Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J3/00—Processes of treating or compounding macromolecular substances
  • C08J3/12—Powdering or granulating

Definitions

• the present invention relates to a cellulose powder for use in the preparation of pharmaceutical compositions having reduced nitrosamine content.
• 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.
• Patent Document 1 reports that by setting the powder properties of cellulose powder, particularly 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 (%) when extracted with 1% NaOH aqueous solution minus the total organic carbon amount (%) when extracted with pure water, within a specific range, it is possible to improve not only the compression moldability but also the flavor release of herbal medicines and the color development of the sugar coating layer.
• Non-Patent Document 1 a synthetic pathway is known in which nitrosamines are generated by a chemical reaction at high temperatures between dimethylamine derived from the raw pharmaceutical ingredients and nitrous acid derived from the additives.
• the present invention provides a cellulose powder that contains very little of the components involved in the generation of nitrosamines and 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.
• the inventors conducted extensive research in light of the current situation described above, and discovered 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 also discovered that by using 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 thus completed the present invention.
• the present invention includes the following aspects.
• [5] The cellulose powder according to any one of [1] to [4], having an iron content of 0.10 ppm or more and 0.80 ppm or less.
• a pharmaceutical composition comprising the cellulose powder according to any one of [1] to [5] above and a pharmaceutical active ingredient.
• 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, (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.
• a method for producing cellulose powder comprising the steps of: [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, (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.
• a method for producing cellulose powder comprising the steps of: [11] Furthermore, (2) Water used in one or more of the processes 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.
• a method for producing a pharmaceutical composition comprising producing the pharmaceutical composition using the cellulose powder according to any one of [1] to [5] above and a medicament active ingredient as raw materials.
• the pharmaceutical composition is a tablet, The method for producing the pharmaceutical composition according to any one of the above [12] to [16], wherein a mixture containing the cellulose powder and the medicament active ingredient is directly compressed into tablets or granulated and then compressed into tablets.
• 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
• a method for producing a cellulose powder characterized in that the water used in one or more of the following 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.
• the cellulose powder of the above embodiment has a low content of components that contribute to the generation of nitrosamines, so 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.
• ppm means “ppm by mass (0.001 mg/g)."
• 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.
• the cellulose powder is preferably crystalline cellulose.
• crystalline cellulose include microcrystalline cellulose described in the 9th edition of the Japanese Pharmacopoeia of Food Additives, crystalline cellulose described in the Japanese Pharmacopoeia (18th revision), and crystalline cellulose described in the United States Pharmacopoeia, European Pharmacopoeia, etc.
• 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 effect of generating nitrosamines in the product (hereinafter sometimes referred to as "nitrosamine generating ability"). Because the cellulose powder according to this embodiment has a low nitrosamine generating ability, it is suitable as a raw material for pharmaceuticals in which the nitrosamine content is strictly limited.
• 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.
• the nitrate ion content affects the amount of nitrosamines generated. The higher the nitrate ion content, the higher the amount of nitrosamines generated.
• the nitrate ion content (mass) of the cellulose powder 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.
• the nitrate ion content (mass) of the cellulose powder is undetectable below 0.008 ppm.
• the reason why the nitrate ion content affects the amount of nitrosamines generated is unclear, but it is presumed that this is because the nitrate ions in the pharmaceutical are reduced and converted to nitrite ions during the pharmaceutical manufacturing process or during storage after manufacturing.
• 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.
• 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.
• the sulfur content affects the amount of nitrosamines generated. The higher the sulfur content, the higher the amount of nitrosamines generated.
• the sulfur content (mass) of the cellulose powder 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.
• the reason why the sulfur content affects the amount of nitrosamines generated is unclear, but it is presumed that this is because the sulfur in the pharmaceutical acts as a reducing agent during the pharmaceutical manufacturing process and during storage after manufacturing, converting nitrate ions into nitrite ions.
• the lower limit of the range of the sulfur content (mass) is 0.10 ppm, which is the detection limit.
• a sulfur content (mass) of cellulose powder of less than 0.10 ppm is undetectable.
• the hydrogen peroxide content (mass) relative to the total amount (mass) of 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.
• the lower limit of the range of the hydrogen peroxide content (mass) is 0.10 ppm, which is the detection limit.
• the hydrogen peroxide content (mass) of the cellulose powder is undetectable below 0.10 ppm. As shown in the examples below, the hydrogen peroxide content affects the amount of nitrosamine generated. The higher the hydrogen peroxide content, the higher the amount of nitrosamine generated.
• the hydrogen peroxide content (mass) relative to the total amount (mass) of the cellulose powder within the above range, the amount of nitrosamine generated when used as a pharmaceutical excipient can be kept low.
• the reason why the hydrogen peroxide content affects the amount of nitrosamine generated is unclear, but it is presumed that this is because the hydrogen peroxide in the pharmaceutical acts as a reducing agent during the pharmaceutical manufacturing process and storage after manufacturing, converting nitrate ions into nitrite ions.
• the iron content (mass) relative to the total amount (mass) of the cellulose powder is preferably 0.10 ppm or more and 0.80 ppm or less, more preferably 0.20 ppm or more and 0.80 ppm or less, even more preferably 0.30 ppm or more and 0.80 ppm or less, and also preferably 0.20 ppm or more and 0.70 ppm or less.
• the iron content (mass) relative to the total amount (mass) of the cellulose powder according to this embodiment is more preferably 0.30 ppm or more and 0.70 ppm or less, and even more preferably 0.30 ppm or more and 0.60 ppm or less.
• the iron content affects the amount of nitrosamines generated. If the iron content is too low, the amount of nitrosamines generated will be high, but if the iron content is too high, the total amount of iron inoculated may be too high, which is not preferable.
• the amount of nitrosamines generated can be kept low when the powder is used as a pharmaceutical excipient, etc.
• 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, the iron in the pharmaceutical 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.
• nitrate ions, nitrite ions, sulfur, hydrogen peroxide, and iron in the cellulose powder can all be measured by the method described in the Examples below.
• the cellulose powder according to this embodiment is particularly Cellulose powder having a nitrate ion content of 1.00 ppm or less and a sulfur content of 30.0 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 hydrogen peroxide content of 0.40 ppm or less; 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
• 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.
• an average degree of polymerization of 100 or more and 350 or less is preferable because it provides a particularly excellent balance of moldability, disintegration properties, and fluidity.
• 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 ⁇ m and not more than 250 ⁇ m, more preferably more than 30 ⁇ m and not more than 180 ⁇ m, and even more preferably 40 ⁇ m or more and not more than 150 ⁇ m.
• By making the weight average particle diameter more than 30 ⁇ m, preferably 40 ⁇ m or more handling is improved without increasing adhesion and cohesion, and furthermore, fluidity is excellent.
• the weight average particle diameter 250 ⁇ m or less preferably 180 ⁇ m or less, more preferably 150 ⁇ m or less, separation and segregation from the active ingredient does not occur, and there is no risk of deteriorating the content uniformity of the formulation, so this is preferable.
• 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 preferably 2 cm 3 /g or more and 15 cm 3 /g or less, more preferably 2 cm 3 /g or more and 13 cm 3 /g or less, even more preferably 2 cm 3 /g or more and 6 cm 3 /g or less, and particularly preferably 2 cm 3 /g or more and less than 4 cm 3 /g.
• the apparent specific volume is 2 cm 3 /g or more, moldability is improved. Since elastic recovery due to fibrous properties is expressed, the upper limit is at most 15 cm 3 /g.
• the apparent specific volume of the cellulose powder according to this embodiment is particularly preferably 2.3 cm 3 /g or more and 3.8 cm 3 /g or less, and even more preferably 3.0 cm 3 /g or more and 3.8 cm 3 /g or less.
• the tapped apparent density of the cellulose powder according to the present embodiment is not particularly limited.
• the tapped apparent density of the cellulose powder according to the present embodiment is preferably 0.2 g/cm 3 or more and 0.6 g/cm 3 or less, more preferably 0.3 g/cm 3 or more and 0.58 g/cm 3 or less, and even more preferably 0.35 g/cm 3 or more and 0.55 g/cm 3 or less. If the tapped apparent density is 0.6 g/cm 3 or less, the moldability is improved.
• 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°.
• the physical properties of the cellulose powder can be measured as follows. 1) Average degree of polymerization (-) The viscosity can be measured by the copper ethylenediamine solution viscositometry described in the 18th Edition of the Japanese Pharmacopoeia, Identification Test for Crystalline Cellulose (3). 2) Loss on drying (%) 1 g of the powder was dried at 105° C. for 3 hours, and the weight loss was expressed as a weight percentage.
• Weight average particle size of cellulose powder ( ⁇ m) The weight average particle size of a powder sample is measured by sieving 10 g of the sample for 10 minutes using a Rotap type sieve shaker (Sieve Shaker Type A manufactured by Hira Kogyosho Co., Ltd.) and a JIS standard sieve (Z8801-1987), to measure the particle size distribution, and is expressed as the particle size at 50% cumulative weight.
• Rotap type sieve shaker Sieve Shaker Type A manufactured by Hira Kogyosho Co., Ltd.
• JIS standard sieve Z8801-1987
• the cellulose powder according to the present 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 redispersion can be performed according to methods and conditions generally used for producing cellulose powders, or by appropriately modifying these.
• the natural cellulosic material used as the raw material may be of vegetable or animal origin.
• natural cellulosic materials include fibrous materials derived from natural products that contain cellulose, such as wood, bamboo, wheat straw, rice straw, cotton, ramie, bagasse, kenaf, beet, sea squirt, and bacterial cellulose.
• Natural cellulosic materials have a cellulose type I crystal structure.
• the raw material one of the above natural cellulosic materials may be used, or a mixture of two or more types may be used.
• the natural cellulosic material used as the raw material is preferably used in the form of refined pulp, and from the viewpoint of production yield, refined pulp with an ⁇ -cellulose content of 85% or more is particularly preferred.
• refined pulp with an ⁇ -cellulose content of 85% or more is particularly preferred.
• any pulp such as dissolving pulp, kraft pulp, or NBKP pulp may be used. From the viewpoints of high ⁇ -cellulose purity, ease of availability, and high supply stability, wood-derived pulp is preferred.
• the hydrolysis of natural cellulosic materials may be 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. In addition, the natural cellulosic materials may be subjected to mechanical treatments such as crushing and grinding before or after hydrolysis.
• the hydrolysis of natural cellulosic materials is carried out by dispersing solids containing the natural cellulosic materials in a suitable medium.
• the medium is preferably water.
• the medium may be any medium other than water, as long as it is industrially used, and for example, a mixture of water and an organic solvent may be used.
• the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; and ketones such as acetone and ethyl methyl ketone.
• organic solvents used in pharmaceuticals are preferred, and examples of such organic solvents include 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 types. The material may be dispersed in one medium, and then the medium may be removed and dispersed in a different medium.
• hydrolysis of natural cellulosic materials 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 cellulose powder with the desired physical properties.
• 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
• the hydrolysis time is preferably 40 to 150 minutes, more preferably 70 to 110 minutes.
• the degree of polymerization of the raw cellulose and the stirring force during the hydrolysis or dispersion process of the natural cellulosic material 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 the desired range.
• the stirring force depends on the width, height, volume, type of blades, blade diameter, and stirring speed of the stirring layer, etc.
• the cellulose dispersion obtained after hydrolysis is subjected to solid-liquid separation to recover insoluble residues, which are then washed.
• neutralization may be performed by alkaline or acid treatment, if necessary.
• the washing liquid used in the washing process may be the same medium used to disperse the natural cellulosic material. Furthermore, when washing is performed multiple times, a different washing liquid may be used for each washing. In the production of the cellulose powder of this embodiment, washing with pure water is preferred.
• the insoluble residue after washing is dispersed again in pure water to prepare a cellulose dispersion.
• the cellulose dispersion is spray-dried to produce cellulose powder.
• the redispersed cellulose dispersion may be subjected to mechanical processing such as pulverization or grinding, centrifugation using a cyclone or centrifuge, classification using a sieve, or other separation processing prior to spray-drying. These processing methods may be used alone or in combination of two or more.
• grinding methods include screen grinding methods using a screen mill, hammer mill, etc.; blade rotary shear screen grinding methods using a flash mill, etc.; airflow grinding methods using a jet mill, etc.; ball grinding methods using a ball mill, vibrating ball mill, etc.; blade stirring grinding methods, etc.
• the grinding method includes, for example, grinding methods using stirring blades such as one-way rotation type, multi-axis rotation type, reciprocating inversion type, up-down movement type, rotation + up-down movement type, and pipeline type, such as portable mixers, three-dimensional mixers, and side mixers; jet type stirring and grinding methods such as line mixers; grinding methods using high-shear homogenizers, high-pressure homogenizers, and ultrasonic homogenizers; and axial rotation extrusion type grinding methods such as kneaders.
• stirring blades such as one-way rotation type, multi-axis rotation type, reciprocating inversion type, up-down movement type, rotation + up-down movement type, and pipeline type, such as portable mixers, three-dimensional mixers, and side mixers
• jet type stirring and grinding methods such as line mixers
• grinding methods using high-shear homogenizers, high-pressure homogenizers, and ultrasonic homogenizers and axial rotation extrusion type grinding methods such as kneader
• the redispersed cellulose dispersion can be spray-dried using a variety of methods, including disk type, pressurized nozzle, pressurized two-fluid nozzle, and pressurized four-fluid nozzle. These spray methods can be used alone or in combination of two or more.
• the spray-drying temperature can be a commonly used inlet temperature of 150°C or higher and 300°C or lower. Freeze drying, drum drying, shelf drying, airflow drying, vacuum drying, etc. can also be used instead of or in combination with spray drying.
• a small amount of a water-soluble polymer or surfactant may be added to the dispersion in order to lower 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.
• water-soluble polymers examples include those listed in the "Dictionary of Pharmaceutical Additives” (published by Yakuji Nipposha Co., Ltd.), such as hydroxypropyl cellulose, hydroxypropyl methyl 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 kinds.
• Surfactants include, for example, 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, monostearate glyceride, monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, sorbitan monopalmitate, sodium lauryl sulfate, and other surfactants classified as surfactants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These surfactants may be used alone or in combination of two or more.
• foaming agents examples 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.
• bicarbonates such as sodium hydrogen carbonate and ammonium hydrogen carbonate that decompose thermally to generate gas
• carbonates such as sodium carbonate and ammonium carbonate that react with acids to generate gas.
• acids include organic acids such as citric acid, acetic acid, ascorbic acid, 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 that are used in pharmaceuticals or foods are preferred, but other acids have the same effect.
• gases such as nitrogen, carbon dioxide, liquefied petroleum gas, and dimethyl ether may be impregnated into the dispersion.
• At least one of the following (1) and (3) is carried out in order to produce cellulose powder with low nitrosamine generating ability by keeping the content of components that contribute to the production of nitrosamines low.
• 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.
• the water used in one or more of the processes 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.
• nitrite ions and nitrate ions in the cellulose powder originate from the natural cellulosic material used as the raw material. Therefore, in this embodiment, by using a natural cellulosic material with a low content of nitrite ions, sulfur ions, or nitrate ions as the raw material, a cellulose powder with low nitrosamine generation potential can be produced.
• 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 it is preferable to use, as the raw material, 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.
• the method for measuring trace substances such as nitrite ions, sulfur ions, and nitrate ions contained in the natural cellulosic material as the raw material is not particularly limited, and any known method may be used.
• the measurement can be performed in the same manner as the measurement of trace substances in the cellulose powder described above.
• pretreatment such as processing the pulp into a cotton-like form in order to improve extraction efficiency and evaluation accuracy.
• pretreatment such as processing the pulp into a cotton-like form
• it can be processed using a general grinder.
• a high-speed mill from LabNext or a home mixer can be used.
• 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 liquid to be spray-dried.
• the amount of carryover from the water can be kept low, making it possible to produce a cellulose powder with a very low content of nitrite ions and nitrate ions and low nitrosamine generation 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.
• 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.
• 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.
• 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.
• the amount of nitrite ions and nitrate ions in the cellulose powder is affected by the gas during spray drying.
• spray drying is performed in a gas that contains almost no nitrite ions or nitrate ions, so that the amount of nitrite ions and nitrate ions carried over from the gas can be kept low, and a cellulose powder with a very low content of nitrite ions and nitrate ions and low nitrosamine generation ability can be produced.
• 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 mainly the total concentration of nitric oxide, nitrogen dioxide, nitrous oxide, and dinitrogen trioxide.
• 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” as the gas used during spray drying, 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.”
• 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 controlled to 0.05 ppm or less is used.
• the nitrogen dioxide concentration of the gas during spray drying is preferably 0.000 ppm or more and 0.050 ppm or less, more preferably 0.00 ppm or more and 0.025 ppm or less, and even more preferably 0.00 ppm or more and 0.020 ppm or less.
• the nitrogen trioxide concentration of the gas during spray drying is preferably 0.000 ppm or more and 0.050 ppm or less, more preferably 0.00 ppm or more and 0.025 ppm or less, and even more preferably 0.00 ppm or more and 0.020 ppm or less.
• 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.
• Methods for removing nitrogen dioxide and nitrogen trioxide from dry air include, for example, a wet adsorption method using a scrubber and a dry adsorption method using a chemical filter.
• adsorbent that can efficiently remove acidic gases such as nitrogen dioxide.
• adsorbents that can efficiently remove acidic gases include "SAAFCarb” (manufactured by AAF), “Pure Smell Filter Adsorbent E3” and “Pure Smell Filter Adsorbent E5" (both manufactured by Nippon Muki), “Gigacol” and “CP Blend Select” (both manufactured by Nitta), “Philofresh VZG” and “Philofresh VCL” (both manufactured by Nippon Vilene), and “RM2B90” (manufactured by Osaka Gas Chemicals).
• the adsorbent can be selected appropriately depending on the size and production capacity of the cellulose powder production facility. There is no restriction on the method of selecting the adsorbent, as long as an adsorbent that can adjust the amount of nitrogen dioxide contained in the dry air to a certain value or less can be selected.
• the steps other than spray drying in the cellulose powder production process are 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 controlled to 0.05 ppm or less, and it is more preferable that all the steps for producing cellulose powder are 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 controlled to 0.05 ppm or less.
• the method for measuring the concentration of nitrogen dioxide and nitrogen trioxide in the air is not particularly limited, and can be measured by conventional methods.
• the concentrations of nitrogen monoxide, nitrogen dioxide, and NOx in the air can be measured by using a general NOx measuring device that employs a chemiluminescence method.
• NOx measuring devices include the "GLN-354D” (manufactured by DKK-TOA Corporation), "APNA-370" (manufactured by Horiba, Ltd.), and "NOA-308Dx” (manufactured by Shimadzu Corporation).
• the concentrations of nitrogen dioxide and nitrogen trioxide in the air can be measured by measuring samples collected using a diffusion sampler for collecting acidic gases using the ion chromatography method or the Satzmann method.
• At least one of the above-mentioned (1) and (3) may be carried out.
• the method for producing 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 in order to reduce the amount of sulfur, hydrogen peroxide, and iron carried over to the final cellulose powder.
• water containing low amounts of not only nitrite nitrogen and nitrate nitrogen, but also sulfur, hydrogen peroxide, and iron e.g., pure water
• the number of washings in washing the insoluble residue can be increased from the conventional number, for example, 3 or more times, preferably 4 or more times, more preferably 5 or more times, and even more preferably 6 or more times.
• the more the number of washings the more the amount of sulfur, hydrogen peroxide, and iron carried over from the raw material can be reduced.
• the cellulose powder of this embodiment can be used as a raw material for various products such as medicines, food and beverages, feed, cosmetics, sanitary products, and agricultural chemicals.
• 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 medicines and food and beverages in which the nitrosamine content is limited.
• the pharmaceutical composition of this embodiment contains the cellulose powder of this embodiment and a pharmaceutical active ingredient.
• the content of the pharmaceutical active ingredient and the cellulose powder of this embodiment in the pharmaceutical composition of this embodiment is not particularly limited, and in the normal use range, the content of the pharmaceutical active ingredient is 0.001% by mass or more and 99.0% by mass or less, and the content of the cellulose powder of this embodiment is 1.0% by mass or more and 99.0% by mass or less, relative to the total mass of the pharmaceutical composition.
• the content of the pharmaceutical active ingredient By making the content of the pharmaceutical active ingredient equal to or more than the above lower limit, an effective amount for treatment can be ensured, while by making the content of the cellulose powder of this embodiment equal to or more than the above upper limit, the content of the cellulose powder of this embodiment can be equal to or more than the above lower limit, and the characteristic of the cellulose powder of this embodiment that it is difficult to generate nitrosamines can be fully utilized.
• the pharmaceutical active ingredient contained in the pharmaceutical composition of this embodiment is not particularly limited.
• the pharmaceutical active ingredient contained in the pharmaceutical composition may be only one type, or may be two or more types.
• Examples of pharmaceutical active ingredients include hyperlipidemic drugs, diabetes drugs, stomachic drugs, antacid drugs, digestive drugs, antipyretic analgesic and anti-inflammatory drugs, hypnotic sedatives, sleepiness prevention drugs, vertigo drugs, pediatric analgesics, cardiac stimulants, arrhythmia drugs, antihypertensive drugs, vasodilators, diuretics, antiulcer drugs, intestinal regulators, osteoporosis drugs, antitussives and expectorants, antiasthmatic drugs, antibacterial agents, agents for improving frequent urination, tonics, vitamins, and other orally administered drugs.
• the pharmaceutical active ingredient contained in the pharmaceutical composition of this embodiment is preferably a secondary amine, a tertiary amine, or a quaternary amine that is prone to generating nitrosamines.
• pharmaceutical active ingredients in which the content of NDMA (N-nitrosodimethylamine) or NDEA (N-nitrosodiethylamine) is problematic are preferred.
• Such pharmaceutical active ingredients include sartan compounds (e.g., valsartan, irbesartan, olmesartan, losartan, etc.), compounds having a dimethylaminomethyl group (e.g., ranitidine, nizatidine, d-chlorpheniramine maleate (MCPA), etc.), and biguanide compounds (e.g., metformin, buformin, etc.).
• sartan compounds e.g., valsartan, irbesartan, olmesartan, losartan, etc.
• compounds having a dimethylaminomethyl group e.g., ranitidine, nizatidine, d-chlorpheniramine maleate (MCPA), etc.
• biguanide compounds e.g., metformin, buformin, etc.
• the pharmaceutical composition of the present embodiment contains, as a medicament active ingredient, a secondary amine, a tertiary amine, or a quaternary amine, Sitagliptin, rifampicin, gliclazide, sitagliptin, orphenadrine, alpraziquantel, ropivacaine, ambroxol, quetiapine, atomoxetine, atenolol, azithromycin, betahistine, benazepril, bisoprolol, bumetanide, bupropion, cilazapril, ciprofloxacin, dabigatran, desloratadine, trimebutine, azithromycin, chloropyramine, Triprolidine, diclofenac, duloxetine, enalapril, fluoxetine, hydrochlorothiazide, ketamine, labetalol, landiolol, levofloxacin, lisinopril, mefenamic acid
• the shape 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 they use a large amount of cellulose powder per product.
• 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 known methods such as mixing, stirring, granulating, sizing, and tableting.
• the pharmaceutical composition of this embodiment may contain, in addition to the pharmaceutical active ingredient and the cellulose powder of this embodiment, excipients, disintegrants, binders, flow agents, lubricants, flavorings, fragrances, colorants, and sweeteners, as necessary.
• 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, ethylcellulose, ethylene-vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrated silicon dioxide, dried yeast, dried aluminum hydroxide gel, dried sodium sulfate, dried sulfuric acid.
• Disintegrants include, for example, celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose; starches such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, and partially pregelatinized starch; and synthetic polymers such as crospovidone and crospovidone copolymer, which are classified as disintegrants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These disintegrants may be used alone or in combination of two or more types.
• Binders include, for example, 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; 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
• the fluidizing agent may be, for example, 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 two or more types may be used in combination.
• Lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, talc, and the like, which are classified as lubricants in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These lubricants may be used alone or in combination of two or more types.
• Flavoring agents include, for example, glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, and the like, which are classified as flavoring agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These flavoring agents may be used alone or in combination of two or more types.
• Flavors include, for example, oils such as orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, and peppermint oil, and green tea powder, which are classified as flavorings and fragrances in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These flavorings and fragrances may be used alone or in combination of two or more types.
• Coloring agents include, for example, food dyes such as Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, etc.; and those classified as coloring agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.), such as sodium copper chlorophyll, titanium oxide, and riboflavin. These coloring agents may be used alone or in combination of two or more types.
• Sweetening agents include, for example, aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and powdered amacha tea, which are classified as sweetening agents in the "Dictionary of Pharmaceutical Additives" (published by Yakuji Nipposha Co., Ltd.). These sweetening agents may be used alone or in combination of two or more types.
• 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 medicament active ingredient as raw materials.
• the raw material cellulose powder of this embodiment 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 production (for example, air 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).
• 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 production.
• the pharmaceutical composition of this embodiment it is preferable to store raw materials other than the cellulose powder 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 production.
• the steps 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, 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).
• 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, 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.
• the pharmaceutical composition in order to produce a pharmaceutical composition that generates a small amount of nitrosamines, the pharmaceutical composition can be produced by a conventional method, except that the cellulose powder of this embodiment is used as the raw cellulose powder.
• the pharmaceutical composition when the pharmaceutical composition is a tablet, the pharmaceutical composition may be produced by preparing a mixture containing cellulose powder and a pharmaceutical active ingredient and directly compressing the mixture (direct tableting method), or by granulating the mixture and then compressing it (granule compression method).
• a post-pulverization method (a method in which a pharmaceutical active ingredient, cellulose powder, and other additives as necessary are mixed, granulated to form granules, and then cellulose powder and other additives as necessary are mixed, and compressed by a conventional method), a method for producing a multi-core tablet with a previously compressed tablet as the inner core, a method for producing a multi-layer tablet in which multiple previously compressed molded bodies are stacked and compressed again, etc. may also be used.
• the method of tableting is not particularly limited as long as it is a commonly used method, but examples include a method of compressing and molding into the desired shape using a mortar and pestle, and a method of compressing and molding into a sheet shape first and then cutting into the desired shape.
• compression molding machines include roller presses such as static pressure presses, briquetting roller presses, and smooth roller presses; single punch tableting machines, rotary tableting machines, etc.
• examples of the granulation method include dry granulation, wet granulation, heat granulation, spray granulation, microencapsulation, etc.
• wet granulation methods are effective: 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 type, hot air is directly brought into contact with the material, and the evaporated water is removed at the same time.
• the sulfur content of the cellulose powder was measured by analyzing with an ion chromatography method using an automatic combustion method. Specifically, about 50 mg of the sample was placed on a quartz board and burned in a combustion furnace at 1000°C, and the gasified components were bubbled into the absorbing liquid. The resulting absorbing liquid was analyzed using a CT device (model: INTEGRATION, manufactured by Thermo Fisher Scientific) to quantify sulfur. The detection limit was 0.1 ppm.
• 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 collected and analyzed by the oxygen electrode method to quantify 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 device and analyzed. The detection limit was 0.1 ppm.
• the iron content of the cellulose powder was measured by inductively coupled plasma mass spectrometry (ICP-MS).
• the measurement samples were pretreated by a closed system acid decomposition method. After the sample was collected and sulfuric acid was added, the sample was subjected to thermal decomposition treatment using a microwave sample decomposition device (product name: ETHOS UP, manufactured by Milestone Corporation). Then, the sample was filled up to a constant volume with ultrapure water and used as the sample for analysis.
• the prepared analytical sample was analyzed using an inductively coupled plasma mass spectrometer (model: iCAP RQ, manufactured by Thermo Fisher Scientific) to measure 56 Fe. The detection limit was 0.1 ppm.
• the ammonia content of the cellulose powder was measured by ion chromatography in accordance with JIS K0127. First, 3 g of a sample (crystalline cellulose powder) was weighed into a 100 mL glass beaker, 60 mL of pure water was added, and the mixture was stirred for 20 minutes at a constant stirring force. After stirring, the mixture was filtered using a quantitative filter paper (5C, Advantec). The collected filtrate was used as an analytical sample. The prepared analytical sample was analyzed using an ion chromatograph (model: INTEGRATION, 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 electric conductivity detector. The detection limit was 0.1 ppm.
• Example 1 Six types of cellulose powder were used to prepare tablets containing active ingredients that may generate nitrosamines, and the amount of nitrosamine generated was compared.
• Cellulose powders (A-F) were prepared from the raw pulp (A-F). From the start to the end of the production of cellulose powder from the raw pulp, this 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.
• 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.
• a cellulose dispersion was prepared while stirring (stirring speed 500 rpm) with a Three-One Motor (HEIDON, Type BLh1200, 8 M/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-C, E, and F.
• cellulose dispersion was prepared while stirring (stirring speed 500 rpm) with a three-one motor (HEIDON, type BLh1200, 8 M/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 powder D.
• the weight-average particle size ( ⁇ m), apparent specific volume (cm 3 /g), apparent tapping density (g/cm 3 ), angle of repose (°), nitrite ion concentration, nitrate ion concentration, hydrogen peroxide concentration, sulfur concentration, iron concentration, and ammonia concentration were measured for the prepared cellulose powders A to F and the commercially available cellulose powders G to J.
• 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.
• NDMA nitrosamine
• NDEA gas chromatography-mass spectrometry
• the prepared sample solution was analyzed using a GC-MS/MS device (Shimadzu Corporation) to quantitatively measure the nitrosamines in the sample solution.
• the GC-MS/MS device 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 ⁇ g/g.
• Cellulose Powder D had a higher apparent specific volume and apparent tapping density than the other cellulose powders, but a higher amount of nitrosamine generated than Cellulose Powder A or B. From this point of view, it was considered that the difference in powder physical properties does not cause a difference in the amount of nitrosamine generated.
• the NDMA concentration in the tablets 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.
• 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.
• 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, and then pure water was added and stirred to prepare a cellulose dispersion.
• the obtained cellulose dispersion was spray-dried with gases having different nitrite ion concentrations, and the nitrite ion concentrations and nitrate ion concentrations of the obtained cellulose powder were examined.
• the chemical filter was able to reduce both the nitrite ion concentration and the nitrate ion concentration in the spray-drying gas to 0.020 ppm or less. Furthermore, the resulting cellulose powder spray-dried with a filter had significantly lower concentrations of both nitrite ion and nitrate ion than the powder spray-dried 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 nitrogen dioxide concentration in the spray-drying gas can be controlled by using a chemical filter, even in air with a high nitrogen dioxide concentration.
• both the nitrite ion concentration and the nitrate ion concentration of 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 the nitrite ion and the nitrate ion than that obtained by spray-drying without a filter.
• the cellulose powder of this embodiment has a reduced content of components that affect the generation of nitrosamines, making it extremely useful as a raw material for pharmaceuticals that require a high level of safety.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Polymers & Plastics (AREA)
• Inorganic Chemistry (AREA)
• Materials Engineering (AREA)
• Biochemistry (AREA)
• Engineering & Computer Science (AREA)
• Medicinal Preparation (AREA)
• Polysaccharides And Polysaccharide Derivatives (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=94923889

Family Applications (1)

Country Status (3)

Citations (4)

• 2024
  • 2024-09-06 JP JP2025544609A patent/JPWO2025053269A1/ja active Pending
  • 2024-09-06 CN CN202480040627.1A patent/CN121335931A/zh active Pending
  • 2024-09-06 WO PCT/JP2024/032087 patent/WO2025053269A1/ja active Pending

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events