same method as in Example 19 except that cellulose powder B was used instead of cellulose powder A.

[Example 21]
Tablets were obtained using the same method as in Example 19 except that cellulose powder C was used instead of cellulose powder A.

[Comparative Example 13]
Tablets were obtained using the same method as in Example 19 except that cellulose powder J was used instead of cellulose powder A.

The evaluation results of the tablets obtained in Examples 19 to 21 and Comparative Example 13 are shown in Table 5.

From Table 5, the tablets using the cellulose powders A to C (Examples 19 to 21) had good hardness, abrasion resistance and disintegration property.

On the other hand, the tablets using the cellulose powder J (Comparative Example 13) were inferior in hardness, abrasion resistance and disintegration property.

[Example 22]
Acetaminophen (manufactured by Shinnihonseiyaku) 37.5% by mass and 200M lactose (manufactured by DFE phama) 62.5% by mass were charged into a stirring granulator (VG-10, manufactured by Paulec), and HPC-SL (manufactured by Nippon Soda). 138 g of a binding solution prepared so as to be a 6% by mass aqueous solution was added all at once in 30 seconds and granulated for 3 minutes (blade: 280 rpm, cloth: 1500 rpm). Then, the resulting granules were dried by a fluidized bed granulator (MP-01, manufactured by Paulec) (drying temperature: 70 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less). The dried granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. 80% by mass of active ingredient-containing granules, 20% by mass of cellulose powder A, and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, Asahi Kasei) were placed in a polyethylene plastic bag. Hand mixed for 3 minutes. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

[Example 23]
Tablets were obtained using the same method as in Example 22 except that cellulose powder B was used instead of cellulose powder A.

[Example 24]
Tablets were obtained using the same method as in Example 22 except that cellulose powder C was used instead of cellulose powder A.

[Comparative Example 14]
Tablets were obtained by using the same method as in Example 22 except that cellulose powder J was used instead of cellulose powder A.

The evaluation results of the tablets obtained in Examples 22 to 24 and Comparative Example 14 are shown in Table 6.

From Table 6, the tablets using the cellulose powders A to C (Examples 22 to 24) had good hardness, abrasion resistance and disintegration property.
Further, in the tablets using the cellulose powders A to C (Examples 22 to 24), the hardness tends to be improved as the bulk density of the cellulose powder decreases and the specific surface area and the degree of compression increase. It was.

On the other hand, the tablets using the cellulose powder J (Comparative Example 14) were inferior in hardness, abrasion resistance and disintegration property.

[Example 25]
30% by mass of etenzamid (manufactured by Iwaki Pharmaceutical Co., Ltd.), 50% by mass of 200M lactose (manufactured by DFE phama), and 20% by mass of cellulose powder A were charged into a fluidized layer granulator (MP-01, manufactured by Paulec), and HPC-SL (Japan). After spraying 300 g of the binder solution prepared so that (manufactured by Soda) becomes a 6 mass% aqueous solution (spray rate: 15 g / min, spray pressure: 1 kg / cm ² ), granulation and drying (granulation temperature: 65 ° C.) , Drying temperature: 75 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less), and the obtained granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. Next, 100% by mass of active ingredient-containing granules and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, Asahi Kasei) were placed in a polyethylene plastic bag and mixed by hand for 3 minutes. did. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

[Comparative Example 15]
Tablets were obtained by using the same method as in Example 25 except that cellulose powder J was used instead of cellulose powder A.

The evaluation results of the tablets obtained in Example 25 and Comparative Example 15 are shown in Table 7.

From Table 7, the tablet using the cellulose powder A (Example 25) was superior in hardness, abrasion resistance and disintegration property to the tablet using the cellulose powder J (Comparative Example 15).

[Example 26]
30% by mass of etenzamid (manufactured by Iwaki Pharmaceutical Co., Ltd.), 50% by mass of 200M lactose (manufactured by DFE phama), and 20% by mass of cellulose powder A were charged into a stirring granulator (VG-10, manufactured by Paulec), and HPC-SL (Nippon Soda). 138 g of a binder solution prepared so as to be a 6 mass% aqueous solution was added all at once in 30 seconds and granulated for 3 minutes (blade: 280 rpm, cloth: 1500 rpm). Then, the resulting granules were dried by a fluidized bed granulator (MP-01, manufactured by Paulec) (drying temperature: 70 ° C., air volume: 30 m ³ / hour or more and 50 m ³ / hour or less). The dried granules were sieved with a 710 μm sieve to obtain active ingredient-containing granules. 100% by mass of active ingredient-containing granules and 1% by mass (outer split) of croscarmellose sodium (Kiccolate (trade name), ND-2HS, manufactured by Asahi Kasei) were placed in a polyethylene plastic bag and mixed by hand for 3 minutes. Then, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. The powder was tableted in the same manner as in Example 7 to obtain tablets.

[Comparative Example 16]
Tablets were obtained by using the same method as in Example 26 except that cellulose powder J was used instead of cellulose powder A.

The evaluation results of the tablets obtained in Example 26 and Comparative Example 16 are shown in Table 8.

From Table 8, the tablets using the cellulose powder A (Example 26) were superior in hardness, abrasion resistance and disintegration property to the tablets using the cellulose powder J (Comparative Example 16).

[Example 27]
Etensamide (manufactured by Iwaki Pharmaceutical Co., Ltd.) 30% by mass, lactose for direct hitting (Super Tab 11SD, manufactured by DFE phama) 50% by mass, cellulose powder A 20% by mass, and croscarmellose sodium (ciccolate (trade name), ND-2HS, Asahi Kasei) 1% by mass (outer split) was placed in a plastic bag and mixed by hand for 3 minutes. Further, 0.5% by mass (outer split) of magnesium stearate (manufactured by Taihei Kagaku Sangyo) was added to the mixed powder, and the mixture was slowly hand-mixed for 30 seconds. Tableting was performed under the same conditions as in Example 7 to obtain tablets.

[Comparative Example 17]
Tablets were obtained by using the same method as in Example 27 except that cellulose powder J was used instead of cellulose powder A.

The evaluation results of the tablets obtained in Example 27 and Comparative Example 17 are shown in Table 9.

From Table 9, the tablet using the cellulose powder A (Example 27) was superior in hardness, abrasion resistance and disintegration property to the tablet using the cellulose powder J (Comparative Example 17).

Further, in tablets having different production methods (Examples 1, 13, 25 to 27), the hardness of the tablets tends to be improved by using the fluidized bed granulation, and the cellulose powder A is obtained by the post-disposal method. There was a tendency that the disintegration property of the tablet was improved by molding the tablet by the direct striking method without adding or granulating.

According to the cellulose powder of the present embodiment, tablets having excellent hardness, abrasion resistance and disintegration property can be obtained.

Claims (8)

The average particle size is 10 μm or more and 40 μm or less.
A cellulose powder in which the ratio of the mass of the powder passed through the sieve having a mesh size of 32 μm to the total mass of the powder provided to the sieve having a mesh size of 32 μm is more than 60% by mass based on the total mass of the powder. The cellulose powder according to claim 1, which has a bulk density of 0.1 g / mL or more and 0.4 g / mL or less. The cellulose powder according to claim 1 or 2, wherein the specific surface area is 1.0 m ² / g or more and 2.6 m ² / g or less. The cellulose powder according to any one of claims 1 to 3, wherein the degree of compression is 35 or more and 60 or less. The cellulose powder according to any one of claims 1 to 4, wherein the tablet plastic deformation rate when a tablet composed of only the cellulose powder is produced is 87% or more. A tablet comprising the cellulose powder according to any one of claims 1 to 5. A method for producing a tablet, which uses the cellulose powder according to any one of claims 1 to 5. The process of granulating a mixture containing an active ingredient to obtain a granulated product,
A step of adding an additive containing the cellulose powder to the granulated product and compression molding.
7. The method for producing a tablet according to claim 7.