TWI734247B - Cellulose composition and lozenge - Google Patents

Abstract

The cellulose composition includes cellulose and cellooligosaccharides of 3 to 7 sugars, and the content of the cellooligosaccharides per 5 g of the cellulose composition is 1.5 mg or more and 9.0 mg or less. The lozenge contains the above-mentioned cellulose composition and one or more active ingredients.

Description

Cellulose composition and lozenge

The present invention relates to a cellulose composition and lozenge.

The tabletization of pharmaceuticals has the advantages of high productivity and easy operation during transportation or use. In tableting, most of the active ingredient raw materials cannot be shaped even if compressed, so the formulation of excipients for tableting requires good formability, fluidity and disintegration. Cellulose is often used as an excipient.

Patent Document 1 discloses that the average degree of polymerization is 100 or more and 350 or less, the weight average particle size exceeds 30 μm and is 250 μm or less, the apparent specific volume is 2 cm ³ /g or more and less than 15 cm ³ /g, Cellulose powder with a sharpness of particle size distribution of 1.5 or more and 2.9 or less. It is revealed that the use of the cellulose powder has the following effects: it has excellent compression moldability, and can uniformly maintain high viscosity or hygroscopicity. Chinese medicine or components with adhesive properties. By making the particle size of the cellulose powder The steep distribution can also make the particle size distribution of the particles steep, thereby shortening the disintegration time, and thereby imparting stable disintegration over time.

On the other hand, in the case of using cellulose powder equivalent to the prior art, in order to make the content of active ingredients in each tablet uniform, there is a tendency to extend the mixing time of the raw materials, which is accompanied by the extension of the mixing time. The decrease in tablet hardness may be a problem. However, in order to prevent the segregation of the active ingredients, sufficient mixing is indispensable, which makes it difficult to prevent the decrease in tablet hardness caused by the extension of the mixing time and at the same time prevent the decrease in content uniformity. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2013/180248

The present invention has been completed in view of the above circumstances, and provides a cellulose composition with good hardness, a bias in the content of an active ingredient, and inhibition of tableting at the time of forming, and a tablet containing the above-mentioned cellulose composition.

That is, the present invention includes the following aspects. (1) A cellulosic composition comprising cellulose and cellooligosaccharides of 3 to 7 sugars, and the content of the cellooligosaccharide is 1.5 mg or more and 9.0 per 5 g of the cellulosic composition. Below mg. (2) The cellulose composition as described in (1), wherein the cellulose composition has a water-soluble content of 2.5 mg or more and 12.5 mg or less per 5 g. (3) The cellulose composition according to (2), wherein the ratio of the cellooligosaccharide to the water-soluble substance is 47% by mass or more and 67% by mass or less.

(4) The cellulose composition according to any one of (1) to (3), wherein the cellulose composition is a powder, and the average particle size of the powder is 10 μm or more and 200 μm or less.

(5) The cellulose composition as described in (4), wherein the aspect ratio L/D of the powder is 1.8 or more and 4.0 or less.

(6) A tablet comprising the cellulose composition as described in any one of (1) to (5) and one or more active ingredients.

(7) The tablet according to (6), which further contains a lubricant, and the content of the lubricant is 0.3% by mass or more and 5% by mass or less with respect to the total mass of the tablet.

(8) The tablet according to (7), wherein the lubricant is one or more selected from the group consisting of fatty acid metal salts, fatty acid esters, and fatty acid ester metal salts.

(9) The tablet as described in (7) or (8), wherein the lubricant is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, and sucrose fatty acid esters And one or more of the group consisting of talc.

(10) The tablet as described in any one of (6) to (9), wherein the content of the above-mentioned active ingredient is 0.01% by mass or more and less than 50% by mass relative to the total mass of the tablet.

According to the cellulosic composition of the above aspect, it is possible to provide a cellulosic composition that has good hardness, the bias of the content of the active ingredient, and the inhibition of tableting at the time of forming are suppressed. The tablet of the above aspect includes the above cellulose composition, has good hardness, and the bias of the content of the active ingredient and the inhibition of tableting during forming are suppressed.

Hereinafter, a mode for implementing the present invention (hereinafter referred to as "this embodiment") will be described in detail. In addition, the present invention is not limited to the following embodiments, and can be implemented with various changes within the scope of the gist.

<Cellulose composition> The cellulose composition of this embodiment contains cellulose and cellooligosaccharides of 3 to 7 sugars (hereinafter, sometimes referred to as "cellooligosaccharides (3-7 sugars)"). The content of cellooligosaccharides (3-7 sugars) per 5 g of the cellulose composition is 1.5 mg or more and 9.0 mg or less, preferably 2.0 mg or more and 8.0 mg or less , more preferably 3.0 mg or more and 7.5 mg or less , More preferably 4.0 mg or more and 7.5 mg or less, and particularly preferably 5.0 mg or more and 7.5 mg or less. By making the content of cellooligosaccharides (3-7 sugars) in 5 g of the cellulose composition within the above-mentioned range, it is possible to effectively prevent the decrease in tablet hardness caused by the prolonged mixing time. Furthermore, when the cellulose composition is a powder, it is preferable to include cellulose and cellooligosaccharides (3-7 sugars) in one particle.

Previously, from the viewpoint of quality assurance, pharmaceutical additives or food additives required higher purity, and the previous cellulose powder used as pharmaceutical additives was pure cellulose with extremely high purity. On the other hand, the cellulose composition of this embodiment may contain the previously excluded water-soluble matter in a specific range. The water soluble substance is mainly composed of monosaccharides such as glucose and sorbitol, and cellooligosaccharides such as cellobiose, cellotriose, cellotetraose, cellopentaose, cellohexaose, and cello-heptaose. What is important is that among these constituents, cellotriose, cellotetraose, cellopentaose, cellohexaose, and cello7ose (hereinafter collectively referred to as "cellooligosaccharides (3-7 sugars)") The content is in a specific range. It is believed that when the raw materials of the tablet are mixed, the abrasion between the particles and the generation of fine powder will reduce the adhesion of the particles, thereby causing the hardness of the tablet to decrease, but by using the cellooligosaccharide content in the above range The cellulose composition inside can moderately improve the adhesion of particles to each other, thereby effectively inhibiting the decrease in tablet hardness.

The content of cellooligosaccharides (3-7 sugars) in 5 g of the cellulose composition was measured by liquid chromatography/mass spectrometry (LC/MS) as shown in the following examples. . Furthermore, when it contains other components that are likely to overlap with the peaks derived from cellooligosaccharides (3-7 sugars), firstly adjust the conditions of the liquid chromatography method appropriately to verify whether the peaks can be separated. When it is assumed that the peaks cannot be separated, in mass analysis, the extracted ion chromatogram of the base peak ions derived from cellooligosaccharides (3-7 sugars) can be used to obtain cellooligosaccharides (3-7 sugars). ) Of the crest area.

The content of cellooligosaccharides (3-7 sugars) in the cellulose composition can be adjusted, for example, by adding cellooligosaccharides (3-7 sugars) when manufacturing the cellulose composition. Cello-oligosaccharides (3-7 sugars) can be purchased from commercially available products and can also be obtained by moderately hydrolyzing natural cellulosic materials such as pulp, and extracting, separating, and refining from the obtained hydrolysate.

In the cellulose composition of this embodiment, the content of the water-soluble matter in 5 g of the cellulose composition is preferably 0.5 mg or more and 12.5 mg or less, more preferably 2.5 mg or more and 12.5 mg or less, and more preferably It is 5.0 mg or more and 12.5 mg or less, particularly preferably 6.0 mg or more and 12.0 mg or less. By making the content of the water soluble matter within the above range, the tablet hardness can be made better. In addition, it can effectively suppress the reactivity with the active ingredient.

Furthermore, the water-soluble content can be measured in 5 g of the cellulose composition by the method according to the Purity Test (2) of Crystalline Cellulose of the Japanese Pharmacopoeia of the 17th Revision as shown in the following examples. The content of water solubles contained.

In the cellulosic composition of this embodiment, the ratio of cellooligosaccharides (3-7 sugars) to water-soluble matter is 47% by mass or more and 68% by mass or less, preferably 50% by mass or more and 67% by mass Hereinafter, it is more preferably 55% by mass or more and 66% by mass or less, and particularly preferably 60% by mass or more and 65% by mass or less. By setting the ratio of cellooligosaccharides (3-7 sugars) to water-soluble matter within the above range, the decrease in hardness due to the prolonged mixing time can be effectively suppressed. In addition, the reactivity with the active ingredient is also suppressed to be low, and the storage stability is also good. The water-soluble matter in the cellulose composition of this embodiment can be measured by the method described in the following examples.

＜Form of cellulose composition＞ The cellulose composition in this embodiment is preferably in any form of powder, granules, paste, and wet cake. From the viewpoint of handleability, cellulose powder is preferred. The so-called cellulose powder is generally called crystalline cellulose, powdered cellulose, etc., and is suitably used as a pharmaceutical additive or food additive. As crystalline cellulose, for example, the microcrystalline cellulose specified in the FAO/WHO Contract Food Additives Expert Meeting (JECFA), the microcrystalline cellulose described in the 8th edition of the Food Additives Convention, and the Japanese Pharmacopoeia (No. 17th revision) the crystalline cellulose described in the United States Pharmacopoeia, the European Pharmacopoeia, etc. Furthermore, from the viewpoint of achieving a good balance of moldability, fluidity, and disintegration properties, the average degree of polymerization of cellulose in the cellulose composition is preferably 400 or less, and more preferably 350 or less. The lower limit of the average degree of polymerization is preferably 100 or more. The average degree of polymerization of cellulose can be measured by the copper ethylene diamine solution viscosity method described in the Confirmation Test of Crystalline Cellulose (3) of the Japanese Pharmacopoeia Act or the Confirmation Test of Powdered Cellulose (3).

<A preferred form as cellulose powder> When the cellulose composition of this embodiment is a powder, it is 10 μm or more and 200 μm or less, preferably 15 μm or more and 100 μm or less, more preferably 20 μm or more and 90 μm or less, and still more preferably 30 μm or more and 70 μm or less, particularly preferably 40 μm or more and 60 μm or less. By making the average particle diameter below the above upper limit, it is easy to uniformly mix with active ingredients such as drugs, and the moldability becomes good. In particular, if the average particle size is 20 μm or more, the fluidity of the powder becomes better.

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

When the cellulose composition of this embodiment is a powder, the bulk density is preferably 0.11 g/mL or more and 0.35 g/mL or less, more preferably 0.13 g/mL or more and 0.33 g/mL or less, and more Preferably, it is 0.18 g/mL or more and 0.31 g/mL. By making the bulk density at least the above lower limit value, the compression moldability can be further improved. On the other hand, by making the bulk density below the above upper limit value, the filling property becomes better. The bulk density can be measured using the method described in the following examples.

When the cellulose composition of this embodiment is a powder, the compact bulk density is preferably 0.25 g/mL or more and 0.50 g/mL or less, more preferably 0.30 g/mL or more and 0.45 g/mL or less, and more Preferably, it is 0.32 g/mL or more and 0.42 g/mL or less. By making the compact bulk density more than the above-mentioned lower limit, it is easy to uniformly mix with active ingredients such as drugs, and the operability becomes better. On the other hand, by making the compact bulk density below the above upper limit, it is possible to more effectively suppress the occurrence of segregation due to the density difference with the particles of the active ingredient or other additives. The compact bulk density can be measured using the method described in the following examples.

In addition, when the bulk density and the compact bulk density both satisfy the above-mentioned range, the tablet obtained by compression molding tends to be excellent in moldability and disintegration.

When the cellulose composition of this embodiment is a powder, the compression rate is preferably 25% or more and 58% or less, more preferably 30% or more and 58% or less, and still more preferably 35% or more and 58% or less . By setting the compression ratio within the above range, the fluidity of the cellulose powder itself becomes better, and the occurrence of segregation can be suppressed more effectively. The compression rate can be calculated using the method described in the following examples.

When the cellulose composition of this embodiment is a powder, in the cellulose powder, the primary particle equivalent average particle diameter (hereinafter, sometimes abbreviated as "primary particle equivalent particle diameter") is preferably 15 μm Above and 30 μm or less, more preferably 16 μm or more and 29 μm or less, and still more preferably 16 μm or more and 27 μm or less. By making the equivalent particle diameter of the primary particles within the above-mentioned range, it is easy to uniformly mix with active ingredients such as drugs, and the disintegration property when it is made into a tablet becomes better. Furthermore, the primary particles are unit particles, and the aggregates of the primary particles are called secondary particles (aggregate, agglomerate). If the secondary particles are dispersed in water, the agglomeration will be dissolved and the secondary particles can be restored to primary particles. The equivalent average particle diameter of the primary particles can be measured by the method described in the following examples.

When the cellulose composition of this embodiment is a powder, the ratio of the long diameter to the short diameter of the cellulose particles, that is, the aspect ratio (L/D), is preferably 1.8 or more and 4.0 or less, more preferably 2.1 or more And 3.5 or less, more preferably 2.2 or more and 3.1 or less. By making the aspect ratio within the above range, the compatibility with the active ingredient is also good, the cross-linking of the elongated particles is also appropriate, and the balance between moldability and disintegration is excellent. The aspect ratio (L/D) can be measured by the method described in the following examples.

<Method for manufacturing cellulose composition> Hereinafter, an example of the manufacturing method of the cellulose composition of this embodiment will be described. The cellulose composition of this embodiment can be obtained, for example, by including the steps of: dispersing the hydrolyzed natural cellulose-based substance in an appropriate medium to obtain an aqueous cellulose dispersion; and the aqueous dispersion Carry out the drying step. The solid content concentration of the aqueous cellulose dispersion is not particularly limited, and it can be set to, for example, 1% by mass or more and 30% by mass or less. In this case, the following dispersion can be dried. The above-mentioned dispersion separates the solid components containing the hydrolyzed cellulose-based substance from the hydrolysis reaction solution obtained by the hydrolysis treatment, and additionally makes It is prepared by dispersing it in a suitable medium. In addition, cellooligosaccharides (3-7 sugars) in the cellulose composition may be added to the cellulose dispersion liquid so that the content of cellooligosaccharides (3-7 sugars) is within a specific range, followed by mixing and drying. In addition, when the hydrolyzed solution is directly formed into a cellulose dispersion in this state, the dispersion may be directly dried.

The so-called natural cellulose-based substances can be plant or animal, for example, fibrous substances derived from natural substances containing cellulose such as wood, bamboo, cotton, ramie, sea squirt, bagasse, kenaf, and bacterial cellulose. It preferably has a cellulose I type crystal structure. As a raw material, one of the above-mentioned natural cellulose-based substances may be used, or a mixture of two or more kinds may be used. In addition, it is preferable to use refined pulp. The method for refining the pulp is not particularly limited, and any pulp such as dissolving pulp, kraft pulp, and NBKP (Needle Bleached Kraft Pulp) pulp can be used.

In the above-mentioned production method, the medium used when dispersing the solid components containing natural cellulose-based substances in an appropriate medium is preferably water. As long as it is industrially used, it is not particularly limited. For example, organic solvents can be used. Examples of organic solvents include alcohols such as methanol, ethanol, isopropanol, butanol, 2-methylbutanol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; acetone, Ketones such as methyl ethyl ketone. In particular, the organic solvent is preferably a user of pharmaceuticals, and examples of such organic solvents include those classified as solvents in the "Pharmaceutical Additives Reference 2016" (issued by Yakuji Daily Co., Ltd.). Water and organic solvents may be used alone, or two or more of them may be used in combination, or one medium may be temporarily used to disperse the medium and then the medium may be removed and dispersed in a different medium.

For example, pulp fibers with 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 put in hydrochloric acid of 0.05% by mass or more and 1.5% by mass or less under pressure at 70°C or more and 140°C or more. Under the temperature below ℃, while rotating the mixer, the hydrolysis is carried out. The progress of the hydrolysis can be controlled by adjusting the motor power (P: unit W) and the stirring capacity (L: unit L) of the mixer. For example, the average particle diameter of the finally obtained cellulose particles can be controlled to 200 μm or less by adjusting P/V expressed by the following formula.

P/V(W/L)=[Actual power of the mixer motor (W)]/[Mixing capacity (L)]

The drying method when drying the cellulose aqueous dispersion to obtain a cellulose composition is not particularly limited. For example, any of freeze drying, spray drying, drum drying, shelf drying, airflow drying, and vacuum drying may be used, and one type may be used alone, or two or more types may be used in combination. The spray method during spray drying can be any spray method such as a disc type, a pressurized nozzle, a pressurized two-fluid nozzle, and a pressurized four-fluid nozzle. It can be used alone or in combination of two or more. In the above spray drying, a small amount of water-soluble polymer and surfactant can be added in order to reduce the surface tension of the dispersion, or a foaming agent or gas can be added to the dispersion in order to promote the vaporization rate of the medium.

It can be obtained by controlling the acid concentration and stirring conditions during the preparation of the cellulose aqueous dispersion to include cellulose dispersed particles with a specific average particle size, water solubles with a specific range of cellulose particles, and water. The content of the soluble matter is an aqueous cellulose dispersion of cellooligosaccharides (3-7 sugars) within a specific range, and the solid form of the cellulose aqueous dispersion can be adjusted when the cellulose aqueous dispersion is dried. The average particle size and compression rate of the obtained cellulose composition are controlled by the concentration of the material components or the drying conditions. For example, in the case of drying the aqueous cellulose dispersion by means of pan spray drying, the stirring power during the preparation of the aqueous cellulose dispersion is set to a specific range, and the difference in the aqueous cellulose dispersion during the spray drying The conditions of the solid content concentration and the rotation speed of the disc spray drying are set in a specific range, and a cellulose powder with an average particle size and a compression rate within a specific range can be obtained.

In addition, as described in the following examples, the content of cellooligosaccharides (3-7 sugars) in the cellulose composition can be obtained by adding cellooligosaccharides to the aqueous cellulose dispersion, mixing and drying. Cellulose composition within the range.

When the average particle diameter of the dried cellulose composition is greater than 200 μm, the average particle diameter can also be adjusted to 10 μm or more and 200 μm or less by submitting it to the following pulverization step.

In the pulverization step, the use of ultracentrifugal pulverizer (ZM-200, manufactured by Retsch), jet mill (STJ-200, manufactured by Qingxin Enterprise), hammer mill (manufactured by H-12, Hosokawa Micron; HM-600 , Nara Machinery Manufacturing Co., Ltd.), crusher (AP-B, manufactured by Hosokawa Micron), pin grinder (160Z, manufactured by Powrex), sharpener (FM, manufactured by Hosokawa Micron), fast crusher (FL-250N, manufactured by Dalton) ), a ball mill (manufactured by Emax, Retsch), a vibrating ball mill (manufactured by 2C, TRU), a sieve mill (U30, manufactured by Powrex) passing through a sieve, etc., to pulverize the dried cellulose composition. In particular, the jet mill grinder (STJ-200, manufactured by Qingxin Enterprise) is a jet grinder that uses higher air pressure to make particles collide with each other and pulverize. The secondary particles are easily broken and become primary particles, so it is better. .

Regarding the crushing conditions of the jet mill, the powder supply and the crushing pressure are more important. When the jet mill (STJ-200, manufactured by Qingxin Enterprise) is used, the supply amount is preferably 10 kg/hour or more and 20 kg/hour or less, more preferably 15 kg/hour or more and 20 kg/hour or less. In addition, the crushing pressure is preferably 0.15 MPa or more and 0.70 MPa or less, and more preferably 0.30 MPa or more and 0.50 MPa or less. If the supply amount of the powder and the crushing pressure are in the above range, it tends to be easy to control the average particle size to 10 μm or more and 200 μm or less. When the average particle size of the dried cellulose powder is less than 100 μm, the average particle size of the cellulose powder can be adjusted to 100 μm or more and 200 μm by using a granulation method such as stirring granulation or fluid bed granulation. The required range is below μm.

＜Use purpose＞ By blending the cellulose composition of this embodiment into a composition containing active ingredients, a tablet with good hardness and the decrease in tablet hardness caused by the prolonged mixing time and the bias in the content of the active ingredient can be obtained. . Especially in tablets with an active ingredient content of less than 50% by mass, the above-mentioned effects become significant. Hereinafter, a mixture obtained by mixing at least one active ingredient, the cellulose composition of this embodiment, and other optional additives when manufacturing tablets is referred to as "a mixture for tablets."

The blending ratio of the above-mentioned cellulose composition with respect to the mixture for tablets is 1% by mass or more and 90% by mass or less, preferably 1% by mass or more and 50% by mass relative to the mass of the entire tablet obtained. Hereinafter, 1 mass% or more and 30 mass% or less are more preferable, 3 mass% or more and 20 mass% or less are more preferable, and 5 mass% or more and 15 mass% or less are especially preferable.

[Active Ingredient] Hereinafter, those suitable as active ingredients contained in the mixture for tablets are exemplified. As the medicinal ingredient of the medicine, the active ingredient of the medicine to be administered orally is preferred. Examples of pharmaceuticals to be administered orally include antipyretic and analgesic anti-inflammatory drugs, hypnotics, drowsiness suppressants, narcotic drugs, children's analgesics, gastric drugs, antacids, digestive agents, cardiotonics, arrhythmia medications, Antihypertensive drugs, vasodilators, diuretics, antiulcer drugs, bowel regulators, osteoporosis treatment drugs, antitussive and antisputum drugs, anti-asthma drugs, antibacterial agents, urinary frequency improvers, nutritional supplements, vitamins, etc. The medicinal ingredients may be used alone, or two or more of them may be used in combination.

Specifically, for example, aspirin, aluminum aspirin, acetaminophen, salicylamine, salicylic acid, salicylamide, lactoethoxyaniline, acepromazine hydrochloride, hydrochloric acid Diphenhydramine, Diphenhydramine Hydrochloride, Diphenterol Hydrochloride, Triprolidine Hydrochloride, Tripiramine Hydrochloride, Sanxiamide Hydrochloride, Fenethazine Hydrochloride, Methiazine Hydrochloride, Diphenhydramine Salicylate Lamin, carbixamine diphenyldisulfonate, alimazine tartrate, diphenhydramine tannate, diphenyllarin theochloric acid, mehedriline, methylene disalicylic acid pramine, horse Carbixamine, dl-Chlorpheniramine Maleate, d-Chlorpheniramine Maleate, Diphenterol Phosphate, Aloramide Hydrochloride, Cloperastine Hydrochloride, Pentovirine Citrate (Vaijingning Citrate), Tipperidine Citrate, Sodium Dibutyrate, Dextromethorphan Hydrobromide, Dextromethorphan Phthaloline, Tipperidine Haifenate, Cloperastine Fendizate, Phosphoric Acid Codeine, codeine dihydrogen phosphate, narcotine hydrochloride, narcotine, dl-methylephedrine hydrochloride, dl-saccharine salt methylephedrine, potassium guaiacol sulfonate, pipefena Caffeine, sodium benzoate, caffeine, caffeine, anhydrous caffeine, vitamin B1 and its derivatives and its salts, vitamin B2 and its derivatives and its salts, vitamin C and its derivatives and its salts Salts, hesperidin and its derivatives and its salts, vitamin B6 and its derivatives and its salts, nicotine amide, calcium pantothenate, amino acetic acid, magnesium silicate, synthetic aluminum silicate , Synthetic aluminum magnesium carbonate, magnesium oxide, dihydroxy aluminum amino acetate (aluminum glycinate), aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/carbonic acid Co-precipitation product of sodium hydrogen, co-precipitation product of aluminum hydroxide/calcium carbonate/magnesium carbonate, co-precipitation product of magnesium hydroxide/potassium aluminum sulfate, magnesium carbonate, magnesium aluminum silicate, ranitidine hydrochloride, cimetidine Din, famotidine, naproxen, diclofenac sodium, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, difenidol hydrochloride, diphenhydrazine hydrochloride, diphenhydramine hydrochloride Lamin, Pramintaidine Hydrochloride, Meclizine Hydrochloride, Dimenhydrinate, Diphenhydramine Tannyl, Fenethizine Tannin, Diphenhydramine Theachlor, Diphenhydramine Fumarate, Substance Praminadine methyldisalicylate, scopolamine hydrobromide, oxybenzylamine hydrochloride, bicyclovirine hydrochloride, methixene hydrochloride, methylbromoatropine, mebromine octopine, methylscopolamine bromide, methyl bromide-1- Scopolamine, Benatiqin Bromide, Belladonna Extract, Isopropylammonium, Diphenylpiperidinyl Methyl Dioxolane Iodide, Papaverine Hydrochloride, Aminobenzoic Acid, Cesium Oxalate, Piperidinyl Ethyl Acetaminobenzoate, Aminophylline, Dihyprophylline, Theophylline, Sodium Bicarbonate, Thiamine, Isosorbide Nitrate, Ephedrine, Cephalexin, Ambicillin, Sulfoisoxazole , Sucralfate, allyl isopropyl acetonide, bromoisoamyl urea; ephedra, geranium, yellow arsenic, polygala, licorice, platycodon, plantain, plantain, Mei Yuanzhi, fritillaria, fennel, Phellodendron, Coptis, Curcuma, Chamomile, Cinnamon Bark, Gentian, Bezoar, Animal Gall (including Bear Gallbladder), Coral Vegetable, Ginger, Atractylodes, Clove, Tangerine Peel, Atractylodes, Earth Dragon, Bamboo Ginseng, Human Ginseng, Valerian, Cortex Moutan, Sansho Pepper and their extracts; Insulin, Vasopressin, Interferon, Urokinase, Serrapeptidase, Somatostatin, etc. "Japanese Pharmacopoeia", "Japanese Pharmacopoeia Non-Japanese Pharmacopoeia Standards" (External Base)", "United States Pharmacy (USP)", "National Medicines Collection (NF)", "European Pharmacy (EP)", etc. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

As an active ingredient of health food, as long as the formulation to enhance the health of the component is not limited. For example: 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, glutamine, glycine, proline, serine, etc.), alginic acid, ginkgo biloba extract, herring peptide, turmeric , Uronic acid, echinacea, acanthopanax senticosus, oligosaccharides, oleic acid, nucleoprotein, dried bonito peptide, catechins, potassium, calcium, carotenoids, garcinia cambogia, L-carnitine, chitin Glycan, conjugated linoleic acid, aloe arborescens, gymnema extract, citric acid, cat's grass, glycerides, glycerin, glucagon, curcumin, glucosamine, L-glutamine, green algae, Moss berry extract, cat's claw, germanium, enzyme, Korean ginseng extract, coenzyme Q10, collagen, collagen peptide, Coleus Forskolin (Coleus Forskolin), chondroitin, Psyllium husk powder , Hawthorn Extract, Saponins, Lipids, L-cystine, Perilla Extract, Garcinia Cambogia (CitriMax), Fatty Acids, Phytosterols, Seed Extracts, Spirulina, Squalene, White Willow, Cerebromine, Selenium, St. John's Wort Extract, Soy Isoflavones, Soy Saponins, Soy Peptides, Soy Lecithin, Monosaccharides, Proteins, Chastity Wood Extract, Iron, Copper, Docosahexaenoic Acid, Tocotrienols, Natto Kinase, Natto bacteria culture extract, sodium nicotinic acid, disaccharides, lactic acid bacteria, garlic, saw palmetto, germinated rice, coix extract, herbal extract, valerian 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, hydroxytyrosol, lactobacillus bifidus, brewer's yeast, fructo-oligosaccharides, etc. Flavonoids, False Leaf Tree Extract, Black Cohosh, Blueberry, Plum Extract, Proanthocyanidins, Protein, Propolis, Bromelain, Probiotics, Phosphatidylcholine, Phosphatidylserine, β-carotene, Peptides, Safflower Extract, Maitake Mushroom Extract, Maca Extract, Magnesium, Milk Thistle, Manganese, Mitochondria, Minerals, Glycosaminoglycans, Melatonin, Phellinus igniarius , Melilotus officinalis Extract, Molybdenum, vegetable powder, folic acid, lactose, lycopene, linoleic acid, lipoic acid, phosphorus (phosphorus), lutein, lecithin, rosmarinic acid, royal jelly, DHA (Docosahexaenoic acid, docosahexaenoic acid) Acid), EPA (Eicosapentaenoic Acid, eicosapentaenoic acid) and the like.

In addition to water solubility, the active ingredient may also be poorly soluble in water. The so-called "insoluble in water", in the 17th revision of the Japanese Pharmacopoeia, means that the amount of water required to dissolve 1 g of solute must be 30 mL or more. Examples of poorly water-soluble and solid active ingredients include: acetaminophen, ibuprofen, benzoic acid, salicylamine, caffeine, camphor, quinine, calcium gluconate, dimethyl propanol, sulfonamides, and theophylline , Theobromine, riboflavin, mephenixin, phenobarbital, aminophylline, thiosemicarbazide, quercetin, rutin, salicylic acid, theophylline sodium salt, pirapidol, quinine hydrochloride, Antipyretic analgesics such as igbilene, digitoxin, griseofulvin, phenacetin, neurological medicine, sedative hypnotics, muscle relaxants, blood pressure hardeners, antihistamines, etc.; acetylspirillum Antibiotics, ampicillin, erythromycin, kitatamycin, chloramphenicol, triacetyletanomycin, nystatin, colistin sulfate and other antibiotics; methyltestosterone, methylandrosterdiol, progesterone, benzene Estradiol formate, ethinyl estradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, prednisolone and other steroid hormone agents; diethylstilbestrol, diethylstilbestrol, Non-steroidal egg yolk hormone agents such as diethylstilbestrol, diethylstilbestrol dipropionate, and chlorodiestrol; other fat-soluble vitamins, such as those described in "Japanese Pharmacopoeia", "Extranet", "USP", "NF", "EP" Effective ingredients of pharmaceuticals, etc. One kind selected from the above may be used alone, or two or more kinds may be used in combination. As long as it is poorly soluble in water, regardless of the degree of sublimation and surface polarity, the effects of the present invention can be obtained by blending as an active ingredient in a mixture for tablets.

The active ingredient can also be in the form of oil or liquid that is poorly soluble in water. Among the active ingredients, poorly water-soluble oily and liquid active ingredients include, for example, teprenone, indomethacin, vitamin K2, chlorophyll menadione, vitamin A oil, and phenylpentyl alcohol. , Vitamin D, vitamin E and other vitamins, DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), liver oil and other higher unsaturated fatty acids, coenzyme Q, sweet orange oil, lemon oil, Peppermint oil and other oil-soluble flavors, such as medicinal ingredients described in the "Japanese Pharmacopoeia", "Exigen", "USP", "NF", and "EP". There are various homologs and derivatives in vitamin E, and there are no particular limitations as long as they are liquid at room temperature. Examples include dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, and d-α-tocopherol acetate. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

The active ingredient can also be a semi-solid active ingredient that is poorly soluble in water. As the insoluble semi-solid form of the active ingredients, for example, include: earthworm, licorice, cinnamon, peony, tree peony bark, valerian, sansho, ginger, tangerine peel, ephedra, tianzhuzi, yellow arsenic, polygala, platycodon , Plantago, Plantago, Lycoris, Polygala, Fritillaria, Fennel, Cork, Coptis, Curcuma, Chamomile, Gentian, Bezoar, Beast Gall, Coral, Ginger, Atractylodes, Clove, Tangerine Peel, Atractylodes, Bamboo Ginseng , Ginseng, Pueraria lobata Decoction, Guizhi Decoction, Xiangsu San, Zihu Guizhi Decoction, Xiaozihu Decoction, Xiaoqinglong Decoction, Maimendong Decoction, Banxia Houpo Decoction, Mahuang Decoction and other traditional Chinese medicine or natural medicine extracts; oyster meat extract Propolis, propolis and propolis extract, coenzyme Q, etc. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

The active ingredient can also be sublimable. Examples of sublimable active ingredients include: benzoic acid, acetosalicylic amine, caffeine, camphor, salicylic acid, phenacetin, ibuprofen and other "Japanese Pharmacopoeia", "extranet", "USP "," "NF", "EP", sublimation drug medicinal ingredients, etc. One kind selected from the above may be used alone, or two or more kinds may be used in combination. Furthermore, the sublimable active ingredient in this specification is not particularly limited as long as it has sublimable properties, and it may be in any state of solid, liquid, or semisolid at room temperature.

Moreover, as an active ingredient, it is particularly preferable to use a medicinal ingredient with a smaller maximum compounding amount per tablet. As the medicinal ingredients with a small maximum compounding amount per tablet, the medicinal ingredients of 100 mg or less and 10 mg or less listed below can be cited.

Examples of medicinal ingredients with a maximum compounding amount exceeding 100 mg per tablet include: Abacavir, Acetazolamide, Acetylsalicylic acid, and aciclovir Lovir, albendazole, Aliskiren Fumarate, Allopurinol, Amiodarone, Amodiaquine, Amoxicllin ), Aprepitant, Artemether, Artesunate, Atazanavir, Calcium, Capecitabine, Carbamazepine Carbidopa, Cefalexin, Cefixime, Celecoxib, Chloroquine, Ciprofloxacin, Ciprofloxacin, Clarithromycin Clavulanate Potassium, Clopidogrel, Clozapine, Cycloserine, Darunavir, Darunavir ethanolate Adduct), Dasabvir, Dasatinib, Deferasirox, Dihydroartemisinin piperaquine phosphate, Diloxanide, Efavirenz, Emtricitabine, Erlotinib hydrochloride, Ethambutol, Ethionamide, Famciclovir, Gefitinib Gefitinib, Griseofulvin, Hydroxycarbamide, Hydroxychloroquine, Ibuprofen, Imatinb, Irbesartan, Isoniazid Isoniazid), Lamivudine, Lamotrigi ne (Lamotrigine), Lanthanum carbonate hydrate, Ledipasvir, Levamisole, Levetiracetam, Levodopa (L-dopa), Levofloxacin (Levofloxacin), Linezolid (linezolid), Lithium carbonate (lithium carbonate), Lopinavir (lopinavir), Lumefantrine (benzofluorenol), Mebendazole (mebendazole), Mefloquine (merquinine), Mesna ( Mesna, Metformin, Methyldopa, Metronidazole, Morphine, Moxifloxacin, Nevirapine, Niclosamide, Nifurtimox (Nifurtimox), Ombitasvir (Obitamivir), p-Aminosalicylic acid (P-Aminosalicylic acid), Paracetamol (Paretoxin), Paritaprevir (Paliprevir), Penicillamine (penicillamine) , Pentamidine, Phenoxymethylpenicillin, Pirfenidone, Praziquantel, Pyrantel, Pyrazinamide, Pyronaridine tetraphosphate ( Pyrolidine tetraphosphate, Quinine, Raltegravir, Ranitidine, Ribavirin, Rifampicin, Rifapentine ), Sevelamer hydrochloride, Sofosbuvir, Sorafenib tosilate, Sulfadiazine, Sulfamethoxazole, Sulfasalazine Sulpyridine), Tenofovir (tenofovir), Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate), Triclabendazole (triclobendazole), Trimethoprim (trimethoprim), Valganciclovir (Valganciclovir), Valproic acid, Velpatasvir, Sodium valproate, Voriconazole, Zidovudine, etc.

Examples of medicinal ingredients with a maximum compounding amount of more than 10 mg and less than 100 mg per tablet include: Aripiprazole, Artesunate, Ascorbic acid, Azathioprine ( Azathioprine, Bazedoxifene acetate, Bicalutamide, Calcium folinate, Clomifene, Cyclizine, Cyclophosphamide Cyclophosphamide, Dasatinib hydrate, Delamanid, Dolutegravir, Eletriptan hydrobromide, Febuxostat, Fluoxetine Xetine), Furosemide, Galantamine Hydrobromide, Hydrochlorothiazide, Hydrochlorothiazide, Hydrocortisone, Memantine Hydrochloride ), Mercaptopurine, Midazolam, Miltefosine, Minodronic Acid Hydrate, Mirtazapine, Neostigmine , Nicotineamide, Olmesartan Medoxomil, Omeprazole, Ondansetron, Pancrelipase, Potassium iodine, Prednisolone Dragon), Primaquine (primaquine), Primethamine (pyrimethamine), Propranolol (propranolol), Propylthiouracil (propylthiouracil), Pyridoxine (pyridoxine), Simvastatin (simvastatin), Sitafloxacinhy drate ( (Sitafloxacin hydrate), Spironolactone (spironolactone), Tadalafil (tadalafil), Tamoxifen (tamoxifen), Thiamine (thiamine), Tioguanine (thioguanine) , Tolvaptan, Ulipristal, Vardenafil Hydrochloride Hydrate, zinc sulfate, Acotiamide hydrochloride hydrate, Amitriptyline (Amitriptyline), Bedaquline, Benznidazole, Bosentan hydrate, Chlorpromazine, Cinacalcet hydrochlorid, Daclatasvir (Dacatavir), Dapsone, Diethylcarbamazine, Doxycycline, Entacapone, Eplerenone, Ferrous sulfate Hydrate), Gliclazide, Ibandronate Sodium Hydrate, Losartan, Miglitol, Nitrofurantoin, Phenobarbital Phenytoin (phenytoin), Pyridostigmine (pyridostigmine), Raloxifene Hydrochloride (raloxifene hydrochloride), Ritonavir (ritonavir), Succimer (2,3-dimercaptosuccinate), telmisartan (for Misartan), Topiramate (topiramate), Verapamil (verapamil) and so on.

As a medicinal ingredient with a maximum compounding amount of 10 mg or less per tablet, for example, Anastrozole, Dienogest, Digoxin, Dutasteride ), Entecavir, Entecavir hydrate, Ethinylestradiol, Finasteride, Fludrocortisone, Glyceryl trinitate, Imidafenacin Danaxine, Levothyroxine, Levonorgestrel, Misoprostol, Repaglinide, Ambrisentan, Amiloride ), Amlodipine, Bepotastine Besilate, Biperiden, Bisoprolol, Blonaserin, Chlorambucil ), Dexamethasone, Diazepam, Enalapril, Ergocalciferol, Escitalopram Oxalate, Esomeprazole magnesium hydrate Magnesium azole hydrate), Escopiclone, Ezetimibe, Fludarabine, Fluticasone furoate, Folicacid, Haloperidol, Haloperidol ), Isosorbide dinitrate (isosorbide dinitrate), Ivermectin (ivermectin), Lenalidomide hydrate (lenalidomide hydrate), Levocetirizine hydrochloride (levocetirizine hydrochloride), Levonorgestrel (levonorgestrel), Loperamide, Loratadine, Medroxyprogesterone acetate, Methadone, Methotrexate, Metoclopramide , Mitiglinide Calcium Hydrate, Montelukast Sodium, Norethisterone, Paliperidone, Phytomenadione or Phytonadione Chlorophyll menadione), Ramelteon, Riboflavin, Risperidone, Rizatriptan benzoate, Ropinirole hydrochloride ), Rosuvastatin Calcium, Senna (senna leaf extract), Silodosin, Solifenacin succinate, Warfarin, etc.

These active ingredients and medicinal ingredients can also be formulated into a mixture for tablets in a finely pulverized state together with the cellulose composition of this embodiment. For example, for the active ingredients used in this specification to improve the dispersibility of the active ingredients or to improve the mixing uniformity of the active ingredients with a small amount of medicinal effect, etc., the average particle size can also be finely pulverized to 1 μm or more and 40 μm or less. The average particle diameter of the active ingredient is more preferably 1 μm or more and 20 μm or less, and still more preferably 1 μm or more and 10 μm or less.

The blending ratio of the above-mentioned active ingredient to the mixture for the tablet is less than 50% by mass relative to the mass of the entire tablet obtained, preferably 40% by mass or less, more preferably 30% by mass or less, and more It is preferably 20% by mass or less, and particularly preferably 10% by mass or less. A lower limit of 0.01% by mass is practical. If the active ingredient is less than 50% by mass, segregation tends to occur easily, and correspondingly, there is a tendency to extend the mixing time. However, by using the cellulose composition of this embodiment, the decrease in tablet hardness caused by the extension of the mixing time can be effectively suppressed. Therefore, by using the cellulose composition of this embodiment for the content of active ingredients Tablets within the above range can achieve particularly significant effects.

[Lubricant] The mixture for the lozenge preferably contains a lubricant in addition to the above-mentioned active ingredients. As the lubricant, at least one compound selected from the group consisting of fatty acid metal salts, fatty acid esters, and fatty acid ester metals can be used. Specifically, they include magnesium stearate, calcium stearate, and stearin. Acids, sucrose fatty acid esters, and talc are equal to those classified as lubricants in the "Drug Additives Reference 2016" (issued by Yakuji Daily Co., Ltd.). One kind selected from the above may be used alone, or two or more kinds may be used in combination.

The blending ratio of the lubricant with respect to the mixture for tablets is 0.3% by mass or more and 5% by mass or less, preferably 0.5% by mass or more and 3% by mass or less with respect to the mass of the entire tablet obtained.

[Other additives] In addition to the above-mentioned active ingredients, the mixture for tablets may further contain other additives. Examples of other additives include excipients, disintegrating agents, binders, plasticizers, flavoring agents, flavors, coloring agents, sweeteners, and the like.

Excipients other than the cellulose composition include acrylic acid starch, L-aspartic acid, amino ethyl sulfonic acid, amino acetic acid, starch sugar (powder), gum arabic, gum arabic powder, alginic acid, Sodium alginate, gelatinized starch, pumice granules, inositol, ethyl cellulose, ethylene-vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice granules, carboxylate Methyl cellulose, sodium carboxymethyl cellulose, hydrous silica, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate, dry magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate , Disodium citrate, glycerin, calcium stearate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, crospovidone, aluminum silicate Magnesium, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose-sodium carboxymethyl cellulose, crystalline cellulose (grain), brown rice koji, synthetic Aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, rice flour, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, oxidation Titanium, magnesium oxide, β-cyclodextrin, dihydroxyaluminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, calcined gypsum , Sucrose fatty acid ester, magnesium aluminum hydroxide, aluminum hydroxide, gel, aluminum hydroxide and sodium bicarbonate co-precipitation, magnesium hydroxide, squalane, stearyl alcohol, stearic acid, calcium stearate, Polyoxyl stearate, magnesium stearate, hydrogenated soybean oil, refined gelatin, refined shellac, refined white sugar, refined white sugar spherical particles, cetearyl alcohol, polyethylene glycol 1000 monocetyl ether , Gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soybean unsaponifiable, soybean lecithin, skimmed milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral Anhydrous sodium sulfate, low-substituted hydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate, corn starch, tragacanth powder, silica, calcium lactate, lactose, lactose granules, Perfiller101, white Shellac, white petrolatum, clay, white sugar, white sugar, spherical starch granules, rye green leaf extract powder, rye malt leaf green juice dry powder, honey, paraffin wax, potato starch, semi-digestible starch, human serum albumin, Hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, phytic acid, glucose, Glucose hydrate, partially alpha starch, pullulan, propylene glycol, powdered reduced maltose syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, poly Ethylene oxide (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethyl Aminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltose Alcohol, maltose, D-mannitol, maltose, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium metasilicate aluminate, methyl cellulose, cottonseed powder, cottonseed oil , Wood wax, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, medicinal carbon, peanut oil, aluminum sulfate, calcium sulfate, granular corn starch, liquid paraffin, dl-malic acid , Calcium Monohydrogen Phosphate, Calcium Hydrogen Phosphate, Calcium Hydrogen Phosphate Granules, Sodium Hydrogen Phosphate, Potassium Dihydrogen Phosphate, Calcium Dihydrogen Phosphate, Sodium Dihydrogen Phosphate are equal to "Pharmaceutical Additives Reference 2016" (Yokuji Daily Co., Ltd. ( Shares) issued) are classified as excipients. These may be used alone, or two or more of them may be used in combination.

Examples of disintegrating agents include celluloses such as croscarmellose sodium, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; carboxyl Sodium methyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, partially gelatinized starch and other starches; cross-linked povidone, cross-linked povidone copolymer and other synthetic polymers are equivalent to "medicine Those who are classified as disintegrating powders in the "Product Additives Reference 2016" (issued by the Pharmaceutical Daily Company (shares)). One kind selected from the above may be used alone, or two or more kinds may be used in combination.

Examples of binding agents include sugars such as white sugar, glucose, lactose, and fructose; sugar alcohols such as mannitol, xylitol, maltitol, erythritol, and sorbitol; gelatin, pullulan, and carrageenan , Locust bean gum, agar, glucomannan, trixian gum, tamarind gum, pectin, sodium alginate, gum arabic and other water-soluble polysaccharides; crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, Celluloses such as methyl cellulose; starches such as alpha starch and starch paste; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol; calcium hydrogen phosphate, calcium carbonate, synthetic aluminum Inorganic compounds such as magnesium carbonate and magnesium aluminosilicate are equivalent to those classified as binding agents in the "Drug Additives Reference 2016" (issued by the Yakuji Daily Co., Ltd.). One kind selected from the above may be used alone, or two or more kinds may be used in combination.

As the plasticizer, silicon compounds such as hydrated silicon dioxide and light anhydrous silicic acid are classified as plasticizers in the "Pharmaceutical Additives Reference 2016" (issued by the Pharmaceutical Daily News Corporation). One kind selected from the above may be used alone, or two or more kinds may be used in combination.

Examples of correctives include: glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, and l-menthol. Equal to "Dictionary of Pharmaceutical Additives 2016" (Issued by Pharmaceutical Daily Company (Stock)) is classified as a flavoring agent. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

Examples of flavors include: orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, bitter orange oil, peppermint oil and other oils, green tea powder equal to "Drug Additives 2016" (Yuji Daily News Companies (shares) issued) are classified as fragrances and fragrances. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

Examples of colorants include food colorings such as Edible Red No. 3, Edible Yellow No. 5, Edible Blue No. 1, Copper Sodium Chlorophyllin, Titanium Oxide, and Riboflavin. (Share) is classified as a coloring agent. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

Examples of sweeteners include: aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, caramel, and dry tea powder. Equal to "Drug Additives 2016" (published by Yakuji Daily Co., Ltd.) ) Are classified as sweeteners. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

＜Manufacturing method of lozenge＞ The method of compressing the mixture for tablets described above to produce tablets (the method of producing tablets of this embodiment) will be described, but this is an example, and the effect of this embodiment is not limited by the following method.

As a method of manufacturing tablets, a method of mixing the active ingredient with the cellulose composition of this embodiment and then performing compression molding is adopted. At this time, in addition to the active ingredients, other additives may be formulated as needed. As other additives, for example, one selected from the above-mentioned lubricants, excipients, disintegrating agents, binders, plasticizers, correctives, fragrances, colorants, sweeteners, solubilizers, etc. above.

The order of addition of the ingredients is not particularly limited, and it can be any of the following methods: i) The active ingredient and the cellulose composition of this embodiment are mixed with other additives as needed at one time and compression molded; ii) The active ingredient A method of pre-mixing with any additives, and then mixing the cellulose composition of this embodiment with any additives to the pre-treatment mixture and then performing compression molding; iii) the active ingredient and the cellulose composition of this embodiment are considered It needs to be pre-mixed with other additives, and then the pre-treated mixture is mixed with other additives as needed and then compressed and formed. In terms of ease of operation, i) is preferred. The addition method of each component is not particularly limited as long as it is a usual method. Small suction conveying devices, air conveying devices, bucket conveyors, pressure conveying devices, vacuum conveyors, and vibrating quantitative filling machines can be used. , Sprayers, funnels, etc. are added continuously, or one-time input. As the spraying method, any of the following methods can be used: a method of spraying the active ingredient solution/dispersion using a pressure nozzle, a two-fluid nozzle, a four-fluid nozzle, a turntable, an ultrasonic nozzle, etc., and dropping the active ingredient solution from a tubular nozzle/ Dispersion method.

The mixing method is not particularly limited as long as it is a normal method. It can be used: V-type, W-type, double-cone type, container swing type mixer and other container rotary mixers; high-speed stirring type, universal stirring type, belt type , Stirring type, conical screw type mixer and other stirring type mixers; high-speed flow type mixer, drum type mixer, fluid layer type mixer. In addition, a container shaker mixer such as an oscillator can also be used.

The compression molding method of the composition is not particularly limited as long as it is a commonly performed method. It can be a method of compression molding into a desired shape using a mortar and a pestle, or a method of pre-compression into a sheet and then cut into a desired shape. As the compression molding machine, for example, roller type presses such as a static pressure press, a block roller type press, and a smooth roller type press; compressors such as a single-punch tablet tableting machine and 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 the usual dissolution and dispersion method. It can be a portable mixer, a three-dimensional mixer, a side mixer, etc., and a unidirectional rotary type can be used. , Multi-axis rotating, reciprocating flipping, up-and-down moving, rotating + up-and-down moving, pipeline type and other stirring wing mixing methods, line mixers and other jet mixing methods, gas blowing type mixing methods, using high The mixing method of shear homogenizer, high pressure homogenizer, ultrasonic homogenizer, etc., can also use the container oscillation type mixing method using an oscillator.

The solvent used in the above-mentioned production method is not particularly limited as long as it is used for pharmaceuticals. For example, at least any one of water and an organic solvent can be used. Examples of organic solvents include alcohols such as methanol, ethanol, isopropanol, butanol, 2-methylbutanol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; acetone, methyl alcohol, etc. Ketones such as ethyl ketones are equal to those classified as solvents in the "Drug Additives Reference 2016" (issued by the Pharmaceutical Daily News Company (Stock)). It may be used alone, or two or more of them may be used in combination, or one medium may be used to temporarily disperse the medium and then the medium may be removed and dispersed in a different medium.

When dissolving the active ingredient in the medium, water-soluble polymers, oils and fats, surfactants, etc. can be used as solubilizers. Water-soluble polymers, oils, and surfactants used as solubilizers can be appropriately used as described in "Drug Additives 2016" (published by Yakuji Daily Co., Ltd.). These may be used alone, or two or more of them may be used in combination.

The so-called forming system in this specification has the form of granules, fine particles, agglomerates, lozenges, etc., and includes the cellulose composition of this embodiment, one or more active ingredients, and other additives as needed. As a method of forming a tablet, for example, the following method can be cited: mixing one or more active ingredients with the cellulose composition of this embodiment or mixing one or more active ingredients with the cellulose of this embodiment The composition and other additives as needed are mixed and directly compressed and formed by the direct ingot method. In addition, manufacturing methods such as a multi-core ingot in which a tablet obtained by compression molding in advance is used as the core, and a multi-core ingot in which a plurality of molded bodies compressed in advance are stacked and then compressed again can also be used. In terms of productivity and ease of step management, the direct ingot method is preferred.

It is also possible to further coat the compressed tablet (molded body). As the coating agent used in this case, for example, the coating agent described in "Drug Additives Reference 2016" (published by Yakuji Daily Co., Ltd.). These may be used alone, or two or more of them may be used in combination.

As a granulation method in the case of granulation in the manufacturing step, there are dry granulation, wet granulation, heating granulation, spray granulation, and microencapsulation. As for the wet granulation method, specifically the fluid bed granulation method, the stirring granulation method, the extrusion granulation method, the crushing granulation method, and the rolling granulation method are more effective. In the granulation device, the fluidized powder is sprayed with a binding liquid to granulate. In the stirring granulation method, while adding the binding liquid, the stirring blade is rotated in the mixing tank, thereby simultaneously mixing, kneading, and granulating the powder in a closed structure. In the extrusion granulation method, the granulation is carried out by the following method: the wet mass kneaded by adding the binding liquid is forcibly extruded from a screen of an appropriate size by a screw type or a basket type method. In the crushing and granulation method, the granulation is carried out by the following method: the wet block kneaded by adding the binding liquid is cut and crushed by the rotating knife of the granulator, and the centrifugal force is thrown out from the outer screen. In the rolling granulation method, the granulation is carried out by the following method: the centrifugal force of the rotating rotor rotates, and at this time, the spherical particles of uniform particle size grow in snowball form by the binding liquid sprayed from the spray gun.

The drying method of the granulated material can also use any method of hot air heating type (shed drying, vacuum drying, fluidized bed drying), thermal conductivity type (pan type, shelf box type, tumbler type) or freeze drying. In the hot-air heating type, the hot air is in direct contact with the additives, and the evaporated moisture is removed at the same time. In the thermally conductive type, the additives are heated indirectly through the thermally conductive wall. In freeze-drying, the additives are previously frozen at -10°C or higher and 40°C or lower, and then ^{heated under high vacuum (1.3×10 -5} MPa or higher and 2.6×10 ^-4 MPa or lower) to sublimate water And remove it. [Example]

Hereinafter, the present embodiment will be described in detail with examples and comparative examples, but the present embodiment is not limited to this. The physical properties and their measurement methods in the examples and comparative examples are as follows. Furthermore, when the sample contains a large amount of water, the moisture content is pre-dried to about 3.5% by mass or more and 4.5% by mass or less, and then various physical properties are measured.

＜Analysis method of cellulose composition＞ [Analysis 1] (Method for measuring the content of water soluble matter in cellulose composition) The content of water-soluble matter in the cellulose composition was determined according to the method of the Purity Test (2) of Crystalline Cellulose of the Japanese Pharmacopoeia of the 17th Revision. To 5.0 g of the cellulose composition, 80 mL of purified water was added, and the mixture was shaken and mixed for 10 minutes. After that, the cellulose composition-containing solution was suction filtered using filter paper for quantitative analysis (5 types C). After the filtrate was evaporated to dryness in a beaker of known mass in a way that would not burn, it was dried at 105°C for 1 hour, and then left to cool in a desiccator to obtain a residue. After that, the mass of the obtained residue is weighed to find the mass of the residue. Each powder was measured twice, and the average value was adopted. In addition, the test performed using only 80 mL of purified water without adding 5.0 g of the cellulose composition in the above operation is set as a blank test, and the measured value is obtained by subtracting the amount of water-soluble substances detected in the blank test. The value. The value is rounded to the second decimal place and used as the measured value of the amount of water soluble matter. The amount of water soluble matter determined by this test method is the amount of water soluble matter contained in 5 g of the cellulose composition.

[Analysis 2] (Method for determining the content of cellooligosaccharides (3-7 sugars)) Add 10 mL of 50% (v/v) acetonitrile aqueous solution to the total amount of dry matter obtained in "Analysis 1" above to dissolve again. In addition, filter with a filter (0.20 μm) and use LC/MS was used to determine the content of cellooligosaccharides (3-7 sugars). Use a precision balance for the preparation and dilution of the measurement solution, and use the weight to obtain the sample concentration and dilution rate. In addition, when determining the content of cellooligosaccharides, cellotriose (3 sugars), cellotetraose (4 sugars), and cellopentaose (5 sugars) were subjected to LC on a solution of known concentration prepared using commercially available products. /MS analysis to obtain the retention time corresponding to each cellooligosaccharide and the peak area of the m/z ion chromatogram to create a calibration curve (sample concentration-peak area). Use this calibration curve to determine the content of each cellooligosaccharide in the water-soluble substance (5 g of cellulose composition). The content of cellohexaose (6 sugars) and celloheptaose (7 sugars) that are not available on the market is used when analyzing the pre-measured glucose (monosaccharide) ~ cellopentaose (5 sugar) at the same concentration The tendency of the peak area is calculated using the following calculation method. In addition, the total content of each oligosaccharide is recorded as the value obtained by rounding the second decimal place.

(Calculation method) Cellohexaose (6 sugars): Using the calibration curve of cellopentaose (5 sugars), substitute the peak area of cellohexaose (6 sugars) into the peak area, and multiply the amount of cellooligosaccharides obtained by the correction coefficient (0.729) ) To calculate the content of cellohexaose (6 sugars). Celloqiose (7 sugars): Using the calibration curve of cellopentaose (5 sugars), substitute the peak area of celloqiose (7 sugars) into the peak area, and multiply the amount of cellooligosaccharides obtained by the correction coefficient (0.531 ) To calculate the content of seven sugars (7 sugars).

According to the following measurement conditions, it is used for LC/MS measurement. Furthermore, when one of the following conditions is changed for measurement, the calibration curve of the above-mentioned cellooligosaccharide also needs to be recreated according to the conditions.

(Measurement conditions) LC device: manufactured by Shimadzu Corporation, Nexera column: manufactured by Shodex, Asahipak NH2P-50 2D (2 mm ID×150 mm) column temperature: 40°C Detector: PDA (Photo-Diode Array, photodiode) Volume array) detector 200～400 nm Flow rate: 0.3 mL/min Mobile phase: A=purified water, B=acetonitrile gradient: the gradient conditions are shown in Table 1 below. Injection volume: 10 μL MS device: manufactured by Waters, Synapt G2 Ionization conditions: ESI ^- Scanning range: m/z 50～2000

[Table 1] Time (min) A(%) B(%) 0 10 90 15 50 50 15.1 10 90 25 10 90

For reference, the detection ions (m/z) and retention time of each component observed under the above measurement conditions are shown in Table 2 below.

[Table 2] Detection ion m/z Hold time (minutes) Cellotriose 3 sugars 549.17 [M+HCOO] ^- 9.2 Cellotetraose 4 sugars 711.22 [M+HCOO] ^- 10.3 Cellopentaose 5 sugars 873.28 [M+HCOO] ^- 11.2 Cellohexaose 6 sugars 989.32 [MH] ^- 11.9 Celluloseptaose 7 sugars 1151.38 [MH] ^- 12.5

＜Measurement method of powder physical properties＞ Hereinafter, the method of measuring the physical properties of the powder when the cellulose composition is a cellulose powder will be described.

[Properties 1] (The average particle size) Using a laser diffraction particle size distribution meter (LA-950 V2 (trade name), manufactured by Horiba Manufacturing Co., Ltd.), in dry measurement mode with compressed air pressure of 0.10 MPa, feeder speed 160, feeder initial velocity coefficient 1.2, and refractive index 1.51 is measured. The average particle size (μm) of the cellulose powder is defined as the cumulative volume of 50% particles obtained by the measurement.

[Properties 2] (Loose bulk density) The measurement uses cellulose powder whose water content is adjusted to 3.5% by mass or more and 4.5% by mass or less. When the moisture content of the cellulose powder is less than 3.5% by mass, use a constant temperature and humidity machine to make the cellulose powder absorb moisture for adjustment. In addition, when it exceeds 4.5% by mass, a hot air oven is used to uniformly supply hot air at 60° C. to the cellulose powder to adjust the moisture content within the range.

Then, the bulk density of the cellulose powder was measured using Scott Volumeter (model ASTM B-329-85, manufactured by Tsutsui Rika Instruments), and the cellulose powder was filled into a 25 mL cylinder through a screen (mesh 1 mm) In a metal container. Scrape the cellulose powder placed in a 25 mL cylindrical metal container, and divide the mass (g) of the cellulose powder placed in the container by 25 mL to obtain the bulk density (g/mL). The measurement was performed 5 times, and the average value was obtained.

[Properties 3] (Compact bulk density) The measurement uses cellulose powder whose water content is adjusted to 3.5% by mass or more and 4.5% by mass or less. The moisture content of the cellulose powder was adjusted to be within this range using the method described in "Properties 2". The compact bulk density (compact apparent specific gravity) (g/mL) was calculated using a powder physical property measuring machine (PT-R, manufactured by Hosokawa Micron). The mesh of the sieve used is 710 μm, and the funnel is made of metal (antistatic spray coating) with an inner diameter of 0.8 cm. Implemented under the condition that VIBRATION is 2.0 (power supply: AC100 V, 60 Hz).

[Properties 4] (Compression ratio) The compressibility of each cellulose powder was calculated by the formula shown below.

Compression rate (%)=([compact bulk density]-[loose bulk density])/[compact bulk density]×100

[Properties 5] (Equivalent particle size of primary particles) Put 0.5 g of cellulose powder in 10 mL of pure water, and after 10 minutes of ultrasonic irradiation (600 W, 40 kHz), use a laser diffraction particle size distribution meter (LA-950 V2 (trade name), Horiba Manufacturing Co., Ltd.) Manufacturing), in a wet measurement mode with refractive index 1.20 (cellulose refractive index 1.59, water refractive index 1.33), pretreatment conditions (ultrasonic irradiation for 1 minute, ultrasonic intensity 1), circulation speed 7, stirring speed 5. Determination. The 50% particles of cumulative volume obtained by the measurement are regarded as the equivalent average particle diameter of cellulose primary particles (primary particle equivalent particle diameter) (μm).

[Properties 6] (The ratio of the long diameter to the short diameter of the cellulose particles L/D) The cellulose powder was dispersed on a glass plate, and a microscope (VHX-1000, manufactured by Keyence) was used to take pictures at a magnification of 500 times. Use image processing analysis system software (Image HyperII, manufactured by DigiMo) to analyze the captured images in the following order to determine the aspect ratio of the particles (the ratio of the long diameter to the short diameter; L/D). Measure at least 50 particles and find the average value.

(1) Sequence 1: Binary processing The image taken by the microscope is input into the analysis software in monochrome, and the scale of the image is set using the distance between two points. Then, use the binarization process to select the "Otsu Method" to set the threshold. The optimal threshold value differs depending on the image. The threshold value is selected by comparing it with the original image and matching the shape of the original particle as much as possible.

(2) Sequence 2: Binary manual correction Compare with the original image taken, delete particles that overlap each other, particles that deviate from the screen, particles that are not clear and have blurred outlines and other particles that cannot obtain proper measurement results, and exclude them from the measurement object.

(3) Sequence 3: Fill the hole In the "Hole Filling" mode, select "8" for "Nearby" to execute "Hole Filling". Then, again use the "two-value image manual correction" to compare with the original image to confirm whether it can be corrected normally. In the case of failure to correct normally, perform manual correction again.

(4) Sequence 4: Image measurement Set the number of deleted pixels to "100", select "8" for "Nearby" and execute "Image measurement". Display the measurement results of "Long Diameter" and "Short Diameter" on the computer for each measured particle. The value obtained by dividing the "long diameter" by the "short diameter" is used as the aspect ratio.

＜Evaluation method of lozenges＞ Tablets were made using the methods shown below, and various evaluations were performed.

[Production of powder for ingots] Add raw materials of any of the following compositions (except magnesium stearate as a lubricant) to a V-type mixer (V-5, Tokuju Manufacturing Co., Ltd.) and mix for 60 minutes.

[table 3] Allocation 1 Allocation 2 Allocation 3 Allocation 4 d-Chlorpheniramine Maleate 20 g - 20 g 20 g Folic acid - 4 g - - Cellulose composition 200 g 200 g 200 g 200 g Mannitol 1760 g 1776 g 1720 g 1770 g Magnesium stearate 20 g 20 g 60 g 10 g

Then, magnesium stearate was added as a lubricant, and mixing was performed for 5 minutes or 30 minutes to obtain powder for tableting (mixing time: 5 minutes and 30 minutes).

[Preparation of lozenges] Use a rotary tableting machine (manufactured by Kikusui Manufacturing Co., Ltd., Clean Press Collect 12HUK, 12 pestles, turntable 54 rpm, using an open filler, pressing 7 kN) for 10 minutes of the powder for tableting (mixing time: 5 minutes and 30 minutes) Make a tablet to obtain a Φ8 mm-12R 200 mg tablet.

[Evaluation 1] (Tablet hardness and reduction rate of tablet hardness) The tablets for hardness measurement are used for tablets sampled 30 seconds before the stop of the rotary tablet machine. For each tablet, the hardness was measured with a hardness meter (DR. SCHLEUNIGER Tablet Tester 8M) after 20 hours or more and 48 hours or less immediately after the tablet was punched. Take the average of 10 tablets each as the hardness of the tablets. Those with a tablet hardness of 55 N or more were evaluated as good.

In addition, the rate of decrease in tablet hardness is based on the hardness (N1) of a tablet made with the powder for tableting (mixing time: 5 minutes) and the hardness of a tablet made with the powder for tableting (mixing time: 30 minutes) ( The difference of N2) is calculated using the following formula.

Tablet hardness reduction rate (%)=(1－N2/N1)×100

[Evaluation 2] (CV value of active ingredient content) First, make a calibration curve of the active ingredient. Specifically, the absorption spectrum of the active ingredient was measured with an absorbance meter, and a calibration curve was prepared based on the wavelength of the peak top (for example: d-chlorpheniramine maleate: 264 nm, folic acid: 290 nm).

Then, the tablets for measuring the CV value of the active ingredient content are used for tablets sampled 30 seconds before the tablet machine is about to stop. After accurately weighing 1 lozenge, place it in a 100 mL measuring flask and dilute it to 100 mL with pure water. After filtering the obtained aqueous solution with a resin filter to remove insoluble components, the amount of active components in the filtrate was quantified by absorbance method. Calculate the content of the active ingredient contained in one tablet. In the case of tablets, calculate the average value and standard deviation of the content of the active ingredient for a total of 10 pieces.

Then, the coefficient of variation (also referred to as "the content CV value of the active ingredient") as a measure of uniformity was obtained by the following formula. The lower the coefficient of variation, the better the uniformity of the active ingredient content is evaluated.

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

[Evaluation 3] (Blocking block) In the above-mentioned "Preparation of Tablets", the pestle under the rotary tableting machine was visually inspected 10 minutes after the tableting, and the blurring of the pestle (adhesion of powder) was evaluated. The evaluation criteria are as follows.

(Evaluation criteria) ○: There is no adhesion of powder Δ: The powder adheres thinly and is in a fuzzy state (the pestle has no metallic luster on the surface) ×: The adhered state of the powder is clearly seen

[Evaluation 4] (Storage stability (evaluation of reactivity between cellulose composition and active ingredient)) Aminofophylline was used as the active ingredient, and the reactivity with the cellulose composition was evaluated in the following manner. First, use a static pressure tableting machine (pressing 7 kN, holding time 10 seconds) to tablet the powder mixed with cellulose composition: aminophylline=1:1 (parts by mass) in a polyethylene bag , To make a flat tablet of ϕ 11.3 mm and 500 mg. For the tablets obtained by the above-mentioned manufacturing method, use a spectrophotometer (SE-2000, manufactured by Nippon Denshoku Industries Co., Ltd.) to find the brightness (L), chroma (green to red) (a), Saturation (blue to yellow) (b) value. Then, the whiteness was calculated using the following formula.

Whiteness=100－[(100－L) ² +a ² +b ² ] ^0.5

In addition, the tablets obtained from the tableting were put into a glass bottle and sealed, and stored in a constant temperature and humidity machine set at a temperature of 40°C and a humidity of 75%RH for 1 month. After storage, a spectrophotometer was also used. Measure the values of L, a, and b, and use the above formula to calculate the whiteness after the storage stability test.

The whiteness change of the tablets immediately after the tableting (before storage) and after the storage stability test (after storage) was calculated using the following formula, and the reactivity between the cellulose composition and the active ingredient was calculated as the whiteness change.

Whiteness change = whiteness (before storage)-whiteness (after storage)

Furthermore, if the absolute value of the whiteness change exceeds 10%, the degree of the color change can be visually recognized. Therefore, the absolute value of the whiteness change is 10% or less as having good storage stability.

＜Preparation of wet flocs＞ [Preparation Example 1] (Preparation of wet floc X) Put 2 kg of commercially available pulp finely cut and 30 L of hydrochloric acid aqueous solution into a low-speed mixer (manufactured by Ikebukuro Enamel Industry Co., Ltd., 30LGL reactor (trade name)), while stirring and hydrolysis (Reaction conditions: hydrochloric acid concentration 0.5%, reaction temperature 120°C, reaction time 1.0 hour, stirring speed 220 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue was thoroughly washed with pure water until the conductivity of the filtrate became less than 100 μS/cm, and then filtered to obtain a wet floc X. The average degree of polymerization of the wet floc X was measured by the copper ethylenediamine solution viscosity method described in the Confirmation Test of Crystalline Cellulose (3) of the Japanese Pharmacopoeia. As a result, the average degree of polymerization was 170.

＜Preparation of cellooligosaccharide extract＞ In the preparation of wet floc X, the filtrate of the hydrolysis reaction liquid separated from the acid-insoluble residue is recovered. The filtrate was neutralized with a strongly basic anion exchange resin, and concentrated with an evaporator to precipitate insoluble matter (cellooligosaccharides). Concentrate until the concentrated liquid becomes a slurry, and stop the concentration when the concentrated liquid does not dry out. The obtained concentrated liquid is ice-cooled, and the glass filter is used for suction filtration, and then the insoluble matter remaining on the glass filter is washed with cold water. The washed insoluble matter is dried under vacuum and reduced pressure drying to obtain a cellooligosaccharide extract. The content of cellooligosaccharides from 3 to 7 sugars in the cellooligosaccharide extract is 72% by mass.

＜Manufacture of cellulose composition＞ [Example 1] (Manufacture of cellulose powder A) The wet floc X was introduced into a 90 L plastic bucket, pure water was added so that the total solid content concentration became 10% by mass, and dispersed by a Trinity motor to prepare 30 kg of dispersion. While stirring the dispersion, neutralize it with ammonia (pH after neutralization is 7.5 or more and 8.0 or less), and add cellooligosaccharide extract (the ratio of cellooligosaccharides from 3 to 7 sugars is 72%) 5.56 g was stirred and spray dried (drying conditions: dispersion supply rate 6 kg/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 composition A. The water soluble matter of the obtained powder was 11.3 mg, the cellooligosaccharide content of 3 to 7 sugars was 7.5 mg, and the ratio of 3-7 sugars to the water soluble matter was 66% by mass.

[Example 2] (Manufacture of cellulose composition B) The wet floc X was introduced into a 90 L plastic bucket, pure water was added so that the total solid content concentration became 10% by mass, and dispersed by a Trinity motor to prepare 30 kg of dispersion. While stirring the dispersion, neutralize it with ammonia (pH after neutralization is 7.5 or more and 8.0 or less), and add cellooligosaccharide extract (the ratio of cellooligosaccharides from 3 to 7 sugars is 72%) 3.39 g was stirred and spray dried (drying conditions: dispersion supply rate 6 kg/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 composition B. The water soluble matter of the obtained powder was 7.8 mg, the cellooligosaccharide content of 3 to 7 sugars was 5.0 mg, and the ratio of 3-7 sugars to the water soluble matter was 64% by mass.

[Example 3] (Manufacture of cellulose composition C) 800 g of the cellulose composition B obtained in Example 2 was added to a high-speed stirring granulator for granulation, dried in a fluidized bed, and then sieved using a 500 μm sieve to obtain a cellulose composition C ( Granulation conditions: 600 g of water, 20 minutes of granulation time, main scraper 400 rpm, cross screw 500 rpm; drying conditions: drying temperature 80°C). The water soluble matter of the obtained powder was 7.4 mg, the content of cellooligosaccharides from 3 to 7 sugars was 4.7 mg, and the ratio of 3 to 7 sugars to the water soluble matter was 64% by mass.

[Example 4] (Manufacture of cellulose composition D) The cellulose composition B obtained in Example 2 was pulverized with a jet mill pulverizer to obtain a cellulose composition D. The water soluble matter of the obtained powder was 8.9 mg, the cellooligosaccharide content of 3 to 7 sugars was 5.8 mg, and the ratio of 3-7 sugars to the water soluble matter was 65% by mass.

[Example 5] (Manufacture of cellulose composition E) The wet floc X was introduced into a 90 L plastic bucket, pure water was added so that the total solid content concentration became 10% by mass, and dispersed by a Trinity motor to prepare 30 kg of dispersion. While stirring the dispersion, neutralize it with ammonia (pH after neutralization is 7.5 or more and 8.0 or less), and add cellooligosaccharide extract (the ratio of cellooligosaccharides from 3 to 7 sugars is 72%) 2.52 g was stirred and spray dried (drying conditions: dispersion supply rate 6 kg/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 a cellulose composition E. The water soluble matter of the obtained powder was 6.4 mg, the content of cellooligosaccharides from 3 to 7 sugars was 4.0 mg, and the ratio of 3 to 7 sugars to the water soluble matter was 62% by mass.

[Comparative Example 1] (Manufacture of cellulose composition F) The wet floc X was introduced into a 90 L plastic bucket, pure water was added so that the total solid content concentration became 10% by mass, and dispersed by a Trinity motor to prepare 30 kg of dispersion. While stirring the dispersion, it was neutralized with ammonia water (pH after neutralization was 7.5 or more and 8.0 or less), and no cellooligosaccharide extract was added, and spray drying was performed (drying conditions: dispersion supply rate 6 kg /Hour, an inlet temperature of 180°C or more and 220°C or less, and an outlet temperature of 50°C or more and 70°C or less) to obtain a cellulose composition F. The water soluble matter of the obtained powder was 2.4 mg, the content of cellooligosaccharides from 3 to 7 sugars was 1.1 mg, and the ratio of 3 to 7 sugars to the water soluble matter was 46% by mass.

[Comparative Example 2] (Manufacture of cellulose composition G) The wet floc X was introduced into a 90 L plastic bucket, pure water was added so that the total solid content concentration became 10% by mass, and dispersed by a Trinity motor to prepare 30 kg of dispersion. While stirring the dispersion, neutralize it with ammonia (pH after neutralization is 7.5 or more and 8.0 or less), and add cellooligosaccharide extract (the ratio of cellooligosaccharides from 3 to 7 sugars is 72%) 7.29 g was stirred and spray dried (drying conditions: dispersion supply rate 6 kg/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 composition G. The water soluble matter of the obtained powder was 14.1 mg, the cellooligosaccharide content of 3 to 7 sugars was 9.5 mg, and the ratio of 3-7 sugars to the water soluble matter was 68% by mass.

For each cellulose composition obtained in the Examples and Comparative Examples, various physical properties were measured using the method described above, and each evaluation was performed after the preparation of tablets. Table 4 shows the measurement results of physical properties, and Table 5 shows the evaluation results. Furthermore, in Table 5, "d-MC" is d-chlorpheniramine maleate.

[Table 4] Example 1 Example 2 Example 3 Example 4 Example 5 Comparative example 1 Comparative example 2 Cellulose composition A B C D E F G composition Water soluble content [mg] 11.3 7.8 7.4 8.9 6.4 2.4 14.1 The content of cellooligosaccharides (3～7 sugars) [mg] 7.5 5.0 4.7 5.8 4.0 1.1 9.5 The ratio of cellooligosaccharides (3～7 sugars) to water soluble matter [quality%] 66 64 64 65 62 46 68 Physical properties The average particle size [μm] 62 59 134 26 56 53 65 Loose bulk density [g/mL] 0.23 0.26 0.31 0.15 0.27 0.29 0.19 Compact bulk density [g/mL] 0.42 0.41 0.41 0.32 0.40 0.41 0.39 Compression ratio [-] 45 36 25 53 32 30 51 Primary particle equivalent particle size [μm] twenty four twenty three 20 twenty four twenty three twenty two twenty three L/D [-] 2.3 2.2 1.9 2.7 2.1 2.1 2.4 Reactivity with active ingredients [%] -8 -5 -4 -6 -4 -3 -11

[table 5] Example 1 Example 2 Example 3 Example 4 Example 5 Comparative example 1 Comparative example 2 Cellulose composition A B C D E F G The composition of the lozenge Deployment Allocation 1 Allocation 1 Allocation 1 Allocation 1 Allocation 1 Allocation 1 Allocation 1 Active ingredient d-MC d-MC d-MC d-MC d-MC d-MC d-MC Active ingredient content [quality%] 1 1 1 1 1 1 1 Content of cellulose composition [quality%] 10 10 10 10 10 10 10 Mannitol content [quality%] 88 88 88 88 88 88 88 Lubricant content [quality%] 1 1 1 1 1 1 1 Evaluation 5 minutes Tablet hardness [N] 78 67 60 96 65 56 84 CV value of active ingredient content [quality%] 1.9 1.7 1.3 2.0 1.6 1.5 2.5 Blockage [-] ○ ○ ○ ○ ○ ○ ○ 30 minutes Tablet hardness [N] 75 62 55 90 58 47 82 CV value of active ingredient content [quality%] 1.8 1.7 1.4 1.7 2.0 3.5 2.4 Blockage [-] ○ ○ ○ ○ ○ ○ ○ Reduction rate of tablet hardness [%] 3.8 7.5 8.3 6.3 10.8 16.1 2.4

According to Tables 4 to 5, the content of cellooligosaccharides of 3 to 7 sugars in 5 g of cellulose composition is 4.0 mg or more and 7.5 mg or less in cellulose compositions A to E (Examples 1 to 5) , The reactivity with the active ingredient is suppressed. In the tablet using the cellulose composition, the tablet hardness, the reduction rate of the tablet hardness, and the CV value of the active ingredient content are good, and the inhibition of tableting during forming is suppressed.

In contrast, in the cellulose composition F (Comparative Example 1), the content of cellooligosaccharides of 3 to 7 sugars in 5 g of the cellulose composition is less than 4.0 mg, although the reactivity with the active ingredient is low However, in the tablets using the cellulose composition, the tablet hardness, the reduction rate of the tablet hardness, and the CV value of the active ingredient content cannot be obtained. In the tablet of cellulose composition G (Comparative Example 2) using cellulosic composition G (Comparative Example 2) containing 3 to 7 sugars in 5 g of the cellulose composition, although the tablet hardness and tablet hardness decreased The rate is good, but the reactivity of the cellulose composition with the active ingredient and the CV value of the active ingredient content of the tablet are not good.

[Examples 6-8] Using the cellulose composition B obtained in Example 2, the formulated tablets shown in Table 6 below were prepared by the above method, and each evaluation was performed. The results are shown in Table 6. Furthermore, in Table 6, "d-MC" is d-chlorpheniramine maleate.

[Table 6] Example 6 Example 7 Example 8 Cellulose composition B B B The composition of the lozenge Deployment Allocation 3 Allocation 4 Allocation 2 Active ingredient d-MC d-MC Folic acid Active ingredient content [quality%] 1 1 0.2 Content of cellulose composition [quality%] 10 10 10 Mannitol content [quality%] 86 88.5 88.8 Lubricant content [quality%] 3 0.5 1 Evaluation 5 minutes Tablet hardness [N] 62 68 66 CV value of active ingredient content [quality%] 2.0 1.7 2.0 Blockage [-] ○ Δ ○ 30 minutes Tablet hardness [N] 57 65 62 CV value of active ingredient content [quality%] 1.7 1.7 1.9 Blockage [-] ○ Δ ○ Reduction rate of tablet hardness [%] 8.1 4.4 6.1

According to Table 6, in tablets with a lubricant content of 0.3% by mass or more and 5% by mass or less (Examples 6-8), tablet hardness, tablet hardness reduction rate, active ingredient content CV value, and The ingots during forming prevent all of them from being good. In addition, according to the comparison of tablets (Examples 2, 6 and 7) with different lubricant content of the cellulose composition B, it was found that the increase in the lubricant content further suppressed the inhibition of tableting during forming. . On the other hand, it has been found that the decrease in the content of the lubricant tends to make the tablet hardness and the decrease rate of the tablet hardness better. [Industrial availability]

According to the cellulosic composition of this embodiment, it is possible to provide a cellulosic composition with good hardness, and the bias of the content of the active ingredient and the inhibition of tableting inhibition during forming can be provided. The tablet of this embodiment contains the above-mentioned cellulose composition, has good hardness, and the bias of the content of the active ingredient and the inhibition of tableting during forming are suppressed.

Claims (11)

A cellulose composition comprising cellulose and cellooligosaccharides of 3 to 7 sugars, and the content of the cellooligosaccharide per 5 g of the cellulose composition is 1.5 mg or more and 9.0 mg or less. The cellulose composition of claim 1, wherein the cellulose composition has a water-soluble content of 2.5 mg or more and 12.5 mg or less per 5 g. The cellulose composition according to claim 2, wherein the ratio of the cellooligosaccharide to the water-soluble substance is 47% by mass or more and 67% by mass or less. The cellulose composition according to any one of claims 1 to 3, wherein the above-mentioned cellulose composition is a powder, and the average particle size of the powder is 10 μm or more and 200 μm or less. The cellulose composition of claim 4, wherein the aspect ratio L/D of the powder is 1.8 or more and 4.0 or less. A tablet comprising the cellulose composition according to any one of claims 1 to 5, and one or more active ingredients. The tablet of claim 6, which further contains a lubricant, and the content of the lubricant is 0.3% by mass or more and 5% by mass or less with respect to the total mass of the tablet. The tablet of claim 7, wherein the lubricant is one or more selected from the group consisting of fatty acid metal salts, fatty acid esters, and fatty acid ester metal salts. The tablet of claim 7 or 8, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, sucrose fatty acid ester and talc One or more of them. The tablet according to any one of claims 6 to 8, wherein the content of the above-mentioned active ingredient is 0.01% by mass or more and less than 50% by mass relative to the total mass of the tablet. Such as the tablet of claim 9, wherein the content of the above-mentioned active ingredient is 0.01% by mass or more and less than 50% by mass relative to the total mass of the tablet.