Cellulose powder and pharmaceutical composition

Abstract

The purpose of the present invention is to provide cellulose powder capable of suppressing a nitrosoamine generation amount to be low when used as a raw material for a pharmaceutical product, and to provide a method for producing same. The present invention provides: cellulose powder having a nitrate ion content of 1.00 ppm or less and a sulfur content of 30.0 ppm or less ; and a method for producing cellulose powder, the method involving hydrolyzing a natural cellulosic material, and subsequently washing same, followed by spray drying, wherein 1) the natural cellulosic material has a nitrite ion content of 0.010 ppm or less or a sulfur ion content of 30.0 ppm or less, and a nitrate ion content of 5.0 ppm or less, or 3) the spray drying is performed in a gas having a nitrogen dioxide content of 0.05 ppm or less or a nitrogen trioxide content of 0.05 ppm or less.

Description

Cellulose powder and pharmaceutical composition

[0001] The present invention relates to a cellulose powder used in the production of a pharmaceutical composition having a reduced nitrosamine content. This application claims priority to Japanese Patent Application No. 2023-144760, filed on September 6, 2023, the contents of which are incorporated herein by reference.

[0002] Conventionally, in the fields of medicine, food, and other chemical industries, it has been common to prepare compacts containing active ingredients by using cellulose powders such as crystalline cellulose and powdered cellulose as excipients. These cellulose powders are required to have functionality that can improve various properties required for pharmaceuticals, such as good moldability and improved bioavailability of active ingredients.

[0003] For example, Patent Document 1 reports that by adjusting the powder properties of cellulose powder, in particular the average degree of polymerization, weight-average particle size, apparent specific volume, and the amount of organic carbon derived from residual impurities, defined as the total organic carbon amount (%) upon extraction with a 1% NaOH aqueous solution minus the total organic carbon amount (%) upon extraction with pure water, within specific ranges, it is possible to improve not only the compression moldability but also the flavor release of herbal medicines and the color development of sugar coating layers.

[0004] On the other hand, the carcinogenicity of nitrosamines has become a problem, and in recent years, strict control of the content of nitrosamines in pharmaceuticals has become a requirement. Nitrite is the main component involved in the generation of nitrosamines in pharmaceuticals, and nitrite introduced not only from the bulk drug substance but also from various additives such as excipients increases the risk of the nitrosamine content exceeding the control index value (Non-Patent Document 1). For example, a synthetic pathway is known in which nitrosamines are generated by a chemical reaction between dimethylamine derived from a drug substance and nitrite derived from an additive at high temperatures.

[0005] Patent No. 6247207

[0006] Boetzel et al, Journal of Pharmaceutical Sciences, 2023, vol.112(6), p.1615-1624.

[0007] The present invention provides a cellulose powder that has an extremely low content of components involved in the generation of nitrosamines and that can suppress the amount of nitrosamines generated when used as a raw material for pharmaceuticals; a method for producing the same; and a pharmaceutical composition made from the cellulose powder.

[0008] The present inventors have conducted extensive research in light of the current situation described above, and have found that in addition to the conventionally known nitrite ion content, the content of nitrate ions, sulfur, hydrogen peroxide, and iron also affect the generation of nitrosamines. They have also found that by using a cellulose powder as a raw material in which the contents of these components have been adjusted to fall within appropriate ranges, the amount of nitrosamines generated during the manufacturing process and storage of pharmaceuticals can be kept lower than when other cellulose powders are used as a raw material, and have completed the present invention.

[0009] That is, the present invention includes the following aspects. [1] A cellulose powder characterized by having a nitrate ion content of 1.00 ppm or less and a sulfur content of 30.0 ppm or less. [2] The cellulose powder of [1] above, having a hydrogen peroxide content of 0.40 ppm or less. [3] A cellulose powder characterized by having a nitrate ion content of 1.00 ppm or less and a hydrogen peroxide content of 0.40 ppm or less. [4] The cellulose powder of any of [1] to [3] above, having a nitrite ion content of 0.200 ppm or less. [5] The cellulose powder of any of [1] to [4] above, having an iron content of 0.10 ppm or more and 0.80 ppm or less. [6] A pharmaceutical composition containing the cellulose powder of any of [1] to [5] above and a pharmaceutically active ingredient. [7] The pharmaceutical composition of [6] above, wherein the pharmaceutically active ingredient is a secondary amine, a tertiary amine, or a quaternary amine. [8] The pharmaceutical composition of [6] above, wherein the pharmaceutical composition is in the form of a tablet. [9] A method for producing a cellulose powder by hydrolyzing a natural cellulosic material, washing any insoluble residue in the cellulose dispersion after hydrolysis, and then spray-drying the cellulose powder, characterized in that (1) the natural cellulosic material has a nitrite ion content of 0.010 ppm or less or a sulfur ion content of 30.0 ppm or less and a nitrate ion content of 5.0 ppm or less, or (3) the spray-drying is carried out in a gas having a nitrogen dioxide concentration of 0.05 ppm or less or a nitrogen trioxide concentration of 0.05 ppm or less.

[10] A method for producing a cellulose powder, comprising hydrolyzing a natural cellulosic material, washing the insoluble residue in the cellulose dispersion after hydrolysis, and then spray-drying the washed cellulose, characterized in that: (1) the natural cellulosic material has a nitrite ion content of 0.010 ppm or less or a sulfur ion content of 30.0 ppm or less, and a nitrate ion content of 5.0 ppm or less; and (3) the spray-drying is carried out in a gas having a nitrogen dioxide concentration of 0.05 ppm or less.

[11] The method for producing a cellulose powder according to [9] or

[10] above, further comprising: (2) water used in one or more processes selected from the group consisting of the hydrolysis reaction of the natural cellulosic material, the washing of the insoluble residue, and the spray drying, the water having a nitrite nitrogen content of 0.02 ppm or less, or a total content of nitrite nitrogen and nitrate nitrogen of 5.0 ppm or less.

[12] A method for producing a pharmaceutical composition, the pharmaceutical composition being produced using the cellulose powder according to any of [1] to [5] above and a pharmaceutically active ingredient as raw materials.

[13] The method for producing a pharmaceutical composition according to

[12] above, wherein the cellulose powder is stored until the start of production in a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less.

[14] The method for producing a pharmaceutical composition according to

[12] or

[13] above, wherein the pharmaceutical composition is produced in a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less.

[15] A method for producing the pharmaceutical composition of any of the above

[12] to

[14] , wherein the pharmaceutically active ingredient is a secondary amine, a tertiary amine, or a quaternary amine.

[16] A method for producing the pharmaceutical composition of any of the above

[12] to

[14] , wherein the pharmaceutically active ingredient is a sartan compound, a compound having a dimethylaminomethyl group, or a biguanide compound.

[17] A method for producing the pharmaceutical composition of any of the above

[12] to

[16] , wherein the pharmaceutical composition is in the form of a tablet, and a mixture containing the cellulose powder and the pharmaceutically active ingredient is directly compressed or granulated and then compressed.

[18] A method for producing a cellulose powder, comprising hydrolyzing a natural cellulosic material, washing the insoluble residue in the cellulose dispersion after hydrolysis, and then spray-drying the cellulose powder, wherein the water used in one or more selected from the group consisting of the hydrolysis reaction of the natural cellulosic material, the washing of the insoluble residue, and the spray-drying has a nitrite nitrogen content of 0.02 ppm or less, or a total content of nitrite nitrogen and nitrate nitrogen of 5.0 ppm or less.

[0010] The cellulose powder of the above-mentioned embodiment has a low content of components that contribute to the generation of nitrosamines. Therefore, by using this cellulose powder as a raw material, it is possible to produce a pharmaceutical composition in which the amount of nitrosamines generated during the manufacturing process and storage is kept low.

[0011] In the present invention and the present specification, unless otherwise specified, "ppm" means "mass ppm (0.001 mg / g)".

[0012] <Cellulose powder> The cellulose powder in this specification is generally referred to as crystalline cellulose, powdered cellulose, etc., and is suitable for use as a pharmaceutical additive or food additive. Among them, crystalline cellulose is preferred as the cellulose powder. Known examples of crystalline cellulose include microcrystalline cellulose described in the 9th edition of the Official Specification of Food Additives, crystalline cellulose described in the Japanese Pharmacopoeia (18th edition), and crystalline cellulose described in the United States Pharmacopoeia, the European Pharmacopoeia, etc.

[0013] The cellulose powder according to one embodiment of the present invention (hereinafter referred to as "this embodiment") has a low content of components that contribute to the generation of nitrosamines, and when used as a raw material for products such as pharmaceuticals, it has a low ability to generate nitrosamines in the product (hereinafter sometimes referred to as "nitrosamine-generating potential"). Because the cellulose powder according to this embodiment has a low nitrosamine-generating potential, it is suitable as a raw material for pharmaceuticals where the nitrosamine content is strictly limited.

[0014] The cellulose powder of this embodiment has a nitrate ion content (mass) of 1.00 ppm or less relative to the total amount (mass) of the cellulose powder. As shown in the examples below, the nitrate ion content affects the amount of nitrosamines generated. The higher the nitrate ion content, the higher the amount of nitrosamines generated. However, by ensuring that the nitrate ion content (mass) of the cellulose powder is 1.00 ppm or less, preferably 0.50 ppm or less, and more preferably 0.20 ppm or less, the amount of nitrosamines generated when used as a pharmaceutical excipient can be kept low. The lower limit of the range of the nitrate ion content (mass) is 0.008 ppm, which is the detection limit. A nitrate ion content (mass) of less than 0.008 ppm in the cellulose powder is undetectable. The reason why the nitrate ion content affects the amount of nitrosamines generated is unclear, but it is presumed to be due to the reduction of nitrate ions in pharmaceuticals to nitrite ions during pharmaceutical manufacturing and storage after manufacturing.

[0015] The cellulose powder according to this embodiment preferably has a lower nitrite ion content (mass). The nitrite ion content relative to the total amount (mass) of the cellulose powder according to this embodiment is preferably 0.200 ppm or less, more preferably 0.100 ppm or less, even more preferably 0.050 ppm or less, even more preferably 0.020 ppm or less, and particularly preferably 0.015 ppm or less. The lower limit of the range of the nitrite ion content (mass) is 0.008 ppm, which is the detection limit. A nitrite ion content (mass) of less than 0.008 ppm in the cellulose powder is undetectable.

[0016] The cellulose powder according to this embodiment has a sulfur content (mass) of 30.0 ppm or less relative to the total amount (mass) of the cellulose powder. As shown in the examples below, the sulfur content affects the amount of nitrosamines generated. The higher the sulfur content, the higher the amount of nitrosamines generated. However, by ensuring that the sulfur content (mass) of the cellulose powder is 30.0 ppm or less, preferably 25.0 ppm or less, more preferably 20.0 ppm or less, and even more preferably 18.0 ppm or less, the amount of nitrosamines generated when used as a pharmaceutical excipient or the like can be kept low. While the reason why sulfur content affects the amount of nitrosamines generated is unclear, it is presumed that sulfur in pharmaceuticals functions as a reducing agent during pharmaceutical manufacturing and storage after manufacture, converting nitrate ions to nitrite ions. The lower limit of the sulfur content (mass) range is 0.10 ppm, which is the detection limit. A sulfur content (mass) of cellulose powder less than 0.10 ppm is undetectable.

[0017] The cellulose powder according to this embodiment preferably has a hydrogen peroxide content (mass) of 0.40 ppm or less, more preferably 0.30 ppm or less, and even more preferably 0.20 ppm or less, relative to the total amount (mass) of the cellulose powder. The lower limit of the hydrogen peroxide content (mass) range is 0.10 ppm, which is the detection limit. A hydrogen peroxide content (mass) of less than 0.10 ppm in the cellulose powder is undetectable. As shown in the examples below, the hydrogen peroxide content affects the amount of nitrosamines generated. The higher the hydrogen peroxide content, the higher the amount of nitrosamines generated. However, by keeping the hydrogen peroxide content (mass) relative to the total amount (mass) of the cellulose powder within the above range, the amount of nitrosamines generated can be kept low when the cellulose powder is used as a pharmaceutical excipient, etc. The reason why the hydrogen peroxide content affects the amount of nitrosamines generated is unclear; however, it is presumed that hydrogen peroxide in pharmaceuticals functions as a reducing agent, converting nitrate ions to nitrite ions during pharmaceutical manufacturing and storage after manufacture.

[0018] The cellulose powder according to this embodiment preferably has an iron content (by mass) of 0.10 ppm to 0.80 ppm, more preferably 0.20 ppm to 0.80 ppm, even more preferably 0.30 ppm to 0.80 ppm, and even more preferably 0.20 ppm to 0.70 ppm, relative to the total amount (by mass) of the cellulose powder. In particular, the iron content (by mass) of the cellulose powder according to this embodiment is more preferably 0.30 ppm to 0.70 ppm, even more preferably 0.30 ppm to 0.60 ppm. As shown in the examples below, the iron content affects the amount of nitrosamines generated. While a low iron content increases the amount of nitrosamines generated, a high iron content is undesirable because it may increase the total amount of iron added. By keeping the iron content (by mass) relative to the total amount (by mass) of cellulose powder within the above range, it is possible to reduce the amount of nitrosamines generated when the cellulose powder is used as a pharmaceutical excipient, etc. The reason why the iron content affects the amount of nitrosamines generated is unclear, but it is presumed that this is because, during the pharmaceutical manufacturing process and storage after manufacture, iron in pharmaceuticals not only functions as a reducing agent but also reacts with nitrate ions to generate nitric oxide, thereby suppressing the conversion of nitrate ions to nitrite ions.

[0019] The contents of nitrate ions, nitrite ions, sulfur, hydrogen peroxide, and iron in the cellulose powder can all be measured by the methods described in the Examples below.

[0020] The cellulose powder according to this embodiment is particularly: a cellulose powder having a nitrate ion content of 1.00 ppm or less and a sulfur content of 30.0 ppm or less; a cellulose powder having a nitrate ion content of 1.00 ppm or less, a sulfur content of 30.0 ppm or less, and a hydrogen peroxide content of 0.40 ppm or less; a cellulose powder having a nitrate ion content of 1.00 ppm or less and a hydrogen peroxide content of 0.40 ppm or less; Cellulose powder having a nitrate ion content of 1.00 ppm or less, a sulfur content of 30.0 ppm or less, and a nitrite ion content of 0.200 ppm or less; cellulose powder having a nitrate ion content of 1.00 ppm or less, a sulfur content of 30.0 ppm or less, a hydrogen peroxide content of 0.40 ppm or less, and a nitrite ion content of 0.200 ppm or less; cellulose powder having a nitrate ion content of 1.00 ppm or less, a hydrogen peroxide content of 0.40 ppm or less, and a nitrite ion content of 0.200 ppm or less; Cellulose powder having a nitrate ion content of 1.00 ppm or less, a sulfur content of 30.0 ppm or less, and an iron content of 0.10 ppm or more and 0.80 ppm or less; cellulose powder having a nitrate ion content of 1.00 ppm or less, a sulfur content of 30.0 ppm or less, a hydrogen peroxide content of 0.40 ppm or less, and an iron content of 0.10 ppm or more and 0.80 ppm or less; cellulose powder having a nitrate ion content of 1.00 ppm or less, a hydrogen peroxide content of 0.40 ppm or less, and an iron content of 0.10 ppm or more and 0.80 ppm or less; Cellulose powder having a nitrate ion content of 1.00 ppm or less, a sulfur content of 30.0 ppm or less, a nitrite ion content of 0.200 ppm or less, and an iron content of 0.10 ppm or more and 0.80 ppm or less; cellulose powder having a nitrate ion content of 1.00 ppm or less, a sulfur content of 30.0 ppm or less, a hydrogen peroxide content of 0.40 ppm or less, a nitrite ion content of 0.200 ppm or less, and an iron content of 0.10 ppm or more and 0.80 ppm or less;Preferred is a cellulose powder having a nitrate ion content of 1.00 ppm or less, a hydrogen peroxide content of 0.40 ppm or less, a nitrite ion content of 0.200 ppm or less, and an iron content of 0.10 ppm or more and 0.80 ppm or less.

[0021] The average degree of polymerization of the cellulose powder according to this embodiment is not particularly limited. The average degree of polymerization of the cellulose powder according to this embodiment is preferably 100 or more and 350 or less, more preferably 150 or more and 300 or less, and even more preferably 180 or more and 250 or less. An average degree of polymerization of 100 or more is preferable because it improves moldability, and an average degree of polymerization of 350 or less is preferable because it does not exhibit fibrous properties and the powder has excellent fluidity and disintegration properties. In other words, an average degree of polymerization of 100 or more and 350 or less is preferable because it provides a particularly excellent balance between moldability, disintegration properties, and fluidity.

[0022] The weight-average particle diameter of the cellulose powder according to this embodiment is not particularly limited. The weight-average particle diameter of the cellulose powder according to this embodiment is preferably more than 30 μm and not more than 250 μm, more preferably more than 30 μm and not more than 180 μm, and even more preferably 40 μm or more and not more than 150 μm. By setting the weight-average particle diameter to more than 30 μm, preferably 40 μm or more, handling is improved without increasing adhesion and cohesion, and fluidity is also excellent. Furthermore, by setting the weight-average particle diameter to 250 μm or less, preferably 180 μm or less, more preferably 150 μm or less, separation and segregation from the active ingredient do not occur, and there is no risk of deterioration in the content uniformity of the formulation, which is preferable.

[0023] The apparent specific volume of the cellulose powder according to this embodiment is not particularly limited. The apparent specific volume of the cellulose powder according to this embodiment is 2 cm ３ / g or more 15cm ３ / g or less, and more preferably 2 cm ３ / g or more 13cm ３ / g or less, more preferably 2 cm ３ / g or more 6cm ３ / g or less, particularly preferably 2 cm ３ / g or more 4cm３ / g. The apparent specific volume is less than 2 cm ３ / g or more, the moldability is improved. Since elastic recovery due to fibrous properties is exhibited, the upper limit is at most 15 cm ３ / g. In terms of improving fluidity and disintegration properties, ３ / g or less is preferable, and 4 cm ３ The apparent specific volume of the cellulose powder according to this embodiment is particularly preferably 2.3 cm ３ / g or more 3.8cm ３ / g or less, and even more preferably 3.0 cm ３ / g or more 3.8cm ３ / g or less.

[0024] The tapped apparent density of the cellulose powder according to this embodiment is not particularly limited. The tapped apparent density of the cellulose powder according to this embodiment is 0.2 g / cm ３ 0.6g / cm or more ３ It is preferably 0.3 g / cm or less, and more preferably 0.3 g / cm ３ 0.58g / cm or more ３ More preferably, 0.35 g / cm ３ 0.55g / cm or more ３ The tapping apparent density is 0.6 g / cm or less. ３ If it is less than this, the moldability is improved.

[0025] The angle of repose of the cellulose powder according to this embodiment is not particularly limited. From the viewpoint of content uniformity, the angle of repose of the cellulose powder according to this embodiment is preferably 36° or more and less than 44°, and more preferably 38° to 42°.

[0026] The physical properties of cellulose powder can be measured as follows. 1) Average degree of polymerization (-) This can be measured by the copper ethylenediamine solution viscosity method described in the 18th edition of the Japanese Pharmacopoeia, Verification Test for Microcrystalline Cellulose (3). 2) Loss on drying (%) 1 g of powder is dried at 105°C for 3 hours, and the weight loss is expressed as a weight percentage. 3) Weight-average particle diameter of cellulose powder (μm) The weight-average particle diameter of a powder sample is measured by sieving 10 g of sample for 10 minutes using a Rotap type sieve shaker (Sieve Shaker Type A manufactured by Hira Kosakusho) and a JIS standard sieve (Z8801-1987), to measure the particle size distribution, and expressed as the particle size at 50% of the cumulative weight. 4) Apparent specific volume (cm ３ / g) 100cm ３ The powder sample is roughly filled into a glass measuring cylinder using a quantitative feeder or the like over a period of 2 to 3 minutes, and the top surface of the powder layer is leveled with a soft brush such as a paintbrush to read the volume, which is then divided by the weight of the powder sample to determine the weight of the powder. ３ 5) Apparent tapping density (g / cm ３ ) Using a commercially available powder property measuring instrument (Hosokawa Micron, Powder Tester PT-R type), ３ The powder is filled into a cup, and after 180 taps, the volume of the cup is divided by the weight of the powder layer remaining in the cup. 6) Angle of repose (°): Using a Sugihara-type angle of repose measuring device (slit size: depth 10 x width 50 x height 140 mm, protractor installed at the 50 mm width position), the dynamic free flow property is measured when cellulose powder is dropped into the slit using a quantitative feeder at a rate of 3 g / min. The angle of repose is the angle between the bottom of the device and the layer of cellulose powder that has formed.

[0027] <Method for producing cellulose powder> The cellulose powder according to this embodiment can be produced, for example, by hydrolyzing a natural cellulosic material, washing the insoluble residue in the cellulose dispersion after hydrolysis, and then spray-drying. The reaction conditions for the hydrolysis reaction, the recovery and washing of the insoluble residue, and the spray-drying after re-dispersion can be determined by methods and conditions generally used for producing cellulose powders, or by appropriately modifying these.

[0028] The natural cellulosic material as the raw material may be of plant or animal origin. Examples of natural cellulosic materials include cellulose-containing fibrous materials derived from natural sources such as wood, bamboo, wheat straw, rice straw, cotton, ramie, bagasse, kenaf, beet, sea squirt, and bacterial cellulose. The natural cellulosic material has a cellulose type I crystal structure. One of the above natural cellulosic materials may be used as the raw material, or a mixture of two or more may be used.

[0029] The natural cellulosic material as the raw material is preferably used in the form of purified pulp, and from the viewpoint of production yield, purified pulp having an α-cellulose content of 85% or more is particularly preferred. There are no particular restrictions on the method of pulp purification, and any pulp such as dissolving pulp, kraft pulp, or NBKP pulp may be used. From the viewpoints of high α-cellulose purity, easy availability, and stable supply, wood-derived pulp is preferred.

[0030] The hydrolysis of natural cellulosic materials may be performed by acid hydrolysis, alkaline oxidative decomposition, hydrothermal decomposition, or steam explosion. Any of these hydrolysis methods may be used alone, or two or more may be used in combination. Furthermore, natural cellulosic materials may be subjected to mechanical treatments such as pulverization or grinding before or after hydrolysis.

[0031] Hydrolysis of natural cellulosic materials is carried out by dispersing solids containing the natural cellulosic material in a suitable medium. Water is preferred. The medium may be any medium other than water, as long as it is industrially used. For example, a mixture of water and an organic solvent may be used. Examples of such organic solvents include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; and ketones such as acetone and ethyl methyl ketone. Organic solvents used in pharmaceuticals are particularly preferred, including those classified as solvents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). Water and organic solvents may be used alone or in combination of two or more. The material may be dispersed in one medium, then the medium removed, and the material may be dispersed in a different medium.

[0032] When hydrolysis of a natural cellulosic material is carried out by acid hydrolysis using hydrochloric acid, conditions such as hydrochloric acid concentration, hydrolysis temperature, and hydrolysis time are not particularly limited and are appropriately adjusted so as to obtain a cellulose powder with the desired physical properties. For example, the hydrochloric acid concentration is preferably 0.05 to 0.3%, more preferably 0.08 to 0.25%, and even more preferably 0.08 to 0.15%, the 100 to 150°C temperature is preferably 80 to 150°C, more preferably 100 to 150°C, and the hydrolysis time is preferably 40 to 150 minutes, more preferably 70 to 110 minutes.

[0033] In general, when hydrolysis is performed, increasing the acid or alkali concentration of the hydrolysis solution or the reaction temperature tends to decrease the degree of cellulose polymerization and decrease the average particle size of cellulose in the dispersion. Furthermore, increasing the stirring force of the solution also tends to decrease the average particle size of cellulose particles in the dispersion. Therefore, by adjusting the degree of polymerization of the raw cellulose and the stirring force during the hydrolysis or dispersion process of the natural cellulosic material, the degree of polymerization and average particle size of the cellulose particles can be controlled within a desired range. The stirring force depends on the width, height, volume, type and diameter of the stirring bed, stirring speed, etc.

[0034] The cellulose dispersion obtained after hydrolysis is subjected to solid-liquid separation to recover insoluble residue, which is then washed. At this time, neutralization may be performed by alkali treatment or acid treatment, if necessary. The washing liquid used in the washing treatment may be the same medium as that used to disperse the natural cellulosic material. Furthermore, when washing treatment is performed multiple times, different washing liquids may be used for each washing. In the production of the cellulose powder of this embodiment, washing with pure water is preferred.

[0035] The insoluble residue after washing is dispersed again in pure water to prepare a cellulose dispersion. The cellulose dispersion is spray-dried to produce a cellulose powder. The redispersed cellulose dispersion may be subjected to mechanical treatments such as pulverization or grinding, centrifugation using a cyclone or centrifuge, or separation using a sieve before spray-drying. These treatment methods may be used alone or in combination of two or more.

[0036] Examples of the pulverization method include screen pulverization methods such as a screen mill and a hammer mill; blade rotary shear screen pulverization methods such as a flash mill; airflow pulverization methods such as a jet mill; ball pulverization methods such as a ball mill and a vibration ball mill; and blade stirring pulverization methods.

[0037] Examples of the grinding method include grinding methods using stirring blades such as unidirectional rotation, multi-axis rotation, reciprocating inversion, up-down movement, rotation + up-down movement, and pipeline type blades of a portable mixer, a three-dimensional mixer, or a side mixer; jet-type stirring and grinding methods such as a line mixer; grinding methods using a high-shear homogenizer, a high-pressure homogenizer, or an ultrasonic homogenizer; and shaft rotation extrusion grinding methods such as a kneader.

[0038] As a method for spray-drying the redispersed cellulose dispersion, various methods can be used, such as a disk type, a pressurized nozzle, a pressurized two-fluid nozzle, or a pressurized four-fluid nozzle. These spray methods can be used alone or in combination of two or more. The spray-drying temperature is a commonly used inlet temperature of 150°C to 300°C. Furthermore, freeze drying, drum drying, shelf drying, flash drying, vacuum drying, etc. can also be used instead of or in combination with spray drying.

[0039] When carrying out the above-mentioned spray drying, a small amount of a water-soluble polymer or a surfactant may be added to the dispersion in order to reduce the surface tension of the dispersion, and a foaming agent or gas may be added to the dispersion in order to accelerate the evaporation rate of the medium.

[0040] Examples of water-soluble polymers include those listed in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, gum arabic, and starch paste. These water-soluble polymers may be used alone or in combination of two or more.

[0041] Examples of surfactants include those classified as surfactants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monolaurate, polysorbate, sorbitan monooleate, glyceride monostearate, monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, sorbitan monopalmitate, and sodium lauryl sulfate. These surfactants may be used alone or in combination of two or more.

[0042] Examples of foaming agents include those listed in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as tartaric acid, sodium bicarbonate, potato starch, anhydrous citric acid, medicated soap, sodium lauryl sulfate, lauric acid diethanolamide, and lauromacrogol. These foaming agents may be used alone or in combination of two or more.

[0043] In addition to pharmaceutical additives, other examples include bicarbonates such as sodium bicarbonate and ammonium bicarbonate that generate gas upon thermal decomposition; and carbonates such as sodium carbonate and ammonium carbonate that generate gas upon reaction with an acid. However, when using the above carbonates, they must be used together with an acid. Examples of acids include organic acids such as citric acid, acetic acid, ascorbic acid, and adipic acid; protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; and Lewis acids such as boron fluoride. Of these, acids used in pharmaceuticals or foods are preferred, but other acids also have similar effects.

[0044] Alternatively, instead of a foaming agent, a gas such as nitrogen, carbon dioxide, liquefied petroleum gas, or dimethyl ether may be impregnated into the dispersion.

[0045] The water-soluble polymer, surfactant, and gas-generating substance such as a foaming agent may be added before drying, and there is no particular limitation on the timing of their addition.

[0046] In the method for producing a cellulose powder according to this embodiment, at least one of the following (1) and (3) is carried out in order to produce a cellulose powder with low nitrosamine-generating potential by keeping the content of components that contribute to the production of nitrosamines low. (1) The natural cellulosic material has a nitrite ion content of 0.010 ppm or less or a sulfur ion content of 30.0 ppm or less and a nitrate ion content of 5.0 ppm or less. (3) The spray drying is carried out in a gas having a nitrogen dioxide concentration of 0.05 ppm or less or a nitrogen trioxide concentration of 0.05 ppm or less. In the method for producing a cellulose powder according to this embodiment, in addition to at least one of the above 1) and (3), it is also preferable to carry out the following (2). (2) The water used in one or more of the processes selected from the group consisting of the hydrolysis reaction of the natural cellulosic material, the washing of the insoluble residue, and the spray drying has a nitrite nitrogen content of 0.02 ppm or less, or a total content of nitrite nitrogen and nitrate nitrogen of 5.0 ppm or less.

[0047] The majority of nitrite ions and nitrate ions in cellulose powder originate from the natural cellulosic material used as the raw material. Therefore, in this embodiment, a cellulose powder with reduced nitrosamine-generating potential can be produced by using a natural cellulosic material with a low content of nitrite ions, sulfur ions, or nitrate ions as the raw material. In this embodiment, it is preferable to use a natural cellulosic material with a nitrite ion content of 0.010 ppm or less and a nitrate ion content of 5.0 ppm or less as the raw material, or a natural cellulosic material with a sulfur ion content of 30.0 ppm or less and a nitrate ion content of 5.0 ppm or less as the raw material.

[0048] The method for measuring trace substances such as nitrite ions, sulfur ions, and nitrate ions contained in the raw natural cellulosic material is not particularly limited, and any known method may be used. For example, the measurement can be performed using the same method as the measurement of trace substances in the cellulose powder described above.

[0049] In measuring trace substances in natural cellulosic materials, it is preferable to perform pretreatment such as treating the pulp to a flocculated state in order to improve extraction efficiency and evaluation accuracy. There are no limitations on the method for treating the pulp to a flocculated state, and it can be treated using a general grinder. For example, a high-speed mill manufactured by LabNext or a home mixer may be used.

[0050] The amounts of nitrite ions, sulfur ions, and nitrate ions in the cellulose powder are affected by the water used in the reaction solution for the hydrolysis reaction, the water used in the washing solution for washing the insoluble residue, and the water used to prepare the cellulose dispersion to be subjected to spray drying. In this embodiment, by using water with a low content of nitrite ions and nitrate ions as these waters, the amount of carryover from the water can be kept low, making it possible to produce a cellulose powder with an extremely low content of nitrite ions and nitrate ions and low nitrosamine-generating ability. More specifically, it is preferable to use water with a nitrite nitrogen content of 0.02 ppm or less, or water with a total content of nitrite nitrogen and nitrate nitrogen of 5.0 ppm or less.

[0051] In the method for producing cellulose powder according to this embodiment, it is preferable that the water used in any one of the hydrolysis reaction of the natural cellulosic material, washing of the insoluble residue, and spray drying be water with a low content of nitrite ions, etc. It is more preferable that the water used in any two of the hydrolysis reaction of the natural cellulosic material, washing of the insoluble residue, and spray drying be water with a low content of nitrite ions, etc. It is particularly preferable that the water used in all of the hydrolysis reaction of the natural cellulosic material, washing of the insoluble residue, and spray drying be water with a low content of nitrite ions, etc.

[0052] The amount of nitrite ions and nitrate ions in the cellulose powder is affected by the gas used during spray drying. In this embodiment, spray drying is performed in a gas containing almost no nitrite ions or nitrate ions, thereby minimizing the amount of nitrite ions and nitrate ions carried over from the gas. This allows the production of a cellulose powder with a very low content of nitrite ions and nitrate ions and low nitrosamine-generating ability. In the method for producing a cellulose powder according to this embodiment, the NOx (nitrogen oxide) concentration of the gas during spray drying is preferably 0.00 ppm or more and 0.20 ppm or less, more preferably 0.00 ppm or more and 0.15 ppm or less, and even more preferably 0.00 ppm or more and 0.10 ppm or less. The NOx concentration of the gas is primarily the total concentration of nitric oxide, nitrogen dioxide, nitrous oxide, and dinitrogen trioxide.

[0053] In the method for producing a cellulose powder according to this embodiment, it is preferable to use, as the gas used during spray drying, "a gas having a nitrogen dioxide concentration of 0.05 ppm or less" or "a gas having a nitrogen trioxide concentration of 0.05 ppm or less," and it is particularly preferable to use "a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less." As the "gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less," for example, air in which the nitrogen dioxide concentration is controlled to 0.05 ppm or less and the nitrogen trioxide concentration is 0.05 ppm or less is used.

[0054] The nitrogen dioxide concentration of the gas during spray drying is preferably 0.000 ppm to 0.050 ppm, more preferably 0.00 ppm to 0.025 ppm, and even more preferably 0.00 ppm to 0.020 ppm. The nitrogen trioxide concentration of the gas during spray drying is preferably 0.000 ppm to 0.050 ppm, more preferably 0.00 ppm to 0.025 ppm, and even more preferably 0.00 ppm to 0.020 ppm.

[0055] The method for controlling the nitrogen dioxide and nitrogen trioxide concentrations in the atmosphere is not particularly limited as long as it can remove nitrogen dioxide and nitrogen trioxide from the atmosphere. Examples of methods for removing nitrogen dioxide and nitrogen trioxide from dry air include a wet adsorption method using a scrubber and a dry adsorption method using a chemical filter.

[0056] In methods using chemical filters, it is important to select an adsorbent that can efficiently remove acidic gases such as nitrogen dioxide. Examples of adsorbents that can efficiently remove acidic gases include "SAAF Carb" (manufactured by AAF), "Pure Smel Filter Adsorbent E3" and "Pure Smel Filter Adsorbent E5" (both manufactured by Nippon Mokukai Co., Ltd.), "Gigacol" and "CP Blend Select" (both manufactured by Nitta Corporation), "Phylofresh VZG" and "Phylofresh VCL" (both manufactured by Nippon Vilene Co., Ltd.), and "RM2B90" (manufactured by Osaka Gas Chemicals Co., Ltd.). These adsorbents can be selected appropriately depending on the size and production capacity of the cellulose powder production equipment. There are no limitations on the method of selecting an adsorbent, as long as it can adjust the amount of nitrogen dioxide contained in dry air to a certain value or less.

[0057] In the method for producing cellulose powder according to this embodiment, it is preferable that not only the gas used for spray drying but also steps other than spray drying in the cellulose powder production process be carried out in a gas in which the nitrogen dioxide concentration is controlled to 0.05 ppm or less or the nitrogen trioxide concentration is 0.05 ppm or less, and it is more preferable that all steps for producing cellulose powder be carried out in a gas in which the nitrogen dioxide concentration is controlled to 0.05 ppm or less or the nitrogen trioxide concentration is 0.05 ppm or less. By producing in air in which the concentrations of nitrogen dioxide and nitrogen trioxide are controlled to be low, the introduction of nitrite nitrogen and nitrate nitrogen from the air is suppressed, and cellulose powder with a low content of nitrite ions and nitrate ions can be stably produced.

[0058] The method for measuring the concentrations of nitrogen dioxide and nitrogen trioxide in the air is not particularly limited, and measurements can be made by conventional methods. For example, the concentrations of nitrogen monoxide, nitrogen dioxide, and NOx in the air can be measured using a general NOx measuring device that employs a chemiluminescence method. Examples of NOx measuring devices include "GLN-354D" (manufactured by DKK-TOA Corporation), "APNA-370" (manufactured by Horiba, Ltd.), and "NOA-308Dx" (manufactured by Shimadzu Corporation). In addition, the concentrations of nitrogen dioxide and nitrogen trioxide in the air can be measured by measuring a sample collected using a diffusion sampler for collecting acidic gases using ion chromatography or the Satzmann method.

[0059] In the method for producing cellulose powder according to this embodiment, it is sufficient to carry out at least one of (1) and (3). In the method for producing cellulose powder according to this embodiment, it is preferable to carry out (1) and (3) above, since the content of components that contribute to the formation of nitrosamines can be kept sufficiently low. In the method for producing cellulose powder according to this embodiment, it is also preferable to carry out (2) above in addition to at least one of (1) and (3). Note that even when cellulose powder is produced by carrying out only (2), it is possible to produce cellulose powder with a reduced content of components that contribute to the formation of nitrosamines.

[0060] Specifically, by using a natural cellulosic material as the raw material that satisfies the above-mentioned (1), it is possible to produce a cellulose powder with an extremely low content of components that contribute to the generation of nitrosamines. Also, by carrying out spray drying in a gas that satisfies the above-mentioned (3), it is possible to produce a cellulose powder with an extremely low content of components that contribute to the generation of nitrosamines. By using water whose nitrite nitrogen content or the total content of nitrite nitrogen and nitrate nitrogen satisfies the above-mentioned (2) as the water used in one or more processes selected from the group consisting of the hydrolysis reaction of the natural cellulosic material, the washing of the insoluble residue, and the spray drying, it is possible to produce a cellulose powder with an extremely low content of components that contribute to the generation of nitrosamines.

[0061] In order to more sufficiently reduce the content of components that contribute to the production of nitrosamines, it is preferable to carry out at least two of the steps (1) to (3) in the method for producing cellulose powder according to this embodiment, and it is particularly preferable to carry out all of the steps (1) to (3).

[0062] In the method for producing a cellulose powder according to this embodiment, in addition to at least one of the above (1) to (3), it is also preferable to carry out various treatments to reduce the amounts of sulfur, hydrogen peroxide, and iron carried over into the final cellulose powder. For example, the water used for washing the insoluble residue and the subsequent spray drying may be water (e.g., pure water) containing not only nitrite nitrogen and nitrate nitrogen, but also low amounts of sulfur, hydrogen peroxide, and iron. Furthermore, the number of washes for washing the insoluble residue may be increased from the conventional number, for example, three or more times, preferably four or more times, more preferably five or more times, and even more preferably six or more times. The more washes, the more the amounts of sulfur, hydrogen peroxide, and iron carried over from the raw materials can be reduced.

[0063] The cellulose powder of this embodiment, like other cellulose powders, can be used as a raw material for various products such as pharmaceuticals, foods and beverages, feed, cosmetics, sanitary products, agricultural chemicals, etc. The cellulose powder of this embodiment has a low ability to generate nitrosamines, which have a significant impact on human health, and is therefore particularly suitable as an excipient for pharmaceuticals and foods and beverages whose nitrosamine content is limited.

[0064] <Pharmaceutical Composition> The pharmaceutical composition of this embodiment contains the cellulose powder of this embodiment and a pharmaceutically active ingredient. The contents of the pharmaceutically active ingredient and the cellulose powder of this embodiment in the pharmaceutical composition of this embodiment are not particularly limited, and in typical use ranges, the content of the pharmaceutically active ingredient is from 0.001% by mass to 99.0% by mass, and the content of the cellulose powder of this embodiment is from 1.0% by mass to 99.0% by mass, relative to the total mass of the pharmaceutical composition. By ensuring that the content of the pharmaceutically active ingredient is at least the lower limit, a therapeutically effective amount can be ensured. On the other hand, by ensuring that the content is at most the upper limit, the content of the cellulose powder of this embodiment can be at least the lower limit, making full use of the characteristic of the cellulose powder of this embodiment, namely, its resistance to generating nitrosamines.

[0065] The pharmaceutically active ingredient contained in the pharmaceutical composition of this embodiment is not particularly limited. Furthermore, the pharmaceutical composition may contain only one type of pharmaceutically active ingredient, or two or more types. Examples of the pharmaceutically active ingredient include orally administered drugs such as hyperlipidemic drugs, diabetes drugs, stomachics, antacids, digestive drugs, antipyretic analgesics, anti-inflammatory drugs, hypnotics, sedatives, antisomnia drugs, antivertigo drugs, pediatric analgesics, cardiac stimulants, antiarrhythmic drugs, antihypertensive drugs, vasodilators, diuretics, antiulcer drugs, intestinal regulators, osteoporosis drugs, antitussives and expectorants, antiasthmatic drugs, antibacterial agents, agents for improving frequent urination, tonics, and vitamins.

[0066] The pharmaceutically active ingredient contained in the pharmaceutical composition of this embodiment is preferably a secondary amine, tertiary amine, or quaternary amine that is prone to generating nitrosamines. Among nitrosamines, pharmaceutically active ingredients that contain NDMA (N-nitrosodimethylamine) or NDEA (N-nitrosodiethylamine) are particularly preferred. Examples of such pharmaceutically active ingredients include sartan compounds (e.g., valsartan, irbesartan, olmesartan, losartan, etc.), compounds containing a dimethylaminomethyl group (e.g., ranitidine, nizatidine, d-chlorpheniramine maleate (MCPA)), etc.), and biguanide compounds (e.g., metformin, buformin, etc.).

[0067] The active pharmaceutical ingredient contained in the pharmaceutical composition of this embodiment may be a secondary amine, a tertiary amine, or a quaternary amine, such as sitagliptin, rifampicin, gliclazide, orphenadrine, alpraziquantel, ropivacaine, ambroxol, quetiapine, atomoxetine, atenolol, azithromycin, betahistine, benazepril, bisoprolol, bumetanide, bupropion, cilazapril, ciprofloxacin, dabigatran, desloratadine, trimebutine, azithromycin, chloropyramine, Preferably, one or more selected from the group consisting of triprolidine, diclofenac, duloxetine, enalapril, fluoxetine, hydrochlorothiazide, ketamine, labetalol, landiolol, levofloxacin, lisinopril, mefenamic acid, methylphenidate, metoprolol, mirabegron, moxifloxacin, nebivolol, valacyclovir, amitriptyline, northoptyline, paroxetine, perindopril, phenylephrine, pracipexole, propranolol, pseudoephedrine, quinapril, ramipril, rasagiline, reboxetine, salbutamol, sertraline, sotalol, tamsulosin, trimetazidine, varenicline, vildagliptin, and vortioxetine are included; Sitagliptin, rifampicin, orphenadrine, alpraziquantel, ropivacaine, ambroxol, quetiapine, atenolol, betahistine, benazepril, bisoprolol, bumetanide, bupropion, cilazapril, ciprofloxacin, dabigatran, desloratadine, trimebutine, chloropyramine, triprolidine, diclofenac, enalapril, ketamine, labetalol, landiolol, levofloxacin, lisinopril, metoprolol, mirabegron, moxifloxacin, nebivolol, valacyclovir, More preferred are one or more selected from the group consisting of perindopril, phenylephrine, pracipexole, propranolol, pseudoephedrine, ramipril, rasagiline, salbutamol, sertraline, sotalol, tamsulosin, trimetazidine, vildagliptin, and vortioxetine.

[0068] The form of the pharmaceutical composition of this embodiment is not particularly limited and may be any of tablets, powders, fine granules, granules, extracts, pills, etc. Among these, tablets and granules are preferred because a large amount of cellulose powder is used per product. For example, a tablet containing the pharmaceutical active ingredient and the cellulose powder of this embodiment can be obtained by processing the pharmaceutical active ingredient and the cellulose powder of this embodiment by a known method such as mixing, stirring, granulating, sizing, and tableting.

[0069] The pharmaceutical composition of this embodiment may contain, in addition to the pharmaceutically active ingredient and the cellulose powder of this embodiment, excipients, disintegrants, binders, flow agents, lubricants, flavoring agents, fragrances, colorants, and sweeteners, as needed.

[0070] Examples of excipients include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, powdered gum arabic, alginic acid, sodium alginate, pregelatinized starch, pumice granules, inositol, ethyl cellulose, ethylene vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrated silicon dioxide, dry yeast, dried aluminum hydroxide gel, dried sodium sulfate, dried magnesium sulfate, agar, and powdered agar. , xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, crospovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (granules), genmai koji, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat germ Ingredients: Wheat flour, wheat germ flour, rice flour, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, calcined gypsum, sucrose fatty acid ester, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitate, magnesium hydroxide, squalane, stearic acid alcohol, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, hardened soybean oil, refined gelatin, refined shellac, refined white sugar, refined white sugar spherical granules, cetostearyl alcohol, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soybean unsaponifiables, soybean lecithin, skim milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropyl cellulose,Dextran, dextrin, natural aluminum silicate, corn starch, tragacanth powder, silicon dioxide, calcium lactate, lactose, lactose granules, Perfiller 101, white shellac, white petrolatum, hakudo, white sugar, white sugar and starch spherical granules, naked barley leaf extract powder, naked malt leaf green juice dried powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (105), polyoxypropylene (5) glycol, polyoxyethylene (16) 0) Examples of excipients include polyoxypropylene (30) glycol, polysodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltitol, maltose, D-mannitol, starch syrup, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium aluminometasilicate, methylcellulose, cottonseed flour, cottonseed oil, Japan wax, aluminum monostearate, glycerin monostearate, sorbitan monostearate, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular corn starch, liquid paraffin, dl-malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, and the like, which are classified as excipients in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These excipients may be used alone or in combination of two or more.

[0071] Examples of disintegrants include those classified as disintegrants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose; starches such as carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, and partially pregelatinized starch; and synthetic polymers such as crospovidone and crospovidone copolymer. These disintegrants may be used alone or in combination of two or more.

[0072] Examples of binders include sugars such as sucrose, glucose, lactose, and fructose; sugar alcohols such as mannitol, xylitol, maltitol, erythritol, and sorbitol; water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin, sodium alginate, and gum arabic; celluloses such as crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, and methylcellulose; starches such as pregelatinized starch and starch paste; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and polyvinyl alcohol; and inorganic compounds such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminosilicate, all of which are classified as binders in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These binders may be used alone or in combination of two or more.

[0073] Examples of the fluidizing agent include silicon compounds such as hydrous silicon dioxide and light anhydrous silicic acid, which are classified as fluidizing agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.) These fluidizing agents may be used alone or in combination of two or more.

[0074] Examples of lubricants include those classified as lubricants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, talc, etc. These lubricants may be used alone or in combination of two or more.

[0075] Examples of flavoring agents include those classified as flavoring agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, etc. These flavoring agents may be used alone or in combination of two or more.

[0076] Examples of flavoring agents include those classified as flavoring agents and fragrances in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as oils such as orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, and peppermint oil, and green tea powder. These flavoring agents and fragrances may be used alone or in combination of two or more.

[0077] Examples of coloring agents include food dyes such as Food Red No. 3, Food Yellow No. 5, and Food Blue No. 1; and those classified as coloring agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as copper chlorophine sodium, titanium oxide, and riboflavin. These coloring agents may be used alone or in combination of two or more.

[0078] Examples of sweeteners include those classified as sweeteners in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and powdered amacha tea. These sweeteners may be used alone or in combination of two or more.

[0079] <Method for producing the pharmaceutical composition of this embodiment> The method for producing the pharmaceutical composition of this embodiment is a method for producing the pharmaceutical composition of this embodiment, in which the pharmaceutical composition is produced using the cellulose powder of this embodiment and a pharmaceutically active ingredient as raw materials.

[0080] In the method for producing the pharmaceutical composition of this embodiment, the raw material cellulose powder of this embodiment is preferably stored in a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less (e.g., an atmosphere in which the nitrogen dioxide concentration is controlled to 0.05 ppm or less and the nitrogen trioxide concentration is 0.05 ppm or less) until the start of production. By storing the raw material in an environment in which the nitrogen dioxide and nitrogen trioxide concentrations are controlled to be low until the start of production, the amounts of nitrite nitrogen and nitrate nitrogen carried over from the raw material to the pharmaceutical composition can be kept low, thereby suppressing the generation of nitrosamines in the pharmaceutical composition. In the production of the pharmaceutical composition of this embodiment, raw materials other than the cellulose powder are also preferably stored in a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less until the start of production.

[0081] In the method for producing a pharmaceutical composition of this embodiment, it is preferable that all steps from the start to the end of production be carried out in a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less (for example, an atmosphere in which the nitrogen dioxide concentration is controlled to 0.05 ppm or less and the nitrogen trioxide concentration is controlled to 0.05 ppm or less). This makes it possible to keep low the amounts of nitrite nitrogen and nitrate nitrogen carried over from the atmosphere during the production process, thereby suppressing the generation of nitrosamines in the pharmaceutical composition.

[0082] In the method for producing the pharmaceutical composition of this embodiment, the cellulose powder according to this embodiment is used as the raw cellulose powder to produce a pharmaceutical composition that generates a low amount of nitrosamines, and the composition can be produced by conventional methods. For example, when the pharmaceutical composition is in the form of a tablet, the composition can be produced by preparing a mixture containing cellulose powder and a pharmaceutically active ingredient and directly compressing the mixture (direct compression method), or by granulating the mixture and then compressing it (granule compression method). Other methods that can be used include a post-pulverization method (a method in which the pharmaceutically active ingredient, cellulose powder, and optionally other additives are mixed, granulated to form granules, and then further mixed with cellulose powder and optionally other additives, and compression-molded by conventional methods), a method for producing a polynuclear tablet using a pre-compressed tablet as the core, and a method for producing a multi-layer tablet in which multiple pre-compressed compacts are stacked and re-compressed.

[0083] The method of tableting (compression molding) is not particularly limited as long as it is a commonly used method, and examples thereof include a method of compressing into a desired shape using a mortar and pestle, a method of compressing into a sheet in advance and then cutting into the desired shape, etc. Examples of compression molding machines include roller presses such as hydrostatic presses, briquetting roller presses, and smooth roller presses, single punch tablet presses, and rotary tablet presses.

[0084] Examples of granulation methods when granulation is used include dry granulation, wet granulation, heat granulation, spray granulation, and microencapsulation. Specific examples of effective wet granulation methods include fluidized bed granulation, stirring granulation, extrusion granulation, crushing granulation, and rolling granulation. Methods for drying the granulated material include hot air heating (shelf drying, vacuum drying, fluidized bed drying), conduction heat transfer (pan type, shelf box type, drum type), and freeze drying. In the hot air heating method, hot air is directly brought into contact with the material, and evaporated moisture is simultaneously removed.

[0085] The present invention will be described based on examples. However, the embodiments of the present invention are not limited to the descriptions of these examples. The methods for measuring and evaluating each physical property in the examples and comparative examples are as follows.

[0086] <Measurement of Content in Cellulose Powder> (1) Measurement of Nitrite Ion and Nitrate Ion The contents of nitrite ion and nitrate ion in cellulose powder were measured by suppression ion chromatography under the following conditions. The contents of nitrite ion and nitrate ion in natural cellulosic materials were also measured in the same manner.

[0087] Column: Anion exchange chromatography column (inner diameter 4.6 mm x 15 cm) Mobile phase: Sodium carbonate / sodium bicarbonate eluent Flow rate: 1.0 mL / min Oven temperature: 40°C Sample injection volume: 30 to 100 μL Detector: UV-VIS detector (wavelength 210 nm) LOD (detection limit): 0.008 μg / g

[0088] (2) Measurement of sulfur The sulfur content of the cellulose powder was measured by ion chromatography using an automatic combustion method. Specifically, approximately 50 mg of the sample was placed on a quartz board and burned in a combustion furnace at 1000 ° C. The gasified components were bubbled into the absorption liquid. The obtained absorption liquid was analyzed using a CT device (model: INTEGRION, manufactured by Thermo Fisher Scientific) to quantify the sulfur. The detection limit was 0.1 ppm.

[0089] (3) Measurement of Hydrogen Peroxide The hydrogen peroxide content of the cellulose powder was measured by the oxygen electrode method. Specifically, 2 g of the sample was extracted with 0.2 mol / L phosphate buffer containing 0.5% potassium bromate, and then filtered under ice cooling to obtain a filtrate. 20 mL of the obtained filtrate was sampled and analyzed by the oxygen electrode method to quantify the hydrogen peroxide. For the measurement, a hydrogen peroxide meter (SUPER ORITECTOR MODEL 5 (trade name), manufactured by Central Scientific Co., Ltd.) was used, and 2 mL of the filtrate was injected into the measuring instrument for analysis. The detection limit was 0.1 ppm.

[0090] (4) Measurement of iron The iron content of the cellulose powder was measured by inductively coupled plasma mass spectrometry (ICP-MS). Pretreatment of the measurement sample was performed by a closed system acid decomposition method. A sample was collected, sulfuric acid was added, and then thermal decomposition treatment was performed using a microwave sample decomposition device (product name: ETHOS UP, manufactured by Milestone Corporation). Then, ultrapure water was added to the sample to make a constant volume, and this was used as the analytical sample. The prepared analytical sample was analyzed using an inductively coupled plasma mass spectrometer (model: iCAP RQ, manufactured by Thermo Fisher Scientific). ５６ The detection limit of Fe was 0.1 ppm.

[0091] (5) Measurement of ammonia The ammonia content of the cellulose powder was measured by ion chromatography in accordance with JIS K0127. First, 3 g of sample (crystalline cellulose powder) was weighed into a 100 mL glass beaker, 60 mL of pure water was added, and the mixture was stirred at a constant stirring force for 20 minutes. After stirring, the mixture was filtered using quantitative filter paper (5C, manufactured by Advantec). The collected filtrate was used as the analytical sample. The prepared analytical sample was analyzed using an ion chromatograph (model: INTEGRION, manufactured by Thermo Fisher Scientific) to measure ammonia. The ion chromatograph was equipped with a separation column (CS12 column), a guard column (CG12 column), and an electrical conductivity detector. The detection limit was 0.1 ppm.

[0092] <Measurement of Content in Gas> (1) Measurement of Nitrogen Dioxide and Nitrogen Trioxide Concentrations The concentrations of nitrogen dioxide and nitrogen trioxide in the gas were measured by the same suppression ion chromatography method as used to measure the nitrite ion and nitrate ion in the cellulose powder. The ambient air samples used for the measurements were sampled for a predetermined period of time using a DSD-TEA sampler. The sampler was recovered after collection was completed, and the sample extracted with pure water was used as the analytical sample.

[0093] <Measurement of Content in Water> (1) Measurement of Nitrite Nitrogen and Nitrate Nitrogen The nitrite nitrogen content and the total content of nitrite nitrogen and nitrate nitrogen in water were measured by the same suppression ion chromatography method as used to measure nitrite ions and nitrate ions in cellulose powder.

[0094] Example 1 Six types of cellulose powder were used to prepare tablets containing active ingredients that may generate nitrosamines, and the amounts of nitrosamines generated were compared.

[0095] (1) Production of Cellulose Powder Seven types of commercially available SP pulp (all with a nitrite ion concentration below 0.008 ppm (detection limit) and a nitrate ion concentration of 0.8 to 4.6 ppm) were appropriately blended as raw materials to prepare six types of cellulose powders (A to F) with different raw material pulps. The nitrite ion concentration, nitrate ion concentration, hydrogen peroxide concentration, sulfur concentration, iron concentration, and ammonia concentration of the raw material pulp (A to F) used were measured. The raw material pulp was processed into a flocculated form, and then the concentration of each component was measured using the same measurement method as for the cellulose powder. The measurement results are shown in Table 1. Note that when the concentration was below the detection limit, the detection limit was used as the concentration of the sample.

[0096]

[0097] Powdered cellulose (A to F) was prepared from each raw pulp (A to F). From the start to the end of the production of cellulose powder from the raw pulp, the process was carried out in an atmospheric environment with a nitrogen dioxide concentration of 0.03 ppm or less and a nitrogen trioxide concentration of 0.03 ppm or less. Furthermore, the water (pure water) used in the production process had a nitrite nitrogen concentration of 0.004 ppm or less and a total of nitrite nitrogen and nitrate nitrogen of 0.1 ppm or less.

[0098] Specifically, 2 kg of raw pulp was shredded and placed in 30 L of a 0.05% aqueous hydrochloric acid solution, and hydrolyzed for 70 minutes at 145°C while stirring (stirring speed: 234 rpm) with a low-speed stirrer (Ikebukuro Horo Kogyo Co., Ltd., 30 LGL reactor, impeller diameter: approximately 30 cm). The resulting acid-insoluble residue was filtered using a Nutsche filter, and the filtration residue (insoluble residue) was washed four times with 70 L of pure water and neutralized with ammonia water. The mixture was then placed in a 90 L plastic bucket, pure water was added, and a cellulose dispersion was prepared while stirring (stirring speed: 500 rpm) with a Three-One Motor (HEIDON, Type BLh1200, 8M / M, impeller diameter: approximately 10 cm). The cellulose dispersion was spray-dried (liquid supply rate 6 L / h, inlet temperature 180-220°C, outlet temperature 50-70°C) to obtain cellulose powders A to C, E, and F.

[0099] In addition, 2 kg of raw pulp was shredded and placed in 30 L of 0.08% aqueous hydrochloric acid solution. The mixture was stirred (stirring speed 234 rpm) with a low-speed mixer (Ikebukuro Horo Kogyo Co., Ltd., 30 LGL reactor, blade diameter approximately 30 cm) and hydrolyzed at 135 ° C for 80 minutes. The resulting acid-insoluble residue was filtered using a Nutsche filter, and the filtration residue (insoluble residue) was washed four times with 70 L of pure water. After neutralization with ammonia water, the mixture was placed in a 90 L plastic bucket, pure water was added, and a cellulose dispersion was prepared by stirring (stirring speed 500 rpm) with a Three-One Motor (HEIDON, Type BLh1200, 8M / M, blade diameter approximately 10 cm). The cellulose dispersion was spray-dried (liquid supply rate 6 L / h, inlet temperature 180-220 ° C, outlet temperature 50-70 ° C) to obtain cellulose powder D.

[0100] The weight-average particle size (μm) and apparent specific volume (cm) of the prepared cellulose powders A to F and the commercially available cellulose powders G to J were measured. ３ / g), apparent tapping density (g / cm ３ The following were measured: angle of repose (°), nitrite ion concentration, nitrate ion concentration, hydrogen peroxide concentration, sulfur concentration, iron concentration, and ammonia concentration. The results are shown in Tables 2 and 3. When the concentration was below the detection limit, the detection limit was used as the concentration of the sample. In the tables, underlined values ​​indicate values ​​below the detection limit.

[0101]

[0102]

[0103] (2) Tablet Production and Storage Tablets were produced using cellulose powders A to J and MCPA, an active ingredient that contains a dimethylaminomethyl group in its skeleton and has been reported to pose a risk of generating nitrosamines. Specifically, 300 mg tablets were produced by direct compression from a mixture of cellulose powder and MCPA in a 5:5 (mass ratio). The produced tablets were stored for one month in an atmospheric environment at 50°C, 80% relative humidity, and with a nitrogen dioxide concentration of 0.03 ppm or less and a nitrogen trioxide concentration of 0.03 ppm or less.

[0104] (3) Measurement of nitrosamine content The content of nitrosamines (NDMA, NDEA) in the tablets after storage was measured. NDMA was measured by gas chromatography mass spectrometry (GC-MS / MS). First, the tablets were pulverized in a mortar, and approximately 25 mg of the pulverized material was precisely weighed. 4 mL of 1 mol / L NaOH solution was added to the pulverized material, and then ultrasonic irradiation was performed for 10 minutes. Then, an internal standard substance (NDMA-d ６ , NDEA-d １０ Exactly 4 mL of the solution was added, and the mixture was infiltrated for 15 minutes, followed by centrifugation (3000 rpm x 5 minutes). After centrifugation, the lower layer was collected and filtered to obtain a sample solution.

[0105] The prepared sample solution was analyzed using a GC-MS / MS system (Shimadzu Corporation) to quantitatively measure the nitrosamines in the sample solution. The GC-MS / MS system used was equipped with a GCMS gas chromatograph (model number: CG-2030), a GCMS mass spectrometer (model number: GCMS-TQ8050NS), and a GCMS autoinjector (model number: AOC-6000plus) (all manufactured by Shimadzu Corporation). The detection limit was 0.05 μg / g.

[0106]

[0107] The measurement results for tablets produced using each cellulose powder are shown in Table 4. In the table, "ND" indicates that the substance in question was not produced.

[0108] According to Table 2, the weight average particle size (μm) and apparent specific volume (cm) of the nine types of cellulose powders other than Cellulose Powder D ３ / g), apparent tapping density (g / cm ３ ), and angle of repose (°), were all similar, indicating that the physical properties of these cellulose powders were similar. On the other hand, according to Tables 3 and 4, the tablets using cellulose powders G to J, which had significantly high nitrite ion and nitrate ion concentrations, also had clearly high NDMA concentrations. These results demonstrate that differences in powder physical properties have little effect on the amount of nitrosamine generated. Furthermore, cellulose powder D had higher apparent specific volume and apparent tapping density than the other cellulose powders, but generated a higher amount of nitrosamine than cellulose powders A or B. From this perspective, it was considered that differences in powder physical properties do not affect the amount of nitrosamine generated.

[0109] Comparing the tablets obtained from cellulose powders A, D, and F, the NDMA concentration in the tablet made from cellulose powder D, which had the lowest total concentration of nitrite ions and nitrate ions, was higher than the NDMA concentration in the tablets made from cellulose powders A or F, which had higher total concentrations of nitrite ions and nitrate ions. These results confirmed that the amount of nitrosamines generated in the tablets is affected by factors other than the nitrate ion concentration derived from the cellulose powder.

[0110] As shown in Tables 3 and 4, the higher the hydrogen peroxide and sulfur concentrations of the cellulose powder, the higher the NDMA concentration. Similarly, the higher the iron, nitrate, and nitrite concentrations of the cellulose powder, the higher the NDMA concentration. These results indicate that hydrogen peroxide, sulfur, iron, nitrite, and nitrate ions derived from the cellulose powder affect the generation of nitrosamines. On the other hand, no significant correlation was observed between the ammonia concentration and NDMA concentration of the cellulose powder.

[0111] Example 2 The effect of the nitrite ion concentration in the gas used for spray drying on the resulting cellulose powder and tablets prepared therefrom was investigated. First, raw pulp A was hydrolyzed in the same manner as for cellulose powder A used in Example 1, and the acid-insoluble residue was washed and neutralized. Pure water was then added and stirred to prepare a cellulose dispersion. The resulting cellulose dispersion was spray-dried using gases with different nitrite ion concentrations, and the nitrite ion and nitrate ion concentrations of the resulting cellulose powder were investigated.

[0112] (1) Production in an atmospheric environment with a sufficiently low nitrogen dioxide concentration A cellulose dispersion was spray-dried using a spray dryer in an environment where the atmospheric nitrogen dioxide concentration was 0.020 ppm. Analysis of the resulting cellulose powder revealed that the nitrite ion concentration was 0.011 ppm and the nitrate ion concentration was 0.072 ppm. These results demonstrate that when the nitrogen dioxide concentration of the gas used for spray drying is sufficiently low, a cellulose powder with sufficiently low concentrations of both nitrite ion and nitrate ion can be obtained.

[0113] (2) Production in an atmospheric environment with a high nitrogen dioxide concentration (A) A cellulose dispersion was spray-dried using a spray dryer in an environment where the atmospheric nitrogen dioxide concentration exceeded 0.020 ppm. Spray drying was performed with and without a chemical filter installed at the spray-drying gas inlet of the spray dryer, which was capable of efficiently removing acidic gases such as nitrogen dioxide. The nitrite ion and nitrate ion concentrations of the spray-drying gas and the resulting cellulose powder were measured. Filter A ("RM2B90", manufactured by Osaka Gas Chemicals Co., Ltd.) was used as the chemical filter. The results are shown in Table 5.

[0114]

[0115] As shown in Table 5, the chemical filter reduced both the nitrite ion concentration and the nitrate ion concentration in the spray-drying gas to 0.020 ppm or less. Furthermore, the cellulose powder obtained by spray-drying with a filter had significantly lower concentrations of both nitrite ion and nitrate ion than the powder obtained by spray-drying without a filter. These results demonstrate that a lower nitrogen dioxide concentration in the gas used for spray-drying can reduce the nitrite ion and nitrate ion concentrations in the resulting cellulose powder, and that the use of a chemical filter can control the nitrogen dioxide concentration in the spray-drying gas even in air with a high nitrogen dioxide concentration.

[0116] (3) Production in an atmospheric environment with a high nitrogen dioxide concentration (B) A cellulose dispersion was spray-dried using a spray dryer in an environment where the atmospheric nitrogen dioxide concentration exceeded 0.020 ppm. Spray drying was performed in the same manner as in (2) above, except that filter B ("Philofresh VZG", manufactured by Japan Vilene Co., Ltd.) was used as the chemical filter. The nitrite ion concentration and nitrate ion concentration of the spray-drying gas and the resulting cellulose powder were measured. The results are shown in Table 6.

[0117]

[0118] As shown in Table 6, when filter B was used, as when filter A was used, both the nitrite ion concentration and the nitrate ion concentration in the spray-drying gas could be reduced to 0.020 ppm or less, and the cellulose powder obtained by spray-drying with a filter had significantly lower concentrations of both nitrite ion and nitrate ion than that obtained by spray-drying without a filter.

[0119] The cellulose powder of this embodiment has a reduced content of components that affect the generation of nitrosamines, and is therefore extremely useful as a raw material for pharmaceuticals that require high safety.

Claims

1. Cellulose powder characterized by having a nitrate ion content of 1.00 ppm or less and a sulfur content of 30.0 ppm or less.

2. The cellulose powder according to claim 1, having a hydrogen peroxide content of 0.40 ppm or less.

3. Cellulose powder characterized by having a nitrate ion content of 1.00 ppm or less and a hydrogen peroxide content of 0.40 ppm or less.

4. The cellulose powder according to claim 1, having a nitrite ion content of 0.200 ppm or less.

5. The cellulose powder according to claim 1, having an iron content of 0.10 ppm or more and 0.80 ppm or less.

6. A pharmaceutical composition comprising the cellulose powder according to any one of claims 1 to 5 and a pharmaceutical active ingredient.

7. The pharmaceutical composition of claim 6, wherein the pharma- ceutical active ingredient is a secondary amine, a tertiary amine, or a quaternary amine.

8. The pharmaceutical composition according to claim 6, which is in the form of a tablet.

9. A method for producing a cellulose powder comprising hydrolyzing a natural cellulosic material, washing the insoluble residue in the cellulose dispersion after hydrolysis, and then spray-drying the resulting cellulose powder, characterized in that: (1) the natural cellulosic material has a nitrite ion content of 0.010 ppm or less or a sulfur ion content of 30.0 ppm or less and a nitrate ion content of 5.0 ppm or less; or (3) the spray-drying is carried out in a gas having a nitrogen dioxide concentration of 0.05 ppm or less or a nitrogen trioxide concentration of 0.05 ppm or less.

10. A method for producing cellulose powder comprising hydrolyzing a natural cellulosic material, washing the insoluble residue in the cellulose dispersion after hydrolysis, and then spray-drying the resulting cellulose powder, characterized in that: (1) the natural cellulosic material has a nitrite ion content of 0.010 ppm or less or a sulfur ion content of 30.0 ppm or less and a nitrate ion content of 5.0 ppm or less; and (3) the spray-drying is carried out in a gas having a nitrogen dioxide concentration of 0.05 ppm or less.

11. The method for producing cellulose powder according to claim 9 or 10, further comprising: (2) using water for one or more selected from the group consisting of the hydrolysis reaction of the natural cellulosic material, the washing of the insoluble residue, and the spray drying, the water having a nitrite nitrogen content of 0.02 ppm or less or a total content of nitrite nitrogen and nitrate nitrogen of 5.0 ppm or less.

12. A method for producing a pharmaceutical composition, comprising producing the pharmaceutical composition using the cellulose powder according to any one of claims 1 to 5 and a medicament active ingredient as raw materials.

13. A method for producing a pharmaceutical composition according to claim 12, wherein the cellulose powder is stored in a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less until the start of production.

14. The method for producing a pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is produced in a gas having a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less.

15. The method of making a pharmaceutical composition according to claim 12, wherein the medicament active ingredient is a secondary amine, a tertiary amine, or a quaternary amine.

16. The method for producing a pharmaceutical composition according to claim 12, wherein the medicament active ingredient is a sartan compound, a compound having a dimethylaminomethyl group, or a biguanide compound.

17. The method for producing a pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is in the form of a tablet, and a mixture containing the cellulose powder and the medicament active ingredient is directly compressed into tablets or granulated and then compressed into tablets.

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