TW202118515A - Cellulose composition, tablet and orally disintegrating tablet including cellulose, glucose and sorbitol - Google Patents

Abstract

Disclosed is a cellulose composition including cellulose, glucose and sorbitol. The sum of contents of the glucose and the sorbitol in every 5g of the cellulose composition is greater than 0.7 mg and less than 4.0 mg. A tablet includes the cellulose composition. The orally disintegrating tablet includes the cellulose composition.

Description

Cellulose composition, lozenge and orally disintegrating tablet

The present invention relates to a cellulose composition, lozenges and orally disintegrating tablets.

Previously, it is widely known in the fields of medicines, health foods, foods, and other chemical industries that cellulose powder is used as an excipient to prepare a molded body containing an active ingredient, such as a lozenge. In particular, the recent lozenges, orally disintegrating tablets that can be taken without water, have become the mainstream, which is a dosage form that has been greatly developed in the field of pharmaceutical preparations. In recent years, oral disintegrating tablets can be manufactured by the same manufacturing method as ordinary tablets, which is not a special manufacturing method, but originally in order to obtain practical tablet hardness and the disintegration or taking feeling that is satisfied as an oral disintegrating tablet. The technology is based on the use of various additives or excipients in the blending ratio. As high value-added preparations based on this technology, in addition to improving the QOL (Quality Of Life) of patients, the PLCM (Product Life Cycle Management) aspect of products has also gradually become important . Furthermore, during the rapid development of an aging society, oral disintegrating tablets that use saliva or a small amount of water to quickly disintegrate are used as a dosage form that is easy to take by patients with weak swallowing power such as the elderly or children. It helps to improve the convenience of the medical site or the adherence or compliance to the patient. However, the history of disintegrating tablets in the oral cavity is relatively short, and there are also technical problems such as the disintegration time in the oral cavity or the feeling of taking, and the hardness of the tablets to ensure that they will not break or wear during manufacture or distribution.

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 then imparting stable disintegration with time. However, in Patent Document 1, on the premise of being a pure cellulose powder, as a cellulose-containing composition, there are still improvements in the disintegration and storage stability required for oral disintegrating tablets. room. [Prior Technical Documents] [Patent Documents]

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

[The problem to be solved by the invention]

The present invention has been completed in view of the above circumstances, and provides a cellulose composition that can obtain a tablet that maintains good disintegration properties as an orally disintegrating tablet and has excellent storage stability, and a tablet containing the above-mentioned cellulose composition And oral disintegrating tablets. [Technical means to solve the problem]

That is, the present invention includes the following aspects. (1) A cellulose composition comprising cellulose, glucose, and sorbitol, and the total content of glucose and sorbitol per 5 g of the cellulose composition is 0.7 mg or more and 4.0 mg or less. (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 as described in (1) or (2), wherein the content of glucose per 5 g of the cellulose composition is 0.3 mg or more and 4.0 mg or less. (4) The cellulose composition according to any one of (1) to (3), wherein the content of sorbitol per 5 g of the cellulose composition is 0.2 mg or more and 4.0 mg or less. (5) The cellulose composition according to any one of (1) to (4), 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. (6) The cellulose composition as described in any one of (1) to (5), which has a water absorption speed of 2.0 g ² /s or more and 9.0 g ² /s or less. (7) A tablet comprising the cellulose composition as described in any one of (1) to (6). (8) An orally disintegrating tablet comprising the cellulose composition as described in any one of (1) to (6). [Effects of Invention]

According to the cellulose composition of the above aspect, it is possible to provide a cellulose composition that can obtain a tablet that maintains good disintegrability as an orally disintegrating tablet and has excellent storage stability. The tablets and orally disintegrating tablets of the above aspects include the above-mentioned cellulose composition, and the disintegrating properties as the orally disintegrating tablets are good, and the storage stability is excellent.

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, glucose, and sorbitol. The total content of monosaccharides, namely glucose and sorbitol per 5 g of the above-mentioned cellulose composition is 0.7 mg or more and 4.0 mg or less, preferably 1.0 mg or more and 3.5 mg or less, more preferably 2.0 mg or more and 3.0 Below mg. By making the content of the monosaccharide per 5 g of the cellulose composition within the above-mentioned range, the disintegration property when it is made into an orally disintegrating tablet can be made good. In addition, the storage stability of the tablet can be improved. Furthermore, when the cellulose composition is a powder, it is preferable to include cellulose, glucose, and sorbitol 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 can contain the water-soluble matter previously excluded as an impurity 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. Among these constituents, by containing glucose and sorbitol as monosaccharides in a specific range, it is possible to effectively suppress the core residue when preparing the orally disintegrating tablets, thereby improving the disintegration properties.

In the cellulose composition of this embodiment, the content of water-soluble matter per 5 g of the cellulose composition is preferably 2.5 mg or more and 12.5 mg or less, more preferably 3.0 mg or more and 12.0 mg or less, and more It is preferably 3.5 mg or more and 11.5 mg or less, and particularly preferably 4.0 mg or more and 11.0 mg or less. By making the water-soluble matter in the cellulose composition within the above-mentioned range, it is possible to suppress the core residue when it is made into an orally disintegrating tablet, and the disintegration property can be improved.

In the cellulose composition of this embodiment, the glucose content per 5 g of the cellulose composition is preferably 0.3 mg or more and 4.0 mg or less, more preferably 0.5 mg or more and 3.5 mg or less, and still more preferably 1.0 mg Above and below 3.0 mg. By making the glucose content in the cellulose composition within the above-mentioned range, it is possible to suppress the core remaining when it is made into an orally disintegrating tablet, and the disintegration property can be improved. In addition, the reaction between the active ingredient contained in the tablet and glucose can be suppressed, and as a result, the storage stability of the tablet can be improved.

In the cellulose composition of this embodiment, the sorbitol content per 5 g of the cellulose composition is preferably 0.2 mg or more and 4.0 mg or less, more preferably 0.3 mg or more and 3.5 mg or less, and more preferably 0.5 mg or more and 3.5 mg or less, particularly preferably 1.0 mg or more and 3.0 mg or less. By making the sorbitol content in the cellulose composition within the above-mentioned range, it is possible to suppress the core residue when preparing the orally disintegrating tablet, and the disintegration property can be improved. In addition, the reaction between the active ingredient contained in the tablet and sorbitol can be suppressed, and as a result, the storage stability of the tablet can be improved.

Glucose and sorbitol are both monosaccharides with similar properties, but from the viewpoint of disintegration and storage stability as an orally disintegrating tablet, there is a tendency that sorbitol is more excellent. Therefore, it is preferable to contain more sorbitol than glucose.

The content of glucose and sorbitol in 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 glucose and sorbitol, first, the conditions of the liquid chromatography method are appropriately adjusted to verify whether the peaks can be separated. Assuming that the peaks cannot be separated, the extracted ion chromatograms of the base peak ions derived from glucose and sorbitol can be used in mass analysis to obtain the peak areas derived from glucose and sorbitol.

The content of glucose and sorbitol in the cellulose composition, for example, can also be adjusted by adding at least one of glucose and sorbitol in an appropriate amount in the manufacturing process of the cellulose composition. Although there is the possibility that the content of glucose and sorbitol can be controlled according to the selection of the raw materials of the cellulose composition or the manufacturing conditions, in order to control them to the required content range, a method of adding an appropriate amount in the manufacturing step Simple and better.

The water absorption speed of the cellulose composition of this embodiment is preferably 2.0 g ² /s or more and 9.0 g ² /s or less, more preferably 2.2 g ² /s or more and 8.2 g ² /s or less, and still more preferably 3.0 g ² /s or more and 8.0 g ² /s or less, particularly ^{preferably 3.4 g 2} /s or more and 7.4 g ² /s or less, and most preferably 3.4 g ² /s or more and 7.2 g ² /s or less. By setting the water absorption speed within the above-mentioned range, it is possible to more effectively suppress the core remaining when the oral disintegrating tablet is prepared, and the disintegrating property can be more favorable.

In addition, the water absorption speed can be measured using a Peneto Analyzer (model: PNT-N, manufactured by Hosokawa Micron) as shown 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 the cellulose powder, crystalline cellulose is preferred. As crystalline cellulose, for example, the microcrystalline cellulose specified in the FAO/WHO Contract Food Additives Expert Meeting (JECFA), and the microcrystalline cellulose described in the 8th edition of the Official Document of Food Additives (issued by the Ministry of Health, Labour and Welfare in Japan) are known. Crystalline cellulose, crystalline cellulose described in the Japanese Pharmacopoeia (17th revision), crystalline cellulose described in the United States Pharmacopoeia, 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 crystalline cellulose confirmation test (3) of the Japanese Pharmacopoeia, or the powdered cellulose confirmation test (3) of the pharmacopoeia, which can be measured by the copper ethylene diamine solution viscosity method. .

<A preferred form as cellulose powder> When the cellulose composition of this embodiment is a powder, the average particle size is preferably 10 μm or more and 200 μm or less, more preferably 15 μm or more and 90 μm or less, and still more preferably 20 μm or more and 80 μm Hereinafter, it is particularly preferably 30 μm or more and 70 μm or less, and most preferably 40 μm or more and 60 μm or less. By making the average particle diameter below the above upper limit value, it is easy to uniformly mix with active ingredients such as drugs, and the disintegration property when being prepared into an orally disintegrating tablet becomes good. On the other hand, by making the average particle diameter more than the above-mentioned lower limit, the handleability becomes good.

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 0.10 g/mL or more and 0.35 g/mL or less, more preferably 0.11 g/mL or more and 0.30 g/mL or less, and more Preferably, it is 0.13 g/mL or more and 0.28 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 0.27 g/mL or more and 0.50 g/mL or less, more preferably 0.28 g/mL or more and 0.48 g/mL or less, and more Preferably, it is 0.28 g/mL or more and 0.44 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 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 22% or more and 58% or less, more preferably 30% or more and 55% or less, and still more preferably 35% or more and 50% or less . If the compression ratio is 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, the ratio of the long diameter to the short diameter of the cellulose particles, that is, the aspect ratio (L/D), is preferably 1.6 or more and 3.8 or less, more preferably 2.0 or more And 3.6 or less, more preferably 2.3 or more and 3.3 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. However, the cellulose composition of this embodiment is not limited to those obtained by the following production method. The cellulose composition of this embodiment can be obtained, for example, by including the steps of: dispersing the hydrolyzed natural cellulose-based substance in a suitable 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, glucose or sorbitol may be added to the cellulose dispersion liquid so that the contents of glucose and sorbitol in the cellulose composition are within a specific range, and the mixture may be dried. 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, organic solvents are preferably used by users of pharmaceuticals, and examples of such organic solvents include those classified as solvents in the "Medicine 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 0.01% by mass or more and 1.0% 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 blender motor (W)]/[Stirring 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, and a foaming agent or gas can also be added to the dispersion in order to promote the vaporization rate of the medium.

An aqueous cellulose dispersion containing cellulose dispersed particles with a specific average particle size can be obtained by controlling the acid concentration and stirring conditions during the preparation of the aqueous cellulose dispersion, and the aqueous cellulose dispersion can be adjusted During drying, the solid content of the aqueous cellulose dispersion or the drying conditions are used to control the average particle size and compression rate of the obtained cellulose composition. 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 glucose and sorbitol in the cellulose composition can be obtained by adding glucose or sorbitol to the aqueous cellulose dispersion, mixing and drying as necessary. Cellulose composition within a specific range.

When the cellulose composition is dried to form a powder, when the average particle size is greater than 200 μm, the average particle size can also be adjusted to 10 μm or more by applying it to the following pulverization step. Less than 200 μm.

In the crushing step, the use of ultracentrifugal crusher (ZM-200, manufactured by Retsch), jet mill (STJ-200, manufactured by Qingxin Enterprise) or hammer mill (H-12, manufactured by Hosokawa Micron), crusher (AP-B, manufactured by Hosokawa Micron), pin grinder (160Z, manufactured by Powrex), sharpener (FM, manufactured by Hosokawa Micron), hammer mill (HM-600, manufactured by Nara Machinery Manufacturing Co., Ltd.), rapid crusher (FL -250N, manufactured by Dalton), ball mill (manufactured by Emax, Retsch), vibrating ball mill (manufactured by 2C, TRU), sieve mill (U30, Powrex manufactured) and other pulverizers to pulverize the dried cellulose composition And implement. 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＞ The cellulose composition of this embodiment is formulated into a composition containing an active ingredient to obtain a tablet that maintains good disintegration properties and is excellent in storage stability. As shown in the following examples, the cellulose composition of this embodiment has excellent disintegration properties when it is made into orally disintegrating tablets, and therefore can be suitably used as an excipient for orally disintegrating tablets. Hereinafter, a composition containing one or more active ingredients and the cellulose composition of this embodiment for tableting is referred to as "the composition of this embodiment".

The blending ratio of the above-mentioned cellulose composition with respect to the composition of this embodiment can be set to any ratio, and the mass of the whole tablet is 90% by mass or less, which is a preferable range in actual use. A lower limit of 0.1% by mass is practical. When used for tablets containing a large amount of active ingredients, it can be set to about 0.1% by mass or more and 50% by mass or less.

Hereinafter, those suitable as the active ingredient contained in the composition of this embodiment 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.

The active ingredients for health foods are not limited as long as they are formulated to enhance health. Examples include: green juice powder, aglycone, Brazilian mushroom, 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, plant sterols, seed extract, spirulina, squalene, European white willow, brain amine, 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 niacin, 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 water-soluble, 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 the composition of this embodiment.

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.

In addition, as the active ingredient, it is also preferable to use medicinal ingredients 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 (Clavulanate Potassium), Clopidogrel (clopidogrel), Clozapine (clozapine), Cycloserine (cycloserine), Darunavir (darunavir), Darunavir ethanolate (darunavir ethanol) 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 (metformin), Methyldopa (methyldopa), Metronidazole (metronidazole), Morphine (morphine), Moxifloxacin (moxifloxacin), Nevirapine (nevirapine), Niclosamide (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 (Valproic acid), Velpatasvir (Vipatavir), Sodium valproate (Valproate), Voriconazole (Voriconazole), Zidovudine (Zidovudine) and so on.

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), Sitafloxacin hydrate ( (Sitafloxacin hydrate), Spironolactone (spironolactone), Tadalafil (tadalafil), Tamoxifen (tamoxifen), Thiamine (thiamine), Tioguanine (thioguanine) Resin), Tolvaptan, Ulipristal, Vardenafil Hydrochloride Hydrate, zinc sulfate, Acotiamide hydrochloride hydrate , Amitriptyline, Bedaquline, Benznidazole, Bosentan hydrate, Chlorpromazine, Cinacalcet hydrochlorid , Daclatasvir, Dapsone, Diethylcarbamazine, Doxycycline, Entacapone, Eplerenone, Ferrous sulfate( Iron sulfate hydrate, Gliclazide, Ibandronate Sodium Hydrate, Losartan, Miglitol, Nitrofurantoin, Phenobarbital Barbital), Phenytoin (phenytoin), Pyridostigmine (pyridostigmine), Raloxifene Hydrochloride (raloxifene hydrochloride), Ritonavir (ritonavir), Succimer (2,3-dimercaptosuccinic acid), telmisartan (Telmisartan), 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 (anastrozole), Dienogest (dienogest), Digoxin (digoxin), Dutasteride (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 (Dexamethasone), Diazepam (Diazepam), Enalapril (Enalapril), Ergocalciferol (ergocalciferol), Escitalopram Oxalate (Escitalopram oxalate), Esomeprazole magnesium hydrate (Omeira) 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 Amine), Mitiglinide Calcium Hydrate, Montelukast Sodium, Norethisterone, Paliperidone, Phytomenadione or Phytonadione Quinone or chlorophyllyl menadione), Rameteon (ramelteamide), Riboflavin (riboflavin), Risperidone (risperidone), Rizatriptan benzoate (Rizatriptan benzoate), Ropinirole hydrochloride Nile), Rosuvastatin Calcium, Senna (senna leaf extract), Silodosin, Solifenacin succinate, Warfarin, etc.

These active ingredients and medicinal ingredients can also be blended into the composition of this embodiment together with the cellulose composition of this embodiment in a finely pulverized state. 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.

[Other additives] In addition to the above-mentioned active ingredients, the composition of this embodiment may further contain other additives. Examples of other additives include excipients, disintegrating powders, binders, plasticizers, lubricants, and flavoring agents.

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-sodium bicarbonate co-precipitation, magnesium hydroxide, squalane, stearyl alcohol, stearic acid, calcium stearate, hard Fatty acid polyoxyester, magnesium stearate, hydrogenated soybean oil, refined gelatin, refined shellac, refined white sugar, refined white sugar spherical particles, cetearyl alcohol, polyethylene glycol 1000 monohexadecyl 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 insects Gum, white petrolatum, clay, sugar, white sugar-starch spherical granules, rye green leaf extract powder, rye sprout leaf green juice dry powder, honey, paraffin, potato starch, semi-digestible starch, human serum albumin, hydroxyl Propyl starch, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, phytic acid, glucose, glucose Hydrate, partially gelatinized starch, pullulan, propylene glycol, powdered reduced maltose syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene Ethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethyl Amino acetate, polyvinylpyrrolidone, polyethylene glycol, maltitol , 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, and sodium dihydrogen phosphate are equivalent to "Pharmaceutical Additives 2016" (Yuji Daily Co., Ltd. ) 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 lubricants include: magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, and talc, which are classified into the "Drug Additives Reference 2016" (issued by Yakuji Daily Co., Ltd.) Lubricant. 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＞ Hereinafter, the method of preparing a tablet by tableting a composition containing one or more active ingredients and the cellulose composition of the present embodiment (the manufacturing method of the tablet of the present embodiment) will be described, but it is an example And the effect of this embodiment is not limited by the following methods.

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 group consisting of excipients, disintegrating agents, binders, plasticizers, lubricants, correctives, fragrances, colorants, sweeteners, solubilizers, etc., as shown above the 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 It is a method of pre-mixing with at least any additive of plasticizer and lubricant, and then mixing the cellulose composition of this embodiment with other additives as needed, and then performing compression molding. In terms of ease of operation, i) is preferred. It is also possible to add a lubricant to the mixed powder for compression molding obtained in i) and ii), and then mix the mixed powder for compression molding. 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 blade mixing methods, line mixers and other jet mixing methods, gas blowing type mixing and 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 can be used alone, or two or more of them can be used in combination, or one medium can be used to temporarily disperse the medium and then the medium can 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 may be mentioned: a method of mixing an active ingredient with the cellulose composition of the present embodiment, or mixing one or more active ingredients with the cellulose composition of the present embodiment, and visual It is a direct ingot method that is directly compressed and molded by mixing other additives that are needed. 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 the composition of cellulose composition＞ [Analysis 1] (Method for measuring the content of water soluble matter in cellulose composition) With reference to the method of Purity Test (2) of Crystalline Cellulose in the Japanese Pharmacopoeia of the 17th Revision, the content of water-soluble matter in the cellulose composition was determined in the following order. 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 amount of water solubles detected in the blank test is obtained from the measured value minus the amount of water solubles detected in the blank test The value obtained. 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] (Determination of the content of sugars (glucose, sorbitol, cellobiose) in the cellulose composition) Add 10 mL of 50% (v/v) acetonitrile aqueous solution to the total amount of dry matter obtained in "Analysis 1" above to redissolve, and filter with a filter (0.20 μm) and use LC /MS measures the content of glucose, sorbitol and cellobiose. The measurement conditions of the LC/MS measurement are as follows. 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 measuring the content of glucose, sorbitol, and cellobiose, glucose, sorbitol, and cellobiose were analyzed by LC/MS on a solution of known concentration prepared using commercially available products, and the results The retention time corresponding to sugar and the peak area of the m/z ion chromatogram were used to create a calibration curve (sample concentration-peak area). Using this calibration curve, the content of each sugar in the water-soluble substance (5 g of the cellulose composition) was determined. Furthermore, the content of each sugar is recorded as the value obtained by rounding to the second decimal place.

(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 conditions of the gradient 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) Sorbitol 181.07 [MH] ^- 5.9 glucose 179.06 [MH] ^- 6.1 Cellobiose 341.11 [MH] ^- 7.8

<Measurement method of powder physical properties> [Properties 1] (Water absorption speed) Peneto Analyzer (model: PNT-N, manufactured by Hosokawa Micron) was used to measure the water absorption speed. Specifically, first, in order to suppress the difference in the measured value caused by static electricity, the bottom surface of the measuring unit is wiped with a towel that contains 1% household lotion and wrung out before the measurement to dry it naturally. . Set the bottom plate and filter paper in the measurement unit, add 5 g of the cellulose composition, and slap with the attached slap device (300 times, 18 mm, hammer 198 g). Install the slapped sample on the unit holder and then install it on the Peneto Analyzer body. Set as the solvent (purified water, 300 mL) at room temperature (25℃), the lifting conditions during measurement ((1) 1.5 mm/s, (2) 0.1 mm/s, (3) 0.5 mm/s, manual 1.5 mm/s) for measurement. Use the vertical axis: the square of the mass (g ² ), the horizontal axis: the measurement time (the elapsed time after the start of water absorption) (s) the linear area of the water absorption curve (the area between 1/3 to 2/3 of the saturation of water absorption) The water absorption curve is approximated by a straight line, and the slope of the approximate straight line is obtained as the coefficient of permeability (g ² /s).

[Properties 2] (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 50% cumulative volume of particles obtained by the measurement is taken as the average particle diameter (μm) of the cellulose composition.

[Properties 3] (Loose bulk density) For the measurement, a cellulose composition adjusted to a moisture content of 3.5% by mass or more and 4.5% by mass or less was used. When the range of the moisture content of the cellulose composition is less than 3.5% by mass, the cellulose composition is adjusted to absorb moisture using a constant temperature and humidity machine or the like. When it exceeds 4.5% by mass, a hot air oven is used to uniformly supply hot air at 60° C. to the cellulose composition to adjust the moisture content within the range. The bulk density of the cellulosic composition was measured using Scott Volumeter (model ASTM B-329-85, manufactured by Tsutsui Rikaki Instruments), and the cellulosic composition was filled into a 25 mL cylinder through a screen (mesh 1 mm) In a metal container. Scrape the cellulose composition placed in a 25 mL cylindrical metal container, and divide the mass (g) of the cellulose composition 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 4] (Compact bulk density) For the measurement, a cellulose composition adjusted to a moisture content of 3.5% by mass or more and 4.5% by mass or less was used. The moisture content of the cellulose composition is adjusted so that it falls within this range using the method described in "Properties 3". 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 5] (Compression ratio) The compressibility of each cellulose composition was calculated by the formula shown below.

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

[Properties 6] (The ratio of the long diameter of the cellulose particles to the short diameter (L/D)) The cellulose composition was dispersed on a glass plate, and images were taken with a microscope (VHX-1000, manufactured by Keyence) 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＞ Orally disintegrating tablets (OD tablets) and tablets were prepared using the methods shown below, and various evaluations were performed.

[Production of OD Ingot] Put the formula powder shown below into a polyethylene bag and shake and mix for 1 minute. Next, the mixed powder was sieved with a sieve of 710 μm, and then a lubricant (sodium stearyl fumarate) was added so as to be 1% by mass relative to the total mass of the OD ingot, and mixed for 30 seconds. Then, the mixed powder was tableted using a rotary tableting machine (manufactured by Kikusui Manufacturing Co., Ltd., Clean Press Collect 12HUK, 12 pestles, turntable 54 rpm) to obtain a Φ8 mm-12R 200 mg tablet. The tableting pressure is appropriately set so that the tablet hardness becomes 80 N or more and 90 N or less.

(formula) Mannitol for direct hitting (Mannogem EZ, manufactured by Asahi Kasei): 70% by mass Partially gelatinized starch (PCS, PC-10, manufactured by Asahi Kasei): 10% by mass Croscarmellose sodium (Kiccolate ND-200, manufactured by Asahi Kasei): 5 mass% Cellulose composition: 15% by mass

Furthermore, the content of each component in the above formula is the ratio of the above component to the total mass.

[Evaluation 1] (hardness) For each OD 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. Set the average value of 5 tablets each to be the hardness (N) of the tablets.

[Evaluation 2] (Time to disintegrate in the mouth) The oral disintegration time was measured using an oral disintegration tablet tester (manufactured by Toyama Industrial Co., Ltd., model ODT-101). Under the conditions of test solution: water (37±1℃), hammer diameter: ϕ20 mm, hammer mass: 20 g, rotation speed: 140 rpm, OD ingot thickness: 4.0 mm, place the OD ingot close to the center of the sample fixing frame Set the left end of the hole, and measure the disintegration time. The average value of 6 tablets was taken as the oral disintegration time of OD tablets.

[Evaluation 3] (Core residue) The core residue of OD tablets was evaluated using an oral disintegration tablet testing machine. First, the oral disintegration time described in "Evaluation 2" was measured to obtain the oral disintegration time. Then, in order to evaluate the core residue of the OD tablet, stop the disintegration tester within "75% of the obtained intraoral disintegration time" after the start of the disintegration time of the OD tablet, and confirm whether there is residue There are hard fragments of OD ingots. The core residue was evaluated based on the following evaluation criteria. The test was performed 3 times, and the judgement (+) was set as (+) if there were 2 or more (+) judges.

(Evaluation criteria) (+) Those with hard fragments of OD ingots (-) No hard fragments of OD ingots remain

[Preparation of tablets for storage stability test] 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, Ingots ϕ 11.3 mm, 500 mg flat tablets.

[Evaluation 4] (Storage stability) The reactivity of the cellulose composition with the drug was confirmed according to the whiteness change of the tablets just after the tableting and after storage. For the tablets obtained by the above-mentioned production method, immediately after the tablets are shot, use a spectrophotometer (SE-2000, manufactured by Nippon Denshoku Industry Co., Ltd.) to determine the brightness (L) and 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) is calculated using the following formula.

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.

＜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 water (the pH after neutralization is 7.5 or more and 8.0 or less), add 1.56 g of glucose, stir, and perform spray drying (conditions: dispersion liquid supply rate 6 kg/hour, The inlet temperature is 180°C or more and 220°C or less, and the outlet temperature is 50°C or more and 70°C or less) to obtain a cellulose composition A. The amount of water-soluble matter in 5 g of the cellulose composition is 4.9 mg, the amount of glucose is 2.9 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.7 mg.

[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 water (the pH after neutralization is 7.5 or more and 8.0 or less), add 0.81 g of glucose, stir, and spray dry (conditions: dispersion liquid supply rate 6 kg/hour, The inlet temperature is 180°C or more and 220°C or less, and the outlet temperature is 50°C or more and 70°C or less) to obtain a cellulose composition B. The amount of water-soluble matter in 5 g of the cellulose composition is 3.7 mg, the amount of glucose is 1.7 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.7 mg.

[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 amount of water soluble matter in 5 g of the cellulose composition is 3.4 mg, the amount of glucose is 1.6 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.6 mg.

[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 amount of water soluble matter in 5 g of the cellulose composition is 4.0 mg, the amount of glucose is 1.8 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.8 mg.

[Example 5] (Manufacture of cellulose composition E) The cellulose composition B obtained in Example 2 was pulverized with an ultracentrifugal pulverizer to obtain a cellulose composition E. The amount of water-soluble matter in 5 g of the cellulose composition is 4.3 mg, the amount of glucose is 2.0 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.8 mg.

[Example 6] (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, neutralize it with ammonia water (pH after neutralization is 7.5 or more and 8.0 or less), add 0.19 g of glucose, stir, and spray dry (conditions: dispersion liquid supply rate 6 kg/hour, The inlet temperature is 180°C or more and 220°C or less, and the outlet temperature is 50°C or more and 70°C or less) to obtain a cellulose composition F. The amount of water-soluble matter in 5 g of the cellulose composition is 2.7 mg, the amount of glucose is 0.7 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.7 mg.

[Example 7] (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 water (the pH after neutralization is 7.5 or more and 8.0 or less), add 2.0 g of sorbitol, stir, and spray dry (condition: dispersion liquid supply rate 6 kg/ Hours, 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 G. The amount of water soluble matter in 5 g of the cellulose composition is 5.6 mg, the amount of glucose is 0.4 mg, the amount of sorbitol is 3.4 mg, and the amount of cellobiose is 0.7 mg.

[Example 8] (Manufacture of cellulose composition H) 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 water (the pH after neutralization is 7.5 or more and 8.0 or less), add 1.0 g of sorbitol, stir, and spray dry (condition: dispersion liquid supply rate 6 kg/ Hours, 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 H. The amount of water soluble matter in 5 g of the cellulose composition is 4.0 mg, the amount of glucose is 0.4 mg, the amount of sorbitol is 1.8 mg, and the amount of cellobiose is 0.7 mg.

[Example 9] (Manufacture of cellulose composition I) 800 g of the cellulose composition H obtained in Example 8 was added to a high-speed stirring granulator for granulation, and after drying in the fluidized bed, it was sieved with a 500 μm sieve to obtain a cellulose composition I. The granulation conditions and drying conditions were the same as in Example 3. The amount of water soluble matter in 5 g of the cellulose composition is 3.8 mg, the amount of glucose is 0.4 mg, the amount of sorbitol is 1.7 mg, and the amount of cellobiose is 0.7 mg.

[Example 10] (Manufacture of cellulose composition J) The cellulose composition H obtained in Example 8 was pulverized by a jet mill pulverizer to obtain a cellulose composition J. The amount of water-soluble matter in 5 g of the cellulose composition is 4.2 mg, the amount of glucose is 0.4 mg, the amount of sorbitol is 1.9 mg, and the amount of cellobiose is 0.7 mg.

[Example 11] (Manufacture of cellulose composition K) The cellulose composition H obtained in Example 8 was pulverized by an ultracentrifugal pulverizer to obtain a cellulose composition K. The amount of water soluble matter in 5 g of the cellulose composition is 4.5 mg, the amount of glucose is 0.5 mg, the amount of sorbitol is 2.0 mg, and the amount of cellobiose is 0.8 mg.

[Example 12] (Manufacture of cellulose composition L) 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 water (the pH after neutralization is 7.5 or more and 8.0 or less), add 0.13 g of sorbitol, stir, and spray dry (condition: dispersion liquid supply rate 6 kg/ Hours, 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 L. The amount of water soluble matter in 5 g of the cellulose composition is 2.6 mg, the amount of glucose is 0.4 mg, the amount of sorbitol is 0.4 mg, and the amount of cellobiose is 0.7 mg.

[Comparative Example 1] (Manufacture of cellulose composition M) 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 water (pH after neutralization is 7.5 or more and 8.0 or less), stir without adding glucose, and perform spray drying (conditions: dispersion liquid supply rate 6 kg/hour, The inlet temperature is 180°C or more and 220°C or less, and the outlet temperature is 50°C or more and 70°C or less) to obtain a cellulose composition M. The amount of water-soluble matter in 5 g of the cellulose composition is 2.4 mg, the amount of glucose is 0.4 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.7 mg.

[Comparative Example 2] (Manufacture of cellulose composition N) 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 water (the pH after neutralization is 7.5 or more and 8.0 or less), add 2.31 g of glucose, stir, and perform spray drying (conditions: dispersion liquid supply rate 6 kg/hour, The inlet temperature is 180°C or more and 220°C or less, and the outlet temperature is 50°C or more and 70°C or less) to obtain a cellulose composition N. The amount of water-soluble matter in 5 g of the cellulose composition is 6.1 mg, the amount of glucose is 4.1 mg, the amount of sorbitol is 0.2 mg, and the amount of cellobiose is 0.7 mg.

[Comparative Example 3] (Manufacturing of Cellulose Mixture O) 50 mg of powdered glucose was added to 100 g of the cellulose composition M obtained in Comparative Example 1, and the mixture was shaken and mixed using a polyethylene bag to obtain a cellulose mixture O as a physical mixture corresponding to the composition of the cellulose composition A.

With respect to each cellulose composition obtained in the Examples and Comparative Examples, various physical properties were measured using the methods described above, and OD tablets and tablets were prepared and each evaluation was performed. The results are shown in Tables 3-6.

[table 3] Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Cellulose composition A B C D E F Manufacturing conditions Wet floc X X X X X X Solid content of flocculation dispersion [quality%] 10 10 10 10 10 10 Glucose addition [g] 1.56 0.81 0.81 0.81 0.81 0.19 Sorbitol added amount [g] 0 0 0 0 0 0 composition The content of water soluble matter in 5 g of cellulose composition [mg] 4.9 3.7 3.4 4.0 4.3 2.7 Glucose content in 5 g of cellulose composition [mg] 2.9 1.7 1.6 1.8 2.0 0.7 Sorbitol content in 5 g of cellulose composition [mg] 0.2 0.2 0.2 0.2 0.2 0.2 Cellulose content in 5 g of cellulose composition [mg] 0.7 0.7 0.6 0.8 0.8 0.7 Monosaccharide (glucose, sorbitol) content in 5 g of cellulose composition [mg] 3.1 1.9 1.7 2.1 2.2 0.9 Physical properties Water absorption speed [g ² /s] 5.1 4.1 3.3 6.2 3.4 2.6 The average particle size [μm] 59 55 131 33 18 52 Loose apparent density [g/mL] 0.29 0.26 0.33 0.19 0.14 0.24 Compact apparent density [g/mL] 0.46 0.42 0.43 0.34 0.33 0.42 Compression ratio [-] 37 38 twenty four 44 58 43 L/D [-] 2.3 2.4 1.8 3.2 2.4 2.3 Evaluation Suppression during the production of oral disintegrating tablets [kN] 8.0 7.5 8.0 7.0 6.5 7.5 Disintegration time in the mouth [s] twenty three 25 27 twenty three 25 29 Core residue [-] (-) (-) (-) (-) (-) (-) Storage stability (whiteness change) [%] -9 -7 -6 -7 -8 -4

[Table 4] Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Cellulose composition G H I J K L Manufacturing conditions Wet floc X X X X X X Solid content of flocculation dispersion [quality%] 10 10 10 10 10 10 Glucose addition [g] 0 0 0 0 0 0 Sorbitol added amount [g] 2.00 1.00 1.00 1.00 1.00 0.13 composition The content of water soluble matter in 5 g of cellulose composition [mg] 5.6 4.0 3.8 4.2 4.5 2.6 Glucose content in 5 g of cellulose composition [mg] 0.4 0.4 0.4 0.4 0.5 0.4 Sorbitol content in 5 g of cellulose composition [mg] 3.4 1.8 1.7 1.9 2.0 0.4 Cellulose content in 5 g of cellulose composition [mg] 0.7 0.7 0.7 0.7 0.8 0.7 Monosaccharide (glucose, sorbitol) content in 5 g of cellulose composition [mg] 3.8 2.2 2.1 2.3 2.5 0.8 Physical properties Water absorption speed [g ² /s] 7.5 5.8 4.4 7.1 4.3 2.5 The average particle size [μm] 66 59 133 37 16 54 Loose apparent density [g/mL] 0.30 0.27 0.34 0.21 0.16 0.24 Compact apparent density [g/mL] 0.47 0.44 0.44 0.37 0.37 0.41 Compression ratio [-] 36 38 twenty two 43 57 41 L/D [-] 2.4 2.3 1.7 3.3 2.6 2.4 Evaluation Suppression during the production of oral disintegrating tablets [kN] 8.0 7.5 8.0 7.0 6.5 7.5 Disintegration time in the mouth [s] 19 twenty two 26 twenty one twenty two 28 Core residue [-] (-) (-) (-) (-) (-) (-) Storage stability (whiteness change) [%] -6 -4 -3 -4 -5 -3

[table 5] Comparative example 1 Comparative example 2 Cellulose composition M N Manufacturing conditions Wet floc X X Solid content of flocculation dispersion [quality%] 10 10 Glucose addition [g] 0 2.31 Sorbitol added amount [g] 0 0 composition The content of water soluble matter in 5 g of cellulose composition [mg] 2.4 6.1 Glucose content in 5 g of cellulose composition [mg] 0.4 4.1 Sorbitol content in 5 g of cellulose composition [mg] 0.2 0.2 Cellulose content in 5 g of cellulose composition [mg] 0.7 0.7 Monosaccharide (glucose, sorbitol) content in 5 g of cellulose composition [mg] 0.6 4.3 Physical properties Water absorption speed [g ² /s] 2.3 6.2 The average particle size [μm] 51 62 Loose apparent density [g/mL] 0.24 0.30 Compact apparent density [g/mL] 0.40 0.48 Compression ratio [-] 40 37 L/D [-] 2.2 2.3 Evaluation Suppression during the production of oral disintegrating tablets [kN] 7.5 8.0 Disintegration time in the mouth [s] 34 twenty one Core residue [-] (+) (-) Storage stability (whiteness change) [%] -3 -12

[Table 6] Comparative example 3 Cellulose mixture O Evaluation Suppression during the production of oral disintegrating tablets [kN] 7.5 Disintegration time in the mouth [s] 33 Core residue [-] (+) Storage stability (whiteness change) [%] -8

According to Tables 3 to 4, when the content of glucose and sorbitol in 5 g of cellulose composition is 0.7 mg or more and 4.0 mg or less, cellulose compositions A to L (Examples 1 to 12) are prepared into OD tablets. It has good disintegration and storage stability when it is made into tablets. In the cellulose compositions A to L (Examples 1 to 12), the tendency was found that as the content of glucose or sorbitol increased, the oral disintegration time became shorter. In addition, the tendency was found that as the content of glucose or sorbitol in 5 g of the cellulose composition decreases, the storage stability is further improved. Furthermore, in the tablet using the cellulose composition A, the whiteness change was -9%, but the color change could not be confirmed visually.

On the other hand, in the cellulose composition M in which the content of glucose and sorbitol in the cellulose composition is less than 0.7 mg (Comparative Example 1), the storage stability is good, but the oral disintegration time is as long as 34 seconds , And found that the core remains. In addition, in the cellulose composition N (Comparative Example 2) with a glucose content of more than 4.0 mg in the cellulose composition, the disintegration time in the mouth was 21 seconds, and no core residue was found, but the whiteness change was as high as -12 %. Compared with before storage, the color change after storage can be confirmed visually, and the storage stability is poor. Furthermore, in the cellulose composition M, glucose was added to the cellulose composition A (Example 1) in an equivalent amount, and the storage stability was good, but the oral cavity disintegration time It took up to 33 seconds, and core residue was found. [Industrial availability]

According to the cellulose powder of this embodiment, it is possible to provide a cellulose composition which can obtain a tablet having good disintegration properties as an orally disintegrating tablet and excellent storage stability. The tablet and the orally disintegrating tablet of this embodiment comprise the above-mentioned cellulose composition, and the disintegration property as an orally disintegrating tablet is good, and it is excellent in storage stability.

Claims (8)

A cellulose composition containing cellulose, glucose, and sorbitol, and The total content of glucose and sorbitol per 5 g of the cellulose composition is 0.7 mg or more and 4.0 mg or less. The cellulose composition of claim 1, wherein the content of water-soluble matter per 5 g of the cellulose composition is 2.5 mg or more and 12.5 mg or less. The cellulose composition of claim 1 or 2, wherein the content of glucose per 5 g of the cellulose composition is 0.3 mg or more and 4.0 mg or less. The cellulose composition according to any one of claims 1 to 3, wherein the content of sorbitol per 5 g of the cellulose composition is 0.2 mg or more and 4.0 mg or less. The cellulose composition according to any one of claims 1 to 4, 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 any one of claims 1 to 5 has a water absorption speed of 2.0 g ² /s or more and 9.0 g ² /s or less. A lozenge comprising the cellulose composition according to any one of claims 1 to 6. An orally disintegrating tablet comprising the cellulose composition according to any one of claims 1 to 6.