WO2019130701A1 - Poudre de cellulose - Google Patents

Poudre de cellulose Download PDF

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Publication number
WO2019130701A1
WO2019130701A1 PCT/JP2018/036319 JP2018036319W WO2019130701A1 WO 2019130701 A1 WO2019130701 A1 WO 2019130701A1 JP 2018036319 W JP2018036319 W JP 2018036319W WO 2019130701 A1 WO2019130701 A1 WO 2019130701A1
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Prior art keywords
cellulose
powder
mass
cellulose powder
acid
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PCT/JP2018/036319
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English (en)
Japanese (ja)
Inventor
将造 金山
浩一郎 江夏
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旭化成株式会社
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Publication of WO2019130701A1 publication Critical patent/WO2019130701A1/fr

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    • 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
    • C08B1/00—Preparatory treatment of cellulose for making derivatives thereof, e.g. pre-treatment, pre-soaking, activation
    • 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 useful as a tablet additive which contributes to the prevention of segregation of active ingredients used in the fields of medicine, health food and the like, and which is excellent in balance between hardness and disintegration.
  • a cellulose powder useful as a tablet additive which contributes to the prevention of segregation of active ingredients used in the fields of medicine, health food and the like, and which is excellent in balance between hardness and disintegration.
  • compositions in which an active ingredient and other additives are mixed.
  • active ingredients used in the pharmaceutical and health food fields have low moldability, so when making compositions such as tablets, granules, and fine granules, an excipient is used as another additive. It is common to use. Among them, crystalline cellulose is widely used as an excipient for tablets because it simultaneously has high moldability and quick disintegration.
  • uniformity of the content of the active ingredient is required.
  • the content of the active ingredient is 20% by mass or less, it is more strongly required to make the content of the active ingredient uniform in the tablet in order to exert the drug effect accurately.
  • a wet tableting method or a wet tableting method is mainly used.
  • the active ingredient and other additives are mixed, then granulated with water and the like together with the binder to form granules, and further a lubricant and the like are added and mixed to make tablets by tableting It is a method.
  • the wet tableting and powdering method is a method of adding crystalline cellulose, a disintegrant and the like to the above granules and mixing, further adding a lubricant and the like, and mixing to make a tablet.
  • the wet tableting after-powder method it is desirable that the granules containing the active ingredient and other additives such as crystalline cellulose and a disintegrant do not separate and segregate in the process through which they are mixed or made into tablets.
  • a direct tableting method is widely used, in which an active ingredient and other additives are mixed, a lubricant and the like are further added and mixed, and tableted.
  • the direct tableting method has no process for processing the active ingredient into granules etc. and is directly affected by the physical properties of the active ingredient, so the content uniformity is generally better than the wet tableting method and the wet tableting after-end method Is difficult to secure. Then, in order to make the influence of the physical property of an active ingredient small, crushing an active ingredient and controlling particle size small is performed.
  • Patent Document 1 a cellulose powder having a specific particle structure by controlling an average particle diameter, a repose angle, a bulk density, a tapping bulk density, a specific surface area, and an internal friction angle segregates active components and other additives. It is described that it is hard to occur. Further, in the example of Patent Document 1, the effect of preventing segregation is verified using acetaminophen.
  • Patent Document 2 describes that powdered cellulose having improved powder flowability while maintaining strength is used in the field of pharmaceuticals and the like by appropriately controlling the acid concentration by an acid hydrolysis method. ing. It is also described that the strength (average particle size) of cellulose powder and powder flowability are contradictory.
  • Patent Document 3 in the conventional powder mixing method, when the concentration of drug is low, the mixing speed of the drug and the additive tends to be low, and the content uniformity of the drug tends to be difficult to improve. There is a description of. In the document, before mixing the drug and the additive, the mixing speed of the drug is increased by mixing the drug and the flow modifier in advance and then further mixing the mixed powder with the other additives. , To improve the content uniformity of the drug is described.
  • Patent Document 4 discloses a cellulose powder blended in tableting, which has an average particle size of more than 30 ⁇ m and 250 ⁇ m or less and an apparent specific volume and an intraparticle pore volume within a specific range. Have been described.
  • the cellulose powder is excellent in compression moldability, and at the time of granulating traditional Chinese medicines, sticky components and the like, these sticky components are uniformly held, and the particle size distribution of the cellulose powder is sharp. It is described that not only the particle size distribution of the granules can be sharpened, and also the disintegration time can be shortened, but also that the disintegration can be stabilized over time.
  • Patent No. 5439366 gazette JP, 2013-189572, A Patent No. 4925526 Patent No. 6104905
  • the inventors of the present invention have conducted intensive studies, and by blending a cellulose powder having a specific particle size distribution, segregation can be suppressed even for active components which are particularly difficult to prevent segregation.
  • the inventors have found that a tablet excellent in the balance between hardness and disintegration can be obtained, and reached the present invention. That is, the present invention is as follows.
  • [4] The cellulose powder according to any one of [1] to [3], which has a repose angle of 45 to 58 °.
  • [5] A molded article comprising the cellulose powder according to any one of [1] to [4].
  • [6] A method for producing a tablet, comprising tableting a composition comprising the cellulose powder according to any one of [1] to [4] and an active ingredient.
  • the cellulose powder of the present embodiment is extremely excellent in the prevention of separation and segregation of the active ingredient in a composition containing the active ingredient in the pharmaceutical, health food, food and industrial fields. Therefore, by using the cellulose powder of the present embodiment as an antisegregation agent in the production of a composition containing an active ingredient, the content uniformity of the active ingredient which is difficult to be uniformly dispersed is improved, and further, the transportation step after mixing. It becomes possible to make it difficult to cause segregation of the active ingredient and other additives even if it receives gravity or vibration in the charging step, the filling step and the like. Furthermore, by using the cellulose powder, the compression moldability of the composition containing the active ingredient is also significantly improved, and a tablet having excellent disintegration can be provided from the composition.
  • the present embodiment modes for carrying out the present invention (hereinafter, simply referred to as "the present embodiment") will be described in detail.
  • the present invention is not limited to the following embodiments, and can be variously modified and implemented within the scope of the invention.
  • Cellulose powder is generally referred to as crystalline cellulose, powdered cellulose and the like, and is suitably used as a pharmaceutical additive or food additive.
  • Preferred as the cellulose powder is crystalline cellulose.
  • Crystalline cellulose is at least one that conforms to the confirmation test of microcrystalline cellulose described in Food Additives Standard 8th Edition, and more preferably, the confirmation test of crystalline cellulose described in Japanese Pharmacopoeia 17th Revision. It fits.
  • the cellulose powder of this embodiment is a type I crystal.
  • the crystalline form of cellulose is known as type I, type II, type III, type IV, etc.
  • type I has the same crystal structure as natural cellulose such as ramie, cotton linter, wood pulp etc. Using it alone does not require any special treatment and is excellent in terms of cost / environmental impact.
  • the cellulose powder of the present embodiment has an average particle size of 45 ⁇ m or less.
  • the average particle size is 45 ⁇ m or less, it is likely to be uniformly mixed with an active ingredient such as a drug.
  • it is 40 micrometers or less. More preferably, it is 30 ⁇ m or less.
  • the lower limit is not particularly limited, but is preferably at least about 5 ⁇ m in view of handleability.
  • the ratio of particles to the total amount of the powder, which passes through the 45 ⁇ m sieve and remains on the 20 ⁇ m sieve exceeds 40% by mass.
  • the proportion of particles having a size in this range exceeds 40% by mass, the cellulose powder intrudes between active ingredients such as drugs and is less likely to cause segregation.
  • the ratio of particles to the total amount of particles remaining on the 20 ⁇ m sieve after passing through the 45 ⁇ m sieve of the cellulose powder of the present embodiment is preferably 50% by mass or more, particularly preferably 60% by mass or more.
  • the proportion of the particles is preferably as high as possible in principle, but 100% by mass or less, 95% by mass or less, or 90% by mass or less is a practical range.
  • the ratio of particles to the total amount of powder passing through the 45 ⁇ m sieve and remaining on the 32 ⁇ m sieve exceeds 6% by mass.
  • the proportion of particles of the cellulose powder of the present embodiment which pass through the 45 ⁇ m sieve and remain on the 32 ⁇ m sieve is preferably 10% by mass or more, more preferably 15% by mass or more, particularly preferably It is 20 mass% or more.
  • the proportion of the particles is preferably basically as high as possible, but 100% by mass or less, 90% by mass or less, or 80% by mass or less is a practical range.
  • the cellulose powder of the present embodiment preferably has a repose angle of 45 to 58 °. If the angle of repose is 58 ° or less, the flowability of the cellulose powder itself is good and segregation is difficult to occur, which is preferable.
  • the angle of repose is an index of fluidity generally used in the field of powder, and the lower the angle of repose, the better the fluidity. The lower the angle of repose of the cellulose powder, the better for uniform mixing with the active ingredient. However, if the flowability of the cellulose powder itself becomes too good, the active component supported on the cellulose powder may be separated during mixing, causing segregation, or only the cellulose powder may flow into the mold, resulting in uniform content. May be difficult to keep. Therefore, from the viewpoint of balance between fluidity and segregation prevention, the repose angle of the cellulose powder of the present embodiment is preferably 45 to 58 ° or more, more preferably 47 to 55 °, and particularly preferably 49 to 53 °.
  • the cellulose powder of the present embodiment preferably has an aspect ratio of 1.2 to 2.3 of particles which pass through a 45 ⁇ m sieve and remain on the 32 ⁇ m sieve.
  • the aspect ratio of the particles is in this range, the mixing property with the active ingredient is also good, the entanglement of the long and narrow particles is appropriate, and the balance between the formability and the disintegrability is excellent.
  • the active ingredient currently carry
  • the aspect ratio of particles passing through a 45 ⁇ m sieve and remaining on a 32 ⁇ m sieve is preferably 1.2 to 2.1, more preferably 1.2 to 1 .9, particularly preferably 1.2 to 1.8.
  • the degree of compression of the cellulose powder of the present embodiment is preferably 32 to 45%. When the degree of compression is in the above range, the flowability of the cellulose powder itself is good, which is preferable from the viewpoint of preventing segregation.
  • the degree of compression of the cellulose powder of the present embodiment is preferably 32 to 43%, and particularly preferably 36 to 42%.
  • the degree of compression is an index that represents the flowability of the powder, and is used as a numerical value that can predict the air transport of the powder and the discharge failure from the hopper.
  • the sharpness of the cellulose powder of the present embodiment is preferably 1.5 to 2.1. When the sharpness is in the above range, the segregation prevention is more excellent.
  • the sharpness of the cellulose powder of the present embodiment is particularly preferably 1.5 to 1.7.
  • sharpness is an index showing fluidity, and the particle size distribution width of powder is quantified. The closer the powder sharpness to 1, the sharper the particle size distribution and the higher the flowability. Therefore, it is preferable that the sharpness of the cellulose powder of the present embodiment be in the above-mentioned range from the viewpoint of balance between flowability and segregation prevention.
  • the pore volume of the cellulose powder of the present embodiment is preferably 1.0 mL / g or more. When the pore volume is 1.0 mL / g or more, the moldability is more excellent.
  • the pore volume of the cellulose powder of the present embodiment is preferably 1.3 mL / g or more, and particularly preferably 1.5 mL / g or more.
  • the upper limit of the pore volume is not particularly limited because it does not affect segregation, hardness, and collapse even if the pore volume is increased, the practical range is 2.7 mL / g or less.
  • a pore volume is an index showing the porous body on the surface of cellulose powder.
  • the pore volume is 1.0 mL / g or more, active ingredients such as drugs are trapped on the surface of the cellulose powder, so it is difficult to separate at the time of flow, and plastic deformation of the cellulose powder works at the time of tableting compression. Hardness becomes higher.
  • water is water-introduced from the contact part of cellulose powder. For this reason, by using a cellulose powder having a pore volume in the above-mentioned range, a tablet having a high hardness and a fast disintegration can be obtained, and a well-balanced tablet can be obtained.
  • the physical-property value of the cellulose powder mentioned above is a value measured by the method described in the Example mentioned later.
  • the method for producing the cellulose powder of the present embodiment will be described below.
  • the cellulose powder of the present embodiment can be obtained, for example, by dispersing a hydrolyzed natural cellulose-based material in a suitable medium to obtain a cellulose dispersion, and drying the dispersion.
  • the solid content concentration of the cellulose dispersion is not particularly limited, and can be, for example, 1 to 10% by mass. In this case, it is possible to isolate the solid content containing the hydrolyzed cellulose-based material from the hydrolysis reaction solution obtained by the hydrolysis treatment, and dry separately the dispersion prepared by dispersing this separately in an appropriate medium. Good. When the cellulose dispersion is formed in the same state of the hydrolyzed solution, this dispersion can be directly dried.
  • the natural cellulose-based material may be vegetable or animal, and is, for example, a fibrous material derived from a natural product containing cellulose such as wood, bamboo, cotton, ramie, bagasse, kenaf, bacterial cellulose, etc. It preferably has a crystalline structure of the type.
  • a raw material one of the above-mentioned natural cellulose-based substances may be used, or a mixture of two or more may be used.
  • it is preferable to use it in the form of a purified pulp but there is no particular limitation on the method of purifying the pulp, and any pulp such as dissolving pulp, kraft pulp, NBKP pulp, etc. may be used.
  • water is preferable as a medium to be used in the case of dispersing the solid content containing a natural cellulose-based substance in a suitable medium, but there is no particular limitation as long as it is used industrially.
  • Organic solvents may be used. Examples of the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane and cyclohexane; acetone, ethyl methyl ketone and the like Ketones can be mentioned.
  • organic solvents are preferably used for pharmaceuticals, and examples of such organic solvents include those classified as solvents in "Pharmaceutical Additives” (issued by Pharmaceutical Jichi Nipponsha Co., Ltd.). Water or an organic solvent may be used alone, or two or more may be used in combination. After being dispersed in one medium, the medium may be removed and dispersed in a different medium. .
  • the average particle diameter of the cellulose particles (cellulose dispersed particles) in the dispersion is preferably 21 to 50 ⁇ m, more preferably 21 to 40 ⁇ m, and particularly preferably 21 to 30 ⁇ m.
  • the average particle size of the cellulose dispersed particles is within the above range, the average particle size of the cellulose particles obtained after drying can be easily controlled to 45 ⁇ m or less, and the ratio of particles in the range of 45-20 ⁇ m tends to easily exceed 40% by mass. There is. Further, also from the viewpoint of controlling the aspect ratio of particles of 45 to 32 ⁇ m in a preferable range, it is desirable to control the average particle diameter of the cellulose dispersed particles in the above-mentioned range.
  • the average particle size of the cellulose dispersed particles can be controlled to a desired range by adjusting the degree of polymerization of the raw material cellulose by hydrolysis and the stirring power in the hydrolysis and / or dispersion step of the cellulose.
  • the degree of polymerization of cellulose decreases, and the average particle size of cellulose in the dispersion tends to be reduced.
  • the average particle size of the particles tends to be smaller.
  • the concentration of the acid when hydrolyzing the natural cellulose-based material is preferably 0.1 to 1.0% by mass.
  • the average particle size of the cellulose dispersed particles can be easily controlled to less than 45 ⁇ m.
  • the angle of repose and the aspect ratio of particles in the range of 45 to 32 ⁇ m also tend to be easily controlled in a predetermined range.
  • pulp fibers having an average width of 2 to 30 ⁇ m and an average thickness of 0.5 to 5 ⁇ m are hydrolyzed while rotating a stirrer at 110 to 140 ° C. in 0.1 to 1.0% by mass hydrochloric acid under pressure. .
  • the progress of the hydrolysis can be controlled by adjusting the motor power (P: unit W) of the stirrer and the stirring volume (L: unit L).
  • P unit W
  • L stirring volume
  • P / V represented by the following formula to a range of 0.2 to 6.0 (W / L)
  • the average particle size of cellulose particles finally obtained is 45 ⁇ m or less, 45 to 20 ⁇ m It is possible to control the proportion of particles in the range of more than 40% by mass.
  • P / V is preferably in the range of 0.2 to 6.0 (W / L), and more preferably 0.2 to 4.0 (W / L). L), more preferably 0.2 to 3.0 (W / L).
  • W / L the natural cellulose-based material
  • the average particle size of the cellulose dispersed particles tends to be 50 ⁇ m or less. Therefore, the average particle size of the dried cellulose powder Also, the proportion of particles of 45 ⁇ m or less and in the range of 45-20 ⁇ m tends to easily exceed 40% by mass.
  • the decomposition of the natural cellulose-based material does not proceed too much, the average particle diameter of the cellulose dispersed particles becomes 21 ⁇ m or more, and the aspect ratio and the angle of repose of the dried product are specified
  • the cellulose powder thus obtained tends to exhibit the effect of preventing separation and segregation.
  • any of lyophilization, spray drying, drum drying, shelf drying, flash drying and vacuum drying may be used, or one may be used alone, or two or more may be used in combination.
  • the spray method for spray drying may be any spray method such as a disk type, a pressure nozzle, a pressure two fluid nozzle, a pressure four fluid nozzle, etc. One type may be used alone, or two or more types may be used. You may use together.
  • a trace amount of water-soluble polymer and surfactant may be added for the purpose of lowering the surface tension of the dispersion, and the foaming agent is added to the dispersion for the purpose of accelerating the evaporation rate of the medium.
  • a gas may be added.
  • the disc-type rotating disk speed and the solid content concentration of the cellulose dispersion to be subjected to spray drying It is preferable to control
  • the solid content concentration of the cellulose dispersion at the time of spray drying is preferably in the range of 1 to 7% by mass. Even if the solid content concentration is less than 1% by mass, the desired physical properties can be achieved, but the productivity is poor and the conditions are not so practical.
  • the obtained cellulose powder tends to have an average particle diameter of 45 ⁇ m or less, and the pore volume is also 1.0 mL / g or more Prone.
  • the peripheral speed of the spray-dried disc is preferably 130 to 220 m / sec.
  • a cellulose dispersion containing cellulose dispersion particles having an average particle diameter of a specific size is obtained by controlling stirring conditions when preparing the cellulose dispersion, and the cellulose dispersion when drying the cellulose dispersion.
  • the average particle size, the degree of compression, the angle of repose, the pore volume, and the particle size distribution (sharpness) of the obtained cellulose powder can be controlled by adjusting the solid content concentration and the drying conditions of the above.
  • the stirring power at the time of preparing the cellulose dispersion is in a specific range, and the solid content concentration of the cellulose dispersion during spray drying and disc spray drying
  • the rotational speed conditions By setting the rotational speed conditions in a specific range, it is possible to obtain a cellulose powder having an average particle size and a particle size distribution in a specific range.
  • the degree of compression, the angle of repose, the sharpness and the pore volume can also be adjusted by controlling the stirring conditions. .
  • composition of the present embodiment By blending the cellulose powder of the present embodiment with a composition containing an active ingredient for tableting, it is possible to obtain a tablet excellent in the balance between hardness and disintegration, in which segregation of the active ingredient is suppressed.
  • a composition for tableting which contains one or more active ingredients and the cellulose powder of the present embodiment is referred to as “the composition of the present embodiment”.
  • the blending ratio of the cellulose powder of the present embodiment to the composition of the present embodiment is preferably about 0.1 to 50% by mass, more preferably 0.1 to 20% by mass, and particularly preferably 0.1 to 10% by mass .
  • the active ingredient is added to the mixed powder, the molded product, the processed product, etc., in order to exhibit the intended function or effect in the pharmaceutical field, health food, food, industrial field etc. Say what to do.
  • the active ingredient in the pharmaceutical field is a medicinal active ingredient.
  • an active ingredient contained in the composition of this embodiment is illustrated.
  • an active ingredient of a drug to be orally administered is preferable.
  • orally administered medicines include antipyretic analgesic anti-inflammatory drugs, hypnotic sedative drugs, anti-sleepiness drugs, antipruritic drugs, pediatric analgesics, antigastric drugs, antacids, digestive medicines, inotropic drugs, antiarrhythmic drugs, antihypertensive drugs, Vasodilators, diuretics, anti-ulcers, anti-aging agents, osteoporosis treatment, antitussives, anti-asthmatics, anti-bacterial agents, frequent urination agents, nourishing agents, vitamins, etc. may be mentioned.
  • the medicinal ingredients may be used alone or in combination of two or more.
  • aspirin for example, aspirin, aspirin aluminum, acetaminophen, etendamide, sazapyrin, salicylamide, lactylphenetidine, isothibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, dipheterol hydrochloride, triprolysine hydrochloride, triperenamine hydrochloride, tondilamine hydrochloride , Phenethazine hydrochloride, methodzirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocorate, mebuhydrolin napadisylate, promethazine methylene disalicylic acid salt, carbinoxamine maleate, chlorphenirin maleate, d -Chlorpheniramine maleate,
  • the pharmaceutical active ingredients described in the United States Pharmacopoeia (USP), the National Pharmaceutical Collection (NF), and the European Pharmacopoeia (EP) can be mentioned.
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • the active ingredient for health foods is not limited as long as it is a component to be formulated for the purpose of health enhancement, but for example, green juice powder, aglycone, agaricus, ashwagandha, astaxanthin, acerola, amino acids (valine, leucine, isoleucine, Lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid, seaweed powder, glutamine, glutamic acid, glycine, proline, serine etc.), alginic acid, ginseng leaf extract, sardine peptide, turmeric, uron Acid, Echinacea, Eleuthero, Oligosaccharides, Oleic Acid, Nucleoprotein, Bonito Scipeptide, Catechins, Potassium, Calcium, Carotenoids, Garcinia, L-Carnitine, Chitosan, Conju
  • the active ingredient may be poorly soluble as well as water soluble.
  • the “poorly soluble” indicates that, in the 17th revised Japanese Pharmacopoeia, the amount of water necessary to dissolve 1 g of solute is required to be 30 mL or more.
  • the poorly water-soluble solid active ingredients include acetaminophen, ibuprofen, benzoic acid, ethensamide, caffeine, camphor, quinine, calcium gluconate, dimethyl caprole, sulfamine, theophylline, theopromine, riboflavin, mephenesin, pheno Antipyretic analgesics such as barbital, aminophylline, thioacetazone, quercetin, rutin, salicylic acid, theophylline sodium salt, pirapital, quinine hydrochloride, irgapirin, dikitoxin, griseofulvin, phenacetin, etc.
  • Japanese Pharmacopoeia Japanese Pharmacopoeia
  • external group such as other fat-soluble vitamins , "USP”, “NF”, and “EP”, and the like.
  • One type selected from the above may be used alone, or two or more types may be used in combination. If it is poorly soluble in water, the effects of the present invention can be obtained by incorporating it as an active ingredient into the composition of the present embodiment regardless of the degree of sublimation and surface polarity.
  • the active ingredient may be a poorly water-soluble oil or liquid.
  • poorly water-soluble oily or liquid active ingredients in active ingredients include teprenone, indomethacin farnesyl, menatetrenone, phytonadione, vitamin A oil, phenipentol, vitamin D, vitamins such as vitamin E, DHA (docosahexaenoic acid) "EPA” (eicosapentaenoic acid), higher unsaturated fatty acids such as liver oil, coenzyme Qs, oil-soluble flavoring agents such as orange oil, lemon oil, peppermint oil etc., "Japanese Pharmacopoeia", "outside group", The pharmaceutical active ingredients described in “USP", “NF”, and “EP” can be mentioned.
  • Vitamin E includes various homologues and derivatives, but is not particularly limited as long as it is liquid at normal temperature.
  • dl- ⁇ -tocopherol, dl- ⁇ -tocopherol acetate, d- ⁇ -tocopherol, d- ⁇ -tocopherol acetate and the like can be mentioned.
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • the active ingredient may be a poorly water-soluble semi-solid active ingredient.
  • poorly water-soluble semi-solid substances in the active ingredient include earthworm, licorice, cauliflower, peony, bokinpi, kanokosou, sansho, cinnabar, chimpanzee, maow, nandizite, ohi, onji, chizinoki, shazenshi, shazenshi, stone Acupuncture needle, Seneca, Bichols, Ginseng, Ginseng, Gaunchian, Gau, Javelin, Ginseng, Ginseng, Ginseng, Ginseng, Ginseng, Ginseng, Ginseng, Ginseng, Ginseng, Ginseng, Ginseng, Chiksetsu ginseng, Carrot, Shikonyu, Koshikushi-yu, Aroma Chinese medicine or herbal medicine extracts such as Sosan, Shigoshi-ji-to, Sho-shi-ko-to, Sho-seiryu
  • the active ingredient may be sublimable.
  • the sublimable active ingredients for example, "Japanese Pharmacopoeia” such as benzoic acid, ethensamide, caffeine, camphor, salicylic acid, phenacetin, ibuprofen, "external group", “USP”, “NF”, “EP”
  • the sublimable medicinal drug active ingredient etc. which are described in can be mentioned.
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • the sublimable active component referred to in the present invention is not particularly limited as long as it has sublimability, and is semisolid even if it is solid or liquid at normal temperature. Or any state.
  • the active ingredients may be incorporated into the composition of the present embodiment together with the cellulose powder of the present embodiment in a finely pulverized state.
  • the active ingredient used in the present invention has an average particle size of 1 to 40 ⁇ m or less for the purpose of improving the dispersibility of the active ingredient or improving the mixing uniformity of the active ingredient having a small amount of medicinal effect. It may be finely ground. The smaller the average particle size of the active ingredient. The effect of the cellulose powder of the present embodiment such as segregation prevention is enhanced.
  • the average particle size of the active ingredient is more preferably 1 to 20 ⁇ m, and still more preferably 1 to 10 ⁇ m.
  • Both of these active ingredients and the cellulose powder of the present embodiment have charging characteristics.
  • the charge of the cellulose powder of the present embodiment is +1 to 10 nC / g.
  • Some of the active ingredients are lowered in charge due to friction when mixed with ingredients such as excipients, etc., and some do not change from the state of standing.
  • the negatively charged active component interacts with and adsorbs to the cellulose powder, segregation hardly occurs.
  • the positively charged active ingredients do not interact with the cellulose powder and are present in each, so when flowing, the high flow excipients flow first and the poor flow active ingredients flow later So segregation is likely to occur.
  • the charge of the active component can be measured with a Faraday gauge (manufactured by Kasuga Denki). For example, about 10 g of the active ingredient can be placed in a glass container, and the amount of charge can be measured after shaking the mixture up and down 120 times by hand.
  • those having a charge amount of 0 to +5 nC / g after shaking include, for example, chlorpheniramine 1-maleate, chlorpheniramine d-maleate, aminophylline, etendamide and the like.
  • Aspirin or the like has a charge of -5 to 0 nC / g after shaking.
  • Examples of the charge amount after shaking of -5 to -20 nC / g include acetaminophen, ibuprofen and the like.
  • the cellulose powder of the present embodiment has an effect of preventing segregation widely in various active ingredients from low to high charge.
  • composition of the present embodiment may further contain other additives in addition to the above-mentioned active ingredient.
  • additives include excipients, disintegrants, binder fluidizers, lubricants, flavors and the like.
  • Excipients such as acrylic acid starch, L-aspartic acid, aminoethyl sulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, pumice grains, inositol, ethyl cellulose , Ethylene vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cocoa butter, casein, fructose, pumice grains, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate, dry magnesium sulfate, Agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, black Carmellose sodium, crospovidone, magnesium alum
  • Disintegrators include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, celluloses such as low substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato List those classified as disintegrants in “Pharmaceutical Additives” (published by Pharmaceutical Jichi Nipponsha Co., Ltd.) such as starches, starches such as partially pregelatinized starch, crospovidone, and synthetic polymers such as crospovidone copolymers. Can. One type selected from the above may be used alone, or two or more types may be used in combination.
  • Binders include sugars such as sucrose, glucose, lactose and fructose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol and sorbitol, gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind Water-soluble polysaccharides such as gum, pectin, sodium alginate and gum arabic, crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, celluloses such as methyl cellulose, starches such as pregelatinized starch and starch paste, polyvinyl pyrrolidone, carboxyvinyl polymer, “Pharmaceutical additives such as synthetic polymers such as polyvinyl alcohol, calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, inorganic compounds such as magnesium aluminum silicate It may include those classified as a binder Dian "(Yakujinipposha
  • a fluidizing agent those classified as a fluidizing agent in "Pharmaceutical additives" (published by Pharmaceutical Jichi Nipponsha Co., Ltd.) such as hydrous silicon dioxide and silicon compounds such as light anhydrous silicic acid can be mentioned. .
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • lubricants mention may be made of those classified as lubricants in "Pharmaceutical Supplements” (published by Pharmaceutical Jichi Nipponsha Co., Ltd.) such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, and talc. .
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • Flavoring agents such as glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, etc. Can be mentioned as those classified as flavoring agents).
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • oils such as orange, vanilla, strawberry, yoghurt, menthol, fennel oil, coffee oil, spruce oil, pepper oil, etc.
  • “Pharmaceutical ingredients such as green tea powder” And those classified as perfumes.
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • coloring agents food colorings such as food red No. 3 and food yellow No. 5 and food blue No. 1, coloring agents such as "drug added matters” such as sodium copper chlorofin, titanium oxide, riboflavin It can be mentioned what is classified as One type selected from the above may be used alone, or two or more types may be used in combination.
  • sweetening agents mention should be made of those classified as sweetening agents in the “Pharmaceutical Additives Dictionary” (published by Pharmaceutical Jichisha Co., Ltd.) such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, mackerel powder etc. Can.
  • One type selected from the above may be used alone, or two or more types may be used in combination.
  • a method for producing a tablet a method may be employed in which the active ingredient and the cellulose powder of the present embodiment are mixed and then compression-molded. At this time, in addition to the active ingredient, if necessary, other additives may be blended.
  • Other additives are selected from, for example, the above-mentioned components such as excipients, disintegrants, binders, fluidizers, lubricants, flavoring agents, flavors, coloring agents, sweeteners, solubilizers, etc. One or more may be mentioned.
  • the order of addition of the respective components is not particularly limited, i) a method of collectively mixing the active component and the cellulose powder of the present embodiment, and other additives as necessary, and compression molding, ii) the active component, and flow
  • the additives such as the agent and / or the lubricant may be pretreated and mixed, and the cellulose powder of the present embodiment and, if necessary, other additives may be mixed and then compression molded. I) is preferable from the easiness of operation.
  • a lubricant may be added to the mixed powder for compression molding obtained in i) and ii), followed by mixing and compression molding.
  • the method of adding each component is not particularly limited as long as it is a commonly used method, but a small suction transfer device, an air transfer device, a bucket conveyor, a pressure transfer device, a vacuum conveyor, a vibratory quantitative feeder, a spray, a funnel
  • the addition may be performed continuously or collectively.
  • a spraying method a method of spraying an active ingredient solution / dispersion liquid using a pressure nozzle, a two fluid nozzle, a four fluid nozzle, a rotary disk, an ultrasonic nozzle etc., a method of dropping an active ingredient solution / dispersion liquid from a tubular nozzle It may be either.
  • the mixing method is not particularly limited as long as it is a method that is usually performed, but a container rotary mixer such as a V-type, W-type, double cone type, container tack type mixer, or high speed stirring type, universal stirring type Stirring mixers such as ribbon type, pug type and nauta type mixers, high speed flow type mixers, drum type mixers and fluidized bed type mixers may be used. Moreover, container shaking type
  • the compression molding method of the composition is not particularly limited as long as it is a commonly used method, but a method of compression molding into a desired shape using a die and a mallet, and after compression molding into a sheet shape in advance into a desired shape It may be a method of cutting.
  • a roller press such as a static pressure press, a briquetting roller press, a smooth roller press, or a compressor such as a single punch tableting machine or a rotary tableting press can be used. .
  • the method for dissolving or dispersing the active ingredient in the medium is not particularly limited as long as it is a commonly used dissolution or dispersion method, but it is a unidirectional mixer such as portable mixer, steric mixer, side mixer, etc., multi-axial rotary, reciprocating Stirrative mixing method using stirring blades such as reversing type, vertical moving type, rotation + vertical moving type, channel type, jet type stirring and mixing method such as line mixer, gas blowing type stirring and mixing method, high shear homogenizer, high pressure
  • a mixing method using a homogenizer, an ultrasonic homogenizer or the like, or a container shaking type mixing method using a shaker may be used.
  • the solvent used in the above-mentioned production method is not particularly limited as long as it is used for pharmaceuticals, and, for example, water and / or an organic solvent may be used.
  • Alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, benzyl alcohol etc .
  • Hydrocarbons such as pentane, hexane, heptane, cyclohexane etc.
  • “Pharmaceutical addition of ketones such as acetone, ethyl methyl ketone etc. Include those classified as solvents in “Drug Encyclopedia” (published by Yakuhin Nippo). It may be used alone, or two or more may be used in combination. After dispersing in one medium, the medium may be removed and dispersed in a different medium.
  • a water-soluble polymer, a fat and oil, a surfactant or the like may be used as a solubilizing agent.
  • the water-soluble polymer, the oil and fat, and the surfactant used as the solubilizing agent those described in the "Additives for pharmaceutical additives" (published by Yakuhin Nipponsha Co., Ltd.) can be appropriately used. These may be used alone or in combination of two or more.
  • the molded body referred to in the present invention is in the form of granules, fine granules, slugs, tablets and the like, and contains the cellulose powder of the present embodiment, one or more active ingredients and optionally other additives. It is a thing.
  • a method of forming into a tablet for example, a mixture of the active ingredient and the cellulose powder of the present embodiment, or one or more active ingredients and the cellulose powder of the present embodiment, and, if necessary, other additives are mixed.
  • the direct compression method which compression-molds what was carried out as it is is mentioned.
  • a manufacturing method such as a multi-core tablet having a tablet, which has been compression-molded in advance, as an inner core, and a multi-layered tablet in which a plurality of previously compressed compacts are stacked and compressed again.
  • Direct tableting is preferred in terms of productivity and ease of process control.
  • the compressed tablets (molded bodies) may be further coated.
  • a coating agent used in this case the coating agent described in "the pharmaceutical additive encyclopedia" (Kazurichi Nippa Publishing Co., Ltd.) is mentioned, for example. These may be used alone or in combination of two or more.
  • Examples of the granulation method in the case of undergoing granulation in the production process include dry granulation, wet granulation, heating granulation, spray granulation, and microcapsulation.
  • wet granulation method specifically, fluidized bed granulation method, stirring granulation method, extrusion granulation method, crushing granulation method, rolling granulation method are effective, and in fluidized bed granulation method, fluidized bed In a granulator, the fluidized powder is granulated by spraying a binder.
  • the stirring granulation method mixing, kneading, and granulation of powders are simultaneously performed in a closed structure by rotating a stirring blade in a mixing tank while adding a binding solution.
  • the wet mass kneaded by the addition of the binding solution is granulated by forcibly pushing it out of a screen of an appropriate size by a screw method, a basket method or the like method.
  • a wet mass kneaded by the addition of a binding solution is sheared and broken with a rotary blade of a granulator, and granulated by repelling it from the screen of the outer periphery by its centrifugal force.
  • granulation is carried out by growing a spherical granule having a uniform particle diameter in a snowball-like manner, by rolling with the centrifugal force of a rotating rotor, and by using a binding solution sprayed from a spray gun at this time. .
  • Granules can be dried by hot air heating (shelf drying, vacuum drying, fluid bed drying), conductive heat transfer (flat pan, tray box, drum) or freeze drying. Can also be used.
  • hot air heating type the additive is brought into direct contact with the hot air, and at the same time the evaporated water is removed.
  • conductive heat transfer type the additive is indirectly heated through the heat transfer wall.
  • lyophilization the additive is frozen at -10 to 40 ° C and then the water is warmed by warming under high vacuum (1.3 x 10 -5 to 2.6 x 10 -4 MPa) Sublimate and remove.
  • the method of adding one or more active ingredients, the cellulose powder of the present embodiment, other additives, or granules is not particularly limited as long as it is a commonly practiced method, but a small suction transport device, an air transport device, It may be continuously added or batched in using a bucket conveyor, a pumping type transport device, a vacuum conveyor, a vibratory type quantitative feeder, a spray, a funnel or the like.
  • a small suction transport device an air transport device
  • a vacuum conveyor a vibratory type quantitative feeder
  • a spray a funnel or the like.
  • the content CV of the active ingredient is expressed by the following formula from the average value and the standard deviation of the content of the active ingredient in the composition or in the molded product.
  • the content of the active ingredient in the tablet or powder can be determined by preparing a calibration curve for each active ingredient as described later and determining it by the method of determination by absorbance method, but it is appropriate according to the circumstances of each active ingredient It is possible to select a quantitative method. For example, when the active ingredient is poorly soluble, a quantitative method using gas chromatography is appropriate, and when multiple active ingredients are contained, a quantitative method using liquid chromatography is appropriate.
  • the description of the general test method of Japanese Pharmacopoeia 17th Edition can be referred to.
  • Average particle size of cellulose dispersed particles ( ⁇ m) The sample dispersed in water was measured with a laser diffraction type particle size distribution analyzer (LA-950 V2 (trade name) manufactured by HORIBA, Ltd.) without ultrasonication and a refractive index of 1.20. The cumulative volume of 50% particles obtained by the measurement was taken as the average particle diameter ( ⁇ m) of the cellulose dispersed particles.
  • LA-950 V2 (trade name) manufactured by HORIBA, Ltd.
  • the proportion of particles remaining on a sieve with 45 ⁇ m openings was used to measure the weight of the powder remaining on a 45 ⁇ m sieve by sucking about 5.0 g of the powder for 5 minutes (more than -2.0 Pa) It was calculated by dividing by the weight of the powder.
  • the ratio of particles passing through a 45 ⁇ m sieve and remaining on the 32 ⁇ m sieve (hereinafter referred to as “particles with a 45 – 32 ⁇ m mesh”) is that the powder passing through a 45 ⁇ m sieve is 32 ⁇ m
  • the weight of the powder remaining on the sieve was calculated by dividing by the weight of the powder used for measurement.
  • particles of 32-20 ⁇ m mesh are also similar to the ratio of particles having passed a 32 ⁇ m mesh screen It was passed through a 20 ⁇ m sieve, and the weight of the powder remaining on the sieve was calculated by dividing it by the weight of the powder used before the measurement.
  • the ratio of 45-20 ⁇ m particles is the sum of 45-32 ⁇ m particles and 32-20 ⁇ m particles.
  • the cumulative mass of 50% was determined from the ratio (% by mass) of the weight of the powder remaining on each sieve to the weight of the powder used in the measurement, and this was used as the average particle size ( ⁇ m) of the powder.
  • the repose angle of the cellulose powder uses a Sugihara-type repose-angle measuring device (slit size: 10 cm wide x 50 mm high 140 mm wide and 50 mm wide with a protractor), and the cellulose powder 50 cc / min with a feeder
  • the dynamic self-fluidity at the time of dropping onto the slit at a speed of 1 was measured and determined.
  • the angle between the bottom of the device and the formed layer of cellulose powder is the repose angle. The measurement was performed 5 times, and the average value was calculated.
  • Step 1 Binarization The image taken with the microscope was taken into analysis software in monochrome, and the setting of the image scale was performed by the distance between two points method. Next, “Otsu method” was selected in the binarization processing, and the threshold was set. Since the optimal threshold value differs for each image, the threshold value was selected to match the original particle shape as much as possible while comparing with the original image.
  • Step 2 Binarized hand correction While comparing with the photographed original image, particles with overlapping particles, particles protruding from the screen, particles with unclear outlines and blurs, etc. do not obtain appropriate measurement results Deleted and excluded from the measurement target.
  • Step 3 Fill in hole In the "fill in hole” mode, select “8" in “Nearby” and execute "fill in hole”. Next, the original image was compared again with "binary image hand correction” to confirm whether correction was successful. If correction was not successful, manual correction was performed again.
  • Step 4 Image Measurement After setting the deletion pixel number to “100” and selecting “Nearby” to be “8”, “image measurement” was executed.
  • the measurement results of “long diameter” and “short diameter” are displayed on a personal computer for each measurement particle.
  • the value obtained by dividing "long diameter” by “short diameter” was taken as the aspect ratio.
  • Pore Volume of Cellulose Powder The pore volume of cellulose powder was measured using a pore distribution measuring apparatus (Autopore 9520: manufactured by Micromeritics (Shimadzu Corp.)) using a mercury intrusion method. The measurement was carried out under the conditions of an initial pressure of 20 kPa (about 3 psia, equivalent to a pore diameter of about 60 ⁇ m) by dividing about 0.12 g of cellulose powder into a 5 cc powder standard cell (4 cc stem volume). The mercury parameters were set at a mercury contact angle of 130.0 degrees and a mercury surface tension of 485.0 dynes / cm. The result is the pore volume of the whole measurement range.
  • the tableting machine is a tableting machine provided with a flat plate (with a base area of 1 cm 2 ) (with a base area of 1 cm 2 ) (using material SUK2, 3 made by Kikusui Seisakusho) and a mortar (using material SUK2, 3 made by Kikusui Seisakusho) (1325 VCW: manufactured by Aiko Engineering Co., Ltd.). Specifically, 500 mg of powder was placed in a die, compressed at 1 kN and 3 kN with a tableting machine, and held at that stress for 10 seconds to produce a tablet.
  • (10) Hardness of Tablet The hardness of the tablet produced only from cellulose powder was measured. Specifically, the hardness of a tablet prepared in (9) was measured with a hardness tester (Tablet Tester 8M: manufactured by DR. SCHLEUNIGER) 20 to 48 hours after immediately after tableting. The tablets prepared in (9) were sealed in Lamijiz so as not to absorb moisture until hardness measurement, and stored at room temperature. The average value of 5 tablets for each hitting pressure was taken as the hardness of the tablet.
  • Weight CV of tablet The weight of 10 tablets obtained by rotary compression is measured, the average weight and the standard deviation of weight are taken, and the weight variation is evaluated from the coefficient of variation (%) defined by (standard deviation / average weight) ⁇ 100. did. The smaller the coefficient of variation, the smaller the variation.
  • a calibration curve of the active ingredient is prepared.
  • the absorption spectrum of the active ingredient was measured with an absorptiometer, and a calibration curve was prepared based on the wavelength of the peak top (example: wavelength of d-chlorpheniramine maleate: 264 nm, aspirin) Wavelength: 276 nm, acetaminophen wavelength: 244 nm).
  • Friability The weight (Wa) of 30 tablets was measured, placed in a tablet friability tester (PTFR-A: manufactured by PHARMA TEST), rotated at 25 rpm for 4 minutes, and adhered to the tablets. The powder was removed, weighed again (Wb), and the friability was calculated according to the following equation.
  • Example 1 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) was shredded, placed in 30 L of 0.2 mass% aqueous hydrochloric acid solution, and stirred with a low-speed stirrer (30 LGL reactor: Ikebukuro Industries) While hydrolyzing at 140 ° C. for 120 minutes, an acid-insoluble residue was obtained.
  • P / V was 0.3 w / L, and the average particle size of the cellulose dispersed particles was 44 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • Example 2 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) was shredded, placed in 30 L of 0.3 mass% hydrochloric acid aqueous solution, and stirred with a low speed stirrer (30 LGL reactor: manufactured by Ikebukuro Industries) While hydrolyzing at 135 ° C. for 100 minutes, an acid-insoluble residue was obtained.
  • P / V was 3.0 w / L, and the average particle size of the cellulose dispersed particles was 39 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • Example 3 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) was shredded, placed in 30 L of a 1.00 mass% aqueous hydrochloric acid solution, and stirred with a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Industries) While hydrolyzing at 130 ° C. for 60 minutes, an acid-insoluble residue was obtained.
  • P / V was 1.0 w / L, and the average particle size of the cellulose dispersed particles was 32 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • Example 4 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, placed in 30 L of a 0.65% by mass aqueous hydrochloric acid solution, and stirred with a low speed stirrer (30 LGL reactor: Ikebukuro Industries) While hydrolyzing at 130 ° C. for 60 minutes, an acid-insoluble residue was obtained.
  • P / V was 1.0 w / L, and the average particle size of the cellulose dispersed particles was 44 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • the residue after neutralization is placed in a 90 L poly bucket, pure water is added, and the solid concentration is 5 mass while stirring (stirring speed 500 rpm) with a three one motor (type BL h 1200, 8 M / M, wing diameter about 10 cm: manufactured by HEIDON).
  • % Cellulose dispersion was prepared (pH 7.8, IC 35 ⁇ S / cm).
  • the cellulose dispersion is spray-dried (disk peripheral speed 170 m / sec, liquid supply rate 6 L / h, inlet temperature 180 to 220 ° C., outlet temperature 50 to 70 ° C.) to obtain cellulose powder D (loss on drying 4.0% by mass) Got).
  • the conditions at the time of production are shown in Table 1, and the physical properties of the cellulose powder D are shown in Table 2.
  • Example 5 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, placed in 30 L of a 0.65% by mass aqueous hydrochloric acid solution, and stirred with a low speed stirrer (30 LGL reactor: Ikebukuro Industries) While hydrolyzing at 130 ° C. for 60 minutes, an acid-insoluble residue was obtained.
  • the P / V was 1.0 w / L, and the average particle size of the cellulose dispersed particles was 44 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • the residue after neutralization is placed in a 90 L poly bucket, pure water is added, and the solid concentration is 5 mass while stirring (stirring speed 500 rpm) with a three one motor (type BL h 1200, 8 M / M, wing diameter about 10 cm: manufactured by HEIDON).
  • % Cellulose dispersion was prepared (pH 7.4, IC 43 ⁇ S / cm).
  • the cellulose dispersion is spray-dried (disk peripheral speed 180 m / sec, liquid supply rate 6 L / h, inlet temperature 180-220 ° C., outlet temperature 50-70 ° C.) to obtain cellulose powder E (dry weight loss 3.9% by mass) Got).
  • the conditions at the time of production are shown in Table 1, and the physical properties of the cellulose powder E are shown in Table 2.
  • Example 6 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, placed in 30 L of a 0.65% by mass aqueous hydrochloric acid solution, and stirred with a low speed stirrer (30 LGL reactor: Ikebukuro Industries) While hydrolyzing at 130 ° C. for 60 minutes, an acid-insoluble residue was obtained.
  • P / V was 1.0 w / L, and the average particle size of the cellulose dispersed particles was 43 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • the residue after neutralization is put in a 90 L poly bucket, pure water is added, and while stirring (stirring speed 500 rpm) with a three one motor (type BL h 1200, 8 M / M, wing diameter about 10 cm: manufactured by HEIDON), solid content concentration 4.
  • a 5% by mass cellulose dispersion was prepared (pH 7.3, IC 53 ⁇ S / cm).
  • the cellulose dispersion is spray-dried (disk peripheral speed 180 m / sec, liquid supply rate 6 L / h, inlet temperature 180-220 ° C., outlet temperature 50-70 ° C.) to obtain cellulose powder F (dry weight loss 3.8 mass% Got).
  • the conditions at the time of production are shown in Table 1, and the physical properties of the cellulose powder F are shown in Table 2.
  • Example 7 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, put into 30 L of 0.85 mass% hydrochloric acid aqueous solution, and stirred with a low speed stirrer (30 LGL reactor: manufactured by Ikebukuro Industries) While hydrolyzing at 110 ° C. for 160 minutes, an acid-insoluble residue was obtained.
  • P / V was 6.0 w / L, and the average particle size of the cellulose dispersed particles was 28 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • Example 8 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, put into 30 L of 0.60 mass% hydrochloric acid aqueous solution, and stirred with a low speed stirrer (30 LGL reactor: Ikebukuro Kogyo) While hydrolyzing at 130 ° C. for 40 minutes, an acid insoluble residue was obtained.
  • P / V was 7 w / L, and the average particle size of the cellulose dispersed particles was 45 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • Comparative Example 2 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, placed in 30 L of a 1.5% by mass aqueous hydrochloric acid solution, and stirred with a low-speed stirrer (30 LGL reactor: manufactured by Ikebukuro Industries) While hydrolyzing at 135 ° C. for 90 minutes, an acid-insoluble residue was obtained.
  • P / V was 7.0 w / L, and the average particle size of the cellulose dispersed particles was 4 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • Comparative Example 3 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, placed in 30 L of 0.8 mass% hydrochloric acid aqueous solution, and stirred with a low speed stirrer (30 LGL reactor: manufactured by Ikebukuro Industries) While hydrolyzing at 130 ° C. for 50 minutes, an acid insoluble residue was obtained.
  • P / V was 7.0 w / L, and the average particle size of the cellulose dispersed particles was 14 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • the residue after neutralization is placed in a 90 L poly bucket, pure water is added, and the solid concentration 8 mass while stirring (stirring speed 500 rpm) with a three one motor (type BL h 1200, 8 M / M, wing diameter about 10 cm: manufactured by HEIDON) % Cellulose dispersion was prepared (pH 7.3, IC 50 ⁇ S / cm).
  • the cellulose dispersion is spray-dried (disk peripheral speed 151 m / sec, liquid supply rate 6 L / h, inlet temperature 180-220 ° C., outlet temperature 50-70 ° C.) to obtain cellulose powder K (dry weight loss 3.8% by mass) Got).
  • the conditions at the time of production are shown in Table 1, and the physical properties of the cellulose powder K are shown in Table 2.
  • Comparative Example 4 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, placed in 30 liters of 0.39 mass% hydrochloric acid aqueous solution, and stirred with a low-speed stirrer (30 LGL reactor: Ikebukuro Industries) While hydrolyzing at 128 ° C. for 145 minutes, an acid-insoluble residue was obtained.
  • P / V was 0.2 w / L, and the average particle size of the cellulose dispersed particles was 85 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • the residue after neutralization is placed in a 90 L poly bucket, pure water is added, and the solid concentration is 18 mass while stirring (stirring speed 500 rpm) with a three one motor (type BL h 1200, 8 M / M, wing diameter about 10 cm: manufactured by HEIDON).
  • % Cellulose dispersion was prepared (pH 7.3, IC 43 ⁇ S / cm).
  • the cellulose dispersion is spray-dried (disk circumferential speed 110 m / sec, liquid supply rate 6 L / h, inlet temperature 180-220 ° C., outlet temperature 50-70 ° C.) to obtain cellulose powder L (dry weight loss 3.8 mass%) Got).
  • the conditions at the time of production are shown in Table 1, and the physical properties of the cellulose powder L are shown in Table 2.
  • Comparative Example 5 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded, put into 30 L of 0.1 mass% hydrochloric acid aqueous solution, and stirred with a low speed stirrer (30 LGL reactor: Ikebukuro Kogyo) While hydrolyzing at 135 ° C. for 120 minutes, an acid-insoluble residue was obtained.
  • P / V was 0.2 w / L, and the average particle size of the cellulose dispersed particles was 110 ⁇ m.
  • the resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • the residue after neutralization is placed in a 90 L poly bucket, pure water is added, and the solid concentration is 20 mass while stirring (stirring speed 500 rpm) with a three one motor (type BL h 1200, 8 M / M, wing diameter about 10 cm: manufactured by HEIDON) % Cellulose dispersion was prepared (pH 7.4, IC 50 ⁇ S / cm).
  • the cellulose dispersion is spray-dried (disk peripheral speed 110 m / sec, liquid supply rate 6 L / h, inlet temperature 180 to 220 ° C., outlet temperature 50 to 70 ° C.) to obtain cellulose powder M (dry weight loss 3.8 mass% Got).
  • the conditions at the time of production are shown in Table 1, and the physical properties of the cellulose powder M are shown in Table 2.
  • Comparative Example 6 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded and placed in 30 L of 0.49 mass% hydrochloric acid aqueous solution, and a low speed stirrer (30 LGL reactor manufactured by Ikebukuro Sakai Kogyo Co., Ltd.) The mixture was hydrolyzed at 121 ° C. for 60 minutes while stirring with stirring to obtain an acid-insoluble residue. P / V was 0.2 w / L, and the average particle size of the cellulose dispersed particles was 65 ⁇ m. The resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • the residue after neutralization is put in a 90 L poly bucket, pure water is added, and the solid concentration 17 mass while stirring (stirring speed 500 rpm) with a three one motor (type BL h 1200, 8 M / M, wing diameter about 10 cm: manufactured by HEIDON).
  • % Cellulose dispersion was prepared (pH 7.2, IC 46 ⁇ S / cm).
  • the cellulose dispersion is spray-dried (disk peripheral speed 120 m / sec, liquid supply rate 6 L / h, inlet temperature 180-220 ° C., outlet temperature 50-70 ° C.) to obtain cellulose powder N (dry loss 4.0% by mass) Got).
  • the conditions at the time of production are shown in Table 1, and the physical properties of cellulose powder N are shown in Table 2.
  • Comparative Example 7 2.0 kg of commercially available KP pulp (polymerization degree 840, level off polymerization degree 145) is shredded and placed in 30 L of 0.7 mass% hydrochloric acid aqueous solution, and a low speed stirrer (30 LGL reactor manufactured by Ikebukuro Sakai Kogyo Co., Ltd.) The mixture was hydrolyzed at 150 ° C. for 30 minutes with stirring to obtain an acid-insoluble residue. P / V was 0.2 w / L, and the average particle size of the cellulose dispersed particles was 53 ⁇ m. The resulting acid insoluble residue was filtered using Nutsche, and the filter residue was further washed 4 times with 70 L of pure water and neutralized with aqueous ammonia.
  • Example 9 to 16 Cellulose powders A to H alone were compressed and formed into tablets. The hardness of the obtained tablet and the result of disintegration test are shown in Table 3 (hardness is 5 tablets, disintegration test is an average value of 6 tablets).
  • the tablets of Examples 9 to 16 produced from cellulose powders A to H have higher hardness and shorter disintegration times than the tablets of Comparative Examples 8 to 14 produced from cellulose powders I to O. Was observed.
  • Examples 17 to 24 10 parts by mass each of cellulose powders A to H, 0.1 parts by mass of d-chlorpheniramine maleate (average particle diameter 12 ⁇ m, charged (after shaking 120 times) 0.5 nC / g: manufactured by Kingo Kagaku Co., Ltd.), lactose (Pharmatose 100M (trade name): manufactured by DFE pharmacist) in a 5 L scale V-type mixer (manufactured by Tokusyu Seisakusho Co., Ltd.), 89.9 parts by mass is mixed for 120 minutes, and then 1.0 part by mass of magnesium stearate % (External division) was added and mixed, and further mixed in a V-type mixer for 3 minutes. The mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of chlorpheniramine maleate was measured with an absorptiometer. It was confirmed that the content CV was 1.9%).
  • the prepared mixed powder is subjected to a tablet weight of 200 mg using a punch (material SUK2, 3 used: Kikusui Manufacturing made) with a diameter of 8 mm ⁇ . Tableting was carried out at 1200 kgf and 30 rpm for 10 minutes. About 300 tablets were sampled 10 minutes after the start of tableting. The weight CV, hardness, disintegration test, friability, content CV of chlorpheniramine maleate were evaluated for the sampled tablets. The results are shown in Table 4.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of chlorpheniramine maleate was measured with an absorptiometer. It was confirmed that the content CV was 1.9%). Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 4.
  • Examples 25 to 32 20 parts by mass each of cellulose powders A to H, 0.1 parts by mass of d-chlorpheniramine maleate (average particle diameter 12 ⁇ m, charge 0.3 nC / g), lactose (Pharmatose 100 M (trade name): manufactured by DFE) 79.9 parts by mass is put into a 5 L scale V-type mixer (manufactured by Tokusyu Seisakusho Co., Ltd.) and mixed for 120 minutes, and then 1.0% (external ratio) of magnesium stearate is added and mixed, and further V Mix for 3 minutes in a mold mixer.
  • V-type mixer manufactured by Tokusyu Seisakusho Co., Ltd.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of d-chlorpheniramine maleate was measured with an absorptiometer. It was confirmed that the content CV was 3 to 1.9%. Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 5.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of d-chlorpheniramine maleate was measured with an absorptiometer. It was confirmed that the content CV was 3 to 1.9%. Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 5.
  • the hardness of the 20% by mass tablet is higher than that of the 10% by mass cellulose tablet, and the disintegration time is It was getting longer.
  • the tablets of Examples 17 to 24 prepared from cellulose powders A to H have smaller contents CV, higher hardness and smaller friability than the tablets of Comparative Examples 15 to 21 prepared from cellulose powders I to O. And collapse time was short (Table 4).
  • the tablets of Examples 25-32 made from Cellulose Powders AH have a smaller content CV, higher hardness, and friability than the tablets of Comparative Examples 22-28 made from Cellulose Powders I-O. It was small and the disintegration time was short (Table 5).
  • Examples 33 to 40 10 parts by mass each of cellulose powders A to H, aspirin (average particle size 14 ⁇ m, charge (after shaking 120 times)-7.8 nC / g: made by Mitsui Chemicals Fine) 12 parts by mass, lactose (Pharmatose 100 M (trade name) : 78 parts by weight of DFE pharma) is put into a 5 L scale V-type mixer (made by Tokuju sakusho) and mixed for 120 minutes, and 1.0 mass% (external ratio) of magnesium stearate is added and mixed, The mixture was further mixed in a V-type mixer for 3 minutes.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of aspirin was measured with an absorbance meter, and 2% or less (1.3 to 1.9% substantial) It confirmed that it was the variation of. Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 6.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of aspirin was measured with an absorbance meter, and 2% or less (1.3 to 1.9% substantial) It confirmed that it was the variation of. Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 6.
  • the tablets of Examples 33 to 40 prepared from cellulose powders A to H were tablets of Comparative Examples 29 to 35 prepared from cellulose powders I to O even if the tablet contains aspirin as an active ingredient.
  • the content CV was smaller, the hardness was higher, the friability was smaller, and the disintegration time was shorter than the tablet.
  • Examples 41 to 48 10 parts by mass of each of cellulose powders A to H, 10 parts by mass of acetaminophen (average particle diameter 17 ⁇ m, charge (after shaking 120 times) -16.8 nC / g: Shin Nippon Pharmaceutical Co., Ltd.), lactose (Pharmatose 100 M (product Name): 80 parts by mass of DFE pharma) is put into a 5 L scale V-type mixer (made by Tokusyu Seisakusho Co., Ltd.) and mixed for 120 minutes, and 1.0 mass% (external ratio) of magnesium stearate is added and mixed And further mixed in a V-type mixer for 3 minutes.
  • V-type mixer made by Tokusyu Seisakusho Co., Ltd.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower portions of the V-type mixer, and the content of acetaminophen was measured with an absorptiometer, and 2% or less (substantially 1.3 to 1. It was confirmed that the variation was 9%. Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 7.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower portions of the V-type mixer, and the content of acetaminophen was measured with an absorptiometer, and 2% or less (substantially 1.3 to 1. It was confirmed that the variation was 9%. Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 7.
  • the content CV was smaller, the hardness was higher, the friability was smaller, and the disintegration time was shorter than the 42 tablets.
  • Example 49 10 parts by mass of cellulose powder D, 5 parts by mass of ethensamide (average particle diameter 15 ⁇ m, electrification (after shaking 120 times) + 3.9 nC / g: Yamamoto Chemical Industries Co., Ltd.), lactose (Pharmatose 100 M (trade name): DFE pharma Made in a 5L scale V-type mixer (made by Tokuju sakusho) and mixed for 120 minutes, add 1.0% by mass (external ratio) of magnesium stearate and mix, and further add V type Mix in a mixer for 3 minutes.
  • the mixed powder of nine points in total was sampled at three points each from the upper, middle and lower parts of the V-type mixer, and the content of etendamide was measured with an absorbance meter, and it was confirmed that the variation was 2% or less. Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 8.
  • Comparative Example 43 The tablet was manufactured on the same conditions as Example 49, except not having added cellulose powder D and having made lactose into 95 mass parts, and evaluation was implemented. The results are shown in Table 8.
  • Example 50 10 parts by mass of cellulose powder D, 0.3 parts by mass of ascorbic acid (average particle diameter: 10 ⁇ m, charged (after shaking 120 times)-0.5 nC / g: manufactured by northeast pharmaceutical group), lactose (Pharmatose 100 M (trade name) ): 89.7 parts by mass of DFE pharma) is placed in a 5 L scale V-type mixer (made by Tokusyu Seisakusho Co., Ltd.) and mixed for 120 minutes, and 1.0% by mass (external division) of magnesium stearate is added. Mix and further mix in a V-blender for 3 minutes.
  • Example 51 10 parts by mass of cellulose powder D, 0.3 parts by mass of sodium salicylate (average particle diameter 6 ⁇ m, charge (after shaking 120 times)-1.4 nC / g: AP corporation), lactose (Pharmatose 100 M (trade name) ): 89.7 parts by mass of DFE pharma) is placed in a 5 L scale V-type mixer (made by Tokusyu Seisakusho Co., Ltd.) and mixed for 120 minutes, and 1.0% by mass (external division) of magnesium stearate is added. Mix and further mix in a V-blender for 3 minutes.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of sodium salicylate was measured with an absorptiometer, and 2% or less (substantially 1.3 to 1.9) It confirmed that it was variation of%). Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 10.
  • Comparative Example 45 A tablet was produced under the same conditions as in Example 51 except that cellulose powder D was not added and lactose was changed to 99.7 parts by mass, and evaluation was carried out. The results are shown in Table 10.
  • Example 52 10 parts by mass of cellulose powder D, 5 parts by mass of ibuprofen (average particle diameter 15 ⁇ m, electrification (after shaking 120 times) -12.0 nC / g: Yonezawa Hama Chemical Co., Ltd.), lactose (Pharmatose 100 M (trade name) : 85 parts by mass of DFE pharma) is put into a 5 L scale V-type mixer (made by Tokuju sakusho) and mixed for 120 minutes, and 1.0 mass% (externally split) of magnesium stearate is added and mixed, The mixture was further mixed in a V-type mixer for 3 minutes.
  • Example 53 20 parts by mass of cellulose powder D, 60 parts by mass of cellulose powder PH-102 (manufactured by Asahi Kasei Co., Ltd.), levothyroxine (average particle diameter 10 ⁇ m, charged (after shaking 120 times)-1.1 nC / g: Chengdu Firster Pharmaceutical Of D-Mannitol (made by PEARLITOL 200SD ROQUETTE) and 27.9 parts by weight of croscarmellose sodium (Kikolate ND-2HS made by Asahi Kasei Co., Ltd.) at 5 L scale.
  • the mixture was placed in a V-type mixer (manufactured by Tokusyu Seisakusho Co., Ltd.) and mixed for 120 minutes, and 1.0% by mass (externally split) of magnesium stearate was added and mixed, and further mixed in a V-type mixer for 3 minutes.
  • the mixed powder of 9 points in total was sampled from each of the upper, middle and lower parts of the V-type mixer, and the content of levothyroxine was measured with an absorptiometer, and 2% or less (substantially 1.3 to 1.9) It confirmed that it was variation of%). Tableting was performed under the same conditions as in Examples 17 to 24 and evaluations were carried out. The results are shown in Table 12.
  • tablets containing cellulose powder D also have a content, compared to tablets corresponding to the respective comparative examples, in tablets containing ethensamide, ascorbic acid, sodium salicylate, ibuprofen and levothyroxine as active ingredients.
  • the CV was small, the hardness was high, the friability was small, and the disintegration time was short.
  • the cellulose powder of the present embodiment is excellent in the prevention of segregation of the active ingredient and in the balance of hardness and disintegrability, and therefore, can be suitably used in the fields of pharmaceutical preparations containing medical drugs and health foods.

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Abstract

La présente invention concerne une poudre de cellulose et analogue ayant une taille moyenne de particule de 45 µm ou moins. Plus de 40 % en masse des particules par rapport à la quantité totale de la poudre passent à travers un tamis ayant des ouvertures de 45 µm et restent sur un tamis ayant des ouvertures de 20 µm.
PCT/JP2018/036319 2017-12-26 2018-09-28 Poudre de cellulose WO2019130701A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022065361A1 (fr) * 2020-09-25 2022-03-31 日本臓器製薬株式会社 Procédé de fabrication de substances granulaires

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11152233A (ja) * 1997-11-20 1999-06-08 Asahi Chem Ind Co Ltd 結晶セルロース及びその製法
JP4721212B2 (ja) * 2001-07-05 2011-07-13 株式会社新日本科学 インスリンの経鼻投与用組成物
JP2015048315A (ja) * 2013-08-30 2015-03-16 旭化成ケミカルズ株式会社 セルロース系核粒子及びその製造方法
JP2015183021A (ja) * 2014-03-20 2015-10-22 日本製紙株式会社 粉末状セルロース

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11152233A (ja) * 1997-11-20 1999-06-08 Asahi Chem Ind Co Ltd 結晶セルロース及びその製法
JP4721212B2 (ja) * 2001-07-05 2011-07-13 株式会社新日本科学 インスリンの経鼻投与用組成物
JP2015048315A (ja) * 2013-08-30 2015-03-16 旭化成ケミカルズ株式会社 セルロース系核粒子及びその製造方法
JP2015183021A (ja) * 2014-03-20 2015-10-22 日本製紙株式会社 粉末状セルロース

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022065361A1 (fr) * 2020-09-25 2022-03-31 日本臓器製薬株式会社 Procédé de fabrication de substances granulaires

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