Cellulose powder and pharmaceutical composition

Abstract

The purpose of the present invention is to provide: a cellulose powder which, when used as a starting material for a pharmaceutical product, can reduce the amount of nitrosamine generated at a low level; and a method for producing the cellulose powder. The present invention relates to a 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 a cellulose powder by hydrolyzing, washing and spray-drying a natural cellulose substance in which 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 content of 0.05 ppm or less or a nitrogen trioxide content of 0.05 ppm or less.

Description

TECHNICAL FIELD

[0001] The present application relates to a cellulose powder for manufacturing a pharmaceutical composition with reduced nitrosamine content.

[0002] This application claims priority based on Japanese Patent Application No. 2023-144760 filed on September 6, 2023, and incorporates the content thereof. BACKGROUND

[0003] In the past, in the fields of pharmaceuticals, foods, and other chemical industries, etc., cellulose powders such as crystalline cellulose, powdered cellulose, etc. have been widely used as excipients to prepare shaped bodies containing active ingredients. These cellulose powders are required to have functionalities that can improve various properties required for pharmaceuticals, such as good formability, improvement of bioavailability of pharmaceutical ingredients, etc.

[0004] For example, it is reported in Patent Literature 1 that by setting the powder physical properties of cellulose powders, particularly the average degree of polymerization, the weight average particle diameter, the apparent specific volume, and the organic carbon amount from residual impurities defined by the total organic carbon amount (%) when extracted with 1% NaOH aqueous solution - the total organic carbon amount (%) when extracted with pure water to a specific range, not only the compression formability, but also the flavor release of Hanpo medicine and the color development of sugar coating layers can be improved.

[0005] On the other hand, the carcinogenicity of nitrosamines has become a problem, and in recent years, the content of nitrosamines in pharmaceuticals has been increasingly strictly regulated. As components related to the generation of nitrosamines in pharmaceuticals, mainly nitrite can be cited, and not only the raw material of the pharmaceutical ingredient, but also nitrite introduced through various additives including excipients increases the risk of exceeding the management index value of the content of nitrosamines (Non-Patent Literature 1). For example, it is known that dimethylamine from the raw drug and nitrite from the additive, etc. chemically react at high temperatures, thereby generating a synthetic pathway of nitrosamines.

[0006] Prior Art Documents

[0007] Patent Literature

[0008] Patent Literature 1: Japanese Patent No. 6247207.

[0009] Non-Patent Literature

[0010] Non-Patent Literature 1: Boetzel et al, Journal of Pharmaceutical Sciences, 2023, vol. 112 (6), p. 1615-1624. SUMMARY

[0011] PROBLEMS TO BE SOLVED BY THE INVENTION

[0012] The present application provides a cellulose powder having a very small amount of components related to the generation of nitrosamines, which can lower the amount of nitrosamines generated when used as a raw material for pharmaceutical products, a method for producing the same, and a pharmaceutical composition using the cellulose powder as a raw material.

[0013] Means for solving the problem

[0014] The present inventors have conducted intensive studies on the above situation, and as a result, have found that, in addition to the nitrite ion content, the nitrate ion, sulfur, hydrogen peroxide, and iron contents also have an influence on the generation of nitrosamines, and by using a cellulose powder having the contents of these components adjusted to be within an appropriate range as a raw material, the amount of nitrosamines generated during the manufacturing process and during storage of pharmaceutical products can be lowered compared to the case of using other cellulose powders as a raw material, thereby completing the present application.

[0015] That is, the present application includes the following modes.

[0016] [1] A cellulose powder, wherein the content of nitrate ions is 1.00 ppm or less, and the content of sulfur is 30.0 ppm or less.

[0017] [2] The cellulose powder according to [1], wherein the content of hydrogen peroxide is 0.40 ppm or less.

[0018] [3] A cellulose powder, characterized by a content of nitrate ions of 1.00 ppm or less and a content of hydrogen peroxide of 0.40 ppm or less.

[0019] [4] The cellulose powder according to any one of [1] to [3], wherein the content of nitrite ions is 0.200 ppm or less.

[0020] [5] The cellulose powder according to any one of [1] to [4], wherein the content of iron is 0.10 ppm or more and 0.80 ppm or less.

[0021] [6] A pharmaceutical composition, comprising the cellulose powder according to any one of [1] to [5] and a pharmaceutically active ingredient.

[0022] [7] The pharmaceutical composition according to [6], wherein the pharmaceutically active ingredient is a secondary amine, a tertiary amine, or a quaternary ammonium.

[0023] [8] The pharmaceutical composition according to [6] or [7], which is a tablet.

[0024] [9] A method for producing a cellulose powder, wherein a natural cellulose substance is hydrolyzed, and the insoluble residue in the cellulose dispersion solution after hydrolysis is washed, and then spray-dried, wherein,

[0025] (1) The nitrite ion content of the natural cellulose material is less than 0.010 ppm or the sulfide ion content is less than 30.0 ppm and the nitrate ion content is less than 5.0 ppm, or

[0026] (3) The spray drying is carried out in a gas with a nitrogen dioxide concentration of less than 0.05 ppm or a nitrogen trioxide concentration of less than 0.05 ppm.

[0027]

[10] A method for manufacturing cellulose powder, wherein natural cellulose material is hydrolyzed, and the insoluble residue in the hydrolyzed cellulose dispersion is washed and then spray-dried, wherein...

[0028] (1) The nitrite ion content of the natural cellulose material is less than 0.010 ppm or the sulfide ion content is less than 30.0 ppm and the nitrate ion content is less than 5.0 ppm.

[0029] (3) The spray drying is carried out in a gas with a nitrogen dioxide concentration of less than 0.05 ppm.

[0030]

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

[10] further satisfies:

[0031] (2) The water used in at least one of the hydrolysis reaction of the natural cellulose material, the washing of the insoluble residue and the spray drying has a nitrite nitrogen content of less than 0.02 ppm or a total content of nitrite nitrogen and nitrate nitrogen of less than 5.0 ppm.

[0032]

[12] A method for manufacturing a pharmaceutical composition, wherein the cellulose powder of any one of [1] to [5] and the active pharmaceutical ingredient are used as raw materials to manufacture the pharmaceutical composition.

[0033]

[13] According to the method for manufacturing the pharmaceutical composition of

[12] , the cellulose powder is stored in a gas with 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 manufacturing.

[0034]

[14] The method for manufacturing the pharmaceutical composition according to

[12] or

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

[0035]

[15] A method for manufacturing a pharmaceutical composition according to any one of

[12] to

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

[0036]

[16] A method for manufacturing a pharmaceutical composition according to any one of

[12] to

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

[0037]

[17] A method for manufacturing a pharmaceutical composition according to any one of

[12] to

[16] , wherein the pharmaceutical composition is a tablet; the mixture containing the cellulose powder and the active pharmaceutical ingredient is directly compressed into tablets or compressed into tablets after granulation.

[0038]

[18] A method for manufacturing cellulose powder, wherein natural cellulose material is hydrolyzed, and the insoluble residue in the hydrolyzed cellulose dispersion is washed and then spray-dried, wherein...

[0039] The water used in at least one of the hydrolysis reaction of the natural cellulose material, the washing of the insoluble residue, and the spray drying has a nitrite nitrogen content of less than 0.02 ppm or a total nitrite nitrogen and nitrate nitrogen content of less than 5.0 ppm.

[0040] The effects of the invention

[0041] Since the content of components that contribute to the formation of nitrosamines in the cellulose powder produced by the above method is suppressed to a low level, a pharmaceutical composition in which the formation of nitrosamines is suppressed to a low level during the manufacturing process and storage can be manufactured by using this cellulose powder as a raw material. Detailed Implementation

[0042] In this invention and in this specification, unless otherwise stated, "ppm" means "mass ppm (0.001 mg / g)".

[0043] <Cellulose powder>

[0044] The cellulose powder in this application specification is a substance commonly referred to as crystalline cellulose, powdered cellulose, etc., suitable for use as a pharmaceutical additive or food additive. Among these, crystalline cellulose is preferred as the cellulose powder.

[0045] As crystalline cellulose, for example, there are microcrystalline cellulose described in the 9th edition of the Food Additives Codex, crystalline cellulose described in the Japanese Pharmacopoeia (18th revised edition), crystalline cellulose described in the United States Pharmacopeia, the European Pharmacopoeia, etc.

[0046] The cellulose powder in one embodiment of the present invention (hereinafter referred to as "this embodiment") helps to suppress the content of components that generate nitrosamines to a low level, and when used as a raw material in pharmaceuticals and other products, its ability to generate nitrosamines (hereinafter sometimes referred to as "nitrosamine-forming capacity") is weak. Because of its weak nitrosamine-forming capacity, the cellulose powder of this embodiment is suitable as a raw material for pharmaceuticals where the content of nitrosamines is strictly limited.

[0047] In this embodiment, the nitrate ion content (by mass) of the cellulose powder relative to the total amount (mass) of the cellulose powder is 1.00 ppm or less. As shown in the examples described later, the nitrate ion content affects the amount of nitrosamines produced. The higher the nitrate ion content, the higher the amount of nitrosamines produced. By keeping the nitrate ion content (by mass) of the cellulose powder at 1.00 ppm or less, preferably 0.50 ppm or less, and more preferably 0.20 ppm or less, the amount of nitrosamines produced in pharmaceutical excipients and the like can be suppressed to a low level. It should be noted that the lower limit of the range of the nitrate ion content (by mass) is 0.008 pppm, the detection limit value. When the nitrate ion content (by mass) of the cellulose powder is less than 0.008 pppm, it cannot be detected. Although the reason why the nitrate ion content affects the amount of nitrosamines produced is not yet clear, it is speculated that during the manufacturing process of the pharmaceutical product and during its storage after manufacturing, nitrate ions in the product are reduced and converted into nitrite ions.

[0048] In this embodiment, the cellulose powder preferably has a low nitrite ion content (by mass). Specifically, relative to the total amount (by mass) of the cellulose powder, the nitrite ion content is preferably 0.200 ppm or less, more preferably 0.100 ppm or less, further preferably 0.050 ppm or less, even more preferably 0.020 ppm or less, and particularly preferably 0.015 ppm or less. It should be noted that the lower limit of the range of nitrite ion content (by mass) is 0.008 ppm, the detection limit value. When the nitrite ion content (by mass) of the cellulose powder is less than 0.008 ppm, it cannot be detected.

[0049] In this embodiment, the sulfur content (by mass) of the cellulose powder is 30.0 ppm or less relative to the total amount (mass) of the cellulose powder. As shown in the examples described later, the sulfur content affects the amount of nitrosamines produced. The higher the sulfur content, the higher the amount of nitrosamines produced. By keeping the sulfur content (by mass) of the cellulose powder at 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 produced can be suppressed to a low level when used as an excipient in pharmaceuticals. Although the reason why the sulfur content affects the amount of nitrosamines produced is not yet clear, it is speculated that this is because sulfur in the pharmaceuticals acts as a reducing agent during the manufacturing process and post-manufacturing storage, converting nitrate ions into nitrite ions. It should be noted that the lower limit of the range of the sulfur content (by mass) is 0.10 ppm, which is the detection limit value. When the sulfur content (by mass) of the cellulose powder is less than 0.10 ppm, it cannot be detected.

[0050] In this embodiment, the hydrogen peroxide content (by mass) in the cellulose powder is preferably 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. It should be noted that the lower limit of the range of the hydrogen peroxide content (by mass) is 0.10 ppm, the detection limit value. When the hydrogen peroxide content (by mass) in the cellulose powder is less than 0.10 ppm, it cannot be detected. As shown in the examples described later, the hydrogen peroxide content affects the amount of nitrosamines produced. The higher the hydrogen peroxide content, the higher the amount of nitrosamines produced. By keeping the hydrogen peroxide content (by mass) within the aforementioned range relative to the total amount (mass) of the cellulose powder, the amount of nitrosamines produced, in cases such as excipients used in pharmaceuticals, can be suppressed to a lower level. While the reason why the hydrogen peroxide content affects the amount of nitrosamines produced is not yet clear, it is speculated that during the manufacturing process and post-manufacturing storage of the pharmaceutical, the hydrogen peroxide in the pharmaceutical acts as a reducing agent, converting nitrate ions into nitrite ions.

[0051] In the cellulose powder of this embodiment, the iron content (by mass) relative to the total amount (mass) of the cellulose powder is preferably 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 also preferably 0.20 ppm to 0.70 ppm. In particular, the iron content (by mass) relative to the total amount (mass) of the cellulose powder of this embodiment is more preferably 0.30 ppm to 0.70 ppm, and even more preferably 0.30 ppm to 0.60 ppm. As shown in the examples described later, the iron content affects the amount of nitrosamines produced. If the iron content is too low, the amount of nitrosamines produced will be high, but if the iron content is too high, the total iron intake may become excessive, which is not preferred. By keeping the iron content (by mass) within the aforementioned range relative to the total amount (mass) of the cellulose powder, the amount of nitrosamines produced in the case of excipients used in pharmaceuticals can be suppressed to a low level. The reason why iron content affects the amount of nitrosamines produced is not yet clear, but it is speculated that during the manufacturing process and storage of the drug, the iron in the drug not only acts as a reducing agent, but also reacts with nitrate ions to produce nitric oxide, which inhibits the conversion of nitrate ions to nitrite ions.

[0052] The contents of nitrate ions, nitrite ions, sulfur, hydrogen peroxide, and iron in cellulose powder can all be determined by the method described in the examples below.

[0053] The cellulose powder used in this embodiment is preferably made of the following material:

[0054] Cellulose powder with a nitrate ion content of less than 1.00 ppm and a sulfur content of less than 30.0 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm, a sulfur content of less than 30.0 ppm and a hydrogen peroxide content of less than 0.40 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm and a hydrogen peroxide content of less than 0.40 ppm;

[0055] Cellulose powder with a nitrate ion content of less than 1.00 ppm, a sulfur content of less than 30.0 ppm, and a nitrite ion content of less than 0.200 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm, a sulfur content of less than 30.0 ppm, a hydrogen peroxide content of less than 0.40 ppm, and a nitrite ion content of less than 0.200 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm, a hydrogen peroxide content of less than 0.40 ppm, and a nitrite ion content of less than 0.200 ppm;

[0056] Cellulose powder with a nitrate ion content of less than 1.00 ppm, a sulfur content of less than 30.0 ppm, and an iron content of more than 0.10 ppm and less than 0.80 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm, a sulfur content of less than 30.0 ppm, a hydrogen peroxide content of less than 0.40 ppm, and an iron content of more than 0.10 ppm and less than 0.80 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm, a hydrogen peroxide content of less than 0.40 ppm, and an iron content of more than 0.10 ppm and less than 0.80 ppm;

[0057] Cellulose powder with a nitrate ion content of less than 1.00 ppm, a sulfur content of less than 30.0 ppm, a nitrite ion content of less than 0.200 ppm, and an iron content of more than 0.10 ppm and less than 0.80 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm, a sulfur content of less than 30.0 ppm, a hydrogen peroxide content of less than 0.40 ppm, a nitrite ion content of less than 0.200 ppm, and an iron content of more than 0.10 ppm and less than 0.80 ppm; cellulose powder with a nitrate ion content of less than 1.00 ppm, a hydrogen peroxide content of less than 0.40 ppm, a nitrite ion content of less than 0.200 ppm, and an iron content of more than 0.10 ppm and less than 0.80 ppm.

[0058] The average degree of polymerization of the cellulose powder in this embodiment is not particularly limited. However, the average degree of polymerization of the cellulose powder in this embodiment is preferably 100 to 350, more preferably 150 to 300, and even more preferably 180 to 250. An average degree of polymerization of 100 or higher improves formability, which is therefore preferred. Furthermore, a degree of polymerization of 350 or lower prevents the formation of fibrous material, resulting in excellent flowability and disintegration properties, which is also preferred. In other words, an average degree of polymerization of 100 to 350 results in a particularly excellent balance between formability, disintegration, and flowability, which is therefore preferred.

[0059] The weight-average particle size of the cellulose powder in this embodiment is not particularly limited. However, the weight-average particle size of the cellulose powder in this embodiment is preferably greater than 30 μm and less than 250 μm, more preferably greater than 30 μm and less than 180 μm, and even more preferably more than 40 μm and less than 150 μm. By making the weight-average particle size greater than 30 μm, preferably more than 40 μm, the workability is improved without increasing adhesion and agglomeration, and the flowability is also excellent. Furthermore, by making the weight-average particle size less than 250 μm, preferably less than 180 μm, and more preferably less than 150 μm, separation and segregation from the active ingredient will not occur, and the uniformity of the formulation content will not deteriorate, which is therefore preferred.

[0060] The apparent specific volume of the cellulose powder in this embodiment is not particularly limited. However, a specific volume of 2 cm³ is preferred for the cellulose powder in this embodiment. 3 / g or more 15cm 3 / g or less, more preferably 2cm 3 / g or more 13cm 3 / g or less, more preferably 2cm 3 / g or more 6cm 3 / g or less, especially preferred is 2cm 3 / g or more, less than 4cm 3 / g. If the apparent specific volume is 2cm³ 3 Above a certain weight (g), the formability improves. Due to its fibrous nature, it exhibits elastic recovery, with a maximum upper limit of 15cm. 3 / g. Based on improving fluidity and disintegration properties, a value of 6cm is preferred. 3 / g or less, more preferably less than 4cm 3 / g. The apparent specific volume of the cellulose powder in this embodiment is particularly preferably 2.3 cm³. 3 / g or more 3.8cm 3 / g or less, more preferably 3.0cm 3 / g or more 3.8cm 3 / g or less.

[0061] The tapped apparent density of the cellulose powder in this embodiment is not particularly limited. However, a tapped apparent density of 0.2 g / cm³ is preferred for the cellulose powder in this embodiment. 3 Above 0.6g / cm 3 The following, or more preferably, is 0.3 g / cm³ 3 Above 0.58g / cm 3 The following, and more preferably, is 0.35 g / cm³. 3 Above 0.55g / cm 3 The following applies if the apparent density after tapping is 0.6 g / cm³. 3The following improves formability.

[0062] The angle of repose of the cellulose powder in this embodiment is not particularly limited. However, from the viewpoint of content uniformity, the angle of repose of the cellulose powder in this embodiment is preferably 36° or more and less than 44°, and more preferably 38° to 42°.

[0063] The various physical properties of cellulose powder can be determined as described below.

[0064] 1) Average degree of polymerization (-)

[0065] The viscosity of the copper ethylenediamine solution can be determined by the confirmation test of crystalline cellulose (3) as described in the 18th revised edition of the Japanese Pharmacopoeia.

[0066] 2) Loss on drying (%)

[0067] 1g of powder is dried at 105°C for 3 hours, and the weight reduction is expressed as a percentage by weight.

[0068] 3) Weight-average particle size (μm) of cellulose powder

[0069] The weight-average particle size of the powder sample was determined using a Ro-Tap type vibrating sieve (a type A sieve made by Pinggong Works) and a JIS standard sieve (Z8801-1987). The particle size distribution was measured by sieving 10g of sample for 10 minutes and expressed as the cumulative weight 50% particle size.

[0070] 4) Apparent specific volume (cm³) 3 / g)

[0071] Using a metering feeder, it takes 2-3 minutes to roughly fill the powder sample to 100 cm³. 3 In a glass graduated cylinder, the surface of the powder layer is brushed horizontally with soft bristles (like a brush), and its volume is read. This volume is then divided by the weight of the powder sample to determine the volume. The volume is typically 70–100 cm³. 3 Determine the weight of the powder appropriately from left to right.

[0072] 5) Apparent tap density (g / cm³) 3 )

[0073] Using a commercially available powder property testing device (Hosokawa Micron Powder Tester PT-R type), the powder was filled to a depth of 100 cm. 3 After the powder is compacted 180 times in the cup, the weight of the remaining powder layer in the cup is divided by the volume of the cup to calculate the weight.

[0074] 6) Anxi Corner (゜)

[0075] Using a Sugihara-type angle of repose measuring device (gap dimensions: depth 10 × width 50 × height 140 mm, with a protractor positioned at the 50 mm width), cellulose powder was fed into the gap at a rate of 3 g / min via a metering feeder, and the dynamic self-flowing properties were measured. The angle between the bottom of the device and the forming layer of the cellulose powder is the angle of repose.

[0076] <Method for manufacturing cellulose powder>

[0077] The cellulose powder of this embodiment can be manufactured, for example, by hydrolyzing natural cellulose material, washing away insoluble residues from the hydrolyzed cellulose dispersion, and then spray-drying it. The reaction conditions for the hydrolysis reaction, the recovery and washing of insoluble residues, and the spray drying after redispersement can be carried out using methods and conditions commonly used in the manufacture of cellulose powder, or with appropriate modifications.

[0078] The natural cellulose material used as raw material can be plant-based or animal-based. Examples of natural cellulose materials include wood, bamboo, wheat straw, rice straw, cotton, ramie, sugarcane bagasse, kenaf, beet, sea squirt, and bacterial cellulose, all derived from cellulose-containing natural products. Natural cellulose materials have a cellulose type I crystal structure. One of the above-mentioned natural cellulose materials can be used as a raw material, or a mixture of two or more can be used.

[0079] The natural cellulose material used as raw material is preferably used in the form of refined pulp. From the viewpoint of manufacturing yield, refined pulp with an α-cellulose content of 85% or more is particularly preferred. The method of pulp refining is not particularly limited; any type of pulp, such as dissolving pulp, kraft pulp, or NBKP pulp, can be used. Based on the viewpoints of high α-cellulose purity, easy availability, and stable supply, wood-derived pulp is preferred.

[0080] Hydrolysis of natural cellulose materials can be achieved through acid hydrolysis, alkaline oxidation decomposition, hot water decomposition, or steam explosion. Any of these methods can be used individually or in combination. Furthermore, natural cellulose materials can be mechanically treated, such as by crushing or grinding, before or after hydrolysis.

[0081] Hydrolysis of natural cellulose materials allows the solid components containing these materials to be dispersed in a suitable medium. Water is preferred as this medium. However, any medium other than water can be used, as long as it is industrially applicable; for example, a mixture of water and an organic solvent can be used. Examples of organic solvents include alcohols such as methanol, ethanol, isopropanol, butanol, 2-methylbutanol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; and ketones such as acetone and ethyl methyl ketone. In particular, organic solvents suitable for pharmaceuticals are preferred, including those classified as solvents in the "Drug Additives Encyclopedia" (published by Pharmacopoeia Inc.). Water and organic solvents can be used alone or in combination. Alternatively, the material can be dispersed in one medium, then that medium can be removed before further dispersion in different media.

[0082] When hydrolyzing natural cellulose materials using hydrochloric acid, the concentration of hydrochloric acid, hydrolysis temperature, and hydrolysis time are not particularly limited and can be appropriately adjusted according to the desired physical properties of the cellulose powder. For example, the hydrochloric acid concentration is preferably 0.05–0.3%, more preferably 0.08–0.25%, and even more preferably 0.08–0.15%; the temperature is preferably 80–150°C, more preferably 100–150°C; and the hydrolysis time is preferably 40–150 minutes, more preferably 70–110 minutes.

[0083] During hydrolysis, setting higher acid and alkali concentrations and reaction temperatures in the hydrolysis solution typically reduces the degree of polymerization of cellulose, leading to a tendency for the average particle size of cellulose in the dispersion to decrease. Furthermore, even with increased stirring force, the average particle size of cellulose particles in the dispersion tends to decrease. Therefore, by adjusting the degree of polymerization of the raw cellulose and the stirring force during the hydrolysis or dispersion process of natural cellulose materials, the degree of polymerization and average particle size of cellulose particles can be controlled within the desired range. The stirring force depends on the width, height, and volume of the stirring layer, the type and diameter of the blades, and the stirring speed.

[0084] The cellulose dispersion obtained after hydrolysis is subjected to solid-liquid separation to recover insoluble residues and then washed. Neutralization can be performed at this time, if necessary, by alkali or acid treatment. The washing solution used in the washing process can be the same medium used in the dispersion of natural cellulose materials. Furthermore, when performing multiple washing processes, a different washing solution can be used for each wash. In the manufacture of the cellulose powder in this embodiment, washing with pure water is preferred.

[0085] The insoluble residue after washing is redispersed in pure water to prepare a cellulose dispersion. Cellulose powder can then be manufactured by spray drying this cellulose dispersion. The redispersed cellulose dispersion can be further processed before spray drying, including mechanical treatment such as pulverization or grinding, centrifugal separation using a cyclone separator or centrifuge, or grading using a sieve. These methods can be used individually or in combination.

[0086] Examples of pulverizing methods include, for instance, sieve milling methods such as screening mills and hammer mills; blade shear sieve milling methods such as flash mills; airflow milling methods such as jet mills; ball milling methods such as ball mills and vibrating ball mills; and blade stirring pulverizing methods.

[0087] Examples of grinding methods include, for instance, grinding methods using mixing blades such as portable mixers, vertical mixers, side mixers, unidirectional rotary, multi-axis rotary, reciprocating, up-and-down moving, rotary + up-and-down moving, and pipeline types; jet-type mixing and grinding methods such as pipeline mixers; grinding methods using high-shear homogenizers, high-pressure homogenizers, and ultrasonic homogenizers; and equiaxial rotary extrusion grinding methods such as kneaders.

[0088] Various methods can be used for spray drying of redispersible cellulose dispersions, including disc spraying, pressurized nozzle spraying, pressurized two-fluid spraying, and pressurized four-fluid spraying. These spraying methods can be used individually or in combination. The spray drying temperature can be a commonly used inlet temperature of 150°C to 300°C. Alternatively, or in combination with spray drying, methods such as freeze drying, drum drying, rack drying, airflow drying, and vacuum drying can also be used.

[0089] During the spray drying process described above, trace amounts of water-soluble polymers or surfactants may be added to reduce the surface tension of the dispersion. Foaming agents or gases may also be added to the dispersion to promote the vaporization rate of the medium.

[0090] Examples of water-soluble polymers include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, gum arabic, and starch paste, which are listed in the "Drug Additives Encyclopedia" (published by Pharmacopoeia Inc.). These water-soluble polymers can be used alone or in combination of two or more.

[0091] Examples of surfactants include phospholipids, fatty acid glycerides, 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, glyceryl monostearate, monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, sorbitan monopalmitate, and sodium lauryl sulfate, all classified as surfactants in the "Dictionary of Pharmaceutical Additives" (published by Pharmacopoeia Inc.). These surfactants can be used alone or in combination of two or more.

[0092] Examples of foaming agents include tartaric acid, sodium bicarbonate, potato starch, anhydrous citric acid, pharmaceutical soap, sodium lauryl sulfate, diethanolamide laurylate, and polidocanol, which are listed in the "Drug Additives Encyclopedia" (published by Pharmacy News Co., Ltd.). These foaming agents can be used alone or in combination of two or more.

[0093] In addition to pharmaceutical additives, bicarbonates such as sodium bicarbonate and ammonium bicarbonate, which produce gas through thermal decomposition, and carbonates such as sodium carbonate and ammonium carbonate, which produce gas through reaction with acids, can also be used. However, when using the above-mentioned 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; protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; and Lewis acids such as boron fluoride. Among these, substances used in pharmaceuticals or food are preferred as acids, but even if not these substances, they have the same effect.

[0094] Alternatively, instead of adding a foaming agent, gases such as nitrogen, carbon dioxide, liquefied petroleum gas, and dimethyl ether can be impregnated in the dispersion.

[0095] These water-soluble polymers, surfactants, and foaming agents, which generate gas, can be added before drying, and there is no particular time limit for their addition.

[0096] In the method for manufacturing cellulose powder according to this embodiment, in order to suppress the content of components that contribute to the formation of nitrosamines and to manufacture cellulose powder with weak nitrosamine-forming ability, at least one of the following steps (1) and (3) needs to be performed.

[0097] (1) The nitrite content of the natural cellulose material is less than 0.010 ppm or the sulfide content is less than 30.0 ppm and the nitrate content is less than 5.0 ppm.

[0098] (3) The spray drying is carried out in a gas with a nitrogen dioxide concentration of less than 0.05 ppm or a nitrogen trioxide concentration of less than 0.05 ppm.

[0099] In the method for manufacturing cellulose powder according to this embodiment, in addition to at least one of the steps (1) and (3) described above, the following (2) is also preferably performed.

[0100] (2) The water used in one or more of the hydrolysis reaction of the natural cellulose material, the washing of the insoluble residue and the spray drying has a nitrite nitrogen content of less than 0.02 ppm, or a total nitrite nitrogen and nitrate nitrogen content of less than 5.0 ppm.

[0101] The nitrite or nitrate ions in cellulose powder mostly originate from the natural cellulose material of the raw material. In this embodiment, by using a natural cellulose material with low nitrite, sulfide, or nitrate ion content as the raw material, a cellulose powder with low nitrosamine-forming ability can be manufactured. In this embodiment, it is preferable to use a natural cellulose material with a nitrite ion content of 0.010 ppm or less and a nitrate ion content of 5.0 ppm or less, or a natural cellulose material with a sulfide ion content of 30.0 ppm or less and a nitrate ion content of 5.0 ppm or less, as the raw material.

[0102] There are no particular limitations on the methods for determining trace amounts of nitrite ions, sulfide ions, nitrate ions, etc., contained in the natural cellulose material of the raw material; any known method can be used. For example, the same method used for determining trace amounts in the cellulose powder can be used.

[0103] In methods for determining trace substances in natural cellulose materials, pretreatment such as pulp flocculentization is preferred to improve extraction efficiency and evaluation accuracy. There are no limitations on the method for pulp flocculentization; a conventional grinder can be used. For example, a high-speed grinder from LabNext or a household blender can be used.

[0104] The amounts of nitrite, sulfide, and nitrate ions in cellulose powder are affected by the water used in the hydrolysis reaction solution, the water used in the washing solution for washing insoluble residues, and the water used in preparing the cellulose dispersion for spray drying. In this embodiment, by using water with low nitrite and nitrate ion content, the amount introduced by water is suppressed to a low level, thus producing cellulose powder with very low nitrite and nitrate ion content and weak nitrosamine formation ability. More specifically, water with a nitrite nitrogen content of 0.02 ppm or less, or water with a total nitrite and nitrate nitrogen content of 5.0 ppm or less, is preferably used.

[0105] In the method for manufacturing cellulose powder according to this embodiment, it is preferable that the water used in any one of the hydrolysis reaction of natural cellulose material, the cleaning of insoluble residue, and spray drying is water with low content of nitrite ions, etc. More preferably, the water used in any two of the hydrolysis reaction of natural cellulose material, the cleaning of insoluble residue, and spray drying is water with low content of nitrite ions, etc. Particularly preferably, the water used in all three steps of the hydrolysis reaction of natural cellulose material, the cleaning of insoluble residue, and spray drying is water with low content of nitrite ions, etc.

[0106] The amount of nitrite and nitrate ions in cellulose powder is affected by the gas used during spray drying. In this embodiment, by conducting spray drying in a gas that is almost free of nitrite and nitrate ions, the amount introduced by the gas is suppressed to a low level, resulting in cellulose powder with very low nitrite and nitrate ion content and weak nitrosamine formation ability. In the method for manufacturing cellulose powder in this embodiment, the NOx (nitrogen oxides) concentration of the gas used during spray drying is preferably 0.00 ppm to 0.20 ppm, more preferably 0.00 ppm to 0.15 ppm, and even more preferably 0.00 ppm to 0.10 ppm. The NOx concentration of the gas is mainly the total concentration of nitric oxide, nitrogen dioxide, nitrous oxide, and dinitrogen trioxide.

[0107] In the method for manufacturing cellulose powder according to this embodiment, the gas used for spray drying is preferably a gas with a nitrogen dioxide concentration of 0.05 ppm or less or a gas with a nitrogen trioxide concentration of 0.05 ppm or less, and particularly preferably a gas with both nitrogen dioxide and nitrogen trioxide concentrations of 0.05 ppm or less. For example, atmospheric air with both nitrogen dioxide and nitrogen trioxide concentrations controlled to be 0.05 ppm or less can be used as the gas with both concentrations controlled to be 0.05 ppm or less.

[0108] 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.

[0109] There are no particular limitations on the control of atmospheric nitrogen dioxide and nitrogen trioxide concentrations, as long as the method can remove nitrogen dioxide and nitrogen trioxide from the atmosphere. Examples of methods for removing nitrogen dioxide and nitrogen trioxide from dry air include wet adsorption methods using scrubbing towers and dry adsorption methods using chemical filters.

[0110] In the use of chemical filters, it is important to select an adsorbent material that can efficiently remove acidic gases such as nitrogen dioxide. Examples of adsorbent materials that can efficiently remove acidic gases include "SAAFCarb" (manufactured by AAF Corporation), "Pure Smell Filter Adsorbent E3" and "Pure Smell Filter Adsorbent E5" (both manufactured by Nippon Inorganic Co., Ltd.), "Gigacol" and "CP Blend Select" (both manufactured by Nitta Corporation), "Philofresh VZG" and "Philofresh VCL" (both manufactured by Vilene Corporation of Japan), and "RM2B90" (manufactured by Osaka Gas Chemical Co., Ltd.). The appropriate material can be selected based on the size and capacity of the cellulose powder manufacturing equipment. There are no restrictions on the method of selecting the adsorbent material, as long as it can adjust the amount of nitrogen dioxide in the dry air to below a certain value.

[0111] In the method for manufacturing cellulose powder according to this embodiment, it is preferable that not only the gas used for spray drying, but also all processes in the cellulose powder manufacturing process other than spray drying are carried out in a gas with a nitrogen dioxide concentration controlled to be 0.05 ppm or less, or a nitrogen trioxide concentration controlled to be 0.05 ppm or less. More preferably, all processes of cellulose powder manufacturing are carried out in a gas with a nitrogen dioxide concentration controlled to be 0.05 ppm or less, or a nitrogen trioxide concentration controlled to be 0.05 ppm or less. By manufacturing in air with low concentrations of nitrogen dioxide and nitrogen trioxide, nitrite and nitrate nitrogen introduced from the air are suppressed, and cellulose powder with low nitrite and nitrate ion content can be stably manufactured.

[0112] There are no particularly limited methods for determining the concentrations of nitrogen dioxide and nitrogen trioxide in the air; conventional methods can be used. For example, the concentrations of nitric oxide, nitrogen dioxide, and NOx in the air can be determined using a standard NOx measuring device employing chemiluminescence immunoassay. Examples of NOx measuring devices include the "GLN-354D" (manufactured by DKK-TOA), the "APNA-370" (manufactured by Horiba), and the "NOA-308Dx" (manufactured by Shimadzu Corporation). Alternatively, the concentrations of nitrogen dioxide and nitrogen trioxide in the air can be determined by using an acid gas collection diffusion sampler to collect samples and then measuring them using ion chromatography or the Saltzman method.

[0113] In the method for manufacturing cellulose powder according to this embodiment, at least one of steps (1) and (3) is performed. In order to more sufficiently and lower the content of components that contribute to the formation of nitrosamines, it is preferable to perform steps (1) and (3) in the method for manufacturing cellulose powder according to this embodiment.

[0114] In the method for manufacturing cellulose powder according to this embodiment, in addition to at least one of the steps (1) and (3), it is also preferable to further perform step (2).

[0115] It should be noted that even when only the cellulose powder is manufactured as described in (2), it is possible to manufacture cellulose powder in which the content of components that help generate nitrosamines is suppressed.

[0116] Specifically, by selecting natural cellulose materials that meet the requirements of (1), cellulose powder with very low content of components related to the generation of nitrosamines can be produced.

[0117] Cellulose powder containing very low amounts of components associated with the generation of nitrosamines can be produced by spray drying in a gas that satisfies (3).

[0118] Water used in one or more of the hydrolysis reaction of natural cellulose materials, the washing of insoluble residues and spray drying, can produce cellulose powder with very low content of components related to the generation of nitrosamines by using water with a nitrite nitrogen content or a total content of nitrite nitrogen and nitrate nitrogen that satisfies the above (2).

[0119] In order to more fully suppress the content of components that contribute to the formation of nitrosamines, the method for manufacturing cellulose powder in this embodiment preferably performs at least two of the steps (1) to (3), and particularly preferably performs all of the steps (1) to (3).

[0120] In the method for manufacturing cellulose powder according to this embodiment, in addition to at least one of (1) to (3) described above, various treatments are preferably performed to further reduce the amount of sulfur, hydrogen peroxide, and iron introduced into the final cellulose powder. For example, water used for washing insoluble residues or subsequent spray drying is used that has low content of not only nitrite and nitrate nitrogen, but also sulfur, hydrogen peroxide, and iron (e.g., pure water). Furthermore, the number of times the insoluble residues are washed can be increased to more than conventional washing, for example, 3 times or more, preferably 4 times or more, more preferably 5 times or more, and even more preferably 6 times or more. The more times the residues are washed, the more the amount of sulfur, hydrogen peroxide, and iron introduced from the raw materials can be suppressed.

[0121] The cellulose powder of this embodiment, like other cellulose powders, can also be used as a raw material for various products such as pharmaceuticals, food products, feed, cosmetics, hygiene products, and pesticides. The cellulose powder of this embodiment can reduce the formation of nitrosamines, which have a significant impact on human health, and is particularly suitable as an excipient in pharmaceuticals and food products where nitrosamine content is limited.

[0122] <Pharmaceutical Compositions>

[0123] The pharmaceutical composition of this embodiment contains the cellulose powder of this embodiment and the active pharmaceutical ingredient. The content of the active pharmaceutical ingredient and the cellulose powder of this embodiment in the pharmaceutical composition is not particularly limited. As a general range of use, the content of the active pharmaceutical ingredient is 0.001% by mass or more and 99.0% by mass or less relative to the total mass of the pharmaceutical composition, and the content of the cellulose powder of this embodiment is 1.0% by mass or more and 99.0% by mass or less. By ensuring that the content of the active pharmaceutical ingredient is at or above the aforementioned lower limit, a therapeutically effective amount can be guaranteed. On the other hand, by ensuring that it is at or below the aforementioned upper limit, the content of the cellulose powder of this embodiment is at or above the aforementioned lower limit, allowing full utilization of the characteristic of the cellulose powder of this embodiment that "is unlikely to generate nitrosamines."

[0124] The active pharmaceutical ingredient contained in the pharmaceutical composition of this embodiment is not particularly limited. Furthermore, the active pharmaceutical ingredient contained in the pharmaceutical composition may be only one type or may be two or more types. Examples of active pharmaceutical ingredients include, for instance, oral medications such as drugs for high cholesterol, diabetes, stomachic drugs, antacids, digestive drugs, antipyretics, analgesics, anti-inflammatory drugs, hypnotics, sedatives, antisleep aids, antivertigo drugs, pediatric analgesics, cardiotonics, antiarrhythmic drugs, antihypertensive drugs, vasodilators, diuretics, antiulcer drugs, intestinal regulators, osteoporosis drugs, antitussives and expectorants, anti-asthmatic drugs, antibacterial drugs, urinary frequency improvers, tonics, and vitamin supplements.

[0125] The active pharmaceutical ingredient in the pharmaceutical composition comprising this embodiment is preferably a secondary amine, tertiary amine, or quaternary ammonium that readily generates nitrosamines. In particular, it is preferable to have an active pharmaceutical ingredient that is subject to content control requirements for NDMA (N-nitrosodimethylamine) or NDEA (N-nitrosodiethylamine) among the nitrosamines. Examples of such active pharmaceutical ingredients include sartan compounds (e.g., valsartan, irbesartan, olmesartan, losartan, etc.), compounds containing dimethylaminomethyl groups (e.g., ranitidine, nizatidine, chlorpheniramine maleate (MCPA), etc.), and biguanide compounds (e.g., metformin, bufomin, etc.).

[0126] The active pharmaceutical ingredient contained in the pharmaceutical composition of this embodiment is preferably selected from secondary amines, tertiary amines, or quaternary ammoniums, including sitagliptin, rifampin, gliclazide, sitagliptin, olphenadrine, alprazolam, ropivacaine, ambroxol, quetiapine, atoxetine, atenolol, azithromycin, betahistine, benazepril, bisoprolol, bumetanide, bupropion, ciprofloxacin, dabigatran, desloratadine, trimebutine, azithromycin, clopidogrel, triprolidine, diclofenac, duloxetine, enalapril, and fluoroquinolones. One or more of the following substances: oxaliplatin, hydrochlorothiazide, ketamine, labetalol, landilolol, levofloxacin, lisinopril, mefenamic acid, methylphenidate, metoprolol, mirabezon, moxifloxacin, nebivolol, valacyclovir, amitriptyline, nortriptyline, paroxetine, perindopril, phenylephrine, pramipexole, propranolol, pseudoephedrine, quinapril, ramipril, rasagiline, reboxetine, salbutamol, sertraline, sotalol, tamsulosin, trimetazidine, varenicline, vildagliptin, and vortioxetine.

[0127] More preferably, it is selected from one or more of the following groups: sitagliptin, rifampin, ophenadrine, alprazolam, ropivacaine, ambroxol, quetiapine, atenolol, betahistine, benazepril, bisoprolol, bumetanide, bupropion, ciprofloxacin, dabigatran, desloratadine, trimebutine, clopidogrel, triprolidine, diclofenac, enalapril, ketamine, labetalol, landilolol, levofloxacin, lisinopril, metoprolol, mirabezonitrogen, moxifloxacin, nebivolol, valacyclovir, perindopril, phenylephrine, pramipexole, propranolol, pseudoephedrine, ramipril, rasagiline, salbutamol, sertraline, sotalol, tamsulosin, trimetazidine, vildagliptin, and vortioxetine.

[0128] The shape of the pharmaceutical composition in this embodiment is not particularly limited, and it can be any of the following: tablets, powders, granules, pellets, extracts, pills, etc. Since the amount of cellulose powder used per unit product is large, tablets or granules are preferred. For example, the active pharmaceutical ingredient and the cellulose powder of this embodiment can be processed by known methods such as mixing, stirring, granulation, sizing, and tableting to obtain tablets containing the active pharmaceutical ingredient and the cellulose powder of this embodiment.

[0129] In addition to the active pharmaceutical ingredient and the cellulose powder of this embodiment, the pharmaceutical composition may also include, as needed, excipients, disintegrants, binders, flow aids, lubricants, flavoring agents, fragrances, coloring agents, and sweeteners.

[0130] Examples of excipients include acrylic starch, L-aspartic acid, taurine, glycine, sugar (powder), gum arabic, gum arabic powder, alginate, sodium alginate, pregelatinized starch, pumice, inositol, ethyl cellulose, ethylene-vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydrated silica, dried yeast, dried aluminum hydroxide gel, dried sodium sulfate, dried magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerol, and glycerophosphates. Calcium gluconate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, croscarmellose, magnesium aluminum silicate, calcium silicate, magnesium silicate, light silicic anhydride, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose / sodium carboxymethyl cellulose, crystalline cellulose (granules), brown rice koji, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ powder, rice flour, rice starch, potassium acetate, calcium acetate, cellulose phthalate, safflower oil, white beeswax, zinc oxide, titanium dioxide, magnesium oxide, β-cyclodextrin, aluminum dihydroxyaminoacetate, 2,6-Dibutyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, calcined gypsum, sucrose fatty acid esters, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitate, magnesium hydroxide, squalene, stearyl alcohol, stearic acid, calcium stearate, polyoxyethylene stearate, magnesium stearate, hydrogenated soybean oil, refined gelatin, refined shellac, refined white sugar, refined white sugar granules, octadecyl alcohol, polyethylene glycol 1000 monohexyl ether, gelatin, sorbitan fatty acid esters, 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 gum powder, silicon dioxide, calcium lactate, lactose, lactose granules, Perfiller 101, white shellac, white petrolatum, white clay, white sugar, white sugar / starch spherical granules, rye green leaf extract powder, dried rye malt leaf juice powder, honey, paraffin wax, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose (ortho-hydroxypropyl methylcellulose) Phthalate esters, hydroxypropyl methylcellulose phthalate, inositol hexaphosphate, 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 (160)polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltitol, maltose D-Mannitol, syrup, isopropyl myristate, anhydrous lactose, anhydrous dicalcium phosphate, anhydrous calcium phosphate granules, magnesium aluminum metasilicate, methylcellulose, cottonseed meal, cottonseed oil, Japanese wax, aluminum monostearate, glyceryl monostearate, sorbitol monostearate, pharmaceutical charcoal, peanut oil, aluminum sulfate, calcium sulfate, granulated corn starch, liquid paraffin, dl-malic acid, calcium monohydrogen phosphate, calcium dicalcium phosphate, calcium dicalcium phosphate granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, etc., are substances classified as excipients in the "Drug Additives Codex" (published by Pharmacopoeia Inc.). These excipients can be used alone or in combination of two or more.

[0131] Examples of disintegrants include cellulose-based substances such as croscarmellose sodium, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; starch-based substances such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, and partially pregelatinized starch; and synthetic polymers such as croscarmellose and croscarmellose copolymers. These substances are classified as disintegrants in the "Drug Additives Encyclopedia" (published by Pharmacopoeia Inc.). These disintegrants can be used alone or in combination of two or more.

[0132] Examples of substances classified as binders in the "Drug Additives Encyclopedia" (published by Pharmacy Affairs Co., Ltd.) include sugars such as white sugar, glucose, lactose, and fructose; sugar alcohols such as mannitol, xylitol, maltitol, erythritol, and sorbitol; water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin, sodium alginate, and gum arabic; celluloses such as crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, and methylcellulose; starches such as pregelatinized starch and starch paste; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymers, and polyvinyl alcohol; and inorganic compounds such as dicalcium phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminum silicate. These binders can be used alone or in combination of two or more.

[0133] Examples of gliding agents include, for instance, silicon compounds such as hydrated silica and light silicic anhydride, which are classified as gliding agents in the "Drug Additives Encyclopedia" (published by Pharmacopoeia Inc.). These gliding agents can be used alone or in combination of two or more.

[0134] Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, and talc, which are classified as lubricants in the "Drug Additives Encyclopedia" (published by Pharmacopoeia Inc.). These lubricants can be used alone or in combination of two or more.

[0135] As flavoring agents, substances classified as flavoring agents in the "Drug Additives Encyclopedia" (published by Pharmacopoeia Inc.) include, for example, glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, and L-menthol. These flavoring agents can be used alone or in combination of two or more.

[0136] Examples of flavorings include, for instance, oils such as orange, vanilla, strawberry, yogurt, menthol, anise oil, cinnamon oil, bitter orange peel oil, peppermint oil, and green tea powder, which are classified as aromatics and flavorings in the "Drug Additives Encyclopedia" (published by Yakujishin Shinkansen Co., Ltd.). These aromatics and flavorings can be used alone or in combination of two or more.

[0137] Examples of coloring agents include, for instance, food colorings such as Edible Red No. 3, Edible Yellow No. 5, and Edible Cyan No. 1, as well as substances classified as coloring agents in the "Drug Additives Encyclopedia" (published by Pharmacopoeia Inc.), such as sodium copper chlorophyllin, titanium dioxide, and riboflavin. These coloring agents can be used alone or in combination of two or more.

[0138] Examples of sweeteners include aspartame, saccharin, dipotassium glycyrrhizate, steviol glycosides, maltose, maltitol, syrup, and sweet tea powder, which are classified as sweeteners in the "Drug Additives Encyclopedia" (published by Pharmacy News Co., Ltd.). These sweeteners can be used alone or in combination of two or more.

[0139] <Method for manufacturing the pharmaceutical composition of this embodiment>

[0140] The method for manufacturing the pharmaceutical composition of this embodiment is the same as the method for manufacturing the pharmaceutical composition of this embodiment, which uses the cellulose powder and the active pharmaceutical ingredient of this embodiment as raw materials to prepare the pharmaceutical composition.

[0141] In the method for manufacturing the pharmaceutical composition of this embodiment, it is preferable to store the cellulose powder of this embodiment, which is used as a raw material, in a gas with a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less (for example, in an atmosphere where the nitrogen dioxide concentration is controlled to be 0.05 ppm or less and the nitrogen trioxide concentration is 0.05 ppm or less) until the start of manufacturing. By storing the raw material in an environment where the nitrogen dioxide and nitrogen trioxide concentrations are controlled to be low until the start of manufacturing, the amount of nitrite and nitrate nitrogen introduced into the pharmaceutical composition from the raw material can be suppressed to a low level, and the formation of nitrosamines in the pharmaceutical composition can be suppressed. In the manufacturing of the pharmaceutical composition of this embodiment, raw materials other than cellulose powder are also preferably stored in a gas with 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 manufacturing.

[0142] In the manufacturing method of the pharmaceutical composition according to this embodiment, it is preferable that all processes from the start to the end of manufacturing are carried out in a gas with a nitrogen dioxide concentration of 0.05 ppm or less and a nitrogen trioxide concentration of 0.05 ppm or less (for example, in an atmosphere where the nitrogen dioxide concentration is controlled to be 0.05 ppm or less and the nitrogen trioxide concentration is 0.05 ppm or less). This allows the amount of nitrite and nitrate nitrogen introduced from the atmosphere during manufacturing to be kept low, thus suppressing the formation of nitrosamines in the pharmaceutical composition.

[0143] In the method for manufacturing the pharmaceutical composition according to this embodiment, in order to manufacture a pharmaceutical composition with low nitrosamine production, apart from using the cellulose powder of this embodiment as a raw material, the rest can be manufactured by conventional methods. For example, when the pharmaceutical composition is a tablet, it can be manufactured by preparing a mixture containing cellulose powder and the active pharmaceutical ingredient, and then directly compressing the mixture (direct compression method), or by granulating the mixture and then compressing it (granule compression method). In addition, it is also possible to use the post-powdering method (a method of mixing the active pharmaceutical ingredient, cellulose powder and other additives as needed, granulating it into granules, further mixing it with cellulose powder and other additives as needed, and compressing it by conventional methods), a method for manufacturing multi-core tablets with a pre-compressed tablet as the core, and a method for manufacturing multilayer tablets by stacking and recompressing multiple pre-compressed molded bodies, etc.

[0144] As for the method of tableting (compression forming), any conventional method can be used, and there are no particular restrictions. For example, methods that use a mortar and pestle to compress and form tablets into the desired shape can be cited; methods that pre-compress and form tablets into sheets and then cut them into the desired shape can also be cited. As for the compression forming machine, examples include roller presses such as static presses, block roller presses, and smooth roller presses; single-punch tablet presses and rotary tablet presses can also be cited.

[0145] Examples of granulation methods include dry granulation, wet granulation, heated granulation, spray granulation, and microencapsulation. Specifically, effective wet granulation methods include fluidized bed granulation, stirred granulation, extrusion granulation, pulverizing granulation, and rolling granulation. Methods for drying the granules include, for example, hot air drying (shelf drying, vacuum drying, fluidized bed drying), conductive heat transfer drying (pan drying, shelf box drying, drum drying), and freeze drying. In hot air drying, hot air is brought into direct contact with the material, simultaneously evaporating and removing moisture.

[0146] Example

[0147] The description is based on embodiments of the present invention. However, the implementation of the present invention is not limited to these embodiments.

[0148] The methods for measuring and evaluating various physical properties in the examples and comparative examples are described below.

[0149] <Determination of content in cellulose powder>

[0150] (1) Determination of nitrite and nitrate ions

[0151] The contents of nitrite and nitrate ions in cellulose powder were determined by suppressed ion chromatography. The determination conditions are described below. In addition, the contents of nitrite and nitrate ions in natural cellulose materials were also determined in the same manner.

[0152] Chromatographic column: Anion exchange column (inner diameter 4.6 mm × 15 cm)

[0153] Mobile phase: Sodium carbonate / sodium bicarbonate eluent

[0154] Flow rate: 1.0 mL / min

[0155] Column oven temperature: 40℃

[0156] Sample injection volume: 30–100 μL

[0157] Detector: UV-VIS detector (wavelength 210nm)

[0158] LOD (limit of detection): 0.008 μg / g

[0159] (2) Determination of sulfur

[0160] The sulfur content of the cellulose powder was determined using an automated combustion method followed by ion chromatography.

[0161] Specifically, approximately 50 mg of sample was loaded into a quartz boat and combusted in a furnace at 1000°C. The vaporized components were then bubbled into an absorbent solution for absorption. The resulting absorbent solution was analyzed using a CT instrument (model: INTEGRION, ThermoFisher Scientific) to determine the amount of sulfur. The detection limit was 0.1 ppm.

[0162] (3) Determination of hydrogen peroxide

[0163] The hydrogen peroxide content of cellulose powder was determined by the oxygen electrode method.

[0164] Specifically, 2g of sample was extracted in a 0.2mol / L phosphate buffer solution containing 0.5% potassium bromate, and then filtered under ice-cold conditions to obtain the filtrate. 20mL of the filtrate was aliquoted and analyzed using the oxygen electrode method to quantify hydrogen peroxide. The determination was performed using a hydrogen peroxide meter (SUPER ORITECTOR MODEL 5, manufactured by Central Scientific Industrial Co., Ltd.), with 2mL of filtrate injected into the analyzer for analysis. The detection limit was 0.1ppm.

[0165] (4) Determination of iron

[0166] The iron content of the cellulose powder was determined by inductively coupled plasma mass spectrometry (ICP-MS).

[0167] Sample pretreatment was performed using a closed-system acid decomposition method. Samples were collected, sulfuric acid was added, and the samples were then subjected to heating decomposition using a microwave sample decomposition device (ETHOS UP, manufactured by Milestone Corporation). The samples were then diluted to the volumetric flask mark with ultrapure water and used as analytical samples.

[0168] The prepared analytical samples were analyzed using an inductively coupled plasma mass spectrometry (ICP-MS) system (model: iCAP RQ, manufactured by Thermo Fisher Scientific) to determine the... 56 Fe determination. The detection limit is 0.1 ppm.

[0169] (5) Determination of ammonia

[0170] The ammonia content of the cellulose powder was determined by ion chromatography based on JIS K0127.

[0171] First, weigh 3g of sample (crystalline cellulose powder) into a 100mL volumetric glass beaker, add 60mL of pure water, and stir for 20 minutes with a certain stirring force. After stirring, filter using quantitative filter paper (5C, Advantec). Use the recovered filtrate as the sample for analysis.

[0172] The prepared analytical sample was analyzed using an ion chromatography analyzer (model: INTEGRION, manufactured by Thermo Fisher Scientific) to determine ammonia. This ion chromatography analyzer is equipped with a separation column (CS12 column), a guard column (CG12 column), and a conductivity detector. The detection limit is 0.1 ppm.

[0173] <Determination of content in gases>

[0174] (1) Determination of nitrogen dioxide and nitrogen trioxide concentrations

[0175] The concentrations of nitrogen dioxide and nitrogen trioxide in the gas were determined by suppressed ion chromatography, just as the concentrations of nitrite and nitrate ions in cellulose powder were determined.

[0176] Atmospheric samples for analysis were collected using a DSD-TEA sampler within a specified time period. After collection, the sampler was retrieved, and the samples were extracted with pure water to obtain the analytical samples.

[0177] <Determination of content in water>

[0178] (1) Determination of nitrite and nitrate nitrogen

[0179] The content of nitrite nitrogen in water, as well as the total content of nitrite nitrogen and nitrate nitrogen, was determined by suppressed ion chromatography in the same manner as the determination of nitrite ions and nitrate ions in cellulose powder.

[0180] [Example 1]

[0181] Six types of cellulose powder were formulated into active ingredients and tablets that pose a risk of generating nitrosamines, and the amount of nitrosamines generated was compared.

[0182] (1) Manufacturing of cellulose powder

[0183] Seven commercially available SP pulps (with nitrite ion concentrations all less than 0.008 ppm (detection limit) and nitrate ion concentrations ranging from 0.8 to 4.6 ppm) were appropriately stirred as raw materials to prepare six cellulose powders (A–F) with different raw pulp concentrations. The concentrations of nitrite, nitrate, hydrogen peroxide, sulfur, iron, and ammonia in the raw pulps (A–F) were determined. After the raw pulps were treated into a flocculent state, the concentrations of each component were determined using the same method as for the cellulose powder. The results are shown in Table 1. It should be noted that when the concentration is less than the detection limit, the concentration of that sample is considered the detection limit.

[0184] [Table 1]

[0185]

[0186] Powdered cellulose (A-F) was prepared separately from raw pulp (A-F). The entire process, from the input of raw pulp to the completion of cellulose powder preparation, was carried out in an atmospheric environment with a nitrogen dioxide concentration of less than 0.03 ppm and a nitrogen trioxide concentration of less than 0.03 ppm. Furthermore, the water (pure water) used in the manufacturing process contained less than 0.004 ppm of nitrite nitrogen and less than 0.1 ppm of the total nitrite and nitrate nitrogen.

[0187] Specifically, 2 kg of raw pulp was shredded and placed in 30 L of 0.05% hydrochloric acid aqueous solution. The mixture was then hydrolyzed at 145°C for 70 minutes while being stirred using a low-speed mixer (Ikebukuro Enamel Industry Co., Ltd., 30 L GL reactor, blade diameter approximately 30 cm). The resulting acid-insoluble residue was filtered through a Buchner funnel. The filtered residue (insoluble residue) was further washed four times with 70 L of pure water, neutralized with ammonia water, and then placed in a 90 L plastic container with added pure water. A cellulose dispersion was prepared by stirring using a three-blade mixer (HEIDON, model BLh1200, 8M / M, blade diameter approximately 10 cm) at 500 rpm. This cellulose dispersion was then spray-dried (liquid supply rate 6 L / h, inlet temperature 180–220°C, outlet temperature 50–70°C) to obtain cellulose powders A–C, E, and F.

[0188] In addition, 2 kg of raw pulp was shredded and placed in 30 L of 0.08% hydrochloric acid aqueous solution. The mixture was hydrolyzed at 135°C for 80 minutes while being stirred using a low-speed mixer (Ikebukuro Enamel Industry Co., Ltd., 30 L GL reactor, blade diameter approximately 30 cm). The resulting acid-insoluble residue was filtered through a Buchner funnel. The filtered residue (insoluble residue) was further washed four times with 70 L of pure water, neutralized with ammonia water, placed in a 90 L plastic container, and pure water was added. A cellulose dispersion was prepared while being stirred using a three-blade mixer (HEIDON, model BLh1200, 8 M / M, blade diameter approximately 10 cm) at 500 rpm. The cellulose dispersion was then spray-dried (liquid supply rate 6 L / h, inlet temperature 180–220°C, outlet temperature 50–70°C) to obtain cellulose powder D.

[0189] The weight-average particle size (μm) and apparent specific volume (cm³) of the prepared cellulose powders A-F and commercially available cellulose powders G-J were determined. 3 / g), apparent tap density (g / cm³) 3 The concentrations of nitrite ions, nitrate ions, hydrogen peroxide, sulfur, iron, and ammonia were measured. The results are shown in Tables 2 and 3. It should be noted that for values ​​below the detection limit, the detection limit is used as the concentration of the sample. In the tables, underlined values ​​indicate values ​​below the detection limit.

[0190] [Table 2]

[0191]

[0192] [Table 3]

[0193]

[0194] (2) After the manufacture and storage of tablets

[0195] Cellulose powders A-J and tablets were manufactured using MCPA, which contains dimethylaminomethyl and is reported to have the risk of generating nitrosamines, as the active ingredient.

[0196] Specifically, 300mg tablets are manufactured from a mixture of cellulose powder and MCPA in a 5:5 (mass ratio) via direct compression. The manufactured tablets are stored for one month at 50°C, 80% relative humidity, and at an atmospheric environment with a nitrogen dioxide concentration below 0.03ppm and a nitrogen trioxide concentration below 0.03ppm.

[0197] (3) Determination of nitrosamine content

[0198] The content of nitrosamines (NDMA, NDEA) in the preserved tablets was determined. NDMA was determined by gas chromatography-mass spectrometry (GC-MS / MS).

[0199] First, the tablets were pulverized using a mortar and pestle, and approximately 25 mg of the pulverized material was accurately weighed. 4 mL of 1 mol / L NaOH solution was added to the pulverized material, followed by ultrasonic irradiation for 10 minutes. Then, internal standards (NDMA-d6, NDEA-d6) were accurately added. 10 4 mL of the solution was soaked for 15 minutes, followed by centrifugation (3000 rpm × 5 minutes). The lower layer after centrifugation was filtered and used as the sample solution.

[0200] The prepared sample solution was analyzed using a GC-MS / MS instrument (manufactured by Shimadzu Corporation) to quantitatively determine the nitrosamines in the sample solution. This GC-MS / MS instrument consisted of a GCMS gas chromatograph (model: CG-2030), a GCMS mass spectrometer (model: GCMS-TQ8050NS), and a GCMS autosampler (model: AOC-6000plus) (all manufactured by Shimadzu Corporation). The detection limit was 0.05 μg / g.

[0201] [Table 4]

[0202]

[0203] The results of the assays using tablets made from various cellulose powders are shown in Table 4. In the table, "ND" indicates that the substance was not formed.

[0204] According to Table 2, the weight-average particle size (μm) and apparent specific volume (cm³) of the nine cellulose powders other than cellulose powder D are... 3 / g), apparent tap density (g / cm³) 3Both the nitrite and nitrate ion concentrations (°) were similar, indicating that these cellulose powders had similar physical properties. On the other hand, according to Tables 3 and 4, tablets made from cellulose powders G-J, which had significantly higher nitrite and nitrate ion concentrations, also showed a significantly higher NDMA concentration. Based on these results, it can be concluded that differences in powder properties have little impact on the amount of nitrosamines produced. Furthermore, while cellulose powder D had higher apparent specific volume and apparent tap density compared to other cellulose powders, it produced a higher amount of nitrosamines compared to cellulose powders A or B. Based on this, it is believed that differences in powder properties do not cause differences in the amount of nitrosamines produced.

[0205] Comparing tablets obtained from cellulose powders A, D, and F, the tablets using cellulose powder D, which has the lowest total concentration of nitrite and nitrate ions, have a higher NDMA concentration than tablets using cellulose powders A or F, which have higher total concentrations of nitrite and nitrate ions. These results indicate that the amount of nitrosamines produced in tablets can be influenced by factors other than the nitrate ion concentration from the cellulose powder.

[0206] As shown in Tables 3 and 4, a tendency was observed that higher concentrations of hydrogen peroxide and sulfur in the cellulose powder were associated with higher NDMA concentrations. Similarly, higher concentrations of iron, nitrate ions, and nitrite ions in the cellulose powder were associated with higher NDMA concentrations. Based on these results, hydrogen peroxide, sulfur, iron, nitrite ions, and nitrate ions from the cellulose powder can influence the formation of nitrosamines. On the other hand, no particular correlation was observed between the ammonia concentration and the NDMA concentration in the cellulose powder.

[0207] [Example 2]

[0208] The effect of nitrite ion concentration in the gas used for spray drying on the resulting cellulose powder and the tablets prepared therefrom was investigated.

[0209] First, raw material pulp A was hydrolyzed in the same manner as cellulose powder A used in Example 1. After washing away acid-insoluble residues and neutralizing, pure water was added and stirred to prepare a cellulose dispersion. The obtained cellulose dispersion was spray-dried with gases of different nitrite ion concentrations, and the nitrite and nitrate ion concentrations of the obtained cellulose powder were examined.

[0210] (1) Manufacturing in an atmospheric environment with sufficiently low nitrogen dioxide concentration

[0211] A cellulose dispersion was spray-dried using a spray dryer in an atmosphere with an atmospheric nitrogen dioxide concentration of 0.020 ppm. Analysis of the resulting cellulose powder showed a nitrite ion concentration of 0.011 ppm and a nitrate ion concentration of 0.072 ppm. These results indicate that when the nitrogen dioxide concentration of the gas used in spray drying is sufficiently low, cellulose powder with sufficiently low concentrations of both nitrite and nitrate ions can be obtained.

[0212] (2) Manufacturing in an atmosphere with high nitrogen dioxide concentration (A)

[0213] Cellulose dispersions were spray-dried using a spray dryer in an environment with an atmospheric nitrogen dioxide concentration greater than 0.020 ppm. Spray drying was performed with or without a chemical filter capable of efficiently removing acidic gases such as nitrogen dioxide at the inlet of the spray drying gas in the spray dryer. The concentrations of nitrite and nitrate ions in the spray drying gas and the resulting cellulose powder were investigated. Filter A (“RM2B90”, manufactured by Osaka Gas Chemical Co., Ltd.) was used as the chemical filter. The results are shown in Table 5.

[0214] [Table 5]

[0215]

[0216] As shown in Table 5, the concentrations of both nitrite and nitrate ions in the spray-drying gas can be reduced to below 0.020 ppm using a chemical filter. Furthermore, the concentrations of both nitrite and nitrate ions in the resulting cellulose powder obtained by spray drying using the filter are significantly lower than those obtained by spray drying without a filter. These results indicate that a lower nitrogen dioxide concentration in the spray-drying gas leads to a reduction in the concentrations of nitrite and nitrate ions in the resulting cellulose powder, and that even in atmospheres with high nitrogen dioxide concentrations, the nitrogen dioxide concentration in the spray-drying gas can be controlled by using a chemical filter.

[0217] (3) Manufacturing in an atmosphere with high nitrogen dioxide concentration (B)

[0218] The cellulose dispersion was spray-dried using a spray dryer in an environment where the atmospheric nitrogen dioxide concentration was greater than 0.020 ppm. Spray drying was performed in the same manner as described in (2), except that filter B (“Philofresh VZG”, manufactured by Vilene Co., Ltd., Japan) was used as a chemical filter. The concentrations of nitrite and nitrate ions in the spray-drying gas and the resulting cellulose powder were examined. The results are shown in Table 6.

[0219] [Table 6]

[0220]

[0221] As shown in Table 6, when using filter B, the concentrations of both nitrite and nitrate ions in the spray drying gas can be reduced to below 0.020 ppm, just like when using filter A. In addition, the concentrations of both nitrite and nitrate ions in the cellulose powder obtained by spray drying using the filter are significantly lower than those obtained by spray drying without the filter.

[0222] Industrial availability

[0223] The cellulose powder of this embodiment is very useful as a raw material for pharmaceuticals requiring high safety because it suppresses the content of components that affect the formation of nitrosamines.

Claims

1. A cellulose powder, characterized in that, The nitrate ion content is below 1.00 ppm, and the sulfur content is below 30.0 ppm.

2. The cellulose powder according to claim 1, wherein, The hydrogen peroxide content is below 0.40 ppm.

3. A cellulose powder, characterized in that, The nitrate ion content is below 1.00 ppm, and the hydrogen peroxide content is below 0.40 ppm.

4. The cellulose powder according to claim 1, wherein, The nitrite ion content is below 0.200 ppm.

5. The cellulose powder according to claim 1, wherein, The iron content is between 0.10 ppm and 0.80 ppm.

6. A pharmaceutical composition, wherein, It contains cellulose powder and pharmaceutical active ingredient as described in any one of claims 1 to 5.

7. The pharmaceutical composition according to claim 6, wherein, The active pharmaceutical ingredient is a secondary amine, a tertiary amine, or a quaternary ammonium.

8. The pharmaceutical composition according to claim 6, wherein it is a tablet.

9. A method for manufacturing cellulose powder, characterized in that, Natural cellulose materials are hydrolyzed, and the insoluble residues in the hydrolyzed cellulose dispersion are washed away and then spray-dried. Wherein, (1) the nitrite ion content in the natural cellulose material is less than 0.010 ppm or the sulfide ion content is less than 30.0 ppm, and the nitrate ion content is less than 5.0 ppm, or (3) The spray drying is carried out in a gas with a nitrogen dioxide concentration of less than 0.05 ppm or a nitrogen trioxide concentration of less than 0.05 ppm.

10. The method for manufacturing cellulose powder according to claim 9, characterized in that, Natural cellulose materials are hydrolyzed, and the insoluble residues in the hydrolyzed cellulose dispersion are washed away and then spray-dried. Wherein, (1) the nitrite ion content in the natural cellulose material is less than 0.010 ppm or the sulfide ion content is less than 30.0 ppm, and the nitrate ion content is less than 5.0 ppm. (3) The spray drying is carried out in a gas with a nitrogen dioxide concentration of less than 0.05 ppm.

11. The method for manufacturing cellulose powder according to claim 9 or 10, wherein, Further satisfying: (2) the water used in at least one of the hydrolysis reaction of the natural cellulose material, the washing of the insoluble residue and the spray drying has a nitrite nitrogen content of less than 0.02 ppm or a total content of nitrite nitrogen and nitrate nitrogen of less than 5.0 ppm.

12. A method for manufacturing a pharmaceutical composition, wherein, A pharmaceutical composition is prepared by using the cellulose powder and the active pharmaceutical ingredient as raw materials according to any one of claims 1 to 5.

13. The method for manufacturing the pharmaceutical composition according to claim 12, wherein, The cellulose powder is stored in a gas with a nitrogen dioxide concentration of less than 0.05 ppm and a nitrogen trioxide concentration of less than 0.05 ppm until the start of manufacturing.

14. The method for manufacturing the pharmaceutical composition according to claim 12, wherein, The pharmaceutical composition is manufactured in a gas with a nitrogen dioxide concentration of less than 0.05 ppm and a nitrogen trioxide concentration of less than 0.05 ppm.

15. The method for manufacturing the pharmaceutical composition according to claim 12, wherein, The active pharmaceutical ingredient is a secondary amine, a tertiary amine, or a quaternary ammonium.

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

17. The method for manufacturing the pharmaceutical composition according to claim 12, wherein, The pharmaceutical composition is a tablet; the mixture containing the cellulose powder and the active pharmaceutical ingredient is directly compressed into tablets or compressed into tablets after granulation.

Images