RU2796502C1 - Cellulose-containing composition, tablet and tablet with intraoral disintegration - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: provided is a cellulose-based composition containing cellulose, glucose and sorbitol, the total content of glucose and sorbitol in which is from 0.7 mg or more to 4.0 mg or less per 5 g of the said cellulose-based composition, and a pharmaceutical composition in the form of a tablet or tablets with intraoral disintegration based on it.

EFFECT: obtaining cellulose-containing composition, tablet and tablet with intraoral disintegration.

8 cl, 6 tbl, 12 ex

Description

FIELD OF TECHNOLOGY

[0001] The present invention relates to a cellulose-containing composition, tablet, and tablet with intraoral disintegration.

BACKGROUND OF THE INVENTION

[0002] Traditionally, in the fields of pharmaceuticals, dietary foods, food and other chemical industries, it is widely known that cellulose powder is used as a filler to obtain a compressed product, such as a tablet or the like, which contains an active ingredient. In particular, tablets with intraoral disintegration, which can be taken without water, have recently become the main type of tablets and are a dosage form that has been largely developed in the field of pharmaceuticals. In recent years, although tablets with intraoral disintegration have also been produced using the same production method as conventional tablets, which is not a special production method, the production method is initially based on a technology created by using the full mixing ratio various additives and excipients to obtain an appropriate tablet hardness and satisfactory disintegration properties, as well as an oral feel. Medicines based on this technology are becoming important value-added medicines not only for improving the quality of life (QQL) of patients, but also for product life cycle management (PLCM). In addition, in a rapidly aging society, an orally disintegrating tablet that quickly disintegrates with saliva or a small amount of water contributes greatly to improving adherence and adherence to the treatment regimen, such as convenience and ease of administration to patients in medical institutions, in the form of a medicinal product. a form that even patients with poor swallowing ability, such as the elderly and children, can easily take. However, the history of tablets with intraoral disintegration is short, and there are also technical problems such as disintegration time and mouthfeel upon administration, as well as providing tablet hardness that does not crack or abrade during manufacture or distribution.

[0003] Patent Document 1 describes a cellulose powder having an average polymerization degree of 100 or more to 350 or less, a weight average particle size of more than 30 µm to 250 µm or less, an apparent specific volume of 2 cm ³ /g or more to less 15 cm ³ /g and the sharpness of the particle size distribution from 1.5 or more to 2.9 or less. It is described that the use of this cellulose powder has the effect of improving compression molding (compressibility), holding sticky and hygroscopic Chinese herbal medicines and viscous components evenly, sharpening the granule particle size distribution by sharpening the cellulose powder particle size distribution, shortening disintegration time, and imparting stable disintegration properties over time.

However, Patent Document 1 is based on the assumption that pure cellulose powder is used, and it is possible to improve the cellulose-containing composition in terms of disintegration properties and storage stability required for an oral disintegration tablet.

PRIOR ART LITERATURE

patent document

[0004] Patent Document 1: International Patent Application Publication No. 2013/180248

SUMMARY OF THE PRESENT INVENTION

Problems solved by the present invention

[0005] The present invention has been made in view of the foregoing and provides a cellulose-containing composition from which it is possible to obtain a tablet having excellent storage stability while maintaining suitable disintegration properties as an intraoral disintegrating tablet, a tablet, and an intraoral disintegrating tablet containing the aforementioned cellulose-based composition.

Way to solve problems

[0006] i.e. the present invention includes the following aspects.

(1) A cellulose-based composition containing cellulose, glucose and sorbitol, in which the total content of glucose and sorbitol is 0.7 mg or more to 4.0 mg or less per 5 g of the above-mentioned cellulose-based composition.

(2) The cellulose-based composition according to (1), the water-soluble substance content of which is 2.5 mg or more to 12.5 mg or less per 5 g of the above-mentioned cellulose-based composition.

(3) The cellulose-based composition according to (1) or (2), the glucose content of which is 0.3 mg or more to 4.0 mg or less per 5 g of the above-mentioned cellulose-based composition.

(4) The cellulose-based composition according to any of (1) to (3), the sorbitol content of which is 0.2 mg or more to 4.0 mg or less per 5 g of the above-mentioned cellulose-based composition.

(5) The cellulose-based composition according to any of (1) to (4), which is a powder, and in which the average particle size of the powder is 10 µm or more to 200 µm or less.

(6) The cellulose-based composition according to any of (1) to (5), the water absorption rate of which is 2.0 g ² /s or more to 9.0 g ² /s or less.

(7) A tablet containing a cellulose-based composition according to any one of (1) to (6).

(8) An orally disintegrating tablet containing a cellulose-based composition according to any one of (1) to (6).

Effects of the present invention

[0007] According to the cellulose-based composition according to the above aspect, it is possible to provide a cellulose-based composition from which a tablet having excellent storage stability can be obtained while maintaining suitable disintegration properties as an intraoral disintegrating tablet. The tablet and the oral tablet according to the above aspect contain the above-mentioned cellulose composition, exhibit suitable disintegration properties as an oral tablet, and have excellent storage stability.

EMBODIMENTS OF THE PRESENT INVENTION

[0008] An embodiment of the present invention (hereinafter, simply referred to as “the present embodiment”) will be described in detail. It should be noted that the present invention is not limited to the following embodiments, and can be modified and implemented in various ways within its spirit.

[0009] < Cellulose-based composition >

The cellulose-based composition according to the present embodiment contains cellulose, glucose and sorbitol. The total content of monosaccharides, i.e. glucose and sorbitol, per 5 g of the above cellulose-based composition is 0.7 mg or more to 4.0 mg or less, preferably 1.0 mg or more to 3.5 mg or less, and more preferably 2, 0 mg or more to 3.0 mg or less.

When the content of monosaccharides per 5 g of the cellulose-based composition is in the above range, it is possible to improve the disintegration properties when molded into a tablet with intraoral disintegration. In addition, storage stability can be improved by molding into a tablet. It should be noted that when the cellulose-based composition is a powder, it is desirable that one particle contains cellulose, glucose and sorbitol.

[0010] Traditionally, in terms of quality assurance, pharmaceutical additives or food additives are required to be of high purity, and conventional cellulose powders used as pharmaceutical additives are pure cellulose with extremely high purity. On the other hand, the cellulose-based composition according to the present embodiment may contain a water-soluble substance, which is usually excluded as an impurity, within a predetermined range. This water-soluble substance is mainly composed of monosaccharides such as glucose and sorbitol and cellooligosaccharides such as cellobiose, cellotriose, cellotetraose, cellopentaose, cellohexaose and celloheptaose. By containing glucose and sorbitol as monosaccharides, among these components, within predetermined ranges, it is possible to effectively suppress the occurrence of a residual core (core residue) when molded into a tablet with intraoral disintegration and improve disintegration properties.

[0011] In the cellulose-based composition according to the present embodiment, the content of water-soluble substance per 5 g of the cellulose-based composition is preferably 2.5 mg or more to 12.5 mg or less, more preferably 3.0 mg or more up to 12.0 mg or less, even more preferably 3.5 mg or more to 11.5 mg or less, and particularly preferably 4.0 mg or more to 11.0 mg or less.

When the water-soluble substance in the cellulose-based composition is in the above range, it is possible to suppress the occurrence of a residual core when molded into a tablet with intraoral disintegration, and the disintegration properties can be improved.

[0012] In the cellulose-based composition according to the present embodiment, the glucose content per 5 g of the cellulose-based composition is preferably 0.3 mg or more to 4.0 mg or less, more preferably 0.5 mg or more to 3.5 mg or less, and even more preferably 1.0 mg or more to 3.0 mg or less.

When the glucose content of the cellulose-based composition is in the above range, it is possible to suppress the occurrence of a residual core when molded into an oral disintegration tablet, and the disintegration properties can be improved. In addition, the reaction between the active ingredient and the glucose contained in the tablet can be suppressed, and as a result, the storage stability when molded into a tablet can be improved.

[0013] In the cellulose-based composition according to the present embodiment, the content of sorbitol per 5 g of the cellulose-based composition is preferably 0.2 mg or more to 4.0 mg or less, more preferably 0.3 mg or more to 3.5 mg or less, even more preferably 0.5 mg or more to 3.5 mg or less, and particularly preferably 1.0 mg or more to 3.0 mg or less.

When the content of sorbitol in the cellulose-based composition is in the above range, it is possible to suppress the occurrence of a residual core when molded into an intraoral disintegration tablet, and the disintegration properties can be improved. In addition, the reaction between the active ingredient and the sorbitol contained in the tablet can be suppressed, and as a result, the storage stability can be improved when molded into a tablet.

[0014] Both glucose and sorbitol are monosaccharides having similar properties, but sorbitol is generally superior in terms of disintegration and storage stability as in the case of an oral disintegrating tablet. Therefore, a higher content of sorbitol than glucose is preferred.

[0015] The content of glucose and sorbitol in the composition based on cellulose is measured using liquid chromatography/mass spectrometry (LC/MS), as demonstrated in the examples below. It should be noted that if other components are present, the peaks of which overlap freely with the peaks related to glucose and sorbitol, the liquid chromatography conditions are first properly adjusted to check the possibility of separation of the peaks. If separation of the peaks is not possible, the area of the peaks generated by glucose and sorbitol can be determined using an extraction ion chromatogram from the ion current of the main peak, related to glucose and sorbitol, in the framework of mass spectrometry.

[0016] The content of glucose and sorbitol in the cellulose-based composition can also be controlled, for example, by adding an appropriate amount of at least one substance selected from glucose and sorbitol, during the production of the cellulose-based composition. There is a possibility that the content of glucose and sorbitol can be adjusted depending on the choice of raw materials for the cellulose-based composition and production conditions, but in order to control their content in the desired ranges, the method of adding the appropriate amount during the production process is simple and preferable.

[0017] The cellulose-based composition according to the present embodiment preferably has a water absorption rate of 2.0 g ² /s or more to 9.0 g ² /s or less, more preferably 2.2 g ² /s or more up to 8.2 g ² /s or less, even more preferably from 3.0 g ² /s or more to 8.0 g ² /s or less, particularly preferably from 3.4 g ² /s or more to 7, 4 g ² /s or less, and most preferably 3.4 g ² /s or more to 7.2 g ² /s or less.

When the water absorption rate is in the above range, the occurrence of the residual core can be suppressed more effectively when molded into a tablet with intraoral disintegration, and the disintegration property can be further improved.

[0018] It should be noted that the water absorption rate can be measured using a Peneto analyzer (model: PNT-N, manufactured by Hosokawa Micron Corporation), as demonstrated in the following examples.

[0019] < Form of cellulose-based composition >

The cellulose-based composition in the present embodiment is preferably in any form of powder, granules, paste or wet cake. From a handling standpoint, cellulose powder is preferred. Cellulose powder is commonly referred to as crystalline cellulose, powdered cellulose, or the like, and is suitably used as a pharmaceutical or food additive. As the cellulose powder, crystalline cellulose is preferred. As crystalline cellulose, for example, microcrystalline cellulose as defined by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), microcrystalline cellulose as described in the 8th edition of the Specifications and Standards for Food Additives of Japan (issued by the Ministry of Health, Labor and Welfare , Japan), crystalline cellulose as described in the 17th Revised Japanese Pharmacopoeia, and crystalline cellulose as described in the USP, European Pharmacopoeia, and the like.

It should be noted that from the viewpoint of improving the balance between formability, flowability and disintegration, the average degree of polymerization of cellulose in the cellulose-based composition is preferably 400 or less, and more preferably 350 or less. The lower limit value of the average degree of polymerization is preferably 100 or more. The average degree of polymerization of cellulose can be determined by the viscosity determination method using the ethylenediamine-copper complex solution described in the identification test (3) of crystalline cellulose or the identification test (3) of powdered cellulose in the Japanese Pharmacopoeia.

[0020] < Preferred cellulose powder form >

When the cellulose-based composition according to the present embodiment is a powder, the average particle size of the powder is preferably 10 µm or more to 200 µm or less, more preferably 15 µm or more to 90 µm or less, even more preferably 20 µm or more to 80 µm or less, particularly preferably 30 µm or more to 70 µm or less, and most preferably 40 µm or more to 60 µm or less.

When the average particle size is equal to or smaller than the above upper limit value, it is easy to mix uniformly with an active ingredient such as a drug, and the disintegration properties are improved when molded into a tablet with intraoral disintegration. On the other hand, when the average particle size is equal to or exceeds the above lower limit value, handling convenience is increased.

[0021] It should be noted that the average particle size of the cellulose powder is the particle size in the total volume=50% measured by a laser diffraction type particle size distribution meter (model: LA-950 V2 (product name) manufactured by Horiba Ltd. ).

[0022] When the cellulose-based composition according to the present embodiment is a powder, the bulk density is preferably 0.10 g/ml or more to 0.35 g/ml or less, more preferably 0.11 g/ml or more to 0.30 g/ml or less, and even more preferably 0.13 g/ml or more to 0.28 g/ml or less.

When the bulk density is equal to or greater than the above lower limit value, the compressibility can be further increased. On the other hand, when the bulk density is equal to or less than the above upper limit value, the loading capacity is further increased.

Bulk density can be measured using the method described in the examples below.

[0023] When the cellulose-based composition according to the present embodiment is a powder, the compaction bulk density is preferably 0.27 g/ml or more to 0.50 g/ml or less, more preferably 0.28 g /ml or more to 0.48 g/ml or less, and still more preferably 0.28 g/ml or more to 0.44 g/ml or less.

When the bulk density at compaction is equal to or exceeds the above lower limit value, it is easy to uniformly mix with an active ingredient such as a drug, and handling convenience is further enhanced. On the other hand, when the packing bulk density is equal to or less than the above upper limit value, the occurrence of segregation due to the difference in density with particles of the active ingredient or other additives can be suppressed more effectively.

Compaction bulk density can be measured using the method described in the examples below.

[0024] In addition, when the bulk density in a free flowing state and the bulk density when compacted simultaneously correspond to the above ranges, tablets obtained by compression molding, as a rule, exhibit excellent compressibility and disintegration properties.

[0025] When the cellulose-based composition according to the present embodiment is a powder, the compression ratio is preferably 22% or more to 58% or less, more preferably 30% or more to 55% or less, and even more preferably 35% or more to 50% or less.

When the compression ratio is in the above range, the fluidity of the cellulose powder itself is further increased, and the occurrence of segregation can be suppressed more effectively.

The compression ratio can be calculated using the method described in the examples below.

[0026] When the cellulose-based composition according to the present embodiment is a powder, the ratio of the major axis to the minor axis of the cellulose particles, i. e. aspect ratio (L/D), preferably 1.6 or more to 3.8 or less, more preferably 2.0 or more to 3.6 or less, and even more preferably 2.3 or more to 3 .3 or less.

When the aspect ratio is in the above range, the miscibility with the active ingredient is also improved, the engagement between elongated particles is appropriate, and the balance between compressibility and disintegration is excellent.

The characteristic ratio (L/D) can be determined in the manner described in the examples below.

[0027] < Method for producing a cellulose-based composition >

An example of a method for producing a cellulose-based composition according to the present embodiment will be described below. However, the cellulose-based composition according to the present embodiment is not limited to compositions obtained by the following production method.

The cellulose-based composition according to the present embodiment can be obtained, for example, by a method comprising a step of dispersing a hydrolyzed natural cellulose-based substance in a suitable medium to obtain an aqueous cellulose dispersion, and a step of drying the aqueous dispersion. The solids concentration in the aqueous cellulose dispersion is not particularly limited, and may be, for example, 1% by weight or more to 30% by weight or less. In this case, it is also possible to separate the solid containing the hydrolyzed cellulose-based substance from the hydrolysis reaction solution obtained by the hydrolysis, and dry the dispersion prepared by separately dispersing the solid in an appropriate medium. In addition, glucose or sorbitol can be added to and mixed with the cellulose dispersion so that the content of glucose and sorbitol in the cellulose-based composition is within predetermined ranges, followed by drying. In addition, when the above hydrolysis solution forms a cellulose dispersion as such, this dispersion can also be directly dried.

[0028] The natural cellulose-based material may be of plant or animal origin and is, for example, a fibrous material derived from a natural cellulose-containing product such as wood, bamboo, cotton, ramie, sea squirt, bagasse, kenaf, and bacterial cellulose, and preferably has the crystalline structure of cellulose I. One of the aforementioned natural cellulose-based substances or a mixture of two or more types thereof can be used as raw material. In addition, it is preferably used in the form of pulp refining, but the pulp refining method is not particularly limited, and any of dissolving pulp, kraft pulp, bleached softwood kraft pulp (NBKP), and the like can be used.

[0029] In the above production method, water is preferable as the medium used when the solid content containing the natural cellulose substance is dispersed in a suitable medium, but there is no particular limitation as long as it is used in industry, and, for example, can be used organic solvent. Examples of the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane and cyclohexane; and ketones such as acetone and ethyl methyl ketone. In particular, the organic solvent is preferably a solvent used in pharmaceutical products, and examples thereof include solvents that are classified as solvents in the Japanese Pharmaceutical Excipients Directory 2016 (published by Yakuji Nippo, Ltd.). Any medium selected from water and organic solvents may be used alone, two or more types thereof may be used in combination, or the solid content may be dispersed once in one medium and then dispersed in another medium after removal of the original medium.

[0030] For example, cellulose fibers having an average width of 2 µm or more to 30 µm or less and an average thickness of 0.5 µm or more to 5 µm or less are subjected to hydrolysis under pressure stirring at a temperature of 70°C or higher to 140°C or lower in hydrochloric acid with a concentration of 0.01% w/w or more to 1.0% w/w or less. The extent of hydrolysis can be controlled by adjusting the motor power (P: unit W) and the stirring volume (L: unit L) of the agitator. For example, by adjusting the P/V ratio represented by the following formula, the average size of the eventually obtained cellulose particles can be adjusted to 200 µm or less.

[0031] P/V (W/L)=[Agitator Actual Motor Power (W)] / [Agitation Volume (L)].

[0032] A method for drying an aqueous dispersion of cellulose to obtain a cellulose-based composition is not particularly limited. For example, any method of lyophilization, spray drying, drum drying, shelf drying, spray drying, and vacuum drying can be used, and one of these methods can be used alone, or two or more types can be used in combination. The spraying method for spray drying can be any type of disk type spraying, pressure nozzle type, two-jet pressure nozzle, four-jet pressure nozzle, and the like, and one of these methods can be used alone, or two or more types can be used in combination.

During the spray drying process described above, microscopic amounts of a water-soluble polymer and a surfactant can be added to reduce the surface tension of the dispersion liquid, and a foaming agent or gas can be added to the dispersion liquid to accelerate the evaporation rate of the medium.

[0033] By adjusting the acid concentration and agitation conditions in the preparation of aqueous cellulose dispersion, an aqueous cellulose dispersion containing dispersed cellulose particles having a certain average particle size can be obtained, and furthermore, the average particle size and compression ratio of the obtained cellulose-based composition can be controlled by adjusting the solids concentration and the drying conditions of the aqueous cellulose dispersion when drying the aqueous cellulose dispersion. For example, when the aqueous dispersion of cellulose is dried using a disc-type spray dryer, by setting the stirring power in a predetermined range when preparing an aqueous pulp dispersion, and setting the conditions: the solids concentration in the aqueous cellulose dispersion and the rotation number of the disc-type spray dryer within the predetermined ranges during spray drying, it is possible to obtain a composition based on cellulose, having an average particle size and a degree of compression in the given ranges.

[0034] In addition, as described in the examples below, a cellulose-based composition in which the contents of glucose and sorbitol in the cellulose-based composition are within predetermined ranges can be obtained by adding and mixing glucose and sorbitol with an aqueous dispersion of cellulose and drying the resulting mixture as needed.

[0035] When the cellulose-based composition is dried and powdered, even if the average particle size exceeds 200 µm, the average particle size can be adjusted to 10 µm or more - 200 µm or less by subjecting the composition to the described pulverization step described later.

[0036] The pulverizing step can be carried out by grinding the dried cellulose-based composition in a crusher such as ultra centrifugal mill (ZM-200, manufactured by Retsch GmbH), jet mill (STJ-200, manufactured by Seishin Enterprise Co., Ltd.) , hammer mill (H-12, manufactured by Hosokawa Micron Corporation), small size mill (AP-B, manufactured by Hosokawa Micron Corporation), pin mill (160Z, manufactured by Powrex Corporation), cycling mill (FM, manufactured by Hosokawa Micron Corporation ), hammer mill (HM-600, manufactured by Nara Machinery Co., Ltd.), very short time mill (FL-250N, manufactured by Dalton Corporation), ball mill (Emax, manufactured by Retsch GmbH), vibrating ball mill ( 2C, manufactured by TRU) and a sieve mill (U30, manufactured by Powrex Corporation). In particular, a jet mill type crusher (STJ-200, manufactured by Seishin Enterprise Co., Ltd.) is preferable because it is an in-line type crusher that crushes particles by colliding with each other under high air pressure, and the secondary particles easily disintegrate into primary particles.

[0037] As for the pulverizing conditions in the jet mill crusher, the feeding amount of powder and the pulverizing pressure are important, and when the jet mill crusher (STJ-200, manufactured by Seishin Enterprise Co., Ltd.) is used, the feeding amount is preferable. is 10 kg/hour or more to 20 kg/hour or less, and more preferably 15 kg/hour or more to 20 kg/hour or less. Further, the pulverizing pressure is preferably 0.15 MPa or more to 0.70 MPa or less, and more preferably 0.30 MPa or more to 0.50 MPa or less. When the feeding amount of the powder and the pulverization pressure are in the above ranges, the average particle size is generally easily controlled from 10 µm or more to 200 µm or less.

Even when the average particle size of the cellulose powder after drying is less than 100 µm, the average particle size of the cellulose powder can be adjusted to a desired range of about 100 µm or more to 200 µm or less using a granulation method such as agitated granulation and fluid bed granulation. .

[0038] < Intended Use >

By mixing the cellulose-based composition according to the present embodiment with the composition containing the active ingredient, a tablet having excellent storage stability can be obtained while maintaining suitable disintegration properties. As shown in the following examples, the cellulose-based composition according to the present embodiment has excellent disintegration properties when molded into an orally disintegrating tablet, and therefore is suitably used as an excipient for an orally disintegrating tablet.

Hereinafter, a tableting composition that contains one or more active ingredients and a cellulose-based composition according to the present embodiment is referred to as a "composition according to the present embodiment".

[0039] Although the blending ratio of the above cellulose-based composition to the composition according to the present embodiment can be any, the preferred range in practice is 90% by weight or less relative to the total weight of the tablet. The lower limit value is in practice 0.1% by weight. When used in tablets containing a large amount of the active ingredient, it can be set at an approximate level of 0.1% by weight or more to 50% by weight or less.

[0040] Examples of suitable active ingredients contained in the composition in accordance with the present embodiment are given below.

As a drug ingredient of a pharmaceutical product, an active ingredient of a pharmaceutical product for oral administration is preferable. Examples of a pharmaceutical product for oral administration include antipyretics, analgesics, anti-inflammatory agents, sedative-hypnotics, anti-drowsiness agents, anti-vertigo agents, analgesics for children, gastric agents, antacids, digestive agents, cardiotonic agents, antiarrhythmic agents, metabolic depressants. agents, vasodilators, diuretics, anti-ulcer agents, intestinal agents, osteoporosis agents, antitussive expectorants, anti-asthma agents, antimicrobials, pollakiuria-improving agents, analeptics and vitamin tablets. One of these medicinal ingredients may be used alone, or two or more types may be used in combination.

[0041] Their specific examples include medicinal ingredients of pharmaceutical products listed in the Japanese Pharmacopoeia, the Japanese Pharmaceutical Code (JPC), the United States Pharmacopoeia (USP), the National Formulary (NF) and the European Pharmacopoeia (EP) such as aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, isotypendyl hydrochloride, diphenylpyralin hydrochloride, diphenhydramine hydrochloride, diferol hydrochloride, triprolidine hydrochloride, tripeleenamine hydrochloride, tonsylamine hydrochloride, phenetazine hydrochloride, methdylazine hydrochloride, diphenhydramine sali cylate, carbinoxamine diphenyl disulfonate, alimemazine tartrate, diphenhydramine tannate, diphenyl pyraline theocrat, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, diferol phosphate, alloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate (carbet apentane citrate), tipepidine citrate, sodium dibunate, dextromethorphan hydrobromide, dextromethorphan-phenolphthalic acid, tipepidine gibenzat, cloperastine fendisoate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guaiacolsulfonate, guaifenesin, sodium caffeine benzoate, caffeine, caffeine anhydrous, vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts, vitamin B6 and its derivatives and their salts, nicotinamide, pantothenate calcium, aminoacetate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel (as dry aluminum hydroxide gel), aluminum hydroxide as dry gel, aluminum hydroxide/magnesium carbonate mixture in dry gel, aluminum hydroxide/sodium bicarbonate coprecipitation, aluminum hydroxide/calcium carbonate/magnesium carbonate coprecipitation, magnesium hydroxide/aluminum potassium sulfate coprecipitation, magnesium carbonate, magnesium aluminometasilicate, ranitidine hydrochloride, cimetidine, famotidine, naproxen, diclofenac sodium , Piroxicam, Azulene, Indomethacin, Ketoprofen, Ibuprofen, Diphenidole Hydrochloride, Diphenylpyralin Hydrochloride, Diphenhydramine Hydrochloride, Promethazine Hydrochloride, Meclizine Hydrochloride, Dimenhydrinate, Diphenhydramine Tannate, Phenetazine Tannate, Diphenylpyralin Theocrat, Diphenhydramine Fumarate, Promethazine Methylene Disalicylate, Scopol mina hydrobromide, oxyphencyclimine hydrochloride, dicycloverine hydrochloride, methixene hydrochloride, methylatropine bromide, methylanisotropine bromide, methylscopolamine bromide, methyl-1-hyoscyamine bromide, methylbenactidium bromide, belladonna extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, papaverine hydrochloride, aminobenzoic acid, cesium oxalate, ethylpiperi diacetylaminobenzoate, aminophylline, diprophylline, theophylline, sodium bicarbonate, fursulthiamine, isosorbide nitrate, ephedrine, cephalexin, ampicillin, sulfisoxazole, sucralfate, allylisopropylacetyl urea, bromovaleryl urea or the like, ephedra, nandine berries, cherry tree bark, istod root, licorice, large-flowered bellflower, psyllium seeds, senega, bulb hazel grouse, fennel, cork tree bark, coptis rhizome, turmeric rhizome, chamomile, cinnamon, gentian, oriental bezoar, beast bile (including bear bile), bells, ginger, Atractylodes lancea rhizome, cloves, satsuma peel, atractylodes rhizome, rain worm, ginseng rhizome, ginseng, valerian, peony root bark, zantoxylum (Japanese pepper) peel and extracts from it; insulin, vasopressin, interferon, urokinase, serratiopeptidase, somatostatin, etc. One of these medicinal ingredients, selected from the list above, may be used alone, or two or more types may be used in combination.

[0042] The dietary food active ingredient is not limited as long as it is a health-mixing component, and examples thereof include green juice powder, aglycone, mushroom, ashwagandha, astaxanthin, acerola, amino acids (valine , leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid, seaweed powder, glutamine, glutamic acid, glycine, proline, serine, etc.), alginic acid, ginkgo biloba extract, sardine peptides, turmeric, uronic acid, echinacea, eleutherococcus, oligosaccharides, oleic acid, nucleoproteins, skipjack tuna dry peptides, catechin, potassium, calcium, carotenoid, garcinia cambogia, L-carnitine, chitosan, conjugated linoleic acid , aloe vera, Gymnema sylvestre extract, citric acid, Orthosiphon stamineus, glycerides, glycerin, glucagon, curcumin, glucosamine, L-glutamine, chlorella, cranberry extract, Uncaria tomentosa, germanium, enzymes, Korean ginseng extract, coenzyme Q10, collagen, collagen peptides, coleus bloom, chondroitin, powdered psyllium husk, hawthorn fruit extract, saponin, lipids, L-cystine, Japanese basil extract, citrimax, fatty acids, phytosterol, seed extract, spirulina, squalene, Salix alba, ceramide, selenium, John's wort extract, soy isoflavone, soy saponin, soy peptides, soy lecithin, monosaccharides, proteins, vitex extract, iron, copper, docosahexaenoic acid, tocotrienol, nattokinase, Bacillus natto culture extract, sodium niacin, nicotinic acid, disaccharides, lactic acid bacteria, garlic , saw palmetto, sprouted rice, pearl barley 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, bifidobacteria, brewer's yeast, fructooligosaccharides, flavonoid, butcher's broom extract, cimicifugu, blueberry, plum concentrate, proanthocyanidin, proteins, propolis, bromelain, probiotics, phosphatidylcholine, phosphatidylserine, β-carotene, peptides, safflower extract, Grifola frondosa extract, maca extract, magnesium, milk thistle, manganese, mitochondria, minerals, mucopolysaccharides, melatonin, Fomes yucatensis, sweet clover extract powder, molybdenum, vegetable powder, folic acid, lactose, lycopene, linoleic acid, lipoic acid , phosphorus, lutein, lecithin, rosmarinic acid, royal jelly, DHA (docasahexaenoic acid) and EPA (eicosapentaenoic acid).

[0043] The active ingredient may be water-soluble or poorly water-soluble. The expression "poorly soluble in water" means that the amount of water required to dissolve 1 g of a substance that dissolves in another is 30 ml or more, as defined in the 17th revised Japanese Pharmacopoeia.

Examples of the solid, poorly water-soluble active ingredient include pharmaceutical product drug ingredients described in Japanese Pharmacopoeia, JPC, USP, NF, and EP, including antipyretic analgesics, drugs for the nervous system, hypnotics and sedatives, muscle relaxants, antihypertensives, antihistamines and the like, such as acetaminophen, ibuprofen, benzoic acid, ethensamide, caffeine, camphor, quinine, calcium gluconate, dimercaprol, sulfamin, theophylline, theobromine, riboflavin, mephenesin, phenobarbital, aminophylline, thioacetazone, quercetin, rutin, salicylic acid, theophylline sodium, pyrapital, quinine hydrochloride, irgapirin, digitoxin, griseofulvin, and phenacetin; antibiotics such as acetylspiramycin, ampicillin, erythromycin, kitasamycin, chloramphenicol, triacetyloleandomycin, nystatin, and colistin sulfate; steroid hormones such as methyltestosterone, methylandrostetrondiol, progesterone, estradiol benzoate, ethinylestradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, and prednisolone; nonsteroidal estrogenic hormones such as dienestrol, hexastrol, diethylstilbestrol, diethylstilbestrol dipropionate and chlortrianisene; and other fat-soluble vitamins. One of these active ingredients, selected from the list above, may be used alone, or two or more types may be used in combination. If the active ingredient is poorly soluble in water, the effects of the present invention can be achieved by mixing it as an active ingredient with the composition according to the present embodiment, regardless of the degree of sublimation and the polarity of the surface.

[0044] The active ingredient may be a poorly water-soluble oil or liquid. Examples of the poorly water-soluble oily or liquid active ingredient include drug ingredients of pharmaceutical products described in Japanese Pharmacopoeia, JPC, USP, NF or EP, including vitamins such as teprenone, indomethacin. farnesil, menatetrenone, phytonadione, vitamin A oil, phenipentol, vitamin D and vitamin E; higher unsaturated fatty acids such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and cod liver oil; group of coenzymes Q; and oil soluble flavorings such as orange oil, lemon oil and peppermint oil. Although there are various homologues and derivatives of vitamin E, there is no particular limitation as long as they are in liquid form at room temperature. Examples thereof include dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol and d-α-tocopherol acetate. One of these, selected from the list above, may be used alone, or two or more types may be used in combination.

[0045] The active ingredient may be a semi-solid active ingredient, poorly soluble in water. Examples of the semi-solid active ingredient poorly soluble in water include Chinese medicinal herbs or crude medicinal extracts such as earthworm, licorice, Chinese cinnamon bark, peony root, peony root bark, Japanese valerian, zantoxylum fruit, ginger, satsuma peel, ephedra herb , nandina berries, yellow bark, istod root, platycodon root, psyllium seeds, psyllium herb, lycoris with short tubular petals, senega root, fritillaria bulb, fennel, phellodendron bark, coptis rhizome, zedoaria, chamomile officinalis, gentian, oriental bezoar, bile beast, bell root, ginger, Atractylodes lancea rhizome, clove, satsuma peel, atractylodes rhizome, panax rhizome, ginseng, kakkonto, keihito, kusosan, saiko-keishito, sesaikoto, shoseiryuto, bakumondoto, hangekobokuto, and maoto; oyster meat extract, propolis or an extract thereof, and coenzyme group Q. One of these active ingredients, selected from the above list, may be used alone, or two or more types thereof may be used in combination.

[0046] The active ingredient may be a sublimable active ingredient. Examples of the freeze-dried active ingredient include freeze-dried drug ingredients of pharmaceutical products described in the Japanese Pharmacopoeia, JPC, USP, NF, or EP, such as benzoic acid, ethensamide, caffeine, camphor, salicylic acid, phenacetin, and ibuprofen. One of these active ingredients, selected from the above list, may be used alone, or two or more types may be used in combination. It should be noted that the sublimable active ingredient mentioned in the present specification is not particularly limited as long as it has the ability to sublimate, and may be in any state of solid, liquid or semi-solid at room temperature.

[0047] In addition, as an active ingredient, a drug ingredient having a small maximum dosage size per tablet can also be preferably used.

Examples of drug ingredients having a small maximum dosage size per tablet include the following drug ingredients whose maximum dosage size per tablet is 100 mg or less or 10 mg or less.

[0048] Examples of medicinal ingredients, the maximum dosage of which is more than 100 mg per tablet, include abacavir, acetazolamide, acetylsalicylic acid, acyclovir, albendazole, aliskirene fumarat, allopurinol, amiodarone, amoxicillin, apprapant, artemeter, artesis, arteter, arteseter Nat, Atazanavir, Calcium , capecitabine, carbamazepine, carbidopa, cephalexin, cefixime, celecoxib, chloroquine, ciprofloxacin, clarithromycin, potassium clavulanate, clopidogrel, clozapine, cycloserine, darunavir, darunavir ethanolate, dasabuvir, dasatinib, deferasirox, dihydroartemisinin piperaquine phosphate, diloxan id, efarirenz, emtricitabine, erlotinib hydrochloride, ethambutol, ethionamide, famciclovir, gefitinib, griseofulvin, hydroxycarbamide, hydroxychloroquine, ibuprofen, imatinib, irbesartan, isoniazid, lamivudine, lamotrigine, lanthanum carbonate hydrate, ledipasvir, levamisole, levetiracetam, levodopa, levofloxacin, linezolid, lithium carbonate, lopinavir, lumefantrine , mebendazole, mefloquine, mesnu, metformin, methyldopa, metronidazole, morphine, moxifloxacin, nevirapine, niclosamide, nifurtimox, ombitasvir, p-aminosalicylic acid, paracetamol, paritaprevir, penicillamine, pentamidine, phenoxymethylpenicillin, pirfenidone, praziquantel, pyrantel, pira zinamide, pyronaridine tetraphosphate , quinine, raltegravir, ranitidine, ribavirin, rifampicin, rifapentine, sevelamer hydrochloride, sofosbuvir, sorafenib tosylate, sulfadiazine, sulfamethoxazole, sulfasalazine, tenofovir, tenofovir disoproxil fumarate, triclabendazole, trimethoprim, valganciclovir, valproic acid , velpatasvir, sodium valproate, voriconazole and zidovudine.

[0049] Examples of drug ingredients whose maximum dosage size is more than 10 mg to 100 mg or less per tablet include aripiprazole, artesunate, ascorbic acid, azathioprine, bazedoxifene acetate, bicalutamide, calcium folinate hydrate, clomiphene, cyclizine, cyclophosphamide, hydrate dasatinib, delamanide, dolutegravir, eletriptan hydrobromide, febuxostat, fluoxetine, furosemide, galantamine hydrobromide, hydralazine, hydrochlorothiazide, hydrocortisone, memantine hydrochloride, mercaptopurine, midazolam, miltefosine, minodronic acid hydrate, mirtazapine, neostigmine, nicotinamide, olmesartan honey oxomil, omeprazole, ondansetron, pancrelipase, potassium iodide, prednisolone, primaquine, pyrimethamine, propranolol, propylthiouracil, pyridoxine, simvastatin, sitafloxacin hydrate, spironolactone, tadalafil, tamoxifen, thiamine, thioguanine, tolvaptan, ulipristal, vardenafil hydrochloride hydrate, zinc sulfate, acotiamid hydro hydrate chloride, amitriptyline, bedaquiline , benznidazole, bosentan hydrate, chlorpromazine, cinacalcet hydrochloride, daclatasvir, dapsone, diethylcarbamazine, doxycycline, entacapone, eplerenone, ferrous sulfate hydrate, gliclazide, sodium ibandronate hydrate, losartan, miglitol, nitrofurantoin, phenobarbital, phenytoin, pyridostigmine, raloxi fena hydrochloride, ritonavir, succimer, telmisartan, topiramate and verapamil.

[0050] Examples of drug ingredients whose maximum dosage size is 10 mg or less per tablet include anastrozole, dienogest, digoxin, dutasteride, entecavir, entecavir hydrate, ethinyl estradiol, finasteride, fludrocortisone, glyceryl trinitrate, imidafenacin, levothyroxine, levonorgestrel, misoprostol, repaglinide . ambrisentan, amiloride, amlodipine, bepotastine besylate, biperiden, bisoprolol, blonanserin, chlorambucil, dexamethasone, diazepam, enalapril, ergocalciferol, escitalopram oxalate, esomeprazole magnesium hydrate, eszopiclone, ezetimibe, fludarabine, fluticasone furoate, folic acid, haloperidol, isosorbide dinitrate, ivermectin , lenalidomide hydrate, levocetirizine hydrochloride, levonorgestrel, loperamide, loratadine, medroxyprogesterone acetate, methadone, methotrexate, metoclopramide, calcium mitiglinide hydrate, montelukast sodium, norethisterone, paliperidone, phytomenadione or phytonadione, ramelteon, riboflavin, risperidone, rhys atriptan benzoate, ropinirole hydrochloride, rosuvastatin calcium, senna extract, silodosin, solifenacin succinate and warfarin.

[0051] These active ingredients and drug ingredients can be blended into the composition according to the present embodiment along with the cellulose-based composition according to the present embodiment in a finely divided state. For example, the active ingredient used in this specification may be finely divided into particles having an average particle size of 1 µm or more to 40 µm or less in order to improve the dispersibility of the active ingredient or improve the uniformity of mixing of the active ingredient having therapeutic effects in microscopic quantities. The average particle size of the active ingredient is more preferably 1 µm or more to 20 µm or less, and even more preferably 1 µm or more to 10 µm or less.

[0052] [ Other additives ]

The composition according to the present embodiment may further contain other additives besides the aforementioned active ingredient.

Examples of other additives include fillers, disintegrants, binders, fluidizers, lubricants, and flavoring agents.

[0053] Examples of excipients include those classified as excipients in "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.) such as starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetate, wheat gluten (powder), gum arabic , Powdered Gum Arabic, Alginic Acid, Sodium Alginate, Peptized Starch, Light Gravel Granules, Inositol, Ethylcellulose, Ethylene Vinyl Acetate Copolymer, Sodium Chloride, Olive Oil, Kaolin, Cocoa Butter, Casein, Fructose, Light Gravel Granules, Carmellose, Sodium Carmellose , Aqueous 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 Glycerophosphate, Sodium Gluconate, L-Glutamine, Clay , Clay 3, Clay Grain, Croscarmellose Sodium, Crospovidone, Magnesium Aluminosilicate, Calcium Silicate, Magnesium Silicate, Fluffy Anhydrous Silicic Acid, Fluid Paraffin, Cinnamon Powder, Crystalline Cellulose, Crystalline Carmellose Sodium Cellulose, Crystalline Cellulose (Grain), Malt brown rice, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, rice powder, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, oxide titanium, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-dibutyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, gypsum, sucrose fatty acid ester, magnesium alumina hydroxide, aluminum hydroxide gel, hydroxide coprecipitate Aluminum/Sodium Bicarbonate, Magnesium Hydroxide, Squalene, Stearyl Alcohol, Stearic Acid, Calcium Stearate, Polyoxyl Stearate, Magnesium Stearate, Rejected Soybean Oil, Refined Gelatin, Refined Shellac, Refined Sucrose, Purified Sucrose Spherical Granular Powder, Cetostearyl Alcohol, Polyethylene Glycol Monocetyl Ether 1000 , gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soy unsaponifiable compounds, soy lecithin, skimmed milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low grade hydroxypropyl cellulose substitution, dextran, dextrin, natural aluminum silicate, corn starch, powdered tragacanth, silicon dioxide, calcium lactate, lactose, lactose granular, Perfiller 101, white shellac, white petrolatum, white clay, sucrose, sucrose/starch spherical granulated powder, green barley leaf extract, dried barley bud and leaf juice powder, honey, paraffin, potato starch, semi-fermented starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, phytic acid, glucose, glucose hydrate, partially peptized starch, pullulan, propylene glycol, low maltose glucose syrup powder, cellulose powder, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene(105)polyoxypropylene(5)glycol, polyoxyethylene( 160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, polyethylene glycol, maltitol, maltose, D-mannitol, lozenges, isopropyl myristate, lactose anhydrous, anhydrous calcium hydrogenorthophosphate, anhydrous calcium phosphate granular, magnesium aluminometasilicate , methylcellulose, cottonseed powder, cottonseed oil, traces of paraffin, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, pharmaceutical charcoal, peanut oil, aluminum sulfate, calcium sulfate, granulated corn starch, liquid paraffin, dl-malic acid, calcium hydrogen orthophosphate, calcium hydrogen phosphate, calcium hydrogen phosphate in the form of a granular substance, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate and sodium dihydrogen phosphate. One of these fillers may be used alone, or two or more types may be used in combination.

[0054] Examples of the disintegrator include those classified as disintegrators in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.), including celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose; starches such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch and partially peptized starch; and synthetic polymers such as crospovidone and crospovidone copolymers. One of these disintegrators may be used alone, selected from the list above, or two or more types may be used in combination.

[0055] Examples of the binder include those classified as binders in "2016 Japanese Pharmaceutical Excipient Handbook" (published by Yakuji Nippo, Ltd.), including sugars such as sucrose, glucose, lactose, and fructose; sugar alcohols such as mannitol, xylitol, maltitol, erythritol and sorbitol; water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin, sodium alginate and gum arabic; celluloses such as crystalline cellulose, powdered cellulose, hydroxypropyl cellulose and methyl cellulose; starches such as peptized starch and starch paste; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymers and polyvinyl alcohols; and inorganic compounds such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminosilicate. One of these binders, selected from the list above, may be used alone, or two or more types may be used in combination.

[0056] Examples of the fluidizer include those classified as fluidizers in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.), including silicon compounds such as hydrous silica and loose anhydrous silicic acid. One of these fluidizers, selected from the above list, may be used alone, or two or more types may be used in combination.

[0057] Examples of the lubricant include those classified as lubricants in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.) such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, and talc . One of these lubricants, selected from the above list, may be used alone, or two or more types may be used in combination.

[0058] Examples of the flavoring agent include those classified as flavoring agents in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.), such as glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride and l-menthol. One of these flavors may be used, selected from the list above, or two or more types may be used in combination.

[0059] Examples of flavoring include those classified as flavorings or flavorings in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.), including orange, vanilla, strawberry, yogurt, menthol, oils such as fennel oil , cinnamon oil, orange peel oil and peppermint oil; and green tea powder. You can use one of these flavors or flavors, selected from the list above, or two or more of their types can be used in combination.

[0060] Examples of colorants include those classified as colorants in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.), including food colorings such as Food Red No. 3, Food Yellow No. 5, and Food Blue No. 1; sodium copper chlorophyllin, titanium oxide and riboflavin. One of these dyes, selected from the list above, may be used alone, or two or more types may be used in combination.

[0061] Examples of sweeteners include those classified as sweeteners in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.) such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and sweet hydrangea leaves. in powder form. One of these sweeteners, selected from the list above, may be used alone, or two or more types thereof may be used in combination.

[0062] < Method of making a tablet >

Next, a method for manufacturing a tablet by tableting a composition containing one or more active ingredients and a cellulose-based composition according to the present embodiment will be described (tablet manufacturing method according to the present embodiment), but this is just an example, and the effects of the present embodiment implementation is not limited to the following way.

[0063] As a tablet manufacturing method, a method in which an active ingredient and a cellulose-based composition according to the present embodiment are mixed and then subjected to compression molding (compression) can be used. At this time, in addition to the active ingredient, other additives can be added, if necessary. Examples of other additives include at least one selected from the aforementioned fillers, disintegrants, binders, fluidizers, lubricants, flavors, flavors, colors, sweeteners, solubilizers, and the like.

[0064] The order of adding each component is not particularly limited, and either i) a method of general mixing of the active ingredient, the cellulose-based composition according to the present embodiment, and, if necessary, other additives, followed by compression molding can be used; or ii) a method in which the active ingredient and at least one additive selected from a fluidizer and a lubricant are pre-treated and mixed, and then the cellulose-based composition according to the present embodiment and, if necessary, other additives are mixed, with subsequent compression molding. From the standpoint of operational convenience, method i) is preferred. It is also possible to add a lubricant to the powdered compression mixture obtained by method i) or ii), which is further mixed and then subjected to compression molding. The addition method of each component is not particularly limited as long as it is a widely used method, and they can be added continuously or loaded together using a small suction conveying device, an air conveying device, a bucket conveyor, a pneumatic conveyor, a vacuum conveyor, a vibratory dispenser. type, atomizer, funnel, etc. As the atomization method, either a method of atomizing the active ingredient solution/dispersed liquid thereof using a pressure nozzle, a two-jet nozzle, a four-jet nozzle, a rotating disk, an ultrasonic nozzle, etc., or a dropwise method of adding the active ingredient solution/dispersed liquid thereof can be used. from a tubular nozzle.

[0065] The mixing method is not particularly limited as long as it is a widely used method, and a rotary container mixer such as a V-type, W-type, double cone type, or container type can be used; an agitated mixer such as a high speed mixer, all-purpose mixer, belt type, pug grinder, or Nauta mixer; high speed fluid type mixer, drum type mixer or fluidized bed mixer. In addition, a shaker container mixer such as a shaker can also be used.

[0066] The method of compression molding the composition is not particularly limited as long as it is a widely used method, and may be a method of compression molding into a desired shape using a mortar and pestle, or a method of cutting into pieces of a desired shape after compression molding into a sheet forms in advance. As the compression molding machine, for example, a compressor such as a hydrostatic press, a roller type press such as a briquetting roller press or a smoothing roller type press, a single punch tableting machine, or a rotary tableting machine can be used.

[0067] The method of dissolving or dispersing the active ingredient in the medium is not particularly limited as long as it is a widely used method of dissolving or dispersing, and a stirring and mixing method using a stirring blade, such as a unidirectional rotation paddle, multi-axis rotation paddle, can be used. reciprocating type, vertical motion type, rotation+vertical motion type, and piping type such as portable mixer, three-dimensional mixer, and side wall mixer; a jet-type mixing and mixing method, for example using an in-line mixer; a method of stirring and mixing by gas purge; a mixing method using a high shear homogenizer, a high pressure homogenizer, an ultrasonic homogenizer, and the like; a mixing method such as shaking the container using a shaker or the like.

[0068] The solvent used in the above manufacturing method is not particularly limited as long as it is used for pharmaceutical products, but at least any solvent selected from water and an organic solvent can be used, for example. Examples of the organic solvent include those classified as solvents in the "2016 Japanese Pharmaceutical Excipients Handbook" (published by Yakuji Nippo, Ltd.), including alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol. alcohol; hydrocarbons such as pentane, hexane, heptane and cyclohexane; and ketones such as acetone and ethyl methyl ketone. One of these solvents may be used alone, two or more types may be used in combination, or the solid content may be dispersed once in one medium and then dispersed in another medium after removal of the original medium.

[0069] When dissolving the active ingredient in a medium, a water-soluble polymer, an oil and fat, a surfactant, or the like can be used as a solubilizer. As the water-soluble polymer, oil and fat, and surfactant used as a solubilizer, those described in "2016 Japanese Pharmaceutical Excipient Handbook" (published by Yakuji Nippo, Ltd.) can be suitably used. One of these may be used alone, or two or more types may be used in combination.

[0070] The shaped product herein is in the form of granules, fine granules, briquettes, tablets, and the like. and contains a cellulose-based composition in accordance with the present embodiment, one or more active ingredients and, if necessary, other additives.

Examples of the tableting method include a direct tableting method that includes direct compression and molding of a mixture of an active ingredient and a cellulose-based composition according to the present embodiment, or mixtures of one or more active ingredients and a cellulose-based composition according to the present embodiment. and, if necessary, other additives. Other methods can be used to make a multi-core tablet having a pre-compressed and molded tablet as an inner core, or a multilayer tablet in which a plurality of pre-compressed molded products are stacked and re-compressed. The direct tableting process is preferred in terms of productivity and ease of process control.

[0071] The compression molded tablet (molded product) can be further coated. Examples of the coating materials used in this case include the coating materials described in "2016 Japanese Pharmaceutical Excipient Handbook" (published by Yakuji Nippo, Ltd.). One of these coating materials may be used alone, or two or more types may be used in combination.

[0072] The granulation method used in the manufacturing process through the granulation step includes dry granulation, wet granulation, heat granulation, spray granulation, and microencapsulation. More specifically, fluidized granulation, agitated granulation, extrusion granulation, crushing granulation, and drum granulation are effective as a wet granulation method, and in the case of the fluidized granulation method, the binding liquid is sprayed onto the fluidized powder for granulation in the fluidized granulator. layer. In the agitated granulation method, powder is mixed, kneaded, and granulated simultaneously in a sealed structure by rotating a mixing paddle in a mixing vessel while adding a binding liquid. In the case of the extrusion granulation method, the wet mass kneaded with the addition of a binder liquid is forcibly extruded from an appropriately sized sieve by the helical or basket granulation method. In the crushing granulation method, the wet mass kneaded with the addition of a binder liquid is cut and pulverized by the rotating blade of the granulator and thrown out of the circular sieve by centrifugal force to granulate. In the drum granulation method, the powder is rolled under the action of the centrifugal force of the rotating rotor, and at this time, spherical granules having the same particle size are built up with the speed of the binder sprayed from the atomizer accelerating for granulation.

[0073] As a method for drying the granular product, any method selected from a hot air heating type method (shelf drying, vacuum drying, and fluid bed drying), a heat conduction type method (tray type, shelf box type) can also be used. and drum type), and lyophilization. In a hot air heating type method, hot air is brought into direct contact with the additive and at the same time evaporating water is removed. In a conductive heat transfer type method, the additive is indirectly heated through the heat transfer wall. In the lyophilization method, the additive is frozen at -10°C or more to 40°C or less, and then heated under high vacuum (1.3×10 ^-5 MPa or more to 2.6×10 ^-4 MPa or less ) to sublimate and remove water.

EXAMPLES

[0074] The present embodiment will be described in detail below with reference to examples and comparative examples, but the present embodiment is not limited to them. The physical properties and methods for determining them in the examples and comparative examples are as follows. It should be noted that when the sample contained a large amount of water, various physical properties were determined by first drying the sample to a water content of about 3.5% by weight or more to 4.5% by weight or less.

[0075] < Method for analyzing the composition of a cellulose-based composition >

[ Analysis 1 ]

(Method for measuring the content of water soluble substance in a cellulose-based composition)

The water soluble content of the cellulose-based composition was measured by the following procedure, taking into account the purity test method (2) of crystalline cellulose described in the 17th Rev. Japanese Pharmacopoeia.

To 5.0 g of the cellulose-based composition was added 80 ml of purified water, and the resulting mixture was shaken and stirred for 10 minutes. Then, the solution containing the cellulose-based composition was subjected to vacuum filtration using a filter paper for quantitative analysis (No. 5C). The filtrate was evaporated to dryness in a beaker of known weight to avoid charring, and then dried at 105°C for 1 hour and allowed to cool in a desiccator to obtain a residue. The weight of the resulting residue was then weighed to determine the weight of the residue. Each powder was measured twice and the average value was taken. In addition, the test carried out with only 80 ml of purified water without adding 5.0 g of the cellulose-based composition in the above operation was determined as a control test, and the amount of water soluble substance found in the control test was subtracted from the measured value to obtain a value. This value was rounded to the first decimal place and taken as the measured value of the amount of water-soluble substance. The amount of water soluble substance obtained using this test method is the amount of water soluble substance contained in 5 g of the cellulose-based composition.

[0076] [ Analysis 2 ]

(Measurement of sugars (glucose, sorbitol and cellobiose) in a cellulose-based composition)

The entire amount of water soluble matter in the form of a dried product obtained in the section entitled "Assay 1" was redissolved by adding 10 ml of 50% (v/v) acetonitrile aqueous solution, followed by filtration through a filter (0.20 μm), and measuring the content glucose, sorbitol and cellobiose were carried out using LC/MS. The measurement conditions for LC/MS measurements are as follows.

When preparing or diluting measuring solutions, an accurate balance was used, and the concentration of the sample and the degree of its dilution were determined using weight.

In addition, when measuring glucose, sorbitol, and cellobiose, solutions of glucose, sorbitol, and cellobiose at known concentrations, which were prepared using commercially available products, were analyzed by LC/MS, retention time and peak area were obtained from m/z ion chromatograms, corresponding to each sugar, and calibration curves are built (sample concentration - peak area). This calibration curve was used to determine the content of each sugar in the water-soluble substance (5 g of the cellulose-based composition). It should be noted that the content of each sugar is indicated by the value obtained by rounding the second decimal place.

[0077] (Measurement conditions)

LC system: Nexera, manufactured by Shimadzu Corporation

Column: Shodex Asahipak NH2P-50 2D (inner diameter 2 mm × 150 mm), manufactured by Showa Denko K.K.

Column temperature: 40°C

Detector: PDA detector, 200 to 400 nm

Flow rate: 0.3 ml/min

Mobile phase: A=purified water, B=acetonitrile

Gradient: The conditions for the gradient are presented in Table 1 below.

Injection volume: 10 µl

MS system: Synapt G2, manufactured by Waters Corporation

Ionization conditions: ESI ^-

Scan Range: m/z 50 to 2000

[0078] Table 1

Time (min) A (%) B(%) 0 10 90 15 50 50 15.1 10 90 25 10 90

[0079] For reference, the detected ions (m/z) and the retention time of each component observed under the above measurement conditions are shown in Table 2 below.

[0080] Table 2

Detected ions (m/z) Retention time (min) Sorbitol 181.07 [MH] ^- 5.9 Glucose 179.06 [MH] ^- 6.1 Cellobiose 341.11 [MH] ^- 7.8

[0081] < Method for determining the physical properties of the powder >

[ Physical Property 1 ]

(Water absorption rate)

The water absorption rate was measured using a Peneto analyzer (model: PNT-N, manufactured by Hosokawa Micron Corporation).

More specifically, first, in order to suppress fluctuations in the measured value due to static electricity, before measurement, the bottom surface of the measuring cell was wiped with a wrung-out towel moistened with an aqueous solution containing 1% household detergent and dried naturally. The bottom plate and filter paper were placed in the measuring cell, 5 g of the cellulose-based composition was placed therein, and tapped with the supplied tapping device (300 times, 18 mm, weight: 198 g). The sample after tapping was put into the cuvette holder and attached to the main body of the Peneto analyzer. The measurement was carried out at room temperature (25°C) using a solvent (purified water, 300 ml) under the following lifting conditions during measurement (1) 1.5 mm/s, 2) 0.1 mm/s, (3) 0 .5 mm/s, manual control: 1.5 mm/s). The water absorption curve, obtained by plotting the square of the mass (g ² ) on the vertical axis and the measurement time (time elapsed since the beginning of water absorption) (s) on the horizontal axis, was linearly approximated in the linear region of the water absorption curve (regions from 1/3 to 2/ 3 saturation water absorption), and the slope of the approximate straight line was obtained as a coefficient of permeability rate (g ² /s).

[0082] [ Physical Property 2 ]

(Average particle size)

The measurement was carried out using a laser diffraction type particle size distribution meter (LA-950 V2 (product name) manufactured by Horiba, Ltd.) in dry measurement mode with compressed air pressure=0.10 MPa, feed rate=160, initial velocity coefficient feed=1.2 and refractive index=1.51. The particle size in the total volume=50%, obtained as a result of the measurement, was taken as the average particle size (μm) of the composition based on cellulose.

[0083] [ Physical Property 3 ]

(Bulk density in bulk state)

For measurement, a cellulose-based composition with a water content adjusted to 3.5% by weight or more to 4.5% by weight or less was used. When the range for the water content of the cellulose-based composition was outside the lower range, the water content was controlled by allowing the cellulose powder to absorb water in a constant temperature and humidity chamber or the like. In addition, when the water content range of the cellulose composition was out of the upper range, the cellulose composition was uniformly supplied with hot air at 60° C. in a hot air oven to adjust the water content within the range.

A Scott volumemeter (Model: ASTM B-329-85, manufactured by Tsutsui Scientific Instruments Co., Ltd.) was used to measure the bulk density of the cellulose-based composition, and the cellulose-based composition was placed in a 25 ml cylindrical metal container through a sieve. (with holes=1mm). The cellulose-based composition contained in a 25 ml cylindrical metal container was leveled, and the weight (g) of the cellulose-based composition in the container was divided by volume=25 ml to determine bulk bulk density (g/ml). The measurement was carried out 5 times, and the average value was determined.

[0084] [ Physical property 4 ]

(Bulk density at compaction)

For measurement, a cellulose-based composition with a water content adjusted to 3.5% by weight or more to 4.5% by weight or less was used. The water content of the cellulose-based composition was adjusted to be within the specified range using the method described in the section entitled "Physical property 3". Compaction bulk density (apparent compaction density) (g/mL) was calculated using a powder physical property measuring device (PT-R, manufactured by Hosokawa Micron Corporation). The sieve used had openings=710 µm, and a funnel made of metal (coated using an antistatic spray) and having an inner diameter=0.8 cm was used. AC, 60 Hz).

[0085] [ Physical Property 5 ]

(Compression ratio)

The compression ratio of each cellulose-based composition was calculated using the formula below.

[0086] Compression ratio (%)=([compacted bulk density] - [bulk bulk density]) / [compacted bulk density] × 100

[0087] [ Physical property 6 ]

(Ratio of major axis to minor axis of cellulose particles (L/D))

The cellulose-based composition was scattered on a glass plate and photographed using a microscope (VHX-1000, manufactured by Keyence Corporation) at a magnification of 500 times. The captured image was analyzed by the following procedure using the image analysis and processing software (Image Hyper II, manufactured by DigiMo Co., Ltd.), and the characteristic ratio (major axis to minor axis ratio; L/D) of the particles was determined. Measurements were made on at least 50 particles and an average value was determined.

[0088] (1) Step 1: Binarization (binarization) process

The microscope image was captured in the analysis software in monochrome mode, and the image scale was set using the two-point calibration method. Further, in the process of binarization, the “Otsu method” was chosen, and a threshold value was set. Since the optimal threshold value differs for each image, the threshold value was chosen to match the shape of the original particle as closely as possible when compared with the original image.

[0089] (2) Stage 2: Manual binarization correction

When compared with the original image, particles that did not give consistent measurement results, such as particles that overlapped with each other, particles that protruded off the screen, and particles that were fuzzy and had fuzzy edges, were removed and excluded from the object. measurements.

[0090] (3) Stage 3: Hole filling

In the "hole filling" mode, "8" was selected for "neighborhood", and the "hole filling" operation was performed. Then, the image was again compared with the original image using "manual binary image correction" and it was verified whether the correction was performed in the direction of normalization. If normalization was not achieved, manual correction was performed again.

[0091] (4) Stage 4: Image measurement

After setting the number of pixels to be removed to "100" and selecting "8" for "neighborhood", the "image measurement" operation was performed. The measurement results of the "major axis" and "minor axis" for each measured particle were displayed on a personal computer. The value obtained by dividing the "major axis" by the "minor axis" was used as the characteristic ratio.

[0092] <Pill Evaluation Method>

Tablets with intraoral disintegration (tablets with OD) and tablets were made and evaluated in various ways, using the methods described below.

[0093] [ Manufacture of tablets with intraoral disintegration (OD )]

The formulated powder below was placed in a plastic bag and shaken for 1 minute to mix. Then, the mixed powder was sieved through a 710 μm sieve, and a lubricant (sodium stearyl fumarate) was further added in an amount of 1% by weight relative to the total weight of the OD tablet, followed by stirring for 30 seconds. Subsequently, the mixed powder was tabletted with a rotary tablet press (Clean Press Correct 12HUK, manufactured by Kikusui Seisakusho Ltd., 12 punches, turntable: 54 rpm) to obtain 200 mg ∅8 mm-12R tablets. The tableting pressure was set appropriately so that the tablet hardness was 80 N or more to 90 N or less.

[0094] (drug)

Mannitol for direct compaction (Mannogem EZ, manufactured by Asahi Kasei Corporation): 70% w/w

Partially peptized starch (PCS, PC-10, manufactured by Asahi Kasei Corporation): 10% w/w

Croscarmellose sodium (Kiccolate ND-200), manufactured by Asahi Kasei Corporation): 5% w/w

Cellulose-based composition: 15% w/w

[0095] It should be noted that the content of each component in the above preparation is its ratio to the total weight of the above components.

[0096] [ Score 1 ]

(Hardness)

The hardness of each OD tablet was measured with a hardness tester (DR. SCHLEUNIGER Tablet Tester 8M) 20 hours or more - 48 hours or less immediately after tableting. The average of 5 tablets at each tableting pressure was taken as the hardness (H) of the OD tablet.

[0097] [ Score 2 ]

(Decomposition time in the oral cavity)

To measure the disintegration time in the oral cavity, an oral disintegration tablet tester (model: ODT-101, manufactured by Toyama Sangyo Co., Ltd.) was used. The disintegration time was measured by placing and setting the OD tablet at the left end of the hole in the center of the sample fixing frame under test liquid conditions: water (37±1°C), weight diameter: ∅20 mm, weight weight: 20 g, rotation speed: 140 rpm, tablet thickness with OD: 4.0 mm. The mean value of 6 tablets was taken during the disintegration of the tablet with OD in the oral cavity

[0098] [ Score 3 ]

(Residual nucleus)

The residual core of the OD tablet was evaluated using an oral disintegration tablet tester. First, the oral disintegration time described in the section entitled "Evaluation 2" was measured to determine the oral disintegration time. Then, in order to evaluate the residual core of the OD tablet, the oral disintegration tablet tester was stopped at "75% of the obtained oral disintegration time" from the start of the OD tablet disintegration time, and it was confirmed whether any solid part of the tablet remained. with OD. The residual nucleus was evaluated according to the following evaluation criteria. The test was carried out three times, and tablets rated (+) more than once were scored as (+).

[0099] (Evaluation criteria)

(+) tablets with remaining tablet solids with OD

(-) tablets without remaining solid tablet parts with OD

[0100] [Production of tablets for storage stability testing]

The powder obtained by mixing the cellulose-based composition and aminophylline (cellulose-based composition: aminophylline=1:1 (parts by weight)) in a plastic bag was tabletted using a static pressure tableting machine (tabletting pressure: 7 kN, holding time: 10 seconds ) to give 500 mg flat tablets (∅11.3 mm).

[0101] [ Score 4 ]

(Storage stability)

The reactivity between the cellulose-based composition and the drug was confirmed by the change in whiteness of the tablet immediately after tableting and after storage.

Tablets obtained by the above-described manufacturing method were used immediately after tabletting to determine the values of brightness (L), color saturation (a) (from green to red) and color saturation (b) (from blue to yellow) using a spectroscopic colorimeter (SE- 2000, manufactured by Nippon Denshoku Industries Co., Ltd.). Subsequently, the whiteness was calculated by the following formula.

[0102] Whiteness=100 - [(100 - L) ² +a ² +b ² ] ^0.5

[0103] In addition, the obtained tablets were placed in a bottle, sealed and stored for 1 month in a constant temperature and humidity chamber at temperature=40°C and relative humidity=75%, and the values of (L), (a) and ( b) after storage was also determined using a spectroscopic colorimeter, and the whiteness after the storage stability test was calculated using the above formula.

[0104] The change in whiteness of the tablet immediately after tableting (before storage) and after the storage stability test (after storage) was calculated by the following formula.

[0105] Change in whiteness=whiteness (before storage) - whiteness (after storage)

[0106] It should be noted that when the absolute value of the change in whiteness exceeds 10%, since the degree of color change can be recognized visually, tablets whose absolute value change in whiteness was 10% or less were judged to have a suitable level of storage stability.

[0107] < Obtaining wet flakes >

[ Sample 1 receive ]

(Getting wet cereal X)

2 kg of crushed commercial pulp and 30 L of an aqueous hydrochloric acid solution were placed in a low-speed stirrer (30 LGL reactor (product name) manufactured by Ikebukuro Horo Kogyo Co., Ltd.), and the resulting mixture was subjected to hydrolysis with stirring (reaction conditions: concentration hydrochloric acid: 0.5%, reaction temperature: 120°C, reaction time: 1.0 hour, stirring speed: 220 rpm) to obtain an acid-insoluble residue. The resulting acid-insoluble residue was thoroughly washed with pure water until the electrical conductivity of the filtrate became less than 100 μS/cm, and then subjected to filtration to obtain wet flakes (wet flocculation) X. When the average degree of polymerization of the wet flakes X was measured by the viscosity method using the ethylenediamine-copper complex solution described in the identification test (3) of crystalline cellulose in the Japanese Pharmacopoeia, the average degree of polymerization was 170.

[0108] < Preparation of a Cellulose-Based Composition >

[ Example 1 ]

(Preparation of composition A based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an aqueous ammonia solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and after adding 1.56 g of glucose, the resulting mixture was stirred and spray dried (conditions: dispersion liquid feed rate: 6 kg/h, inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain cellulose-based composition A. In 5 g of the cellulose-based composition, the amount of water soluble substance was 4.9 mg, the amount of glucose was 2.9 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.7 mg.

[0109] [ Example 2 ]

(Preparation of composition B based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an ammonia aqueous solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and after adding 0.81 g of glucose, the resulting mixture was stirred and spray dried (conditions: dispersion liquid feed rate: 6 kg/h, inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain a composition B based on cellulose. In 5 g of the cellulose-based composition, the amount of water soluble substance was 3.7 mg, the amount of glucose was 1.7 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.7 mg.

[0110] [ Example 3 ]

(Preparation of composition C based on cellulose)

800 g of cellulose-based composition B obtained in Example 2 was loaded into a high-speed agitator granulator and granulated, fluidized-bed dried, and then sieved through a 500 μm sieve to obtain cellulose-based composition C (granulation conditions: amount of added water: 600 g; granulation time: 20 minutes; main blade: 400 rpm; cross screw: 500 rpm; drying conditions: drying temperature 80°C). In 5 g of the cellulose-based composition, the amount of water soluble substance was 3.4 mg, the amount of glucose was 1.6 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.6 mg.

[0111] [ Example 4 ]

(Preparation of composition D based on cellulose)

Cellulose-based composition B obtained in Example 2 was pulverized with a jet mill to obtain cellulose-based composition D. In 5 g of the cellulose-based composition, the amount of water soluble substance was 4.0 mg, the amount of glucose was 1.8 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.8 mg.

[0112] [ Example 5 ]

(Preparation of composition E based on cellulose)

Cellulose-based composition B obtained in Example 2 was ground with an ultracentrifugal grinder to obtain cellulose-based composition E. In 5 g of the cellulose-based composition, the amount of water soluble substance was 4.3 mg, the amount of glucose was 2.0 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.8 mg.

[0113] [ Example 6 ]

(Preparation of composition F based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an ammonia aqueous solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and after adding 0.19 g of glucose, the resulting mixture was stirred and spray dried (conditions: dispersion liquid feed rate: 6 kg/h, inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain a composition F based on cellulose. In 5 g of the cellulose-based composition, the amount of water soluble substance was 2.7 mg, the amount of glucose was 0.7 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.7 mg.

[0114] [ Example 7 ]

(Preparation of composition G based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an ammonia aqueous solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and after adding 2.0 g of sorbitol, the resulting mixture was stirred and spray dried (conditions: dispersion liquid feed rate: 6 kg/h, inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain a composition G based on cellulose. In 5 g of the cellulose-based composition, the amount of water soluble substance was 5.6 mg, the amount of glucose was 0.4 mg, the amount of sorbitol was 3.4 mg, and the amount of cellobiose was 0.7 mg.

[0115] [ Example 8 ]

(Preparation of composition H based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an aqueous ammonia solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and after adding 1.0 g of sorbitol, the resulting mixture was stirred and spray dried (conditions: dispersion liquid feed rate: 6 kg/hour, inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain a composition H based on cellulose. In 5 g of the cellulose-based composition, the amount of water soluble substance was 4.0 mg, the amount of glucose was 0.4 mg, the amount of sorbitol was 1.8 mg, and the amount of cellobiose was 0.7 mg.

[0116] [ Example 9 ]

(Preparation of composition I based on cellulose)

800 g of cellulose-based composition H obtained in Example 8 was loaded into a granulator with a high-speed agitator and granulated, fluidized-bed dried, and then sifted through a 500 μm sieve to obtain cellulose-based composition I. The granulation conditions and drying conditions were the same as in Example 3. In 5 g of the cellulose-based composition, the amount of water soluble substance was 3.8 mg, the amount of glucose was 0.4 mg, the amount of sorbitol was 1.7 mg, and the amount of cellobiose was 0.7 mg.

[0117] [ Example 10 ]

(Preparation of composition J based on cellulose)

Cellulose-based composition H obtained in Example 8 was pulverized with a jet mill grinder to obtain cellulose-based composition J. In 5 g of the cellulose-based composition, the amount of water soluble substance was 4.2 mg, the amount of glucose was 0.4 mg, the amount of sorbitol was 1.9 mg, and the amount of cellobiose was 0.7 mg.

[0118] [ Example 11 ]

(Preparation of composition K based on cellulose)

The cellulose-based composition H obtained in Example 8 was ground using an ultracentrifugal grinder to obtain a cellulose-based composition K. In 5 g of the cellulose-based composition, the amount of water soluble substance was 4.5 mg, the amount of glucose was 0.5 mg, the amount of sorbitol was 2.0 mg, and the amount of cellobiose was 0.8 mg.

[0119] [ Example 12 ]

(Preparation of composition L based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an aqueous ammonia solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and after adding 0.13 g of sorbitol, the resulting mixture was stirred and spray dried (conditions: dispersion liquid feed rate: 6 kg/hour, inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain a composition L based on cellulose. In 5 g of the cellulose-based composition, the amount of water soluble substance was 2.6 mg, the amount of glucose was 0.4 mg, the amount of sorbitol was 0.4 mg, and the amount of cellobiose was 0.7 mg.

[0120] [ Comparative example 1 ]

(Preparation of composition M based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an aqueous ammonia solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and the obtained mixture was stirred and spray dried without adding glucose (conditions: dispersion liquid feeding rate: 6 kg/h; inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain a composition M based on cellulose. In 5 g of the cellulose-based composition, the amount of water-soluble substance was 2.4 mg, the amount of glucose was 0.4 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.7 mg.

[0121] [ Comparative example 2 ]

(Preparation of composition N based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added thereto so that the total solid concentration was 10% by weight, and the resulting mixture was dispersed with a three-in-one motor to prepare 30 kg of a dispersion liquid. The dispersion liquid was neutralized with an ammonia aqueous solution with stirring (pH was 7.5 or more to 8.0 or less after neutralization), and after adding 2.31 g of glucose, the resulting mixture was stirred and spray dried (conditions: dispersion liquid feed rate: 6 kg/hour, inlet temperature: 180°C or more to 220°C or less, outlet temperature: 50°C or more to 70°C or less) to obtain a composition N based on cellulose. In 5 g of the cellulose-based composition, the amount of water soluble substance was 6.1 mg, the amount of glucose was 4.1 mg, the amount of sorbitol was 0.2 mg, and the amount of cellobiose was 0.7 mg.

[0122] [ Comparative Example 3 ]

(Preparation of composition O based on cellulose)

50 mg of powdered glucose was added to 100 g of cellulose-based composition M obtained in Comparative Example 1, and the resulting mixture was shaken and stirred using a plastic bag to obtain cellulose-containing mixture O as a physical mixture corresponding in composition to cellulose-based composition A .

[0123] For each cellulose-based composition obtained in the Examples and Comparative Examples, various physical properties were determined using the methods described above, and after the manufacture of OD tablets and tablets, each of the evaluations was performed. The results are presented in tables 3 to 6.

[124] Table 3

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Cellulose based composition A B C D E F Terms of receipt wet flakes X X X X X X Solid content in flake dispersion [weight%] 10 10 10 10 10 10 Amount of added glucose [G] 1.56 0.81 0.81 0.81 0.81 0.19 Amount of added sorbitol [G] 0 0 0 0 0 0 Compound Content of water soluble substance in 5 g of cellulose-based composition [mg] 4.9 3.7 3.4 4.0 4.3 2.7 Glucose content in 5 g of cellulose-based composition [mg] 2.9 1.7 1.6 1.8 2.0 0.7 The content of sorbitol in 5 g of the composition based on cellulose [mg] 0.2 0.2 0.2 0.2 0.2 0.2 The content of cellobiose in 5 g of the composition based on cellulose [mg] 0.7 0.7 0.6 0.8 0.8 0.7 The content of monosaccharides (glucose, sorbitol) in 5 g of a composition based on cellulose [mg] 3.1 1.9 1.7 2.1 2.2 0.9 Physical properties Water absorption rate [g ² /s] 5.1 4.1 3.3 6.2 3.4 2.6 Average particle size [µm] 59 55 131 33 18 52 Bulk density [g/ml] 0.29 0.26 0.33 0.19 0.14 0.24 Bulk density at compaction [g/ml] 0.46 0.42 0.43 0.34 0.33 0.42 Compression ratio [-] 37 38 24 44 58 43 L/D [-] 2.3 2.4 1.8 3.2 2.4 2.3 Grade Tableting pressure during manufacture of an orally disintegrating tablet [kN] 8.0 7.5 8.0 7.0 6.5 7.5 Decay time in the mouth [With] 23 25 27 23 25 29 Residual core [-] (-) (-) (-) (-) (-) (-) Storage stability (change in whiteness) [%] -9 -7 -6 -7 -8 -4

[125] Table 4

Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Cellulose based composition G H I J K L Terms of receipt wet flakes X X X X X X Solid content in flake dispersion [weight%] 10 10 10 10 10 10 Amount of added glucose [G] 0 0 0 0 0 0 Amount of added sorbitol [G] 2.00 1.00 1.00 1.00 1.00 0.13 Compound Content of water soluble substance in 5 g of cellulose-based composition [mg] 5.6 4.0 3.8 4.2 4.5 2.6 Glucose content in 5 g of cellulose-based composition [mg] 0.4 0.4 0.4 0.4 0.5 0.4 The content of sorbitol in 5 g of the composition based on cellulose [mg] 3.4 1.8 1.7 1.9 2.0 0.4 The content of cellobiose in 5 g of the composition based on cellulose [mg] 0.7 0.7 0.7 0.7 0.8 0.7 The content of monosaccharides (glucose, sorbitol) in 5 g of a composition based on cellulose [mg] 3.8 2.2 2.1 2.3 2.5 0.8 Physical Properties Water absorption rate [g ² /s] 7.5 5.8 4.4 7.1 4.3 2.5 Average particle size [µm] 66 59 133 37 16 54 Bulk density [g/ml] 0.30 0.27 0.34 0.21 0.16 0.24 Bulk density at compaction [g/ml] 0.47 0.44 0.44 0.37 0.37 0.41 Compression ratio [-] 36 38 22 43 57 41 L/D [-] 2.4 2.3 1.7 3.3 2.6 2.4 Grade Tableting pressure during manufacture of an orally disintegrating tablet [kN] 8.0 7.5 8.0 7.0 6.5 7.5 Decay time in the mouth [With] 19 22 26 21 22 28 Residual core [-] (-) (-) (-) (-) (-) (-) Storage stability (change in whiteness) [%] -6 -4 -3 -4 -5 -3

[126] Table 5

Comparative Example 1 Comparative Example 2 Cellulose based composition M N Terms of receipt wet flakes X X Solid content in flake dispersion [weight%] 10 10 Amount of added glucose [G] 0 2.31 Amount of added sorbitol [G] 0 0 Compound Content of water soluble substance in 5 g of cellulose-based composition [mg] 2.4 6.1 Glucose content in 5 g of cellulose-based composition [mg] 0.4 4.1 The content of sorbitol in 5 g of the composition based on cellulose [mg] 0.2 0.2 The content of cellobiose in 5 g of the composition based on cellulose [mg] 0.7 0.7 The content of monosaccharides (glucose, sorbitol) in 5 g of a composition based on cellulose [mg] 0.6 4.3 Physical Properties Water absorption rate [g ² /s] 2.3 6.2 Average particle size [µm] 51 62 Bulk density [g/ml] 0.16 0.24 Bulk density at compaction [g/ml] 0.37 0.41 Compression ratio [-] 57 41 L/D [-] 2.6 2.4 Grade Tableting pressure during manufacture of an orally disintegrating tablet [kN] 6.5 7.5 Decay time in the mouth [With] 22 28 Residual core [-] (-) (-) Storage stability (change in whiteness) [%] -5 -3

[127] Table 6

Comparative Example 3 Cellulose mixture O Grade Tableting pressure during manufacture of an orally disintegrating tablet [kN] 7.5 Decay time in the mouth [With] 33 Residual core [-] (+) Storage stability (change in whiteness) [%] -8

[128] Based on Tables 3-6, it was found that disintegration properties when molded into tablets with OD and storage stability when molded into tablets were suitable when cellulose-based compositions A-L (Examples 1-12) were used, in which the content of glucose and sorbitol in 5 g of the composition based on cellulose ranged from 0.7 mg or more to 4.0 mg or less.

In the cellulose-based formulations A-L (examples 1-12), the disintegration time in the oral cavity was generally shorter as the glucose or sorbitol content increased.

In addition, storage stability tended to further increase as the glucose or sorbitol content per 5 g of the cellulose-based composition decreased.

It should be noted that in the tablet for which cellulose composition A was used, the change in whiteness was -9%, but the change in color could not be confirmed visually.

[0129] On the other hand, in the cellulose-based composition M (Comparative Example 1), in which the content of glucose and sorbitol in the cellulose-based composition was less than 0.7 mg, although the storage stability was suitable, the disintegration time in the oral cavity reached up to 34 seconds, and a residual nucleus was observed.

In addition, in the cellulose-based composition N (Comparative Example 2), in which the glucose content of the cellulose-based composition was more than 4.0 mg, the disintegration time in the oral cavity was 21 seconds, and although there was no residual nucleus, the discoloration after storage, represented by a change in whiteness of -12%, was so large that it could be confirmed visually when compared with the state before storage, and the storage stability was lower.

In addition, in the cellulose-containing mixture O (comparative example 3), in which glucose was added to the cellulose-based composition M in the same amount as in the case of the cellulose-based composition A (example 1), although the storage stability was suitable, the disintegration time in the oral cavity was 33 seconds, and a residual nucleus was observed.

INDUSTRIAL APPLICABILITY

[130] According to the cellulose powder of the present embodiment, a cellulose-based composition can be obtained from which a tablet having excellent storage stability can be obtained while maintaining suitable disintegration properties as an oral disintegrating tablet. The tablet and the oral disintegrating tablet according to the present embodiment contain the above-mentioned base composition, exhibit suitable disintegration properties as an oral disintegrating tablet, and have excellent storage stability.

Claims (8)

1. A cellulose-based tablet composition containing cellulose, glucose and sorbitol, in which the total content of glucose and sorbitol is 0.7 mg or more to 4.0 mg or less per 5 g of the above cellulose-based composition. 2. Cellulose-based composition according to claim 1, where additionally containing cello-oligosaccharides, such as cellobiose, cellotriose, cellotetraose, cellopentose, cellohexaose and celloheptaose, as a water-soluble substance, where the total content of water-soluble substance, including cello-oligosaccharides, glucose and sorbitol is from 2 .5 mg or more to 12.5 mg or less per 5 g of said cellulose-based composition. 3. A cellulose-based composition according to claim 1 or 2, wherein the glucose content is from 0.3 mg or more to 3.5 mg or less per 5 g of said cellulose-based composition. 4. Composition based on cellulose according to any one of paragraphs. 1-3, where the content of sorbitol in which is from 0.2 mg or more to 3.5 mg or less per 5 g of said composition based on cellulose. 5. Composition based on cellulose according to any one of paragraphs. 1-4, which is a powder, and in which the average particle size of the powder is 10 µm or more to 200 µm or less. 6. Composition based on cellulose according to any one of paragraphs. 1-5, wherein the water absorption rate is 2.0 g ² /s or more to 9.0 g ² /s or less. 7. Pharmaceutical composition in the form of a tablet containing a composition based on cellulose according to any one of paragraphs. 1-6. 8. Pharmaceutical composition in the form of a tablet with intraoral disintegration, containing a composition based on cellulose according to any one of paragraphs. 1-6.