JP2021105172A - Cellulose powder, tablet, and tablet production method - Google Patents

Abstract

To provide a cellulose powder that makes it possible to obtain a tablet having a high recovery rate of an active pharmaceutical ingredient while maintaining excellent collapsibility, and to provide a tablet and a tablet production method.SOLUTION: The present invention provides a cellulose powder which is converted by sulfuric acid into a hydrolysate having a mannose content of 0.2 mass% or more relative to the total mass of glucose, mannose and xylose in the hydrolysate and having a xylose content of 0.5 mass% or more relative to the total mass of glucose, mannose and xylose in the hydrolysate, the mannose content and the xylose content being measured by high performance liquid chromatography.SELECTED DRAWING: None

Description

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

Conventionally, as a method for producing a compressed tablet, a direct tableting method, a semi-direct tableting method, a dry granule compression method, a wet granule compression method and the like are known. The wet granule compression method is a method in which an active ingredient and an additive are mixed and granulated, and a lubricant is added to the obtained granulated product for compression molding. In the wet granule compression method, when the highly charged active ingredient and the additive are mixed and granulated, the active ingredient tends to adhere to the wall surface of the apparatus, and the drug substance recovery rate may decrease.

In addition, tableting of pharmaceutical products has the advantages of high productivity and easy handling during transportation and use. Since many active ingredient raw materials cannot be molded even when compressed, they are tableted by blending an excipient, and good moldability, fluidity and disintegration are required. Crystalline cellulose is often used as an excipient.

Patent Document 1 states that the average degree of polymerization is 100 or more and 350 or less, the weight average particle size is more than 30 μm and 250 μm or less, the apparent specific volume is 2 cm ³ / g or more and ^{less than 15 cm 3} / g, and the particle size distribution sharpness is 1.5 or more. Cellulose powders of 9 or less are disclosed. By using this cellulose powder, Chinese herbs with excellent compression moldability and high stickiness and hygroscopicity and sticky ingredients are uniformly retained, and the particle size distribution of the granules is also sharp due to the sharp particle size distribution of the granules. It is disclosed that it can be sharpened, the disintegration time is shortened, and the effect of imparting stable disintegration over time is obtained.

In Patent Document 2, the average degree of polymerization is 150 or more and 450 or less, the average L / D (major axis / minor axis ratio) of particles of 75 μm or less is 2.0 or more and 4.5 or less, and the average particle size is 20 μm or more and 250 μm or less. specific volume 4.0 cm ³ / g or more 7.0 cm ³ / g or less, an apparent tapping specific volume of 2.4 cm ³ / g or more 4.5 cm ³ / g or less, the cellulose powder is disclosed repose angle is 55 ° or less Has been done. It is disclosed that the cellulose powder is excellent in moldability, fluidity and disintegration property.

International Publication No. 2013/180248 International Publication No. 02/02643

However, there is no known conventional cellulose powder that can solve the problem that occurs when the highly charged active ingredient and the additive are mixed and granulated.

Further, in the pharmaceutical field, when the amount of the active ingredient such as a drug is large, the collapse time of the obtained tablet tends to be delayed, so that it is necessary to increase the addition ratio of the disintegrant. However, the disintegrant may have high reactivity with the active ingredient or may deteriorate the moldability, and further, since the disintegrant has a property of easily absorbing water, the storage stability of the tablet may be lowered. There is a limit to the increase in the proportion of disintegrants.
Further, conventionally, there is no known cellulose powder capable of improving the storage stability of tablets while maintaining good disintegration property.

The present invention has been made in view of the above circumstances, and provides a cellulose powder and a method for producing the cellulose powder, which can obtain a tablet having an excellent drug substance recovery rate while maintaining good disintegration property. Further, the present invention provides a tablet having excellent storage stability while maintaining good disintegration property, and a method for producing the tablet.

That is, the present invention includes the following aspects.
[1] The cellulose powder, which is a hydrolyzate of the cellulose powder with sulfuric acid, has a mannose content of 0.2% by mass or more based on the total mass of glucose, mannose and xylose in the hydrolyzate. The content of xylose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate was 0.5% by mass or more, and the content of the mannose and the content of the xylose were measured by a high-speed liquid chromatograph method. The thing, cellulose powder.
[2] The hydrolyzate of the cellulose powder with sulfuric acid has a glucose content of 87% by mass or more and 99.3% by mass or less based on the total mass of glucose, mannose and xylose in the hydrolyzate. The content of the mannose with respect to the total mass of glucose, mannose and xylose in the substance is 0.2% by mass or more and 5.0% by mass or less, and the xylose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate. The cellulose powder according to [1], wherein the content of is 0.5% by mass or more and 8.0% by mass or less.
[3] The total content of the mannose and the xylose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate is 0.7% by mass or more and 13.0% by mass or less, [1] or [2]. The cellulose powder described in.
[4] The cellulose powder according to any one of [1] to [3], wherein the mass ratio of the xylose to the mannose is 0.5 or more and 10 or less.
[5] The cellulose powder according to any one of [1] to [4], wherein the loose bulk density is 0.10 g / cm ³ or more and 0.40 g / cm ^{3 or less.}
[6] harder bulk density is less than 0.25 g / cm ³ or more 0.57g / cm ^3, [1] Cellulose powder according to any one of to [5].
[7] The cellulose powder according to any one of [1] to [6], which has a degree of compression of 21% or more and 70% or less.
[8] The cellulose powder according to one of [1] to [7], wherein the average particle size of the cellulose powder is 10 μm or more and 300 μm or less.
[9] Any one of [1] to [8], which is 50% by mass or more and 99% by mass or less based on the total mass of the tablet, and 1% by mass or more and 49% by mass or less based on the total mass of the tablet. A tablet comprising the cellulose powder according to the section.
[10] The tablet according to [9], which further contains a disintegrant of 0.5% by mass or more and 5.0% by mass or less based on the total mass of the tablet.
[11] The disintegrant is croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch. The tablet according to [10], which is at least one selected from the group consisting of partially pregelatinized starch, crospovidone, and crospovidone copolymer.
[12] A method for producing a tablet, which comprises a granulation step and a molding step, wherein the granulation step comprises the cellulose powder according to any one of [1] to [8] and an active ingredient. A method for producing tablets, which is a step of mixing and granulating.
[13] The method for producing a tablet according to [12], wherein the granulation step is performed by a wet granulation method.
[14] A method for wet granulation of an active ingredient, which comprises adding the cellulose powder according to any one of [1] to [8].
[15] The method according to [14], wherein the triboelectric amount of the active ingredient is +0.1 nC / g or more or −0.1 nC / g or less.

According to the cellulose powder of the above aspect, it is possible to provide a cellulose powder having an excellent drug substance recovery rate while maintaining good disintegration property.

According to the tablet of the above aspect, it is possible to provide a tablet having excellent storage stability while maintaining good disintegration property.

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

<Cellulose powder>
Cellulose powder is generally referred to as crystalline cellulose, powdered cellulose, or the like, and is preferably used as a pharmaceutical additive or a food additive. Crystalline cellulose is preferable as the cellulose powder. Examples of crystalline cellulose include microcrystalline cellulose described in the 8th edition of the Food Additives Official Regulations, crystalline cellulose described in the Japanese Pharmacopoeia (17th revision), the United States Pharmacopeia, and the European Pharmacopoeia. The described crystalline celluloses are known.

The cellulose powder of the present embodiment has an average particle size of 10 μm or more, preferably 13 μm or more, more preferably 15 μm or more, further preferably 17 μm or more, further preferably 20 μm or more, further preferably 25 μm or more, and particularly preferably 30 μm or more. preferable. The cellulose powder of the present embodiment has an average particle size of 300 μm or less, preferably 200 μm or less, more preferably 100 μm or less, further preferably 80 μm or less, and particularly preferably 60 μm or less.
When the average particle size is not more than the above upper limit value, it is easy to be uniformly mixed with the active ingredient such as a drug, and the disintegration property when made into a tablet becomes better. On the other hand, when the average particle size is at least the above lower limit value, the handleability becomes better.

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

Conventionally, cellulose powder used as a pharmaceutical additive or a food additive has a purity of 99.5% or more. On the other hand, the cellulose powder of the present embodiment contains hemicellulose, which has been conventionally excluded as an impurity, in a certain amount or more. It is presumed that hemicellulose has no electric charge, reduces the influence of static electricity, and improves the recovery rate of highly charged active ingredients. Further, since hemicellulose has a property of easily absorbing water and drawing water into the tablet more easily than cellulose, it is presumed that the disintegration property is improved in the tablet described later. It has also been confirmed that the storage stability of tablets is improved by containing an appropriate amount of hemicellulose in the cellulose powder. Even if a desired effect can be obtained by a mechanism different from the above mechanism, it is included in the technical scope.

The hemicellulose contained in the cellulose powder of the present embodiment can indirectly detect hemicellulose from the constituent sugars contained in the obtained hydrolyzate by hydrolyzing the cellulose powder with an acid. Typical constituent sugars of hemicellulose are mannose and xylose, and these are used as indicators of hemicellulose.
For the constituent sugars of the polysaccharide contained in the tablet of the present embodiment, after recovering the polysaccharide from the tablet, the polysaccharide is hydrolyzed with an acid, and the obtained hydrolyzate is obtained by using a high-speed liquid chromatograph method. It can be detected by measuring. As a method for recovering the polysaccharide from the tablet, for example, the tablet is washed with a solvent (acetone, ethanol, cold water, etc.) in which cellulose and hemicellulose are insoluble, and the residue is recovered.

Next, as a method for calculating the ratio of the constituent sugars of the polysaccharide, specifically, first, 0.6 g of the polysaccharide is collected, 72% sulfuric acid: 5 mL is added, and the mixture is stirred at room temperature for 1 hour. Further, it is diluted 18-fold with pure water (4% sulfuric acid) and reacted in an autoclave (121 ° C.) for 1 hour to carry out a sulfuric acid hydrolysis reaction. After cooling, neutralize with 2N aqueous sodium hydroxide solution, make a constant volume (200 mL) with pure water, and filter with filter paper. The obtained filtrate is appropriately diluted with pure water, and the obtained diluted solution is analyzed by high performance liquid chromatography under the conditions shown below to quantify the content of each sugar. The ratio of each constituent sugar is determined as a mass fraction to the total of glucose, xylose and mannose.

(Measurement condition)
Model: LC-20AD (Shimadzu Corporation)
Detector: Fluorescence spectrophotometer RF-20Axs (Shimadzu Corporation), fluorescence excitation wavelength 320 nm, fluorescence measurement wavelength 430 nm
Column: TSKgel SUGAR AXI, φ4.6mm x 150mm (Tosoh)
Column temperature: 60 ° C
Mobile phase: 0.5 mol / L borate buffer (pH 8.7), 0.4 mL / min
Injection volume: 20 μL
Post column: Reaction solution 1 w / v% L-arginine solution, reaction solution flow rate 0.7 mL / min, reaction temperature 150 ° C.

In the cellulose powder of the present embodiment, the content of glucose in the hydrolyzate with respect to the total mass of glucose, mannose and xylose is preferably 87.0% by mass or more and 99.3% by mass or less. 89.0% by mass or more and 99.0% by mass or less is preferable, 90.0% by mass or more and 99.0% by mass or less is more preferable, 91.0% by mass or more and 98.5% by mass or less is further preferable, and 92.0% by mass or less. It is particularly preferable that it is by mass% or more and 98.0% by mass or less.

In the cellulose powder of the present embodiment, the content of mannose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate is 0.2% by mass or more, and 0.2% by mass or more and 5.0% by mass or less. Is more preferable, 0.3% by mass or more and 4.5% by mass or less is more preferable, 0.3% by mass or more and 4.0% by mass or less is further preferable, and 0.4% by mass or more and 3.8% by mass or less is particularly preferable. ..
When the content of mannose is at least the above lower limit value, the capacitance of the obtained granules can be made lower, and the disintegration property of the tablet tends to be better. On the other hand, when the content of mannose is not more than the above upper limit value, the uniformity of the active ingredient in the tablet tends to be improved. Also, the storage stability of tablets tends to be better.
The content of xylose in the hydrolyzate with respect to the total mass of glucose, mannose and xylose is 0.5% by mass or more, preferably 0.5% by mass or more and 8.0% by mass or less, preferably 1.0% by mass. % Or more and 7.0% by mass or less is more preferable, 1.3% by mass or more and 6.5% by mass or less is further preferable, and 1.6% by mass or more and 6.3% by mass or less is particularly preferable.
When the xylose content is at least the above lower limit, tablets having a higher drug substance recovery rate can be obtained. On the other hand, when the content of xylose is not more than the above upper limit value, the uniformity of the active ingredient in the tablet tends to be improved. Also, the disintegration of tablets tends to be better. On the other hand, when the content of xylose is not more than the above upper limit value, the storage stability of the tablet tends to be better.

The lower limit of the total content of mannose and xylose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate is preferably 0.7% by mass or more, and the upper limit is 13.0 mass. % Or less is preferable. Further, 1.3% by mass or more and 11.5% by mass or less is more preferable, 2.0% by mass or more and 10.5% by mass or less is further preferable, and 3.0% by mass or more and 10.1% by mass or less is particularly preferable. Most preferably, it is 3.5% by mass or more and 9.0% by mass or less.
When the total content of mannose and xylose is at least the above lower limit, a tablet having a better drug substance recovery rate can be obtained while maintaining better disintegration of the tablet. On the other hand, when the total content of mannose and xylose is not more than the above upper limit value, the uniformity of the active ingredient in the tablet tends to be improved. Also, the storage stability of tablets tends to be better.

The mass ratio of xylose (xylose / mannose) to mannose in the hydrolyzate is preferably 0.5 or more and 10 or less, more preferably 0.7 or more and 8.0 or less, and 1.0 or more and 6.0 or less. Is more preferable, 1.2 or more and 5.0 or less is particularly preferable, and 1.3 or more and 4.5 or less is most preferable.
When xylose / mannose is at least the above lower limit value, a tablet having better disintegration property tends to be obtained, while when it is at least the above upper limit value, a tablet having a better drug substance recovery rate tends to be obtained. Also, the storage stability of tablets tends to be better.

The content of hemicellulose in the cellulose powder and the ratio of the constituent sugars in the hemicellulose can be adjusted, for example, by appropriately changing the selection of the type of raw material pulp to be used, the purification conditions at the time of producing the cellulose powder, and the like. Specifically, for example, a method using a raw material pulp containing a large amount of hemicellulose, a method using a raw material pulp containing mannose and xylose in a desired ratio in hemicellulose, a method using cold water when purifying the cellulose powder, or the like, in the cellulose powder. The content of hemicellulose can be increased. Further, the ratio of hemicellulose (content of mannose and xylose in the hydrolyzate) is arbitrarily adjusted by adding hemicellulose to the cellulose powder or mixing two or more kinds of aqueous cellulose dispersions and drying them. be able to.

The cellulose powder of the present embodiment preferably has a loose bulk density of 0.10 g / cm ³ or more and 0.40 g / cm ³ or less, more preferably 0.10 g / cm ³ or more and 0.39 g / cm ³ or less, and 0.11 g. / cm ³ or more 0.38 g / cm ³ or less is more preferred. When the loose bulk density is at least the above lower limit value, the compression moldability can be further improved. On the other hand, when the loose bulk density is not more than the above upper limit value, the filling property becomes better.
The loose bulk density can be measured using the method described in Examples described later.

Cellulose powder of the present embodiment is preferably stiffer bulk density of 0.25 g / cm ³ or more 0.57 g / cm ³ or less, 0.25 g / cm ³ or more 0.56 g / cm ³ and more preferably less, 0. More preferably, it is 26 g / cm ³ or more and 0.55 g / cm ^{3 or less.} When the bulk density is at least the above lower limit value, it is easy to be uniformly mixed with the active ingredient such as a drug, and the handleability is improved. On the other hand, when the bulk density is not more than the above upper limit value, segregation due to the density difference between the particles of the active ingredient and other additives can be more effectively suppressed.
The bulk density can be measured by using the method described in Examples described later.

In the cellulose powder of the present embodiment, the range of compressibility is preferably 21% or more and 70% or less, more preferably 23% or more and 65% or less, and more preferably 25%, from the viewpoint of segregation prevention and powder handleability. More preferably 60% or less. Further, when the degree of compression is 30% or more and 58% or less, the fluidity of the cellulose powder itself becomes further improved, which is preferable. From the viewpoint of the fluidity of the cellulose powder, 30% or more and 54% or less are more preferable, 30% or more and 48% or less are further preferable, and 31% or more and 44% or less are most preferable.
The degree of compression can be calculated by using the method described in Examples described later.

In the cellulose powder of the present embodiment, the average particle size corresponding to the primary particles (hereinafter, may be abbreviated as "primary particle equivalent diameter") is preferably 10 μm or more and 50 μm or less, more preferably 13 μm or more and 35 μm or less, and 14 μm or more and 30 μm. The following is more preferable. When the particle size equivalent to the primary particles is within the above range, it is easy to be uniformly mixed with the active ingredient such as a drug, and the disintegration property when made into a tablet becomes better.
The primary particles are unit particles, and those in which the primary particles are aggregated are called secondary particles (aggregate, aggregate). When the secondary particles are dispersed in water, the agglutination is released and the secondary particles can be returned to the primary particles.
The average particle size corresponding to the primary particles can be measured by using the method described in Examples described later.

In the cellulose powder of the present embodiment, the ratio of the major axis to the minor axis of the cellulose particles, that is, the aspect ratio (L / D) is preferably 1.7 or more and 4.5 or less, and more preferably 1.8 or more and 4.0 or less. , 2.0 or more and 3.8 or less is more preferable, and 2.2 or more and 3.5 or less is particularly preferable. When the aspect ratio is within the above range, the mixing property with the active ingredient is good, the entanglement of elongated particles is appropriate, and the balance between moldability and disintegration is excellent.
The aspect ratio (L / D) can be measured by using the method described in Examples described later.

In the cellulose powder of the present embodiment, the lower limit of the angle of repose is preferably 44 °, more preferably 45 °, further preferably 46 °, and particularly preferably 48 °. When the angle of repose is equal to or higher than the above lower limit, it is easy to fly up in the granulation tank during granulation, prevent the powder from adhering to the granulation apparatus, and improve the recovery rate of the powder. Can be done. In addition, when the powder is compression-molded and tableted, voids in the tablet are likely to be formed, which is more excellent in the disintegration property of the tablet.
On the other hand, the upper limit of the angle of repose is not particularly limited, but is theoretically less than 90 °. The angle of repose is an index of fluidity generally used in the field of powders, and the lower the angle of repose, the better the fluidity, and it becomes easier to mix uniformly with medicinal ingredients and other ingredients. From the viewpoint of the balance between the amount of powder recovered and the fluidity and the balance between the disintegration property and the fluidity, the upper limit of the angle of repose is preferably 80 °, more preferably 70 °, and even more preferably 60 °.

<Manufacturing method of cellulose powder>
The method for producing the cellulose powder of the present embodiment will be described below.
The cellulose powder of the present embodiment can be obtained, for example, by including a step of dispersing a hydrolyzed natural cellulose-based substance in an appropriate medium to obtain a cellulose aqueous dispersion, and a step of drying the aqueous dispersion. The solid content concentration of the aqueous cellulose dispersion is not particularly limited, and can be, for example, 1% by mass or more and 30% by mass or less. In this case, even if the solid content containing the hydrolyzed cellulosic substance is isolated from the hydrolysis reaction solution obtained by the hydrolysis treatment, and the dispersion prepared by separately dispersing this in an appropriate medium is dried. good. Further, when the cellulose dispersion liquid is formed in the same state as the hydrolyzed solution, the dispersion liquid can be directly dried.

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

In the above-mentioned production method, water is preferable as the medium used when the solid content containing the natural cellulosic substance is dispersed in an appropriate medium, but there is no particular limitation as long as it is used industrially, for example. An organic solvent may be used. Examples of the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane and cyclohexane; acetone, ethyl methyl ketone and the like. Examples include ketones. In particular, organic solvents are preferably used in pharmaceutical products, and such organic solvents are classified as solvents in "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.). Water and the organic solvent may be used alone or in combination of two or more, or may be dispersed once in one medium, then the medium may be removed and dispersed in different media. ..

For example, pulp fibers having an average width of 2 μm or more and 30 μm or less and an average thickness of 0.5 μm or more and 5 μm or less are subjected to a temperature of 70 ° C. or more and 140 ° C. or less in hydrochloric acid of 0.01% by mass or more and 1.0% by mass or less under pressure. Hydrolyze while turning the stirrer.
The progress of hydrolysis can be controlled by adjusting the motor power (P: unit W) and the stirring capacity (L: unit L) of the stirrer. For example, by adjusting the P / V represented by the following formula, it is possible to control the average particle size of the finally obtained cellulose particles to 200 μm or less.

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

It is preferable to wash the insoluble residue obtained after hydrolysis of the natural cellulosic substance with water, an organic solvent, or the like, and then prepare an aqueous cellulose dispersion using the washed insoluble residue. The temperature of the water or organic solvent used for cleaning is preferably 0 ° C. or higher and 10 ° C. or lower. When the temperature is within the above range, the content of mannose, which is a constituent sugar of hemicellulose, is easily controlled to 0.2% by mass or more, and the content of xylose, which is a constituent sugar of hemicellulose, is easily controlled to 0.5% by mass or more.

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

By controlling the temperature of the solution for washing the insoluble residue obtained after the hydrolysis of the natural cellulosic substance, an insoluble residue having a specific range of the contents of mannose and xylose, which are constituent sugars of hemicellulose, can be obtained. By controlling the acid concentration and stirring conditions when preparing the cellulose aqueous dispersion, a cellulose aqueous dispersion containing cellulose dispersion particles having a specific average particle size can be obtained, and further, the cellulose aqueous dispersion is obtained. The average particle size, compression ratio, and rest angle of the obtained cellulose powder can be controlled by adjusting the solid content concentration of the cellulose aqueous dispersion and the drying conditions at the time of drying. For example, when the cellulose aqueous dispersion is dried by a disc-type spray drying, the stirring power when preparing the cellulose aqueous dispersion is set within a specific range, and the solid content concentration of the cellulose aqueous dispersion during spray drying and the disc type are used. By setting the spray drying rotation speed condition to a specific range, a cellulose powder having an average particle size, a compression ratio, and a rest angle within a specific range can be obtained.

Further, as described in Examples described later, two or more kinds of aqueous cellulose dispersions produced under different conditions are mixed and dried to obtain an average particle size and each of mannose and xylose, which are constituent sugars of hemicellulose. Cellulose powder having a content within a specific range may be obtained.

Even when the average particle size of the dried cellulose powder is larger than 300 μm, the average particle size can be adjusted to 10 μm or more and 300 μm or less by subjecting it to a pulverization step described later.

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

As for the crushing conditions of the jet mill crusher, the powder supply amount and the crushing pressure are important, and when the jet mill crusher (STJ-200, manufactured by Seishin Enterprise Co., Ltd.) is used, the supply amount is 10 kg / hour or more and 20 kg / hour. The following is preferable, and more preferably 15 kg / hour or more and 20 kg / hour or less. The crushing pressure is preferably 0.15 MPa or more and 0.70 MPa or less, and more preferably 0.30 MPa or more and 0.50 MPa or less. When the powder supply amount and the crushing pressure are within the above ranges, the average particle size tends to be easily controlled to 10 μm or more and 300 μm or less.

<Usage>
By blending the cellulose powder of the present embodiment with a composition containing an active ingredient, a tablet having an excellent drug substance recovery rate can be obtained while maintaining good disintegration property.
<Tablet>

The tablet of the present embodiment contains a medicinal ingredient of 50% by mass or more and 99% by mass or less based on the total mass of the tablet, and a polysaccharide of 1% by mass or more and 49% by mass or less based on the total mass of the tablet. The hydrolyzate of the polysaccharide with sulfuric acid has a glucose content of 89% by mass or more and 99% by mass or less based on the total mass of glucose, mannose and xylose in the hydrolyzate. The content of mannose with respect to the total mass of mannose and xylose is 0.2% by mass or more, and the content of xylose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate is 0.5% by mass or more.

The tablet of the present embodiment contains 50% by mass or more of a medicinal ingredient, but by containing a polysaccharide having the above composition, it is excellent in storage stability while maintaining good disintegration property.

[Polysaccharide]
The content of the polysaccharide in the tablet of the present embodiment is 1% by mass or more and 49% by mass or less, preferably 3% by mass or more and 30% by mass or less, and 5% by mass or more and 20% by mass or less with respect to the total mass of the tablet. Is more preferable, and 7% by mass or more and 17% by mass or less is further preferable.
When the content of the polysaccharide is within the above range, the tablet of the present embodiment has excellent storage stability while maintaining good disintegration property.

The polysaccharide contained in the tablet of the present embodiment may be any polysaccharide containing glucose, mannose and xylose as constituent sugars, and is not particularly limited. Among them, the polysaccharide is preferably the cellulose powder of the present embodiment.

The blending ratio of the cellulose powder to the tablet of the present embodiment can be mixed at any ratio, but 90% by mass or less with respect to the total mass of the tablet is a practically preferable range. The lower limit is practically 0.1% by mass. When used in tablets containing a large amount of active ingredient, it is preferably about 0.1% by mass or more and 50% by mass or less, more preferably 0.1% by mass or more and 20% by mass or less, and 0.1% by mass or more and 10% by mass or less. More preferred.

[Active ingredient]
The content of the medicinal ingredient in the tablet of the present embodiment is 50% by mass or more and 99% by mass or less, preferably 50% by mass or more and 95% by mass or less, based on the total mass of the tablet. The tablet of the present embodiment contains as much as 50% by mass or more of a medicinal ingredient, but by containing the above-mentioned polysaccharide, it is excellent in storage stability while maintaining good disintegration property.
In the present specification, the active ingredient is an ingredient added to a mixed powder, a molded product, a processed product, etc. in order to exert a desired function or effect in a pharmaceutical product, a health food, a food product, an industrial field, or the like. say. For example, an active ingredient in the pharmaceutical field is a pharmaceutical medicinal ingredient.
As the active ingredient contained in the tablet of the present embodiment, a highly chargeable active ingredient is preferable because the effect of the present invention can be remarkably exhibited. Specifically, the triboelectric charge amount is preferably +0.1 nC / g or more or -0.1 nC / g or less, and is +0.5 nC / g or more or -0.5 nC / g or less. Is more preferable, and 1.0 nC / g or more, or −1.0 nC / g or less is further preferable. The triboelectric charge of the active ingredient can be measured by using the method described in Examples described later.
Hereinafter, suitable active ingredients contained in the tablets of the present embodiment will be illustrated.

Pharmaceuticals As medicinal ingredients, for example, antipyretic analgesics, anti-inflammatory drugs, hypnotic sedatives, anti-drowsiness drugs, expectorants, pediatric analgesics, stomachic drugs, antacids, digestive drugs, cardiotonic drugs, arrhythmia drugs, antihypertensive drugs, vasodilation. Drugs, diuretics, anti-ulcer drugs, intestinal regulators, osteoporosis remedies, antitussive expectorants, anti-asthmatic drugs, antibacterial agents, frequent urine improving agents, nourishing tonics, vitamins and the like can be mentioned. The medicinal ingredient may be used alone or in combination of two or more.

Specifically, for example, aspirin (-8.6 nC / g), aspirin aluminum, acetaminophen (-16.7 nC / g), ethenzamid (+3.9 nC / g), sazapyrin, salicylamide, lactylphenetidine, Isotibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diferrol hydrochloride, triprolysine hydrochloride, tryperenamine hydrochloride, tonzilamine hydrochloride, phenetazine hydrochloride, metodylazine hydrochloride, diphenhydramine salicylate, sodium salicylate (-1.4 nC / g), carbinoxamine diphenyldisulfonate, tartrate acid Alimemazine, sulpyrine (+4.9 nC / g), diphenhydramine tannate, diphenylpyraline theocrate, mebuhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate (d-chlorpheniramine maleate) +0.1 nC / g), diferrol phosphate, allocramide hydrochloride, cloperastine hydrochloride, pentoxiberin citrate (carbetapentane citrate), tipepidin citrate, dibunato sodium, dextrometholphan hydrobromide, dextrometholphan Phenolphthalic acid, tipepidin hibenzate, cloperastine fendyzoate, codeine phosphate, dihydrocodein phosphate, noscapine hydrochloride, noscapin, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guayacol sulfonate, guayphenesin, sodium benzoate cafe Inn, caffeine, anhydrous caffeine, vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C (-0.5 nC / g) and its derivatives and their salts, hesperidin and its Derivatives and their salts, Vitamin B6 and its derivatives and their salts, nicotinic acid amide, calcium pantothenate, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (Aluminum glycinate), aluminum hydroxide gel (as dry aluminum hydroxide gel), dry aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium hydrogen carbonate co-precipitate product, hydroxylation Aluminum / calcium carbonate・ Co-precipitated product of magnesium carbonate, co-precipitated product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, magnesium aluminometasilicate, lanitidine hydrochloride, simethidine, famotidine, naproxene, diphenhydramine sodium, pyroxicum, azulene, indomethacin, ketoprofen , Ibuprofen (-12.0 nC / g), diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, promethazine hydrochloride, mecrydin hydrochloride (+4.0 nC / g), dimenhydrinate, diphenhydramine tannate, phenetazine tannate, diphenylpyraline theocrate , Diphenhydramine fumarate, promethazine methylene disalicylate, spocoramine hydrobromide, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methylatropine bromide, methylanisotropine bromide, methylspocoramine bromide, methyl bromide- 1-Hyostiamine, methylbenactidium bromide, veradonna extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, papaverin hydrochloride, aminobenzoic acid, cesium oxalate, ethyl piperidylacetylaminobenzoate, aminophilin (-0) .1nC / g), diprofillin, theophylline, sodium hydrogencarbonate, fursultiamine, isosorbide nitrate, ephedrine, cephalexin, ampicillin, sulfixazole, scralfate, allylisopropylacetylurea, bromvalerylurea, etc. , Kanzo, Kikyo, Shazenshi, Shazensou, Senega, Baimo, Uikyo, Oubaku, Ouren, Gajutsu, Kamitsure, Keihi, Gentiana, Goou, Beast (including Yutan), Shajin, Shokyo, Sojutsu, Chouji, Chinpi, Byakujutsu Diphenhydramine, diphenhydramine, carrot, kanokosou, buttonpi, sansho and their extracts, insulin, bazopressin, interferon, urokinase, seratiopeptidase, somatostatin, etc. (External group) ”,“ US Pharmacopoeia (USP) ”,“ National Pharmaceuticals (NF) ”,“ European Pharmacopoeia (EP) ”, and the like. One type selected from the above may be used alone, or two or more types may be used in combination.

The active ingredient for health foods is not limited as long as it is an ingredient blended for the purpose of enhancing health, but for example, green juice powder, aglycon, agarix, ashwaganda, astaxanthin, acerola, amino acids (valine, leucine, isoleucine, etc. Lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, cysteine (-0.4 nC / g), tyrosine, arginine, alanine, aspartic acid, seaweed powder, glutamine, glutamic acid, glycine, proline, serine, etc.), alginic acid, Ginkgo biloba extract, sardine peptide, turmeric, uronic acid, echinacea, eleuthero, oligosaccharide, oleic acid, nuclear protein, cuttlefish peptide, catechin, potassium, calcium, carotinoid, garcinia, L-carnitine, chitosan, conjugated linoleic acid, kidati aloe, Gymnema sylvestre extract, citric acid, kumiskutin, glyceride, glycenol, glucagon, curcumin, glucosamine, L-glutamine, chlorella, cranberry extract, cat's claw, germanium, enzyme, ginseng extract, coenzyme Q10, collagen, collagen peptide, corius forskolin , Chondroitin, psyllium husk powder, sanzashi extract, saponin, lipid, L-cystine, perilla extract, citrimax, fatty acid, plant sterol, seed extract, spirulina, squalane, white yanagi, ceramide, selenium, St. Jones wort extract, soy isoflavone, soybean Saponin, soybean peptide, soybean lecithin, monosaccharide, protein, chest tree extract, iron, copper, docosahexaenoic acid, tocotrienol, natto kinase, natto fungus culture extract, niacin sodium, nicotinic acid, disaccharide, lactic acid bacteria, garlic, sawtooth palm, germination Rice, honeybee extract, herb extract, valeryan extract, pantothenic acid, hyaluronic acid, biotin, chromium picolinate, vitamin A, vitamin A2 vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, Vitamin K, hydroxytyrosol, bifidus, beer yeast, fructo-oligosaccharide, flavonoid, butcher's bloom extract, black kohosh, blueberry, prune extract, proanthocyanidin, protein, propolis, bromeline, probiotics, phosphatidylcholine, phosphatidyl Serine, β-carotene, peptide, safflower extract, maitake extract, maca extract, magnesium, maria thistle, manganese, mitochondria, minerals, mucopolysaccharide, melatonin, phellinus linteus, melilot extract powder, molybdenum, vegetable powder, folic acid, lactose, lycopene, linoleic Examples thereof include acid, lipoic acid, phosphorus, lutein, lecithin, rosmarinic acid, royal jelly, DHA and EPA.

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

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

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

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

In the tablet of the present embodiment, 50% by mass or more and 99% by mass or less of the total mass of the tablet is the medicinal ingredient, so it is preferable to use the medicinal ingredient having a large dose per tablet. Specifically, a medicinal ingredient having a maximum compounding amount of more than 100 mg per tablet is preferable. However, a medicinal ingredient having a medium maximum compounding amount per tablet (more than 10 mg and 100 mg or less) or a medicinal ingredient having a small maximum compounding amount per tablet (10 mg or less) may be used.

Examples of medicinal ingredients having a maximum compounding amount of more than 100 mg per tablet include Abacavir, acetazolamide, acetylsalicylic acid, aciclovir, albendazole, and Aliskiren Fumarate. Alate, Allopurinol, Amiodarone, Amodiaquine, Amoxicllin, Aprepitant, Artemether, Artesunate, Atazanavir, calc capecitabine, carbamazepine, carbidopa, cefalexin, cefixime, Celecoxib, Chloroquine, Ciprofloxacin, Clarithromycin, Clarithromycin Clavulanate Potassium, clopidogrel, clozapine, cycloserine, darunavir, Darunavir ethanolate, dasabvir, dasatinib, Deferasirox Dihydroartemisinin piperaquine phosphate, Dihydroartemisinin piperaquine phosphate, Diloxanide, Efavirenz, emtricitabine, Erlotinib hydrochloride, Erlotinib hydrochloride, erlotinib hydrochloride, ethambutol (Famcyclovir), Gefitinib, Griseofulvin, Hydroxycarbamide, Hydroxychloroquine, ibuprofen, imatinb, Irbesartan, Isoniazid, lamivudine, lamotrigine hydrate, Lanthanum carbonate Ledipasvir, Levamisole, Levetiracetam, Levodopa, levofloxacin, linezolid, lithium carbonate, lopinavir, lumef Phantrin, mebendazole, mefloquine, mesna, metformin, methyldopa, metronidazole, morphine, moxifloxacin, nevirapine ), Niclosamide, nifurtimox, ombitasvir, p-aminosalicylic acid, paracetamol, paritaprevir, paritaprevir, penicillamine, penicillamine, pentamidine Phenoxymethylpenicillin, Pirfenidone, praziquantel, pyrantel, pyrazinamide, pyronaridine tetraphosphate, quinine, raltegravir, ranitidine, ranitidine (Rifampicin), rifampicin, rifampicin e (rifapentin), Sevelamer hydrochloride, Sofosbuvir, Sorafenib tosilate, Sulfadiazine, sulfamethoxazole, sulfasalazine, tenofovir , Tenofovir disoproxil fumarate, triclabendazole, trimethoprim, valganciclovir, valproic acid, velpatasvir, sodium valproate , Voriconazole, Zidovudine and the like.

Examples of the maximum compounding amount per tablet of more than 10 mg and 100 mg or less include Aripiprazole, Artesunate, ascorbic acid, azathioprine, Bazedoxifene acetate, and the like. Bicalutamide, calcium folinate, cromifene, cyclizine, cyclophosphamide, Dasatinib hydrate, Delamanid, Dolutegravir ), Eletriptan hydrobromide, Febuxostat, Fluoxetine, Furosemide, Galantamine Hydrobromide, Hydroazine, Hydrochlorothiazide , Hydrocortisone, Memantine Hydrochloride, Mercaptopurine, Midazolam, Miltefosine, Minodoronic Acid Hydrate, Mirtazapine, Neostigmine , Nicotineamide, Olmesartan Medoxomil, Omeprazole, Ondansetron, Pancrelipase, potassium iodine, prednisolone, primaquine , Primethamine, propranolol, propylthiouracil, pyridox ine, simvastatin, Sitafloxacin hydrate, Spironolactone, Tadalafil, Tamoxifen, Thiamine, Tioguanine, Tolvaptan, Tolvaptan (Uripristal), Vardenafil Hydrochloride Hydrate, zinc sulfate (zinc sulfate), Acotiamide hydrochloride hydrate, Amitriptyline, Bedaquline, Bennzidazole, Bosentan hydrate, Chlorpromazine, Cinacalcet hydrochlorid, Daclatasvir, Dapsone, Diethylcarbamazine, Doxycycline, entacapone, entacapone (Eplerenone), Ferrous sulfate (iron sulphate hydrate), gliclazide (glyclazide), Ibandronate SodiumHydrate (sodium ibandronate hydrate), Losartan (rosartan), Miglitol (migritol), Nitrofurantoin (nitrofurantoin), Phenobarbital (phenobarbital) Barbital, Phenytoin, Pyridostigmine, Raloxifene Hydrochloride, Ritonavir, Succimer, telmisartan, Topiramate, Verapamil, etc.

Examples of medicinal ingredients having a maximum compounding amount of 10 mg or less per tablet include Anastrozole, Dienogest, digoxin, Dustaride, Entecavir, and Entecavir hydrate. Japanese), Ethinylestradiol, Finasteride, Fludrocortisone, glycoryl trinitate, Imidafenacin, Levothyroxine, Levonorgestrel, Levonorgestrel Prostor, Repaglinide, Ambrisentan, Amilolide, Amrodipine, Bepotastine Besilate, Biperiden, Bisoprolol, Blonanserin , Chlorambucil, Dexamethasone, Diazepam, Enalapril, Ergocalciferol, Escitalopram Oxalate, Esomeprazole magnesium hydrate Eszopiclone, Ezetimibe, Fludarabine, Flutyasone furoate, folic acid, haloperidol, isosorbide dinitrate, ivermectin Lenalidomide hydrate, Levocetirizine hydrochloride, Levonorgestrel Bonolgestrel, Loperamide, Loratadine, medroxyprogesterone acetate, methadone, methotrexate, metoclopramide, Mitiglinide Calcium Hydrate, Mitiglinide Calcium Hydrate Montelukast Sodium, Norethisterone, Paliperidone, Phytomenadione, Ramelteon, Riboflavin, Risperidone, Risperidone, Risperidone, Rizatriptan benzoate (Ropinilol hydrochloride), Rosuvastatin Calcium, Senna (senna extract), Silodosin (silodosin), Solifenacin succinate (solifenacin succinate), Warfarin (warfarin) and the like.

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

[Other additives]
The tablet of the present embodiment may contain other additives in addition to the cellulose powder and the active ingredient. Other additives include excipients, disintegrants, binder fluidizers, lubricants, flavoring agents and the like.

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

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

The content of the disintegrant in the tablet of the present embodiment is preferably 0.5% by mass or more and 5.0% by mass or less with respect to the total mass of the tablet.
In the tablet of the present embodiment, by using the above-mentioned polysaccharide, the content of the disintegrant can be further reduced, and a tablet having better storage stability while maintaining better disintegration property can be obtained.

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

Examples of the fluidizing agent include those classified as fluidizing agents in the "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.) such as silicon compounds such as hydrous silicon dioxide and light anhydrous silicic acid. can. One type selected from the above may be used alone, or two or more types may be used in combination.
As a lubricant, those classified as a lubricant in the "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nippo Co., Ltd.) such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, and talc. Can be mentioned. One type selected from the above may be used alone, or two or more types may be used in combination.
As a flavoring agent, "Pharmaceutical Additives Dictionary 2016" (Yakuji Nihonsha Co., Ltd.) such as glutamate, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, l-menthol, etc. (Issue) can be mentioned as a flavoring agent. One type selected from the above may be used alone, or two or more types may be used in combination.

As fragrances, oils such as orange, vanilla, strawberry, yogurt, menthol, fennel oil, kehi oil, pepper oil, mentha oil, green tea powder, etc. "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nihonsha Co., Ltd.) Examples include those classified as fragrances and fragrances. One type selected from the above may be used alone, or two or more types may be used in combination.
Coloring agents include edible pigments such as edible red No. 3, edible yellow No. 5, edible blue No. 1, and "Pharmaceutical Additives Dictionary 2016" such as copper chlorofin sodium, titanium oxide, and riboflavin (published by Yakuji Nihonsha Co., Ltd.). ) Can be classified as a colorant. One type selected from the above may be used alone, or two or more types may be used in combination.
As a sweetener, it is classified as a sweetener in "Pharmaceutical Additives Dictionary 2016" (published by Yakuji Nihonsha Co., Ltd.) such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and amacha powder. I can mention things. One type selected from the above may be used alone, or two or more types may be used in combination.

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

The method for producing a tablet includes a granulation step and a molding step.
In the granulation step, the cellulose powder of the present embodiment and the active ingredient are mixed and granulated. By using the cellulose powder of the present embodiment, the drug substance recovery rate of the granulated product obtained in the granulation step can be improved. In the granulation step, other additives may be added, if necessary, in addition to the active ingredient. Other additives are selected from, for example, the above-mentioned excipients, disintegrants, binders, fluidizers, lubricants, flavoring agents, flavors, colorants, sweeteners, solubilizing agents and the like. One or more types can be mentioned.

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

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

The solvent used in the above-mentioned production method is not particularly limited as long as it is used for pharmaceutical products, and for example, at least one of water and an organic solvent may be used. Examples of the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane and cyclohexane; and ketones such as acetone and ethyl methyl ketone. Etc., which are classified as solvents in "Pharmaceutical Additives Dictionary 2016" (published by Pharmaceutical Affairs Daily Co., Ltd.). It may be used alone or in combination of two or more, and may be dispersed once in one medium, then the medium may be removed and dispersed in different media.

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

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

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

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

In the molding step, the granulated product obtained in the granulation step is compression molded. The compression molding method is not particularly limited as long as it is a usual method, but a method of compression molding into a desired shape using a mortar and a pestle, and a method of compressing and molding into a sheet shape in advance and then cutting into a desired shape. It may be. As the compression molding machine, for example, a static pressure press, a briquetting roller type press, a roller type press such as a smoothing roller type press, a single punch tableting machine, a compressor such as a rotary tableting machine can be used. ..

As a method for forming a tablet, for example, the active ingredient and the cellulose powder of the present embodiment are mixed and granulated, or one or more active ingredients and the cellulose powder of the present embodiment are added, if necessary. Examples thereof include a wet granule compression method (direct tableting method) in which agents are mixed and granulated products are compression-molded. In addition, a method for producing a polynuclear tablet having a pre-compressed tablet as an inner core, a method for producing a multi-layer tablet in which a plurality of pre-compressed molded products are stacked and recompressed may be used. The direct locking method is preferable from the viewpoint of productivity and ease of process control.

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

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

<Analyzing method of composition of cellulose powder>
A sample (pulp piece or cellulose powder): 0.6 g was collected, 72% sulfuric acid: 5 mL was added, and the mixture was stirred at room temperature for 1 hour. Further, the reaction solution was diluted 18 times (4% sulfuric acid) and reacted in an autoclave (121 ° C.) for 1 hour to carry out a sulfuric acid hydrolysis reaction. After cooling, the mixture was neutralized with a 2N aqueous sodium hydroxide solution, the volume was adjusted with pure water (200 mL), and the reaction solution was filtered with a filter paper.
The obtained filtrate was diluted 100-fold with pure water in the analysis of glucose, and diluted 2-fold with pure water in the analysis of xylose and mannose.
The obtained diluted solution was analyzed by high performance liquid chromatography under the conditions shown below, and the content of each sugar was quantified. The ratio of each constituent sugar was determined as a mass fraction to the total of glucose, xylose and mannose.

(Measurement condition)
Model: LC-20AD (Shimadzu Corporation)
Detector: Fluorescence spectrophotometer RF-20Axs (Shimadzu Corporation), fluorescence excitation wavelength 320 nm, fluorescence measurement wavelength 430 nm
Column: TSKgel SUGAR AXI, φ4.6mm x 150mm (Tosoh)
Column temperature: 60 ° C
Mobile phase: 0.5 mol / L borate buffer (pH 8.7), 0.4 mL / min
Injection volume: 20 μL
Post column: Reaction solution 1 w / v% L-arginine solution, reaction solution flow rate 0.7 mL / min, reaction temperature 150 ° C.

<Measuring method of powder physical properties>
[Physical characteristics 1] For the angle of repose measurement, cellulose powder having a water content adjusted to 3.5% by mass or more and 4.5% by mass or less was used. When the water content range of the cellulose powder was out of the lower range, the cellulose powder was adjusted by absorbing water with a constant temperature and humidity chamber or the like. When it came off to the upper side, hot air at 60 ° C. was evenly applied to the cellulose powder in a hot air oven to adjust the water content within the range.
A Sugihara-type angle of repose measuring device (slit size: depth 10 x width 50 x height 140 mm, width 50 mm with a protractor installed) was used to measure the angle of repose of the cellulose powder. Cellulose powder was dropped into the slit at a rate of 50 cc / min with a quantitative feeder to deposit the cellulose powder on the bottom of the device. The deposited cellulose powder gradually formed a slope, and the addition of the cellulose powder was continued until the slope formed a stable angle. When the charged cellulose powder formed a stable slope, the angle between this slope and the bottom of the device was read. This angle is the angle of repose. The measurement was carried out 5 times and the average value was calculated.

[Physical characteristics 2] Average particle size Using a laser diffraction type particle size distribution meter (LA-950 V2 (trade name), manufactured by HORIBA, Ltd.), compressed air pressure 0.10 MPa, feeder speed 160, feeder initial speed coefficient in dry measurement mode. It was measured at 1.2 and a refractive index of 1.51. The cumulative volume of 50% particles obtained by the measurement was taken as the average particle size (μm) of the cellulose powder.

[Physical characteristics 3] For the measurement of loose bulk density, cellulose powder having a water content adjusted to 3.5% by mass or more and 4.5% by mass or less was used. The water content of the cellulose powder was adjusted so as to fall within the range by using the method described in "Physical Properties 1".
A Scott volume meter (model ASTM B-329-85, manufactured by Tsutsui Rikagaku Kikai) was used to measure the loose bulk density of the cellulose powder, and the cellulose powder was filled in a 25 cc cylindrical metal container through a sieve (opening 1 mm). The cellulose powder contained in a 25 cc cylindrical metal container was scraped off, and the mass (g) of the cellulose powder contained in the container was divided by 25 cc to determine the loose bulk density. The measurement was carried out 5 times and the average value was calculated.

[Physical characteristics 4] For the measurement of bulk density, cellulose powder having a water content adjusted to 3.5% by mass or more and 4.5% by mass or less was used. The water content of the cellulose powder was adjusted so as to fall within the range by using the method described in "Physical Properties 1". The firm bulk density (hard apparent specific gravity) (g / cc) was calculated with a powder physical property measuring machine (PT-R, manufactured by Hosokawa Micron). The sieve used had a mesh opening of 710 μm, and the funnel was made of metal (coated with antistatic spray) and had an inner diameter of 0.8 cm. The vibration was carried out at 2.0 (supply power source: AC100V, 60Hz).

[Physical characteristics 5] Decompression degree The compressibility of each cellulose powder was calculated by the formula shown below.

Degree of compression (%) = ([Hard bulk density]-[Loose bulk density]) / [Hard bulk density] x 100

[Physical properties 6] Particle size equivalent to primary particles 0.5 g of cellulose powder is placed in 10 mL of pure water, ultrasonically irradiated for 10 minutes (600 W, 40 kHz), and then subjected to a laser diffraction type particle size distribution meter (LA-950 V2 (trade name)). ), Made by Horiba Seisakusho), refractive index 1.20 (cellulose refractive index 1.59, water refractive index 1.33), pretreatment conditions (ultrasonic irradiation 1 minute, ultrasonic intensity 1) in wet measurement mode. ), Circulation speed 7 and stirring speed 5. The 50% cumulative volume particles obtained by the measurement were defined as the average particle size (μm) of the particle size equivalent to the primary cellulose particles.

[Physical characteristics 7] L / D
Cellulose powder was dispersed on a glass plate, and an image was taken with a microscope (VHX-1000, manufactured by KEYENCE) at a magnification of 500 times. The captured image was analyzed by the following procedure using image processing analysis system software (Image HyperII, manufactured by DigiMo), and the aspect ratio of the particles (ratio of major axis to minor axis; L / D) was measured. Measurements were made on at least 50 particles and the average value was calculated.

(1) Step 1: Binarization processing An image taken with a microscope was imported into analysis software in monochrome, and the scale of the image was set by the two-point distance method. Next, the "Otsu method" was selected in the binarization process, and the threshold value was set. Since the optimum threshold value differs for each image, the threshold value was selected so as to match the shape of the original particle as much as possible while comparing with the original image.

(2) Step 2: Binarization Hand correction While comparing with the original image taken, appropriate measurement results such as overlapping particles, particles protruding from the screen, particles with unclear and blurred outlines, etc. can be obtained. Particles that could not be measured were deleted and excluded from the measurement target.

(3) Step 3: Filling a hole In the "filling a hole" mode, "8" was selected for "neighborhood" and "filling a hole" was executed. Next, the image was compared with the original image again by "binary image manual correction", and it was confirmed whether the correction was performed normally. If the correction was not performed normally, the manual correction was performed again.

(4) Step 4: Image measurement After setting the number of deleted pixels to "100" and selecting "8" for "neighborhood", "image measurement" was executed. The measurement results of "major diameter" and "minor diameter" for each measurement particle are displayed on the personal computer. The value obtained by dividing "major axis" by "minor axis" was used as the aspect ratio.

<Evaluation method for granules and tablets>
Granules and tablets were prepared using the methods shown below and evaluated in various ways. The results are shown in Table 1.

<Making granules>
Ethenzamid (friction charge +3.9 nC / g, average particle size 20 μm): 210 g, 200 mesh lactose: 420 g, and cellulose powder: 70 g were mixed in a polyethylene bag for 1 minute, and a fluidized bed granulator (manufactured by Paulec, mulch) was mixed. It was put into a plex, MP-01 type), sprayed with a solution prepared by dissolving 14.0 g of HPC-L in 219 g of purified water, and dried to obtain granules. At the time of collecting the granules, the granules were discharged only by tilting the column of the fluidized bed granulator, and the fine particles adhering to the wall surface of the column were collected so as not to be dropped as much as possible.

[Evaluation 1] Powder recovery rate The powder recovery rate was determined by dividing the mass of the recovered granules by the mass of the solid content contained in the charged powder and the bonding liquid. When the powder recovery rate was low, the powder adhered to the apparatus of the fluidized bed granulator in a large amount.

[Evaluation 2] Electrostatic value of granules Immediately after granulation of the fluidized bed, the charge amount (unit: nC / g: charge amount per unit weight) of the powder sampled from the granulation apparatus is measured with a Faraday cage (manufacturer Kasuga Electric). did. In addition, in order to prioritize the measurement of the amount of charge, the mass of the granules sampled from the fluidized bed granulator was calculated in addition to the mass of the powder recovered when determining the powder recovery rate.

[Evaluation 3] Recovery rate of API during granule production The prepared granules are further screened to 710 μm to remove coarse particles, and then the obtained granules are sampled at 9 locations in an amount of 500 mg each and contained in the granules. The content of ethenzamid was measured using the method shown below, and the average content of the drug substance was determined.

(1) Measurement of average content of drug substance First, a calibration curve of ethenzamide was prepared. In this example, the absorption spectrum of ethenzamide was measured with an absorptiometer, and a calibration curve was prepared based on the wavelength of the peak top (wavelength of ethenzamide: 292 nm). 500 mg of granules were sampled, placed in a 100 mL volumetric flask, and adjusted to 100 mL with the first solution (pH 1.2) of the Japanese Pharmacopoeia dissolution test. The obtained aqueous solution was filtered through a resin filter to remove insoluble matter, and then the content of ethenzamide with respect to the sampled granule mass of the active ingredient in the filtrate was quantified by an absorptiometry. A total of 9 points were measured for the granules, and the average value of the content of the drug substance was calculated.

(2) Calculation of drug substance recovery rate Next, the average content of the drug substance obtained in (1) was divided by the drug substance content (theoretical value) at the time of preparation to obtain the drug substance recovery rate in the granules.

<Making tablets>
Granules: Magnesium stearate: 1 part by mass was added to 99 parts by mass, and the powder slowly mixed in a plastic bag for 30 seconds was used as a tableting powder for rotary tableting.
Using a rotary tableting machine (model: Libra 2, manufacturer: Kikusui Seisakusho, using 12 punches out of 36, turntable rotation speed: 30 rpm, using open feed shoe), a diameter of 8 mm and a mass of 200 mg / tablet were produced. The tableting pressure was set so that the tablet hardness immediately after tableting was 60 N or more and 70 N or less.

[Evaluation 4] Drug substance content CV value of the tablet After precisely weighing one tablet, the average content and standard deviation of the drug substance were determined using the same method as in (1) of "Evaluation 3". Next, the coefficient of variation (also referred to as “drug content CV value (%)”), which is a measure of uniformity, was calculated using the formula shown below. The lower the coefficient of variation, the better the uniformity of the content of the API.

API content CV value (%) = ([standard deviation] / [average content of API]) x 100

[Evaluation 5] Disintegration of tablets The disintegration of each tablet was examined according to the 17th revised Japanese Pharmacopoeia, general test method "disintegration test method" (test solution: water, with disc). Using a disintegration tester (NT-40HS type (trade name), manufactured by Toyama Sangyo Co., Ltd.), the disintegration time (minutes) in pure water at 37 ° C. was determined. The average value of 6 samples was taken as the tablet disintegration time. The disintegration property was evaluated according to the following evaluation criteria.

(Evaluation criteria)
〇: Collapse time within 15 seconds ×: Collapse time exceeds 15 seconds

[Evaluation 6] Storage Stability Test The tablets obtained in Examples and Comparative Examples were placed in a glass bottle, sealed, and stored in a constant temperature and humidity chamber set at a temperature of 40 ° C. and a humidity of 75% RH for 1 month. The amount of related substances generated and the change in whiteness were evaluated for the tablets after storage. It should be noted that those in which all of the above two evaluation items were good were evaluated as having good storage stability (◯), and those in which they were not were evaluated as having poor storage stability (x).

(1) Amount of related substances generated The “related substances” referred to here are compounds produced by oxidation or hydrolysis of a medicinal ingredient by water.
One tablet obtained in Examples and Comparative Examples was dissolved in 100 mL of purified water, and the solution filtered through a 0.45 μm cellulose acetate filter was analyzed by liquid chromatography (model LC-20AD, Shimadzu Corporation) according to the following conditions. did. The chromatograms obtained before and after the storage stability test were compared, and the peak that was not seen after the storage stability test and appeared after the storage stability test was defined as an analog peak. When there are a plurality of related product peaks, the sum of the areas of the related product peaks is taken as the related product peak area. The amount of related substances generated (%) was calculated by dividing the area of the peak of related substances by the peak area of the medicinal ingredient. The amount of related substances generated was evaluated according to the evaluation criteria shown below.

(Analytical conditions) ・ Aminophylline detector: Ultraviolet absorptiometer (measurement wavelength: 270 nm)
Column: Inner diameter 6 mm, length 15 cm, octadecylsilylated silica gel column for liquid chromatography (silica gel particle size 5 μm)
Column temperature: 40 ° C
Mobile phase: 25% aqueous methanol solution (1% acetic acid added)
Flow rate: The retention time of aminophylline was adjusted to about 5 minutes.・ Ascorbic acid detector: Ultraviolet absorptiometer (measurement wavelength: 300 nm)
Column: Imtaket Unison UK-C18 (3 μm, 4.6 mm × 150 mm)
Column temperature: 40 ° C
Mobile phase (eluent): 2 mM perchloric acid (HClO4)
Eluent flow rate: 1.0 mL / min
Post-column reaction solution: 100 mM sodium hydroxide (NaOH), 100 mM sodium borohydride (NaBH4)
Post-column reaction solution flow rate: 0.5 mL / min

(Evaluation criteria)
Good: The amount of relatives generated is 0.05% or less Poor: The amount of relatives generated exceeds 0.05%

(2) Changes in whiteness Brightness (L) and saturation (green to red) (a) of tablets before and after the storage stability test using a spectroscopic colorimeter (SE-2000, manufactured by Nippon Denshoku Kogyo). , The values of saturation (blue to yellow) (b) were obtained, and the whiteness was calculated by the formula shown below. Next, the change in whiteness (%) was calculated by subtracting the whiteness before the storage test from the whiteness after the storage stability test. The change in whiteness was evaluated according to the evaluation criteria shown below.

Whiteness = 100-[(100-L) 2+ (a2 + b2)] 0.5
Whiteness change = Whiteness (after storage stability test) -Whiteness (before storage stability test)

(Evaluation criteria)
Good: Whiteness change is -20% or more and 0% or less Bad: Whiteness change is less than -20%

<Preparation of wet flocs>
[Preparation Example 1-1] Preparation of Wet Flock X As a constituent sugar of commercially available pulp, a pulp having a glucose ratio of less than 95% (constituent sugar: glucose 90.8%, mannose 1.8%, xylose 7.4%) Was selected. 2 kg of shredded selected pulp was placed in a low-speed stirrer (30 LGL reactor (trade name) manufactured by Ikebukuro Ryo Kogyo Co., Ltd.) and preheated to the reaction temperature under pressure. Warm hydrochloric acid: 30 L Was put into a reactor and hydrolyzed while stirring (reaction conditions: hydrochloric acid concentration 0.5%, reaction temperature 110 ° C., reaction time 30 minutes, stirring speed 350 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue was sufficiently washed with pure water (cold water at 5 ° C.) until the electrical conductivity of the filtrate became less than 100 μS / cm, and then filtered to obtain wet floc X.

[Preparation Example 1-2] Preparation of Wet Flock Y Commercially available pulp (constituent sugar: glucose 97.0%, mannose 0.6%, xylose 2.4%) was selected. 2 kg of shredded selected pulp was placed in a low-speed stirrer (30 LGL reactor (trade name) manufactured by Ikebukuro Ryo Kogyo Co., Ltd.) and preheated to the reaction temperature under pressure. Warm hydrochloric acid: 30 L Was put into a reactor and hydrolyzed while stirring (reaction conditions: hydrochloric acid concentration 1.0%, reaction temperature 130 ° C., reaction time 60 minutes, stirring speed 350 rpm) to obtain an acid-insoluble residue. The obtained acid-insoluble residue was sufficiently washed with pure water (hot water at 90 ° C.) until the electrical conductivity of the filtrate became less than 100 μS / cm, and then filtered to obtain wet floc Y.

[Preparation Example 1-3] Preparation of Wet Flock Z1 Among commercially available pulps, pulp having a glucose ratio of less than 95% (constituent sugar: glucose 93.0%, mannose 2.7%, xylose 4.3%) Was selected. 30 g of shredded pulp and 200 mL of hydrochloric acid aqueous solution were hydrolyzed using a microwave sample pretreatment device (Milestone General Co., Ltd., ETHOS ONE (product name)) (reaction condition: hydrochloric acid concentration 0). 5.5%, reaction temperature 110 ° C., reaction time 30 minutes, stirring speed 200 rpm), an acid-insoluble residue was obtained. The obtained acid-insoluble residue was thoroughly washed with pure water (cold water at 5 ° C.) until the electrical conductivity of the filtrate became less than 100 μS / cm, and then filtered to obtain wet floc Z1.

[Preparation Example 1-4] Preparation of Wet Flock Z2 Pulp with a glucose ratio of less than 95% as a constituent sugar among commercially available pulp (constituent sugar: glucose 93.0%, mannose 1.0%, xylose 6.0%) Wet floc Z2 was obtained by using the same method as in Preparation Example 1-3 except that.

[Preparation Example 1-5] Preparation of Wet Flock Z3 Pulp with a glucose ratio of less than 95% as a constituent sugar among commercially available pulp (constituent sugar: glucose 93.0%, mannose 3.5%, xylose 3.5%) Wet floc Z3 was obtained using the same method as in Preparation Example 1-3 except that.

[Preparation Example 1-6] Preparation of Wet Flock Z4 Pulp with a glucose ratio of less than 95% as a constituent sugar among commercially available pulp (constituent sugar: glucose 88.0%, mannose 4.6%, xylose 7.4%) Was selected. 30 g of shredded pulp and 200 mL of hydrochloric acid aqueous solution were hydrolyzed using a microwave sample pretreatment device (Milestone General Co., Ltd., ETHOS ONE (product name)) (reaction condition: hydrochloric acid concentration 0). 5.5%, reaction temperature 105 ° C., reaction time 30 minutes, stirring speed 200 rpm), an acid-insoluble residue was obtained. The obtained acid-insoluble residue was thoroughly washed with pure water (cold water at 5 ° C.) until the electrical conductivity of the filtrate became less than 100 μS / cm, and then filtered to obtain wet floc Z4.

<Manufacturing of cellulose powder>
[Example 1-1] Production of cellulose powder A Wet floc X obtained in Preparation Example 1-1 was introduced into a 90 L poly bucket, pure water was added so that the total solid content concentration was 25% by mass, and a three-one motor was used. Neutralize with aqueous ammonia while stirring (pH 7.5 or more and 8.0 or less after neutralization), and spray dry this (conditions: dispersion supply rate 6 kg / hour, inlet temperature 180 ° C or more and 220 ° C or less, Outlet temperature 50 ° C. or higher and 70 ° C. or lower), cellulose powder A was obtained.

[Example 1-2] Production of cellulose powder B Except that the wet flocs X and wet flocs Y obtained in Preparation Examples 1-1 and 1-2 were introduced into a 90 L poly bucket at 60:40 (solid content mass ratio). Obtained cellulose powder B by the same method as in Example 1-1.

[Example 1-3] Production of cellulose powder C Except that the wet flocs X and wet flocs Y obtained in Preparation Examples 1-1 and 1-2 were introduced into a 90 L poly bucket at 20:80 (solid content mass ratio). Obtained cellulose powder C by the same method as in Example 1-1.

[Example 1-4] Production of cellulose powder D Wet floc Z1 obtained in Preparation Example 1-3 was introduced into a 2L polybeaker, pure water was added so that the total solid content concentration became 7% by mass, and a three-one motor was used. Neutralize with aqueous ammonia (pH 7.5 or more and 8.0 or less after neutralization), and dry this with a spray dryer (Tokyo Rikaki, SD-1000 (model)) (conditions: Dispersion liquid supply rate 4 mL / min, inlet temperature 180 ° C. or higher and 190 ° C. or lower, outlet temperature 90 ° C. ° C. or higher and 100 ° C. or lower), cellulose powder D was obtained.

[Example 1-5] Production of cellulose powder E Cellulose powder E was prepared by using the same method as in Example 1-4 except that the wet floc Z2 obtained in Preparation Example 1-4 was introduced into a 2L polybeaker. Obtained.

[Example 1-6] Production of Cellulose Powder F Cellulose powder F was prepared by using the same method as in Example 1-4 except that the wet floc Z3 obtained in Preparation Example 1-5 was introduced into a 2L polybeaker. Obtained.

[Example 1-7] Production of Cellulose Powder G Using the same method as in Example 1-4 except that the wet floc Z4 obtained in Preparation Example 1-6 was introduced into a 2L polybeaker, the cellulose powder G was prepared. Obtained.

[Example 1-8] Production of cellulose powder H The cellulose powder C produced in Example 1-3 was pulverized with a jet mill (crushing pressure 0.4 MPa) to obtain cellulose powder H.

[Example 1-9] Production of Cellulose Powder I Cellulose powder E produced in Example 1-5 was pulverized with a jet mill (crushing pressure 0.4 MPa) to obtain cellulose powder I.
[Comparative Example 1-1] Production of Cellulose Powder J Cellulose powder J was obtained by using the same method as in Example 1-1 except that the wet floc Y obtained in Preparation Example 1-2 was introduced into a 90 L poly bucket. rice field.

From Table 1, the granules using the cellulose powders A to G (Examples 1-1 to 1-9) had a good drug substance recovery rate, and the disintegration property of the tablets using the granules was also excellent.
Further, in the cellulose powders A to G (Examples 1-1 to 1-9), as the content of mannose increased, the capacitance of the granules decreased, and the powder recovery rate tended to be more excellent. The higher the content, the better the drug substance recovery rate tended to be.
Further, in the cellulose powders A to C (Examples 1-1 to 1-3), the smaller the total content of mannose and xylose, the lower the degree of compression and the lower the drug substance content CV value of the tablet. That is, the uniformity of the drug substance content in the tablet tended to be more excellent, and the larger the total content of mannose and xylose, the more excellent the disintegration property of the tablet was.
Further, in the cellulose powders D to F (Examples 1-4 to 1-6), the smaller the mass ratio of xylose to mannose (xylose / mannose), the more excellent the disintegration property of the tablet was observed.
Further, in the cellulose powders C, E, H and I (Examples 1-3, 1-5, 1-8 and 1-9), the smaller the average particle size, the lower the capacitance of the granules and the powder recovery. The rate tended to be better, and the drug substance recovery rate also tended to be better.

On the other hand, in the granules using cellulose powder J (Comparative Example 1-1), the drug substance recovery rate was less than 90%, and the disintegration property of the tablets using the granules was also inferior.

[Example 1-10] Evaluation of Granules and Tablets Using Cellulose Powder B In the cellulose powder B produced in Example 1-2, the drug was acetaminophen (friction charge amount -16.7 nC / g, average particle size). The granules and tablets were evaluated using the same method as the above-mentioned evaluation method for granules and tablets, except that the measurement wavelength of the absorbance was changed to 244 nm). The results are shown in Table 1-2.

[Example 1-11] Evaluation of granules and tablets using cellulose powder B In the cellulose powder B produced in Example 1-2, a drug was used as sodium salicylate (friction charge -1.4 nC / g, average particle size 20 μm). ), The granules and tablets were evaluated using the same method as the above-mentioned evaluation method for granules and tablets, except that the measurement wavelength of the absorbance was changed to 302 nm. The results are shown in Table 1-2.

From Table 1-2, in the granules and tablets (Examples 1-2, 1-10 and 1-11) using the drugs having different charge amounts and the cellulose powder B, the electrostatic amounts were all reduced, and the granules. The powder recovery rate and drug substance recovery rate were good, and the tablet content CV value and disintegration property were also excellent.

<Manufacturing of tablets>
[Example 2-1]
Aminophylline: 250 g, cellulose powder A: 75 g, lactose: 167.5 g, and crospovidone: 2.5 g are placed in a polyethylene bag and mixed for 3 minutes, magnesium stearate 5 g is added, and the mixture is further mixed for 30 seconds and then tableted. Rotary tableting was performed as a powder for use. Using a rotary tableting machine (model: Libra 2, manufacturer: Kikusui Seisakusho, using 12 punches out of 36, turntable rotation speed: 30 rpm, using open feed shoe), a diameter of 8 mm and a mass of 200 mg / tablet were produced. The tableting pressure was set so that the tablet hardness immediately after tableting was 60 N or more and 70 N or less. The obtained tablets were evaluated in various ways using the above methods. The results are shown in Table 2-2.

[Examples 2-2 to 2-9 and Comparative Examples 2-1 to 2-2]
Each tablet was prepared by using the same method as in Example 2-1 except that the compositions and blending ratios were set to those shown in Table 2-2. Each of the obtained tablets was evaluated in various ways using the above method. The results are shown in Table 2-2.

From Table 2-2, the tablets using cellulose powders A to F (Examples 2-1 to 2-9) were excellent in storage stability while maintaining good disintegration property, but cellulose powder J In the tablets using (Comparative Examples 2-1 to 2-2), neither good disintegration property nor good storage stability was obtained.
Further, in tablets (Examples 2-1 to 2-3) having the same formulation except that any of cellulose powders A to C is used, the larger the total content of mannose and xylose, the more excellent the disintegration property tends to be. It was seen. It is presumed that this is because hemicellulose containing mannose and xylose as constituent sugars has a property of easily absorbing water, and thus assists the action of the disintegrant. On the other hand, as the total content of mannose and xylose decreased, the amount of related substances generated and the change in whiteness decreased, and the storage stability tended to be better.

According to the cellulose powder of the present embodiment, it is possible to provide a cellulose powder capable of obtaining a tablet having an excellent drug substance recovery rate while maintaining good disintegration property.

Further, according to the tablet of the present embodiment, it is possible to provide a tablet having excellent storage stability while maintaining good disintegration property.

Claims (15)

Cellulose powder
The hydrolyzate of the cellulose powder with sulfuric acid has a mannose content of 0.2% by mass or more based on the total mass of glucose, mannose and xylose in the hydrolyzate.
The content of xylose in the hydrolyzate with respect to the total mass of glucose, mannose and xylose is 0.5% by mass or more.
The content of mannose and the content of xylose are those measured by high performance liquid chromatography, cellulose powder. The sulfuric acid hydrolyzate of the cellulose powder has a glucose content of 87% by mass or more and 99.3% by mass or less with respect to the total mass of glucose, mannose and xylose in the hydrolyzate.
The content of the mannose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate is 0.2% by mass or more and 5.0% by mass or less.
The cellulose powder according to claim 1, wherein the content of the xylose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate is 0.5% by mass or more and 8.0% by mass or less. The cellulose powder according to claim 1 or 2, wherein the total content of the mannose and the xylose with respect to the total mass of glucose, mannose and xylose in the hydrolyzate is 0.7% by mass or more and 13.0% by mass or less. .. The cellulose powder according to any one of claims 1 to 3, wherein the mass ratio of the xylose to the mannose is 0.5 or more and 10 or less. The cellulose powder according to any one of claims 1 to 4, wherein the loose bulk density is 0.10 g / cm ³ or more and 0.40 g / cm ^{3 or less.} Firm bulk density is less than 0.25 g / cm ³ or more 0.57 g / cm ^3, a cellulose powder according to any one of claims 1 to 5. The cellulose powder according to any one of claims 1 to 6, wherein the degree of compression is 21% or more and 70% or less. The cellulose powder according to claim 1, wherein the average particle size of the cellulose powder is 10 μm or more and 300 μm or less. The active ingredient of 50% by mass or more and 99% by mass or less with respect to the total mass of the tablet,
A tablet comprising the cellulose powder according to any one of claims 1 to 8, which is 1% by mass or more and 49% by mass or less based on the total mass of the tablet. The tablet according to claim 9, further comprising a disintegrant of 0.5% by mass or more and 5.0% by mass or less based on the total mass of the tablet. The disintegrant is croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, partial alpha. The tablet according to claim 10, which is at least one selected from the group consisting of starch-forming starch, crospovidone, and crospovidone copolymer. A method for producing a tablet, which comprises a granulation step and a molding step.
A method for producing a tablet, wherein the granulation step is a step of mixing the cellulose powder according to any one of claims 1 to 8 and an active ingredient to granulate. The method for producing a tablet according to claim 12, wherein the granulation step is performed by a wet granulation method. A method for wet granulation of an active ingredient, which comprises adding the cellulose powder according to any one of claims 1 to 8. The method according to claim 14, wherein the triboelectric amount of the active ingredient is +0.1 nC / g or more, or −0.1 nC / g or less.