RU2798266C1 - Cellulose-containing composition and tablet - Google Patents

Abstract

FIELD: medicines.

SUBSTANCE: group of inventions is related to a composition containing cellulose and a tablet. The cellulose-based composition for the tablet production contains cellulose and cello-oligosaccharides from trisaccharides to heptasaccharides, which are a water-soluble substance, in which the content of cello-oligosaccharides per 5 g of the cellulose-based composition is at least 1.5 mg, but not more than 9.0 mg. A tablet containing the cellulose-based composition and at least one active ingredient is also claimed, wherein the proportion of the mixture of the cellulose-based composition is at least 1% by weight, but not more than 90% by weight.

EFFECT: possibility to create a cellulose-based tablet which has a suitable hardness and sufficient suppression of both variation in the content of the active ingredient and moulding failure during the tableting process.

10 cl, 6 tbl, 16 ex

Description

FIELD OF TECHNOLOGY

[0001] The present invention relates to a composition containing cellulose and a tablet.

BACKGROUND OF THE INVENTION

[0002] Pharmaceutical tableting provides the advantages of high productivity and ease of handling in transportation and application. During tabletting, since many active ingredient raw materials cannot be molded even when compressed, excipients are added to enable tableting, and these excipients require suitable formability, flowability, and disintegration. Cellulose is widely used as a filler.

[0003] Patent Document 1 describes a cellulose powder having an average degree of polymerization of at least 100 but not more than 350, a weight average particle size of not less than 30 µm, but not more than 250 µm, an apparent specific volume of at least 2 ^cm3 /g but less than 15 cm3/g, and a particle size distribution sharpness of at least 1.5 but not more than 2.9. It is described that the use of this cellulose powder provides excellent compressibility and allows the components of traditional Chinese medicine having a high level of stickiness and hygroscopicity and other components having stickiness to be uniformly preserved, which provides a sharper particle size distribution of the granules due to the sharp distribution in size. particle size of the cellulose powder, provides a reduction in disintegration time and gives a more stable disintegration over a long period of time.

[0004] On the other hand, when cellulose powder is used in conventional technology, to ensure the uniformity of the content of the active ingredient in each tablet, it is generally necessary to lengthen the mixing time of the starting material, and the decrease in tablet hardness that accompanies this lengthening of the mixing time can become problematic. However, satisfactory mixing is necessary to prevent uneven distribution of the active ingredient, and preventing any decrease in tablet hardness caused by prolonged mixing time, while preventing any deterioration in content uniformity, has proven difficult.

PRIOR ART LITERATURE

patent document

[0005] Patent Document 1: International Patent Application Publication No. 2013/180248

SUMMARY OF THE PRESENT INVENTION

Problems solved by the present invention

[0006] The present invention has been developed in view of the above circumstances and provides a cellulose-based composition having a suitable hardness and sufficient suppression of both deviation in the content of the active ingredient and molding failure during tableting, as well as a tablet containing a cellulose-based composition.

Way to solve problems

[0007] In other words, the present invention includes the following aspects.

(1) A cellulose-based composition containing cellulose and cellooligosaccharides from trisaccharides to heptasaccharides, in which the content of cellooligosaccharides per 5 g of the cellulose-based composition is at least 1.5 mg but not more than 9.0 mg.

(2) The cellulose-based composition according to (1), in which the content of water-soluble substances per 5 g of the cellulose-based composition is at least 2.5 mg but not more than 12.5 mg.

(3) The cellulose-based composition according to (2), in which the proportion of cellooligosaccharides in the composition of water-soluble substances is at least 47% by weight, but not more than 67% by weight.

(4) The cellulose-based composition according to any of (1) to (3), which is a powder, and in which the average particle size of the powder is at least 10 µm, but not more than 200 µm.

(5) The cellulose-based composition according to (4), in which the L/D aspect ratio of the powder is at least 1.8 but not more than 4.0.

(6) A tablet containing the cellulose composition according to any one of (1) to (5) and at least one active ingredient.

(7) The tablet according to (6), in which the lubricant content, relative to the total weight of the tablet, is at least 0.3% by weight, but not more than 5% by weight.

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

(9) The tablet according to (7) or (8), wherein the lubricant is at least one selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, sucrose esters and fatty acids and talc.

(10) The tablet according to any (6) to (9), wherein the content of the active ingredient, based on the total weight of the tablet, is at least 0.01% by weight but more than 50% by weight.

Effects of the present invention

[0008] By using the cellulose-based composition according to the aspect described above, it is possible to provide a cellulose-based composition that has a suitable hardness and sufficient suppression of both fluctuation in active ingredient content and molding failure during tableting. The tablet according to the aspect described above contains a cellulose-based composition and exhibits suitable hardness and sufficient suppression of both fluctuation in active ingredient content and molding failure during tabletting.

EMBODIMENTS OF THE PRESENT INVENTION

[0009] Embodiments of the present invention (hereinafter referred to simply as "embodiments of the present invention") are described in detail below. The present invention is not limited to the following embodiments, and various modifications can be made within the scope of the present invention.

[0010] < Cellulose-based composition >

The cellulose-based composition according to an embodiment of the present invention comprises cellulose and cellooligosaccharides ranging from trisaccharides to heptasaccharides (hereinafter sometimes referred to as "cellooligosaccharides (3-7)" for short). The content of cellooligosaccharides (3-7) per 5 g of the cellulose-based composition is at least 1.5 mg, but not more than 9.0 mg, and preferably at least 2.0 mg, but not more than 8.0 mg, more preferably at least 3.0 mg but not more than 7.5 mg, even more preferably at least 4.0 mg but not more than 7.5 mg and particularly preferably at least 5.0 mg but not more than 7 .5 mg.

By ensuring that the content of cellooligosaccharides (3-7) per 5 g of the composition is within the above range, any decrease in tablet hardness accompanying an increase in mixing time can be effectively prevented. Where the cellulose-based composition is a powder, it is preferred that each individual particle contains cellulose and cellooligosaccharides (3-7).

[0011] Traditionally, in terms of quality assurance, pharmaceutical additives and nutritional supplements contain the required substances of high purity, and conventional cellulose powders used as pharmaceutical additives are made from pure cellulose with an extremely high degree of purity. In contrast, the cellulose-based composition according to an embodiment of the present invention may contain a predetermined amount of the types of water soluble substances that have typically been removed. These water-soluble substances are composed primarily of monosaccharides such as glucose and sorbitol and cellooligosaccharides such as cellobiose, cellotriose, cellotetraose, cellopentaose, cellohexaose, and celloheptaose. It is important that the total amount of cellotriose, cellotetraze, cellopentose, cellohexaose, and celloheptaose (hereinafter, these components are collectively referred to as "cellooligosaccharides (3-7)"), among these constituent components, is within a predetermined range. When tablet raw materials are mixed, attrition between particles and formation of powders and the like are believed. lead to degradation of interparticle binding properties, causing a decrease in tablet hardness, but it is believed that by using a cellulose-based composition whose cellooligosaccharide content is within the range described above, interparticle binding can be suitably enhanced, which can effectively suppress any decrease in tablet hardness.

[0012] As illustrated in the examples below, the content of cellooligosaccharides (3-7) in 5 g of the cellulose-based composition is measured using liquid chromatography/mass spectrometry (LC/MS). Where the composition contains other components that are likely to overlap with cellooligosaccharide peaks (3-7), liquid chromatography conditions are first adjusted appropriately to allow separation of the peaks. If peak separation is not possible, then in the framework of mass spectrometry, to determine the area of the peak related to cellooligosaccharides (3-7), you can use the extraction ion chromatogram by the ion current of the main peak related to cellooligosaccharides (3-7).

[0013] The content of cellooligosaccharides (3-7) in the cellulose-based composition can be adjusted, for example, by adding cellooligosaccharides (3-7) during preparation of the cellulose-based composition. Commercially available products can be purchased and used as cellooligosaccharides (3-7), or cellooligosaccharides (3-7) can be obtained by appropriate hydrolysis of natural cellulosic material, such as pulp, and then extraction, separation and purification of the desired cellooligosaccharides from the resulting hydrolyzate.

[0014] In the cellulose-based composition according to an embodiment of the present invention, the content of water-soluble substances per 5 g of the cellulose-based composition is preferably at least 0.5 mg, but not more than 12.5 mg, more preferably at least 2, 5 mg but not more than 12.5 mg, even more preferably at least 5.0 mg but not more than 12.5 mg and particularly preferably at least 6.0 mg but not more than 12.0 mg.

By ensuring that the content of water soluble substances is in the above range, it is possible to bring the hardness of the tablet to a more suitable level. In addition, the reactivity with the active component(s) can be effectively suppressed.

[0015] As described in the examples below, the content of water soluble substances can be measured in accordance with the method for testing the purity of crystalline cellulose (2) described in the 17th edition of the Japanese Pharmacopoeia, which allows measurement of the content of water soluble substances per 5 g of a cellulose-based composition.

[0016] In the cellulose-based composition according to an embodiment of the present invention, the proportion of cellooligosaccharides (3-7) in the composition of all water-soluble substances is at least 47% by weight, but not more than 68% by weight, preferably at least 50% w/w but not more than 67% w/w, even more preferably at least 55% w/w but not more than 66% w/w and particularly preferably at least 60% w/w but not more 65% by weight.

By ensuring that the proportion of cellooligosaccharides (3-7) in the composition of water-soluble substances is in the above range, any decrease in hardness due to lengthening of the mixing time can be effectively suppressed. In addition, the reactivity with the active component(s) can also be suppressed to a low level, which also means more suitable storage stability.

The water-soluble substances in the cellulose-based composition according to an embodiment of the present invention can be measured using the method described in the examples below.

[0017] < Form of cellulose-based composition >

The cellulose-based composition according to an embodiment of the present invention preferably exists in the form of a powder, granules, paste or wet cake. From a handling standpoint, cellulose powder is preferred. Cellulose powder is generally described as crystalline cellulose or powdered cellulose or the like, and can be suitably used as a pharmaceutical or food additive. Notable examples of crystalline cellulose include 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 Japanese Standards for Food Additives, crystalline cellulose as described in the Japanese Pharmacopoeia (17th edition) , and crystalline cellulose as described in the USP and the European Pharmacopoeia.

From the point of view of achieving a suitable balance between formability, flowability and disintegration, the average degree of polymerization of cellulose in the cellulose-based composition is preferably not more than 400, and more preferably 350 or less. The lower limit for the average polymerization degree is preferably at least 100. The average polymerization degree of cellulose can be determined using the ethylenediamine-copper complex solution viscosity determination method described in the specification test (3) for crystalline cellulose or the compliance test specifications (3) for powdered cellulose, described in the Japanese Pharmacopoeia.

[0018] < Preferred form of cellulose powder >

When the cellulose-based composition according to an embodiment of the present invention is a powder, the average particle size of the powder is at least 10 µm, but not more than 200 µm, and preferably at least 15 µm, but not more than 100, more preferably at least 20 µm, but not more than 90 µm, even more preferably at least 30 µm, but not more than 70 µm, and particularly preferably at least 40 µm, but not more than 60 µm.

By ensuring that the average particle size does not exceed the above upper limit, the cellulose powder can be more uniformly mixed with active ingredients such as drugs, and compressibility is also improved. In particular, as long as the average particle size is at least 20 μm, the fluidity of the powder generally becomes more suitable.

[0019] The average particle size of the cellulose powder is the particle size in the total volume=50% measured with a laser diffraction type particle size distribution meter (LA-950 V2 (brand) manufactured by Horiba Ltd.).

[0020] When the cellulose-based composition according to an embodiment of the present invention is a powder, the bulk density is preferably at least 0.11 g/ml but not more than 0.35 g/ml, more preferably at least 0.13 g/ml but not more than 0.33 g/ml, and even more preferably at least 0.18 g/ml but not more than 0.31 g/ml.

By ensuring that the bulk density is at least as large as the above lower limit, compressibility can be increased. On the other hand, by ensuring that the free-flowing bulk density does not exceed the above upper limit, sealing properties can be improved.

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

[0021] In cases where the cellulose-based composition according to an embodiment of the present invention is a powder, the bulk density at compaction is preferably at least 0.25 g/ml, but not more than 0.50 g/ml, more preferably at least 0.30 g/ml but not more than 0.45, and yet more preferably at least 0.32 g/ml but not 0.42 g/ml.

By ensuring that the bulk density at compaction is at least as large as the above lower limit, the powder can be more uniformly mixed with active ingredients such as drugs, and handling properties are also improved. On the other hand, by ensuring that the bulk density at compaction does not exceed the above upper limit, any uneven distribution resulting from density differences of the active component(s) or other additives can be more effectively suppressed.

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

[0022] In addition, in cases where the bulk density in a flowable state and the bulk density when compacted simultaneously correspond to the above ranges, tablets obtained by compression molding, as a rule, show excellent compressibility and disintegration.

[0023] When the cellulose-based composition according to an embodiment of the present invention is a powder, the compressibility is preferably at least 25% but not 58%, more preferably at least 30% but not more than 58%. , and even more preferably at least 35% but not more than 58%.

Provided that the compressibility is in the above range, it is possible to increase the flowability of the cellulose powder itself and more effectively suppress uneven distribution of components in the powder.

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

[0024] In cases where the cellulose-based composition according to an embodiment of the present invention is a powder, the average primary particle equivalent particle size (hereinafter, sometimes abbreviated as "primary particle equivalent particle size") is preferably at least at least 15 µm, but not more than 30 µm, more preferably at least 16 µm, but not more than 29 µm, and even more preferably at least 16 µm, but not more than 27 µm.

By ensuring that the particle size equivalent to the primary particle is in the above range, the cellulose powder can be homogeneously mixed with active ingredients such as drugs, and tablet disintegration becomes more suitable.

A primary particle refers to a single particle, and an aggregate or agglomeration of primary particles is called a secondary particle. Aggregates of secondary particles can be broken down and converted into primary particles by dispersion in water. The average particle size equivalent to the primary particles can be determined using the method disclosed in the examples below.

[0025] In cases where the cellulose-based composition according to an embodiment of the present invention is a powder, the ratio of the major axis to the minor axis of the cellulose particles, i. e. aspect ratio (L/D), preferably at least 1.8 but not more than 4.0, more preferably at least 2.1 but not more than 3.5, and even more preferably at least 2.2 , but not more than 3.1.

By ensuring that the aspect ratio is in the above range, miscibility with the active ingredients is also appropriate and the degree of elongated particle engagement is also appropriate, resulting in an excellent balance between compressibility and disintegration.

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

[0026] < Method for producing a cellulose-based composition >

One example of a method for producing a cellulose-based composition according to an embodiment of the present invention is described below.

The cellulose-based composition according to an embodiment of the present invention can be obtained, for example, by a method which includes a step of dispersing a hydrolyzed natural cellulose-based substance in a suitable solvent to obtain an aqueous cellulose dispersion and a step of drying the aqueous cellulose dispersion. There is no particular limitation on the concentration of solids in the aqueous cellulose dispersion, and it can be set, for example, at a value of at least 1% w/w but not more than 30% w/w. In such a case, it is also possible to separate the solid fraction containing the hydrolyzed cellulose-based substance from the hydrolysis reaction solution obtained by hydrolysis, and then dry the dispersion prepared by dispersing the solid fraction in a suitable solvent. In addition, in order to ensure that the content of cellooligosaccharides (3-7) in the cellulose-based composition is within a predetermined range, cellooligosaccharides can be added and mixed with the cellulose dispersion prior to drying. In addition, in cases where the hydrolysis solution itself forms a cellulose dispersion, this dispersion can be directly dried.

[0027] The natural cellulose material may be of plant or animal origin, and examples include cellulose-containing fibrous materials derived from natural material such as wood, bamboo, cotton, ramie, waxwood, bagasse, kenaf, and bacterial cellulose, although said substance preferably has the crystalline structure of cellulose I. As a raw material, one of the above-mentioned natural cellulose-based substances may be used, or a mixture of two or more substances may be used. In addition, it is preferable that the substance is used in the form of refined pulp, but there is no particular limitation on the method of refining the pulp, and any pulp such as dissolving pulp, kraft pulp or NBKP (bleached softwood kraft pulp) can be used.

[0028] In the above production method, water is preferred as the solvent used when dispersing the solid fraction containing the natural cellulose substance in a suitable solvent, but any commercially used solvent can be used without any particular limitation, and, for example, can use an organic solvent. Examples of such organic solvents 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. Particularly preferred are organic solvents used in pharmaceutical products, and examples of such solvents include those classified as solvents in the "Pharmaceutical Excipients Directory 2016" (Published by Yakuji Nippo, Ltd.). Either water or a single organic solvent may be used alone, or a mixture of two or more solvents may be used, and the substance may also be first dispersed in one solvent and, after removal of that solvent, subsequently dispersed in another solvent.

[0029] For example, cellulosic fibers having an average width of at least 2 µm, but not more than 30 µm, and an average thickness of at least 0.5 µm, but not more than 5 µm, can be hydrolyzed with agitation. with a pressure stirrer in hydrochloric acid at a concentration of at least 0.05% w/w but not more than 1.5% w/w at a temperature of at least 70°C but not more than 140° WITH.

The degree of hydrolysis can be controlled by adjusting the power of the agitator motor (P: unit W) and the mixing volume (L: unit L). For example, by adjusting the P/V value represented by the formula below, it is possible to adjust the average size of the ultimately obtained cellulose particles to a value not exceeding 200 μm.

[0030] P/V (W/L)=[actual agitator motor power (W) agitator] / [agitation volume (L)].

[0031] There are no particular restrictions on the drying method used in drying an aqueous dispersion of cellulose to obtain a composition based on cellulose. For example, lyophilization, spray drying, drum drying, rack drying, convection drying, or vacuum drying may be used, and either a single drying method or a combination of two or more drying methods may be used. In the case of spray drying, the spray method may use any of disk spray, pressure nozzle spray, dual jet pressure nozzle spray, and four jet pressure nozzle spray, and either one of these methods may be used, or a combination of two or more methods may be used.

In the case of the above spray drying, a microscopic amount of a water-soluble polymer or surfactant may be added to reduce the surface tension of the dispersion, and a blowing agent or gas may be added to the dispersion in order to accelerate the evaporation rate of the solvent.

[0032] By adjusting the acid concentration and the stirring conditions during the preparation of the aqueous cellulose dispersion, it is possible to obtain an aqueous cellulose dispersion that contains dispersed cellulose particles with an average particle size that corresponds to a given size, water-soluble substances that are included in the cellulose particles in an amount that is within a predetermined range, and cellooligosaccharides (3-7), which are included in the composition of water-soluble substances in an amount that is within a predetermined range, and by adjusting the concentration of solid particles in the aqueous cellulose dispersion and the drying conditions when drying this aqueous cellulose dispersion, it is possible to adjust the average particle size and compressibility of the resulting cellulose-based composition. For example, when drying an aqueous dispersion of cellulose is carried out using a disc-type spray dryer, by ensuring that the stirring power is in the predetermined range when preparing an aqueous dispersion of cellulose, and that the conditions: the concentration of solids in the aqueous dispersion of cellulose and the rotational drying disk type during the spray drying process was within the specified ranges, it is possible to obtain a cellulose-based composition whose average particle size and compressibility are within the specified ranges.

[0033] Further, as described in the following examples, a cellulose-based composition having a content of cellooligosaccharides (3-7) in a predetermined range can be obtained by adding and mixing cellooligosaccharides with an aqueous dispersion of cellulose, and then drying the resulting dispersion mixture.

[0034] Even in cases where the average particle size of the cellulose-based composition after drying exceeds 200 microns, the average particle size can be brought to a value of at least 10 microns, but not more than 200 microns, by feeding the composition to the grinding stage, described below.

[0035] The pulverizing step can be carried out by pulverizing 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 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), very short time mill (FL-250N, manufactured by Dalton Corporation), ball mill (Emax, manufactured by Retsch GmbH), vibrating ball mill (2C, manufactured by TRU) or screen mill, in which case the composition is passed through a sieve (U30 , manufactured by Powrex Corporation). In particular, the jet mill (STJ-200, manufactured by Seishin Enterprise Co., Ltd.) is a convection type crusher in which grinding occurs by causing particles to collide with each other under high air pressure, which facilitates the process of breaking secondary particles into primary particles. and hence is preferred.

[0036] Among the pulverizing conditions in the jet mill crusher, the powder feeding amount and the pulverization pressure are important, and when using the jet mill crusher (STJ-200, manufactured by Seishin Enterprise Co., Ltd.), the feeding amount is preferably at least 10 kg/hour but not more than 20 kg/hour, and more preferably at least 15 kg/hour but not more than 20 kg/hour. Further, the grinding pressure is preferably at least 0.15 MPa but not more than 0.70 MPa, and more preferably at least 0.30 MPa but not more than 0.50 MPa. Provided that the amount of powder supplied and the grinding pressure are within the above ranges, the average particle size is generally easily adjusted to a value in the desired range of at least 10 µm to no more than 200 µm.

Even in cases where the average particle size of the dried cellulose powder is less than 100 µm, by subjecting the cellulose powder to a granulation such as agitated granulation or fluid bed granulation, the average particle size can be adjusted to a value within a desired range of at least 100 µm to no more than about 200 µm.

[0037] <Applications>

By mixing a cellulose-based composition according to an embodiment of the present invention with a composition containing an active ingredient, tablets can be obtained having a suitable hardness and sufficient suppression of both the reduction in tablet hardness caused by the lengthening of the mixing time and the fluctuation in the content of the active ingredient. These effects are particularly pronounced in the case of tablets with an active ingredient content of less than 50% by weight.

In the following description, when discussing the production of a tablet, mixtures obtained by mixing at least one active ingredient, a cellulose-based composition in accordance with an embodiment of the present invention, and any other optional additives, are referred to as a "tablet mixture".

[0038] The proportion of the above-described cellulose-based composition in the composition of the tablet mixture, presented relative to the total weight of the resulting tablet, is usually at least 1% by weight, but not more than 90% by weight, preferably at least 1% by weight ratio, but not more than 50% by weight, more preferably at least 1% by weight, but not more than 30% by weight, even more preferably at least 3% by weight, but not more than 20% by weight ratio, and particularly preferably at least 5% by weight, but not more than 15% by weight.

[0039] [ Active Component ]

Examples of components ideally suited as an active ingredient for inclusion in a tablet mixture are described below.

The pharmaceutical drug component is preferably an active component of a pharmaceutical preparation for oral administration. Examples of pharmaceutical preparations for oral administration include antipyretic analgesics, anti-inflammatory agents, sedative hypnotics, anti-drowsiness agents, anti-vertigo agents, analgesics for children, gastric agents, antacids, digestive aids, cardiotonic agents, antiarrhythmic agents, antihypertensive agents, vasodilators , diuretics, anti-ulcer agents, intestinal regulators, osteoporosis agents, anti-cough agents, anti-asthma agents, antimicrobial agents, pollakiuria ameliorators, nutritional tonics and vitamins. Any of these drug components may be used alone, or a combination of two or more components may be used.

[0040] Specific examples of drug components include aspirin, aspirin aluminum, acetaminophen, ethensamide, sazapyrin, salicylamide, lactylfenetidine, isotypendyl hydrochloride, diphenylpyralin hydrochloride, diphenhydramine hydrochloride, diferol hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, tonsylamine hydrochloride, phenetazine hydrochloride, methdylazine hydro chloride, diphenhydramine salicylate, carbinoxamine diphenyl disulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyralin theocrat, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, diferol phosphate, alloclamide hydrochloride, clopera styne hydrochloride, pentoxyverine citrate (carbetapentane citrate), tipepidine citrate, sodium dibunate, dextromethorphan hydrobromide, dextromethorphan phenol phthalate, tipepidine gibenzat, cloperastine fendisoate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guaiacolsulfonate, guaifenesin , caffeine-sodium benzoate , caffeine, caffeine anhydrous, vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts, vitamin B6 and its derivatives and their salts, nicotinamide, calcium pantothenate, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, aluminum hydroxide dry gel, mixture of aluminum hydroxide and magnesium carbonate dry gel, coprecipitation of aluminum hydroxide and sodium bicarbonate, coprecipitation of aluminum hydroxide, calcium carbonate and magnesium carbonate, coprecipitation of magnesium hydroxide and aluminum potassium sulfate, 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, diphenylpyraline theocrat, diphenhydramine fumarate, promethazine methylene disalicylate, scopolamine hydrobromide, oxyphencyl imine hydrochloride, dicyclomine 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, ethylpiperidylacetylaminobenzoate , aminophylline, diprophylline, theophylline, sodium bicarbonate, fursulthiamine , isosorbide mononitrate, ephedrine, cephalexin, ampicillin, sulfisoxazole, sucralfate, allylisopropylacetylurea, bromovaleryl urea, as well as ephedra, nantensite, oochi, istod root, licorice, broadbell, psyllium seeds, psyllium plant, senegu, hazel grouse, fennel, cork tree bark, rhizome coptis, turmeric rhizome, chamomile, cassia bark, gentian, oriental bezoar, animal bile (including bear bile), syazin, ginger, Atractylodes lancea rhizome, clove, satsumu, atractylodes rhizome, ziryuu, common ginseng rhizome, ginseng, Japanese valerian , peony root bark, zanthoxylum (Japanese pepper) and extracts of these plants; and pharmaceutical drug components described in the Japanese Pharmacopoeia, Japanese Pharmaceutical Code (JPC), United States Pharmacopeia (USP), National Formulary (NF) and European Pharmacopoeia (EP) such as insulin, vasopressin , interferon, urokinase, serratiopeptidase and somatostatin. One substance selected from the above substances may be used alone, or a combination of two or more substances may be used.

[0041] There are no particular restrictions on the dietary food active ingredients that can be used, as long as the ingredient is added for the purpose of improving health, and examples include green juice powder, aglycone, mushroom, ashwagandha, astaxanthin, acerola, amino acids (such as valine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid, seaweed powder, glutamine, glutamic acid, glycine, proline, and serine) , alginic acid, ginkgo biloba extract, sardine peptides, turmeric, uronic acid, echinacea, eleutherococcus, oligosaccharides, oleic acid, nuclear proteins, bonito peptide, catechin, potassium, calcium, carotenoids, garcinia, L-carnitine, chitosan, conjugated linoleic acid , Aloe arborescens, Gymnema sylvestre extract, Citric acid, Orthosiphon stamineus, Glycerides, Glycerin, Glucagon, Curcumin, Glucosamine, L-glutamine, Chlorella, Cranberry extract, Ucaria pubis, Germanium, Enzymes, Ginseng extract, Coenzyme Q10, Collagen, Peptides collagen, Coleus forskolin, chondroitin, psyllium husk powder, hawthorn extract, saponin, lipids, L-cystine, perilla extract, citrimax, fatty acids, phytosterols, seed extracts, spirulina, squalene, white willow, ceramides, selenium, St. John's wort extract, soy isoflavone, soy saponin, soy peptide, 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, cob extract, herbal extracts, 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, flavonoids, butcher's broom extract, cimicifugu, blueberry, plum extract, proanthocyanidin, proteins, propolis, bromelain, probiotics, phosphatidylcholine, phosphatidylserine, β-carotene, peptides, safflower extract, extract curly vulture, maca extract, magnesium, milk thistle, manganese, mitochondria, minerals, mucopolysaccharides, melatonin, Fomes yucatensis, sweet clover extract powder, molybdenum, vegetable powders, folic acid, lactose, lycopene, linoleic acid, lipoic acid, phosphorus , lutein, lecithin, rosmarinic acid, royal jelly, DHA (docasahexaenoic acid) and EPA (eicosapentaenoic acid).

[0042] The active ingredient may be water soluble or may be sparingly soluble in water. The term sparingly soluble in water is defined in the 17th edition of the Japanese Pharmacopoeia as requiring 30 ml or more of water to dissolve 1 g of a substance that is soluble in another.

Examples of solid, sparingly water-soluble active ingredients include pharmaceutical drug ingredients described in the Japanese Pharmacopoeia, Japanese Pharmaceutical Code, USP, NF, and EP, including antipyretic analgesics, drugs for the nervous system, hypnotics, sedatives, muscle relaxants, antihypertensives, and antihistamines 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, sodium theophylline, 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, methylandrostenediol, progesterone, estradiol benzoate, ethinylestradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, and prednisolone; non-steroidal estrogenic hormones such as dienestrol, hexestrol, diethylstilbesterol, diethylstilbestrol dipropionate and chlortrianisene; and other fat-soluble vitamins. One substance selected from the above substances may be used alone, or a combination of two or more substances may be used. If the substance is sparingly soluble in water, then regardless of the sublimability and the degree of surface polarity, the effects of the present invention can be achieved by mixing the active ingredient with the tablet mixture.

[0043] The active ingredient may also be a sparingly water-soluble oil or liquid. Examples of sparingly water-soluble oily or liquid ingredients that can be used as active ingredients include pharmaceutical drug ingredients described in the Japanese Pharmacopoeia, Japanese Pharmaceutical Code, 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 DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid) and cod liver oil; substances of the group of coenzymes Q; and oil soluble flavorings such as orange oil, lemon oil and peppermint oil. Vitamin E has various homologues and derivatives, but there is no particular restriction on the form of vitamin E, as long as it is a liquid at normal temperatures. Specific examples include dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol and d-α-tocopherol acetate. One substance selected from the listed substances may be used alone, or a combination of two or more substances may be used.

[0044] The active ingredient may be a semi-solid active ingredient that is sparingly soluble in water. Examples of semi-solid active ingredients sparingly soluble in water among the various active ingredients include traditional Chinese medicine components or crude medicinal extracts such as ziryuu, licorice, Chinese cinnamon bark, Chinese peony, peony root bark, Japanese valerian, zanthoxylum, ginger, satsuma, ephedra , nantenzizu, oohi, istoda root, platycodon root, plantain seeds, plantain herb, licorice radiata bulb, senega, fritillaria bulb, fennel, phellodendron bark, coptis rhizome, zedoaria turmeric, chamomile, gentian, oriental bezoar, animal bile, syazin, ginger , Atractylodes lancea rhizome, clove, satsuma, atractylodes rhizome, panax rhizome, ginseng, kakkon-to, keishi-to, kusosan, saiko-keishi-to, sho-saiko-to, sho-seiryu-to, bakumondo-to, hange - koboku something and mao something; as well as oyster meat extract, propolis or propolis extract and coenzyme group Q substances. A single substance selected from the above substances may be used alone, or a combination of two or more substances may be used.

[0045] The active ingredient may be a sublimate. Examples of such ingredients include freeze-dried pharmaceutical drug ingredients described in the Japanese Pharmacopoeia, Japanese Pharmaceutical Code, USP, NF, or EP, including benzoic acid, ethensamide, caffeine, camphor, salicylic acid, phenacetin. and ibuprofen. One substance selected from these substances may be used alone, or a combination of two or more substances may be used. In this description, there is no particular limitation on the sublimable component, provided that it has the ability to sublimate, and the component can be in any state: solid, liquid or semi-solid at normal temperatures.

[0046] Further, as the active ingredient, drug ingredients whose maximum dosage size per tablet is small can be used particularly suitably.

Examples of drug ingredients whose maximum dosage size per tablet is small include the following drug ingredients, which are added in amounts of not more than 100 mg or not more than 10 mg.

[0047] Examples of medicinal components, the maximum dosage of which exceeds 100 mg per tablet, include abakavir, acetazolamide, acetylsalicylic acid, acyclovir, albendazole, Alicine Fumarat, Allopurinol, Amiodaron, Amoxicillin, Abstract, Artemometer, Arctesunom T, 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, diloxanide, 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, pyrazines e, 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.

[0048] Examples of drug components, the maximum dosage size of which exceeds 10 mg, but is not more than 100 mg 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, gliclazide, sodium ibandronate hydrate, losartan, miglitol, nitrofurantoin, phenobarbital, phenytoin, pyridostigmine, raloxifene hydrochloride, ritonavir, succimer , telmisartan, topiramate and verapamil.

[0049] Examples of drug components whose maximum dosage size does not exceed 10 mg 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 besilate, 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, silodosin, solifenacin succinate, and warfarin.

[0050] These active ingredients and drug ingredients can be mixed in a finely divided state, together with a cellulose-based composition in accordance with an embodiment of the present invention, into a tablet mixture. For example, the active ingredient used in the present invention can be finely divided to an average particle size of at least 1 µm, but not more than 40 µm, for purposes such as improving the dispersibility of the active ingredient or increasing the uniformity of mixing of the therapeutic active ingredient. action in very small quantities. The average particle size of the active ingredient is more preferably at least 1 µm, but not more than 20 µm, and even more preferably at least 1 µm, but not more than 10 µm.

[0051] The proportion of the above active ingredient in the composition of the tablet mixture, given relative to the total weight of the resulting tablet, is generally less than 50% by weight and preferably not more than 40% by weight, more preferably not more than 30% by weight, even more preferably not more than 20% by weight, and particularly preferably 10% by weight or less. In practice, a lower limit=0.01% w/w is applicable. If the proportion of the active ingredient is less than 50% by weight, uneven distribution tends to occur more easily, requiring a concomitant lengthening of the mixing time. However, when using the cellulose-based composition according to the embodiment of the present invention, since any decrease in tablet hardness caused by lengthening the mixing time can be effectively suppressed, the cellulose-based composition according to the embodiment of the present invention exhibits particularly remarkable effects when used in tablets, the content of the active ingredient in which is within the range described above.

[0052] [ Lubricant ]

The tablet mixture preferably contains a lubricant in addition to the active ingredient described above.

One or more compounds selected from the group consisting of fatty acid metal salts, fatty acid esters, and fatty acid metal ester salts may be used as a lubricant, and specific examples include those compounds classified as lubricants in the Pharmaceutical Compendium. excipients 2016" (published by Yakuji Nippo, Ltd.), such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters and talc. A single compound selected from the above lubricants may be used alone, or a combination of two or more lubricants may be used.

[0053] The proportion of the above lubricant in the composition of the tablet mixture, presented relative to the total weight of the resulting tablet, is usually at least 0.3% w/w, but not more than 5% w/w, and preferably at least 0 .5% by weight, but not more than 3% by weight.

[0054] [ Other Additives ]

The tablet mixture may also contain other additives in addition to the active ingredient described above.

Examples of these other additives include bulking agents, disintegrants, binders, fluidizers, flavoring agents, flavoring agents, colorants, and sweeteners.

[0055] Examples of excipients other than the cellulose-based composition include those substances classified as excipients in the 2016 Pharmaceutical Excipients Handbook (published by Yakuji Nippo, Ltd.), such as starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic Acid, Corn Syrup (Powder), Gum Arabic, Powdered Gum Arabic, Alginic Acid, Sodium Alginate, Peptized Starch, Pumice Particles, Inositol, Ethylcellulose, Ethylene Vinyl Acetate, Sodium Chloride, Olive Oil, Kaolin, Cocoa Butter, Casein, Fructose, Particles Pumice Stones, Carmellose, Carmellose Sodium, Hydrous Silica, Dry Yeast, Dry Aluminum Hydroxide Gel, Dry Sodium Sulfate, Dry Magnesium Sulfate, Agar, Agar Powder, Xylitol, Citric Acid, Sodium Citrate, Disodium Citrate, Glycerin, Calcium Glycerophosphate, Sodium Gluconate , L-Glutamine, Clay, Clay 3, Clay Particles, Croscarmellose Sodium, Crospovidone, Magnesium Aluminosilicate, Calcium Silicate, Magnesium Silicate, Fluffy Anhydrous Silicate, Fluid Liquid Paraffin, Cinnamon Powder, Crystalline Cellulose, Crystalline Cellulose Carmellose Sodium, Crystalline cellulose (particles), koji on brown rice, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, rice flour, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-dibutyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, calcined gypsum, sucrose fatty acid ester, aluminum oxide Magnesium Hydroxide Gel, Aluminum Hydroxide and Sodium Bicarbonate Coprecipitate, Magnesium Hydroxide, Squalene, Stearyl Alcohol, Stearic Acid, Calcium Stearate, Polyoxyl Stearate, Magnesium Stearate, Rejected Soybean Oil, Refined Gelatin, Refined Shellac, Refined White Sugar, Refined White Sugar Granules , cetostearyl alcohol, polyethylene glycol monocetyl ether 1000, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soy unsaponifiables, soy lecithin, skimmed milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral Sodium Sulfate Anhydrous, Low Substitution Hydroxypropyl Cellulose, Dextran, Dextrin, Natural Aluminum Silicate, Corn Starch, Powdered Tragacanth, Silicon Dioxide, Calcium Lactate, Lactose, Lactose Granules, Perfiller 101, White Shellac, White Vaseline, White Clay, White Sugar, white starch sugar granules, green barley leaf extract powder, dried barley bud 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, Reduced Maltose 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 polystyrenesulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltitol, maltose, D-mannitol, glucose syrup, isopropyl myristate, lactose anhydrous, anhydrous calcium orthophosphate, anhydrous calcium phosphate in granular form, magnesium aluminometasilicate, methylcellulose, cottonseed powder, cottonseed oil, wood wax, aluminum monostearate, glycerol monostearate, sorbitan monostearate, pharmaceutical charcoal, peanut oil, aluminum sulfate, calcium sulfate, granulated cornstarch, liquid paraffin, dl- malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate in the form of granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate and sodium dihydrogen phosphate. One of these excipients may be used alone, or a combination of two or more excipients may be used.

[0056] Examples of disintegrants include those substances that are classified as disintegrants in the 2016 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. You can use one substance selected from the above disintegrators, or you can use a combination of two or more disintegrators.

[0057] Examples of binders include those classified as binders in the 2016 Pharmaceutical Excipients Handbook (published by Yakuji Nippo, Ltd.), including sugars such as white sugar, 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. A single agent selected from the above binders may be used alone, or a combination of two or more binders may be used.

[0058] Examples of fluidizers include those substances classified as fluidizers in the 2016 Pharmaceutical Excipients Handbook (published by Yakuji Nippo, Ltd.), including silicon compounds such as hydrous silica and loose anhydrous silicate. One substance selected from the above fluidizers can be used alone, or a combination of two or more fluidizers can be used.

[0059] Examples of flavoring agents include those substances that are classified as flavoring agents in the 2016 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. A single substance selected from the above flavors may be used alone, or a combination of two or more flavors may be used.

[0060] Examples of flavors include those substances classified as flavors in the 2016 Pharmaceutical Excipients Handbook (published by Yakuji Nippo, Ltd.), including orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil and peppermint oil; and green tea powder. A single substance selected from the flavors mentioned above may be used alone, or a combination of two or more flavors may be used.

[0061] Examples of colorants include those substances that are classified as colorants in the 2016 Pharmaceutical Excipients Handbook (published by Yakuji Nippo, Ltd.), including food colorings such as Food Red #3, Food Yellow #5, and Food Blue # 1; sodium copper chlorophyllin, titanium oxide and riboflavin. A single substance selected from the above dyes may be used alone, or a combination of two or more dyes may be used.

[0062] Examples of sweeteners include those substances classified as sweeteners in the 2016 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. A single substance selected from the above sweeteners may be used alone, or a combination of two or more sweeteners may be used.

[0063] < Method of making a tablet >

The method for manufacturing a tablet by compressing the above tablet mixture (the method for manufacturing a tablet according to an embodiment of the present invention) is described in detail below, but this method is just one example, and the effects of the embodiments of the present invention are not limited to the method described below.

[0064] As a tablet manufacturing method, a method in which an active ingredient and a cellulose-based composition according to an embodiment of the present invention are mixed together and then subjected to compression molding (compression) can be used. During this process, besides the active ingredient, other additives can be mixed into the mixture, if necessary. Examples of other additives include one or more components selected from such components as lubricants, fillers, disintegrators, binders, fluidizers, flavors, flavors, colors, sweeteners and solubilizers described above.

[0065] There are no particular restrictions on the order in which the various components are added, and any of (i) a method in which the active component, the cellulose-based composition according to an embodiment of the present invention, and any other necessary additives are mixed in one kneading, and the resulting mixture is then subjected to compression molding, (ii) a method in which the active ingredient and some optional additives are premixed, the obtained premix is then mixed with a cellulose-based composition in accordance with an embodiment of the present invention and other optional additives, and the resulting the mixture is then subjected to compression molding, and (iii) a method in which the active ingredient, the cellulose-based composition according to the embodiment of the present invention and other necessary additives are premixed, the resulting premixture is then mixed with other additives if necessary, and then the resulting mixture subjected to compression molding. Method (i) is preferred in terms of ease of operation. There are no particular restrictions on the method used to add each of the components, and any commonly used method can be used to add the components either continuously or in batches, using a small suction conveying device, an air conveying device, a bucket conveyor, a conveying device displacement feed, vacuum conveyor, vibratory type dispenser, sprayer or funnel, or the like. Examples of atomization methods that can be used include methods for spraying a solution or dispersion of an active ingredient using a pressure nozzle, a two-jet nozzle, a four-jet nozzle, a rotating disc, or an ultrasonic nozzle, and the like, as well as methods for dropping a solution or dispersion of the active ingredient from tubular nozzle.

[0066] There are no particular restrictions on the mixing method, and any commonly used method can be used using a rotary vessel mixer such as a V-type mixer, a W-type mixer, a double cone type mixer, or a container type mixer; an agitated mixer such as a high speed agitator, general purpose agitator, ribbon agitator, pug grinder, or Nauta mixer; or a super mixer, drum mixer or fluidized bed mixer. In addition, a shaker vessel mixer such as a shaker or the like may also be used.

[0067] There are no particular restrictions on the method used to compress the composition, and any commonly used method can be used, including methods in which a mortar and pestle is used to achieve compression molding into the desired shape, or methods in which the composition is first subjected to compression molding into a sheet shape, and then this sheet is cut into pieces of the desired shape. Examples of compression molding devices that can be used include roller presses such as a hydrostatic press, a briquette roller press or a smoothing roller press, and compressors such as a single punch tablet machine or a rotary tablet machine.

[0068] There is no particular limitation on the method used to dissolve or disperse the active ingredient in the medium, and commonly used methods of dissolution or dispersion can be used, including mixing methods using stirring paddles, for example, unidirectional rotation paddles, multi-axis rotation paddles , a reciprocating blade, a vertically moving blade, a rotating and vertically moving blade, and a tubular blade, such as a portable mixer, an spatial mixer, and a mixer with a side wall; jet-type agitation mixing methods, for example using an in-line mixer; mixing methods with agitation by gas purge; mixing methods using a high shear homogenizer, high pressure homogenizer or ultrasonic homogenizer or the like; and shaking mixing methods using a shaker or the like.

[0069] There is no particular limitation on the solvent used in the above-described manufacturing method, as long as the solvent is suitable for use in pharmaceutical products, and, for example, at least one solvent selected from water and an organic solvent can be used. Examples of organic solvents include those compounds classified as solvents in the 2016 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 can be used alone, a combination of two or more solvents can be used, or the initial dispersion can be done in one solvent and then that solvent can be removed and the product can be dispersed in another solvent.

[0070] When dissolving the active ingredient in a medium, a water-soluble polymer, an oil or fat, or a surfactant or the like can be used as a solubilizer. Examples of water-soluble polymers, oils and fats, and surfactants that can be used as solubilizers include those described in the 2016 Pharmaceutical Excipients Handbook (published by Yakuji Nippo, Ltd.). One of these solubilizers may be used alone, or a combination of two or more solubilizers may be used.

[0071] In this specification, the term "shaped article" refers to an article in the form of a granule, fine granule, briquette, or tablet, or the like, containing a cellulose-based composition according to an embodiment of the present invention, at least one active ingredient, and , if necessary, other additives.

Examples of the method used to form tablets include direct tableting methods in which a mixture prepared by mixing at least one active ingredient and a cellulose-based composition according to an embodiment of the present invention is subjected to compression molding, or a mixture prepared by mixing at least one active ingredient, a cellulose-based composition according to an embodiment of the present invention and, if necessary, other additives. Other manufacturing methods can be used, including a multi-core tablet manufacturing method in which a pre-compression molded tablet is used as the inner core, and a multi-core tablet manufacturing method in which a plurality of pre-compression molded articles are stacked and compressed again. The direct tableting process is preferred in terms of productivity and ease of process control.

[0072] The compression molded tablet (molded article) can be further coated. Examples of coating materials that can be used in such cases include the coating materials described in the 2016 Pharmaceutical Excipients Handbook (published by Yakuji Nippo, Ltd.). One of these coating materials may be used alone, or a combination of two or more coating materials may be used.

[0073] Where the manufacturing process includes a granulation step, examples of the granulation method include dry granulation, wet granulation, heat granulation, spray granulation, and microencapsulation. More specifically, among various wet granulation methods, fluid bed granulation, agitation granulation, extrusion granulation, crushing granulation, and rolling granulation are effective. In the fluidized bed granulation method, granulation is carried out in a fluidized bed granulator by spraying a binder solution onto the fluidized powder. The agitated granulation method simultaneously mixes, kneads, and granulates the powder in a sealed structure by rotating the agitating paddle in the mixing tank while adding the binder solution. In the extrusion granulation method, granulation is carried out by forcibly squeezing out the wet mass, kneaded with the addition of a binder solution, from a sieve of suitable size by the helical or basket method. In the crusher granulation method, granulation is carried out by cutting and crushing the wet mass, kneaded with the addition of a binder solution, by a rotating blade of the granulator, and the resulting centrifugal force pushes the crushed wet mass through the outer circumferential sieve. In the rolling granulation method, spherical granules are rolled by the centrifugal force of a rotating rotor while the binder solution is atomized from the atomizer, whereby spherical granules having the same particle size grow like a snowball.

[0074] Any of various methods can be used in the method for drying the granules, including hot air heating (shelf drying, vacuum drying, fluid bed drying), heat transfer by conduction (flat tray drying, shelf box drying, and drum drying). ) and lyophilization. Hot air heating brings the hot air into direct contact with the additive and at the same time removes the evaporating water. In the case of heat transfer by conduction, the additive is indirectly heated through the heat transfer wall. In freeze-drying, the additive is frozen at a temperature of at least -10°C, but not higher than 40°C, and the water is then removed by sublimation under high vacuum heating (at least 1.3×10 ^-5 MPa, but not above 2.6×10 ^-4 MPa).

EXAMPLES

[0075] Embodiments of the present invention are described in detail below using a number of examples and comparative examples, but the embodiments of the present invention are not limited to these examples. The various physical properties described in these examples and comparative examples and the methods used to determine these properties are those described below. Where the sample contained a large amount of water, the sample was pre-dried to reduce the water content to at least 3.5% w/w but not more than 4.5% w/w before various physical properties.

[0076] < Method for analyzing compositions based on cellulose >

[ Analysis 1 ]

(Method for determining the content of water-soluble substances in a composition based on cellulose)

The content of water-soluble substances in the cellulose-based composition was determined in accordance with the purity test method (2) of crystalline cellulose described in the 17th edition of the Japanese Pharmacopoeia.

Specifically, 80 ml of purified water was added to 5.0 g of the cellulose-based composition, and the mixture was shaken and stirred for 10 minutes. Subsequently, the solution containing the cellulose-based composition was subjected to vacuum filtration using a filter paper for quantitative analysis (type 5C). The filtrate was evaporated to dryness without charring in a beaker of known weight, subsequently dried at 105° C. for one hour, and then allowed to cool in a desiccator to obtain a residue. Then, the weight of the residue thus obtained was weighed to determine the weight of the residue. Each powder was measured twice and the average value was used. In addition, a control test was also carried out by the above operations using only 80 ml of purified water without adding 5.0 g of the cellulose-based composition, and the content of water soluble substances found in the control test was subtracted from the measured value to obtain a value. This value was rounded to the second decimal place to obtain the measured value for the content of water soluble substances. The content of water soluble substances, determined using this test method, is the amount of water soluble substances contained in 5 g of the composition based on cellulose.

[0077] [ Analysis 2 ]

(Method for measuring cellooligosaccharides content (3-7)

The total mass of water-soluble substances as a dried solid obtained in the above "Assay 1" was redissolved in 10 ml of 50% (v/v) acetonitrile aqueous solution, the resulting solution was filtered through a filter (0.20 μm), and then LC/ MS to measure cellooligosaccharides (3-7).

During the preparation and dilution of the measuring solution, an accurate balance was used, and a certain weight was used to determine the concentration of the sample and the degree of dilution.

In addition, to measure cellooligosaccharide content, solutions of known concentrations prepared using commercially available products of cellotriose (trisaccharide), cellotetraz (tetrasaccharide) and cellopentose (pentasaccharide) were analyzed by LC/MS, retention time and peak area on m/z ionic chromatograms for each cellooligosaccharide, and built calibration curves (sample concentration versus peak area). Using these calibration curves, the amount of each cellooligosaccharide in the composition of water-soluble substances was determined (in 5 g of the composition based on cellulose).

The amounts of cellohexaose (hexasaccharide) and celloheptaose (heptasaccharide) for which there are no commercially available products were determined using the following calculation method using the trends observed in peak areas when previously measured solutions from glucose (monosaccharide) to cellopentaose (pentasaccharide) were analyzed in those the same concentrations. The total amount of each oligosaccharide was recorded as a value rounded to the second decimal place.

[0078] (Calculation method)

Cellohexaose (hexasaccharide): Using the cellopentose (pentasaccharide) calibration curve, the peak area was replaced with the cellohexaose (hexasaccharide) peak area, and the thus obtained cellooligosaccharide content was multiplied by a correction factor (0.729) to calculate the amount of cellohexaose (hexasaccharide).

Celloheptaose (heptasaccharide): Using the calibration curve for cellopentaose (pentasaccharide), the peak area was replaced with the peak area for celloheptaose (heptasaccharide), and the cellooligosaccharide content thus obtained was multiplied by a correction factor (0.531) to calculate the amount of celloheptaose (heptasaccharide).

[0079] The LC/MS measurements were carried out in accordance with the measurement conditions listed below. If measurements are made while changing part of the following conditions, then the calibration curves for cellooligosaccharides described above should be reproduced according to the changed conditions.

[0080] (Measurement conditions)

LC apparatus: Nexera, manufactured by Shimadzu Corporation

Column: Asahipak NH2P-50 2D (inner diameter 2 mm × 150 mm), manufactured by Shodex 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 shown in Table 1 below.

Injection volume: 10 µl

MS Apparatus: Synapt G2, manufactured by Waters Corporation

Ionization conditions: ESI ^-

Scan Range: m/z 50 to 2000

[0081] [Table 1]

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

[0082] For reference, the detected ion (m/z) and retention time for each structural component observed under the measurement conditions described above are shown in Table 2 below.

[0083] [Table 2]

Detected ion m/z Retention time (min) Cellotriose trisaccharide 549.17 [M+HCOO] ^- 9.2 Cellotetraose tetrasaccharide 711.22 [M+HCOO] ^- 10.3 cellopentaose pentasaccharide 873.28 [M+HCOO] ^- 11.2 Cellohexaose hexasaccharide 989.32 [MH] ^- 11.9 Celloheptaose heptasaccharide 1151.38 [MH] ^- 12.5

[0084] < Method for determining the physical properties of the powder >

Methods for determining the physical properties of the powder when the cellulose-based composition is a cellulose powder are described below.

[0085] [ Physical Property 1 ]

(Average particle size)

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

[0086] [ Physical property 2 ]

(Bulk density in bulk state)

For this measurement, cellulose powder was used, the water content of which was adjusted to a value of at least 3.5% w/w but not more than 4.5% w/w. When the water content of the cellulose powder was below this range, the water content of the cellulose powder was controlled to allow the powder to absorb moisture in a constant temperature and humidity chamber or the like. In cases where the water content exceeded the above range, the water content was adjusted to within the above range by evenly blowing hot air at 60° C. onto the pulp powder in a hot air oven.

[0087] Subsequently, a Scott volumemeter (Model: ASTM B-329-85, manufactured by Tsutsui Rikagaku Kikai) was used to measure the bulk density of the cellulose powder by passing the cellulose powder through a sieve (hole size=1 mm) and filling a cylindrical metal container 25 ml. The powder on top of a 25 ml cylindrical metal container containing cellulose powder was flattened, and the weight (g) of cellulose powder 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.

[0088] [ Physical property 3 ]

(Bulk density at compaction)

For this measurement, cellulose powder was used, the water content of which was adjusted to a value of at least 3.5% w/w but not more than 4.5% w/w. The water content was adjusted to within this range using the method described in the Physical Property 2 section above. Compaction bulk density (apparent compaction density) (g/mL) was calculated using a powder physical property measuring apparatus (PT-R, manufactured by Hosokawa Micron Corporation). The sieve used had a mesh size of 710 µm and the funnel used was made of metal (coated with an antistatic spray liquid) and had an inside diameter of 0.8 cm. VAC, 60Hz).

[0089] [ Physical property 4 ]

(Compressibility)

The compressibility of each cellulose powder was calculated using the following formula.

[0090] Compressibility (%)=([Compacted Bulk Density] - [Free-flowing Bulk Density]) / [Compacted Bulk Density] × 100

[0091] [ Physical property 5 ]

(Particle size equivalent to primary particle)

First, 0.5 g of cellulose powder was placed in 10 ml of pure water, and after sonication (600 W, 40 kHz) for 10 minutes, a laser diffraction type particle size distribution meter (LA-950 V2 (brand), manufactured by Horiba, Ltd.) for wet measurements under conditions including refractive index=1.20 (cellulose refractive index: 1.59, water refractive index=1.33), pre-treatment conditions (sonication=1 minute, sonication intensity waves=1), circulation rate=7 and agitation rate=5. Particle size in total volume=50% distribution obtained by measurement was considered to be the average particle size equivalent to primary cellulose particles (particle size equivalent to primary particle) (µm).

[0092] [ Physical Property 6 ]

(L/D ratio (long axis to short axis of cellulose particles))

The cellulose powder was scattered on a glass plate, and an image was taken with a microscope (VHX-1000, manufactured by Keyence Corporation) at a magnification of 500X. The captured image was analyzed with an image analysis and processing system software (Image Hyper II, manufactured by DigiMo Co., Ltd.) using the procedures described below, and the aspect ratio (long axis to short axis ratio; L/D) of the particles was determined. Measurements were made on at least 50 particles and an average value was determined.

[0093] (1) Procedure 1 : Binary conversion (binarization) process

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

[0094] (2) Procedure 2 : Manual override binarization

When compared with the original image, particles that failed to obtain a suitable measurement result, such as overlapping particles, particles that protrude from the edges of the image, and particles with fuzzy or blurry outlines, were removed and excluded from the image of the measurement target.

[0095] (3) Procedure 3 : Filling Holes

Hole filling was performed using the "hole filling" mode, with "8" selected for the "neighborhood" setting. Subsequently, a second comparison was made with the original image using "manual correction binarization", and it was checked whether correction could be performed in the direction of normalization. In cases where normalization could not be achieved, another manual correction was performed.

[0096] (4) Procedure 4 : Image measurement

The number of pixels to be removed was set to "100" and "neighborhood" to "8", and then the "image measurement" operation was performed. The measurement results of "long axis" and "short axis" for each measured particle were displayed on a personal computer. As a characteristic ratio, a numerical value obtained by dividing the "long axis" by the "short axis" was used.

[0097] < Method for Evaluating Tablets >

The tablets were made and subjected to a series of evaluations using the methods described below.

[0098] [ Preparation of powder for tableting ]

The raw materials described below (excluding magnesium stearate as a lubricant) for making the mixture were placed in a V-type mixer (V-5, manufactured by Tokuju Corporation) and mixed for 60 minutes.

[0099] [Table 3]

Blend 1 Blend 2 Blend 3 Blend 4 d-chlorpheniramine maleate 20 g - 20 g 20 g Folic acid - 4g - - Cellulose based composition 200 g 200g 200 g 200 g Mannitol 1760 1776g 1720 1770 magnesium stearate 20 g 20g 60 g 10 g

[0100] Subsequently, magnesium stearate was added as a lubricant, and mixing was carried out for either 5 minutes or 30 minutes to obtain a tableting powder (mixing time: 5 minutes or 30 minutes).

[0101] [Production of tablets]

Tableting powder (mixing time: 5 minutes or 30 minutes) was tabletted for 10 minutes using a rotary tableting machine (Clean Press Correct 12HUK, manufactured by Kikusui Seisakusho Ltd., 12 production units, turntable: 54 rpm, open feeding mechanism, applied pressure: 7 kN), thus obtaining 200 mg Ø8 mm-12R tablets.

[0102] [ Score 1 ]

(Tablet hardness and tablet hardness reduction rate)

The hardness tablets were those taken within 30 seconds immediately prior to the shutdown of the rotary tablet machine. The hardness of each tablet was measured at least 20 hours but not more than 48 hours after tableting using a hardness tester (Dr. Schleuniger Tablet Tester 8M). The average value for 10 tablets at each tableting pressure was considered tablet hardness. Tablets having a hardness of at least 55 N were considered suitable.

[0103] In addition, the tablet hardness reduction rate was determined using the following formula based on the difference between the hardness (N1) of tablets obtained from tableting powder (mixing time: 5 minutes) and the hardness (N2) of tablets obtained from tableting powder. tableting (mixing time: 30 minutes).

[0104] Tablet hardness reduction rate (%)=(1-N2/N1)×100

[0105] [ Score 2 ]

(CV value (coefficient of variation) of active ingredient content)

First, a calibration curve was built for the active ingredient. Specifically, an absorption spectrum of the active ingredient was determined using an absorption spectrometer, and a calibration curve was generated based on the peak tip wavelength (for example, in the case of d-chlorpheniramine maleate: 264 nm, in the case of folic acid: 290 nm).

[0106] Tablets for measuring the CV value of the content of the active ingredient were tablets taken within 30 seconds immediately before stopping the tableting machine. One tablet was weighed and then placed in a 100 ml volumetric flask, which was subsequently made up to 100 ml with pure water. The resulting aqueous solution was filtered through a polymer filter to remove the insoluble fraction, and the amount of the active component in the filtrate was determined using absorptiometry. The content of the active component in one tablet was calculated. In the case of tablets, a total of ten tablets were measured, and the mean value and standard deviation for the active ingredient content were determined.

[0107] Subsequently, using the formula below, the coefficient of variation (also referred to as the "active component content CV value"), which acts as an index of uniformity, was determined. A lower coefficient of variation was evaluated as an indicator of suitable content uniformity of the active ingredient.

[0108] CV value of active ingredient content (%)=([standard deviation] / [average value for active ingredient content]) × 100

[0109] [ Score 3 ]

(Failure in tableting process)

In the Tablet Production section above, the bottom pestles of the rotary tableting machine were visually inspected after a 10-minute tableting operation, and the level of pestle staining (powder sticking) was assessed. The evaluation criteria used were as follows.

[0110] (Evaluation criteria)

○: no powder sticking

Δ: thin layer of adhering powder creating a light spotted condition (no visible metallic sheen on the surface of the pestle)

x: clearly visible powder adhesion

[0111] [ Score 4 ]

(Storage stability (Evaluation of the reactivity of the composition based on cellulose and the active ingredient))

Using aminophylline as the active ingredient, the reactivity with the cellulose-based composition was evaluated by the method described below.

First, a powder prepared by mixing a composition based on cellulose and aminophylline in a ratio of 1:1 (weight parts) in a plastic bag was tabletted in a tablet machine under static pressure (applied pressure: 7 kN, holding time: 10 seconds), thereby obtaining flat tablets Ø11.3 mm, 500 mg.

Immediately after tableting, the tablet obtained using the above-described production method was analyzed using a spectroscopic colorimeter (SE-2000, manufactured by Nippon Denshoku Industries Co., Ltd.) to determine the values of brightness (L), color saturation (from green to red) ( a) and color saturation (from blue to yellow) (b). Then, the whiteness was calculated by the following formula.

[0112] Whiteness=100 - [(100 - L) ² +a ² +b ² ] ^0.5

[0113] In addition, the tablets after tabletting were placed in a bottle, the bottle was sealed and stored for one month in a constant temperature and humidity chamber at a temperature of 40°C and a relative humidity of 75%, and then after storage, the values of L, a and b using a spectroscopic colorimeter, and the above formula was used to calculate the brightness after the storage stability test.

[0114] The change in whiteness from the time point - immediately after tabletting (before storage) to the time point - after the storage stability test (after storage) was calculated by the formula below, and this change in whiteness was considered to indicate the reactivity between the composition on cellulose base and active ingredient.

[0115] Whiteness change = whiteness (before storage) - whiteness (after storage)

[0116] If the absolute value of the change in whiteness exceeds 10%, then the color change is noticeable even visually, and therefore, tablets whose absolute value of the change in whiteness was 10% or less were judged to have suitable storage stability.

[0117] < Obtaining wet flakes >

[ Sample 1 receive ]

(Getting wet cereal X)

Two kg of crushed commercial pulp and 30 L of hydrochloric acid aqueous solution were placed in a low-speed stirrer (reactor 30 LGL (brand) manufactured by Ikebukuro Horo Kogyo Co., Ltd.) and subjected to hydrolysis with stirring (reaction conditions: hydrochloric acid concentration: 0 5%, reaction temperature: 120° C., reaction time: 1.0 hour, and stirring speed: 220 rpm), thus obtaining an acid-insoluble residue. The obtained 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. Measurement of the average degree of polymerization of wet flakes X using the determination method viscosity using an ethylenediamine-copper complex solution described in the specification test (3) for crystalline cellulose in the Japanese Pharmacopoeia showed that the average degree of polymerization was 170.

[0118] < Preparation of cellooligosaccharide extract >

When preparing wet flakes X, the filtrate from the hydrolysis reaction was collected, which was separated from the acid-insoluble residue. This filtrate was neutralized using a strong base anion exchange resin and then concentrated using an evaporator to precipitate insolubles (cellooligosaccharides). Concentration was continued until the concentrate reached a state like suspension, after which the concentration was stopped until the concentrate was dried to form a solid. The concentrate thus obtained was cooled on ice and subjected to vacuum filtration using a glass filter, and the insoluble matter remaining on the glass filter was washed with cold water.

The washed insoluble matter was dried by vacuum drying under reduced pressure to obtain a cellooligosaccharide extract.

The amount of cellooligosaccharides from trisaccharides to heptasaccharides in the cellooligosaccharide extract was 72% by weight.

[0119] < Manufacture of cellulose-based compositions >

[ Example 1 ]

(Preparation of cellulose powder A)

Wet flake X was placed in a 90 L plastic bucket, pure water was added to bring the total solids concentration to 10% by weight, and the mixture was dispersed using a three-in-one motor to prepare a 30 kg dispersion. With constant stirring, the dispersion was neutralized with an aqueous ammonia solution (pH after neutralization: at least 7.5, but not more than 8.0). 5.56 g of cellooligosaccharide extract (trisaccharide-heptasaccharide ratio: 72%) was added and stirred, and the resulting mixture was spray dried (drying conditions: dispersion feed rate=6 kg/h, inlet temperature=at least 180° C., but not more than 220°C, and outlet temperature=at least 50°C, but not more than 70°C), thus obtaining composition A based on cellulose. The content of water-soluble substances in the obtained powder was 11.3 mg, the amount of cellooligosaccharides from trisaccharides to heptasaccharides was 7.5 mg, and the proportion of trisaccharides-heptasaccharides in the composition of water-soluble substances was 66% by weight.

[0120] [ Example 2 ]

(Getting Powder In Pulp)

Wet flake X was placed in a 90 L plastic bucket, pure water was added to bring the total solids concentration to 10% by weight, and the mixture was dispersed using a three-in-one motor to prepare a 30 kg dispersion. With constant stirring, the dispersion was neutralized with an aqueous ammonia solution (pH after neutralization: at least 7.5, but not more than 8.0). 3.39 g of cellooligosaccharide extract (trisaccharide-heptasaccharide ratio: 72%) was added and stirred, and the resulting mixture was spray dried (drying conditions: dispersion feed rate=6 kg/h, inlet temperature=at least 180° C., but not more than 220°C, and outlet temperature=at least 50°C, but not more than 70°C), thus obtaining composition B based on cellulose. The content of water-soluble substances in the obtained powder was 7.8 mg, the amount of cellooligosaccharides from trisaccharides to heptasaccharides was 5.0 mg, and the proportion of trisaccharides-heptasaccharides in the composition of water-soluble substances was 64% by weight.

[0121] [ Example 3 ]

(Obtaining Powder From Cellulose)

800 g of cellulose-based composition B obtained in Example 2 was charged to a high-speed agitator granulator, and after granulation and subsequent fluid-bed drying, the granules were sieved through a 500 μm sieve to obtain cellulose-based composition C (granulation conditions: amount of water added =600 g, granulation time=20 minutes, main blade 400 rpm, cross screw 500 rpm; drying conditions: drying temperature=80°C). The content of water-soluble substances in the obtained powder was 7.4 mg, the amount of cellooligosaccharides from trisaccharides to heptasaccharides was 4.7 mg, and the proportion of trisaccharides-heptasaccharides in the composition of water-soluble substances was 64% by weight.

[0122] [ Example 4 ]

(Preparation of composition D based on cellulose)

The cellulose-based composition B obtained in Example 2 was pulverized with a jet mill to obtain a cellulose-based composition D. The content of water-soluble substances in the obtained powder was 8.9 mg, the amount of cellooligosaccharides from trisaccharides to heptasaccharides was 5.8 mg, and the proportion of trisaccharides-heptasaccharides in the composition of water-soluble substances was 65% by weight.

[0123] [ Example 5 ]

(Preparation of composition E based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added to bring the total solids concentration to 10% by weight, and the mixture was dispersed using a three-in-one motor to prepare a 30 kg dispersion. With constant stirring, the dispersion was neutralized with an aqueous ammonia solution (pH after neutralization: at least 7.5, but not more than 8.0), 2.52 g of cellooligosaccharide extract (trisaccharide-heptasaccharide ratio: 72%) was added and stirred, and the resulting the mixture was subjected to spray drying (drying conditions: dispersion feed rate=6 kg/h, inlet temperature=at least 180°C, but not more than 220°C, and outlet temperature=at least 50°C, but not more 70°C), thus obtaining composition E based on cellulose. The content of water-soluble substances in the obtained powder was 6.4 mg, the amount of cellooligosaccharides from trisaccharides to heptasaccharides was 4.0 mg, and the proportion of trisaccharides-heptasaccharides in the composition of water-soluble substances was 62% by weight.

[0124] [ Comparative example 1 ]

(Preparation of composition F based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added to bring the total solids concentration to 10% by weight, and the mixture was dispersed using a three-in-one motor to prepare a 30 kg dispersion. With constant stirring, the dispersion was neutralized with an aqueous ammonia solution (pH after neutralization: at least 7.5 but not more than 8.0), and then, without adding any cellooligosaccharide extract, the dispersion was spray dried (drying conditions: dispersion feed rate= 6 kg/hour, inlet temperature=at least 180°C but not more than 220°C, and outlet temperature=at least 50°C but not more than 70°C), thus obtaining composition F based on cellulose. The content of water-soluble substances in the obtained powder was 2.4 mg, the amount of cellooligosaccharides from trisaccharides to heptasaccharides was 1.1 mg, and the proportion of trisaccharides-heptasaccharides in the composition of water-soluble substances was 46% by weight.

[0125] [ Comparative Example 2 ]

(Preparation of composition G based on cellulose)

Wet flake X was placed in a 90 L plastic bucket, pure water was added to bring the total solids concentration to 10% by weight, and the mixture was dispersed using a three-in-one motor to prepare a 30 kg dispersion. With constant stirring, the dispersion was neutralized with an aqueous ammonia solution (pH after neutralization: at least 7.5, but not more than 8.0). 7.29 g of cellooligosaccharide extract (trisaccharide-heptasaccharide ratio: 72%) was added and mixed, and the resulting mixture was spray dried (drying conditions: dispersion feed rate=6 kg/h, inlet temperature=at least 180° C., but not more than 220°C, and outlet temperature=at least 50°C but not more than 70°C), thus obtaining a composition G based on cellulose. The content of water-soluble substances in the obtained powder was 14.1 mg, the amount of cellooligosaccharides from trisaccharides to heptasaccharides was 9.5 mg, and the proportion of trisaccharides-heptasaccharides in the composition of water-soluble substances was 68% by weight.

[0126] When using each of the cellulose-based compositions obtained in the examples and comparative examples, physical properties were determined using the methods described above, and tablets were obtained and subjected to various evaluations. The physical property determination results are shown in Table 4, and the evaluation results are shown in Table 5. In Table 5, "d-MC" is an abbreviation for d-chlorpheniramine maleate.

[0127] [Table 4]

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Cellulose based composition A B C D E F G Compound Content of water-soluble substances [mg] 11.3 7.8 7.4 8.9 6.4 2.4 14.1 Content of cellooligosaccharides (3-7) [mg] 7.5 5.0 4.7 5.8 4.0 1.1 9.5 The proportion of cellooligosaccharides (3-7) in the composition of water-soluble substances [% by weight] 66 64 64 65 62 46 68 Physical Properties Average particle size [µm] 62 59 134 26 56 53 65 Bulk density [g/ml] 0.23 0.26 0.31 0.15 0.27 0.29 0.19 Bulk density at compaction [g/ml] 0.42 0.41 0.41 0.32 0.40 0.41 0.39 Compressibility [-] 45 36 25 53 32 thirty 51 The size of the particle equivalent to the primary particle. [µm] 24 23 20 24 23 22 23 L/D [-] 2.3 2.2 1.9 2.7 2.1 2.1 2.4 Reactivity with active ingredient [%] -8 -5 -4 -6 -4 -3 -eleven

[0128] [Table 5]

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Cellulose based composition A B C D E F G Tablet composition Mixture Blend 1 Blend 1 Blend 1 Blend 1 Blend 1 Blend 1 Blend 1 Active ingredient d-MC d-MC d-MC d-MC d-MC d-MC d-MC The content of the active ingredient [% by weight] 1 1 1 1 1 1 1 The content of the composition based on cellulose [% by weight] 10 10 10 10 10 10 10 Mannitol content [% by weight] 88 88 88 88 88 88 88 Lubricant content [% by weight] 1 1 1 1 1 1 1 Ratings 5 minutes Tablet hardness [N] 78 67 60 96 65 56 84 The value of CV (coefficient of variation) content of the active ingredient [% by weight] 1.9 1.7 1.3 2.0 1.6 1.5 2.5 Failure in tableting process [-] ο ο ο ο ο ο ο 30 minutes Tablet hardness [N] 75 62 55 90 58 47 82 CV value of active ingredient content [% by weight] 1.8 1.7 1.4 1.7 2.0 3.5 2.4 Failure in tableting process [-] ο ο ο ο ο ο ο The degree of reduction in tablet hardness [%] 3.8 7.5 8.3 6.3 10.8 16.1 2.4

[0129] From the results presented in tables 4 and 5, it can be seen that the reactivity with the active component was suppressed in the compositions A-E based on cellulose (examples 1-5), in which the amount of cellooligosaccharides from trisaccharides to heptasaccharides per 5 g of the composition based on of cellulose was at least 4.0 mg but not more than 7.5 mg, and that, for tablets made using these cellulose-based compositions, all results on tablet hardness, tablet hardness reduction rate, and CV value of active ingredient content were suitable, and molding failure in the tableting process could be prevented.

[0130] In contrast, in the case of the cellulose-based composition F (Comparative Example 1), in which the amount of cellooligosaccharides from trisaccharides to heptasaccharides per 5 g of the cellulose-based composition was less than 4.0 mg, although the reactivity with the active ingredient was low, in In the case of tablets made using this cellulose-based composition, tablets having suitable results in tablet hardness, tablet hardness reduction rate and active component content CV value cannot be obtained.

In the case of tablets made using cellulose-based composition G (Comparative Example 2), in which the amount of cellooligosaccharides from trisaccharides to heptasaccharides per 5 g of the cellulose-based composition exceeded 7.5 mg, although the tablet hardness and tablet hardness reduction rate were suitable, the reactivity between the cellulose-based composition and the active ingredient and the CV value of the content of the active ingredient were unsatisfactory.

[0131] [ Examples 6-8 ]

Using composition B based on cellulose, obtained in example 2, tablets with the composition of the mixture shown below in Table 6 were obtained using the method described above, and then subjected to each of the various evaluations. The results are shown in Table 6. In Table 6, "d-MC" is the abbreviation for d-chlorpheniramine maleate.

[0132] [Table 6]

Example 6 Example 7 Example 8 Cellulose based composition B B B Tablet composition Mixture Blend 3 Blend 4 Blend 2 Active ingredient d-MC d-MC folic acid The content of the active ingredient [% by weight] 1 1 1 The content of the composition based on cellulose [% by weight] 10 10 10 Mannitol content [% by weight] 86 88.5 88.8 Lubricant content [% by weight] 3 0.5 1 Ratings 5 minutes Tablet hardness [N] 62 68 66 CV value of active ingredient content [% by weight] 2.0 1.7 2.0 Failure in tableting process [-] ο Δ ο 30 minutes Tablet hardness [N] 57 65 62 CV value of active ingredient content [% by weight] 1.7 1.7 1.9 Failure in tableting process [-] ο Δο ο The degree of reduction in tablet hardness [%] 8.1 4.4 6.1

[0133] Table 6 shows that in those tablets in which the lubricant content was at least 0.3% w/w, but not more than 5% w/w (Examples 6-8), tablet hardness, reduction rate tablet hardness, CV value of active ingredient content, and molding failure rate during tableting were all appropriate.

In addition, based on a comparison of tablets for which cellulose composition B was used but which contained different amounts of lubricant (Examples 2, 6 and 7), there was a trend towards greater suppression of mold failure during tabletting as the amount of lubricant was increased. .

On the other hand, reducing the amount of lubricant tends to lead to more favorable results in terms of tablet hardness and tablet hardness reduction rate.

INDUSTRIAL APPLICABILITY

[0134] By using a cellulose-based composition according to an embodiment of the present invention, a cellulose-based composition can be provided that has a suitable hardness and sufficient suppression of both variation in active ingredient content and molding failure during tableting. A tablet according to an embodiment of the present invention contains a cellulose-based composition and exhibits suitable hardness and sufficient suppression of both variation in active ingredient content and mold failure during tableting.

Claims (10)

1. Cellulose-based tablet composition containing cellulose and cellooligosaccharides from trisaccharides to heptasaccharides, which are water-soluble substances, in which the content of cellooligosaccharides per 5 g of the cellulose-based composition is at least 1.5 mg, but not more than 9.0 mg . 2. A cellulose-based composition according to claim 1, further comprising a water-soluble substance other than cellooligosaccharides, wherein the total content of water-soluble substances per 5 g of the cellulose-based composition is at least 2.5 mg, but not more than 12.5 mg. 3. A cellulose-based composition according to claim 2, wherein the proportion of cellooligosaccharides in the composition of water-soluble substances is at least 47% by weight, but not more than 67% by weight. 4. Composition based on cellulose according to any one of paragraphs. 1-3, which is a powder, and in the case of which the average particle size of the powder is at least 10 μm, but not more than 200 μm. 5. The cellulose-based composition of claim 4, wherein the L/D aspect ratio of the powder is at least 1.8, but not more than 4.0, and the L/D aspect ratio of the powder is the ratio of the major axis to the minor powder axis. 6. Tablet containing the composition based on cellulose according to any one of paragraphs. 1-5 and at least one active component, where the proportion of the mixture of the cellulose-based composition is at least 1% by weight, but not more than 90% by weight. 7. The tablet according to claim 6, which additionally contains a lubricant, where the lubricant content, relative to the total weight of the tablet, is at least 0.3% by weight, but not more than 5% by weight. 8. The tablet of claim 7 wherein the lubricant is at least one selected from the group consisting of fatty acid metal salts, fatty acid esters and fatty acid metal salts of esters. 9. Tablet according to claim 7 or 8, wherein the lubricant is at least one selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, sucrose fatty acid esters and talc. 10. Tablet according to any one of paragraphs. 6-9, where the content of the active ingredient, relative to the total weight of the tablet, is at least 0.01% by weight, but more than 50% by weight.