WO2017195796A1 - アセトアミノフェン製剤の製造方法 - Google Patents

アセトアミノフェン製剤の製造方法 Download PDF

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WO2017195796A1
WO2017195796A1 PCT/JP2017/017603 JP2017017603W WO2017195796A1 WO 2017195796 A1 WO2017195796 A1 WO 2017195796A1 JP 2017017603 W JP2017017603 W JP 2017017603W WO 2017195796 A1 WO2017195796 A1 WO 2017195796A1
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Prior art keywords
acetaminophen
production method
tablet
preparation
weight
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PCT/JP2017/017603
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English (en)
French (fr)
Japanese (ja)
Inventor
坂本　浩
邦男 駒居
賢司 榊原
宏和 番場
清 福田
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Nippon Zoki Pharmaceutical Co Ltd
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Nippon Zoki Pharmaceutical Co Ltd
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Priority to KR1020187035431A priority Critical patent/KR102408085B1/ko
Priority to US16/099,961 priority patent/US11033501B2/en
Priority to CA3023478A priority patent/CA3023478C/en
Priority to CN201780029088.1A priority patent/CN109069455B/zh
Priority to SG11201809835UA priority patent/SG11201809835UA/en
Priority to JP2017545607A priority patent/JP6310164B1/ja
Priority to EP17796157.0A priority patent/EP3456324B1/en
Publication of WO2017195796A1 publication Critical patent/WO2017195796A1/ja
Anticipated expiration legal-status Critical
Priority to US17/222,237 priority patent/US11433031B2/en
Ceased legal-status Critical Current

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    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a method for producing a preparation produced using acetaminophen having a predetermined particle size distribution described below (hereinafter sometimes referred to as “the present acetaminophen”).
  • compositions are manufactured through various preparation processes, and the most suitable manufacturing method is selected in consideration of various factors so that the functions of each preparation can be performed well. It is necessary to consider conditions.
  • the preparation method for tablets is dry direct compression, dry granulation (dry roller compactor, roll granulator, etc.), wet granulation (spray granulation, stirring granulation, Extrusion granulation method, fluidized bed granulation method, etc.).
  • the dry roller compactor method of the dry granulation method is a method in which an additive is added to a drug and compressed into a flake shape, then crushed and sized, classified, and the fine powder is recompressed and compressed into tablets. .
  • the amount of powder scattering is large at the time of pulverization and sizing, the yield is poor, and the tablet hardness tends to be low because there is a step of compression once (Japanese Patent Publication No. 2010-506540).
  • the agitation granulation method is a method in which a drug and an additive are charged in a granulation container and mixed by rotation of a stirring blade, and a binder solution is dropped or sprayed thereon to obtain an appropriate wet state. It is a method of granulating.
  • the dispersion of the binder solution tends to be heterogeneous, resulting in a partially hard granulated product, slightly more powder that remains ungranulated, and a slight difficulty in content uniformity. For this reason, since it is necessary to wet crush and size and dry, the number of processes increases, and tablet hardness tends to decrease.
  • the dry direct tableting method (also referred to as dry direct compression method) is the simplest method in which a drug and an additive are mixed in powder form and tableted.
  • the dry direct compression method includes a method in which the additive is liquefied in advance and dried for direct compression with a spray drier, etc., and the resulting powder is mixed with a drug powder and compressed into tablets.
  • a wet method is used for the treatment, and the number of steps is large.
  • the dry direct compression method does not produce granules, so it has the advantages of having the fewest number of formulation steps, reducing the production cost, and increasing the production speed, but mixing compared to dry granulation methods and wet granulation methods to produce granules Due to the low fluidity of the powder, there are disadvantages such as a large variation in mass and a problem in compression moldability. Therefore, the dry direct hitting method was widely used in Europe and the United States when the particle size of drugs and additives before the 1970s was relatively large and there were few problems of secondary aggregation. However, in recent years, since drugs in recent years have become increasingly insoluble, they are pulverized by pin mills, jet mills, etc., and secondary agglomeration is likely to occur, and there is a problem in content uniformity. No longer adopted.
  • the fluidized bed granulation method of the wet granulation method is generally used most widely (Japanese Patent Laid-Open No. 2013-216610, Japanese Patent Publication No. 2015-63521).
  • a drug and an additive are usually charged into a fluidized bed granulator and fluidized, and a binder solution or a binder solution in which a drug is dissolved or suspended is sprayed.
  • This method is excellent in content uniformity, has a high yield, and a granulated material suitable for tableting can be obtained.
  • air classification may result in impaired content uniformity, and skill in the operation technique is required. It is done.
  • Acetaminophen is an antipyretic analgesic that has been widely used since ancient times, and is a highly safe drug that is administered not only to adults but also to children.
  • acetaminophen is used as an acetaminophen for adults with a total daily dose of 4000 mg, and a dose of 300 to 1000 mg at a dosage interval of 4 to 4 times. It is supposed to be administered orally after 6 hours.
  • acetaminophen tablets include 500 mg tablets, 300 mg tablets and 200 mg tablets according to the amount of active ingredient.
  • the tablet Since the content of the drug itself is such a high dose, the tablet is relatively large, and since sustained-release tablets with long-lasting effects are not sold, it is necessary to take several times a day. Due to the current situation, doctors and patients in the medical field have a smaller tablet size for better quality of life and compliance, more preferably twice a day in the morning and evening. There is a demand for development of tablets. Moreover, since acetaminophen has a peculiar bitter taste, formulation-like devices such as masking for suppressing the bitter taste are also required.
  • acetaminophen has a very low drug price (500 mg tablet: 9.80 yen / tablet, 300 mg tablet: 8.50 yen / tablet, 200 mg tablet: 7.60 yen / tablet), and thus the production cost Therefore, the selection of the raw materials and the manufacturing method, the contrivance, etc. are considered as the issues to be studied.
  • the price of the additive to be added is often equivalent to several times that of acetaminophen, and reducing or reducing the additive is important for the problem of reducing the production cost.
  • the fluidized bed granulation method is the most widely used method for producing pharmaceutical preparations.
  • it is necessary to add a relatively large amount of additives to improve fluidity and moldability. It is difficult to reduce the size of the tablet.
  • the fluidized bed granulation method is a method in which granules are once prepared by wet granulation, and tableting is performed by adding a lubricant or the like, so that the number of steps is increased and the production cost is also increased.
  • the dry direct compression method directly compresses the mixed powder, which reduces the number of steps and leads to a reduction in manufacturing costs, but compared to the dry granulation method and wet granulation method that produce granules. Since the fluidity of the mixed powder is poor, there is a problem in mass variation and compression moldability.
  • acetaminophen is a powder with extremely strong secondary cohesion due to intermolecular force (van der Waals force), electrostatic charging, etc., extremely poor fluidity, and complicated particle shape.
  • van der Waals force intermolecular force
  • electrostatic charging etc.
  • extremely poor fluidity and complicated particle shape.
  • the dry direct hitting method to formulate fen.
  • acetaminophen crystals produced in the crystallization process in API production are difficult to control the hardness and particle size of crystals due to the size of the equipment used and the outside air conditions that change depending on the season.
  • the generated crystals need to be pulverized and made uniform.
  • acetaminophen of various hardness and particle size is uniformly pulverized with a pin mill or hammer mill
  • acetaminophen with a small particle size may be excessively pulverized. Since the surface area is large, the chargeability is enhanced, and the fluidity is further deteriorated, the adhesion to the inner surface of the apparatus is also increased, which is a major factor that the workability is deteriorated.
  • the particle shape and particle size distribution also fluctuate, and the secondary agglomeration situation also fluctuates, so the dissolution rate of the final product (tablet) may also fluctuate.
  • the present inventors examined the use of the acetaminophen drug substance in order to enable the formulation by the dry direct compression method by improving the fluidity of acetaminophen.
  • tablets obtained by compressing the crushed and sized powder by blending the additive with the acetaminophen drug substance, and powders blended with the acetaminophen drug substance with a dispersant or solubilizer We conducted extensive research on premixed drug substances that were crushed and sized.
  • acetaminophen is usually acetaminophen which does not undergo a pulverization step described later, in the present invention, “unground” acetaminophen, acetaminophen “unground product” or simply “unground” However, it is not limited to those that have not been subjected to a pulverization step.
  • Patent Document 1 The method for producing an acetaminophen preparation by a dry direct hitting method is disclosed in Patent Document 1, but using unmilled acetaminophen as in the present invention or adding an additive to acetaminophen.
  • acetaminophen is a crystal or crystalline powder, and currently three types of crystal polymorphs (types I, II, and III) have been reported.
  • the uncrushed acetaminophen used in the present invention is type II.
  • the acetaminophen used in Patent Document 1 is preferably in the form of granules, it is different from the shape of acetaminophen of the present application.
  • Patent Document 1 is described as a direct compression method, in the examples, as a pretreatment, wet cake-like microcrystalline cellulose and water are mixed, and the solid content is about 15%. After forming a slurry, colloidal silicon dioxide is mixed and spray-dried to form aggregates in which microcrystalline cellulose and silicon dioxide are closely associated with each other, and then acetaminophen and other additives are mixed. And then tableting.
  • the production method of Patent Document 1 is a direct hitting method in which the additive is preliminarily liquefied as a pretreatment and is dried for direct hitting with a spray dryer or the like.
  • the production method of the present application is the simplest direct compression method that does not require such pretreatment, and mixes and compresses the drug and additive in powder form.
  • Patent Document 2 discloses that when a drug and an additive are mixed as a pre-process in the preparation by direct tableting, the drug content in the preparation of a drug having an average particle size of 40 ⁇ m or less is particularly high. A method of mixing a drug and a flow modifier when the content is as low as 20% by weight or less is described.
  • Patent Document 3 discloses that a medicinal component-containing surface-modified powder obtained by mixing a medicinal component and a surface-modified base material to improve the surface is excellent in fluidity, and is a tablet produced by dry direct compression.
  • the present invention relates to a preparation containing a high content of acetaminophen, particularly a miniaturized tablet (ordinary tablet, slow-release tablet) obtained by a dry direct compression method having excellent dissolution properties, hardness, and drug content uniformity. It is an object of the present invention to provide a method for producing a premixed drug substance consisting of acetaminophen, a dispersing agent, and optionally a solubilizing agent with improved fluidity and increased manufacturability. . In particular, the present invention improves the chargeability and fluidity of acetaminophen, and does not require pretreatment by a wet method. It is an object of the present invention to provide a method for producing a tablet by a dry direct hitting method.
  • acetaminophen As a result of intensive research to solve the above problems, the present inventors have used unmilled acetaminophen as a drug substance when formulating acetaminophen. It has been found that the flowability and chargeability of acetaminophen can be improved by blending additives such as dispersants and crushing and sizing without using a large amount of various additives. As a result, it has become possible to formulate acetaminophen by the simplest dry direct hitting method, which has been conventionally difficult to produce acetaminophen formulations.
  • a pulverizing and sizing machine is used.
  • a pulverizing and sizing machine By selectively pulverizing and sizing crystals and agglomerates with a large particle size and uniformly dispersing and adhering additives such as a dispersant on the surface of acetaminophen particles, It has been found that low flowability is improved, and preparations such as miniaturized tablets and sustained release tablets with excellent dissolution and moldability and bitterness masking can be produced.
  • the moldability may be poor and the hardness may be insufficient, but the unmilled acetaminophen and the additive are blended.
  • a tablet having excellent hardness can be obtained by adding a small amount of water by spraying or the like and adjusting the water content of the powder before blending the water-soluble additive. .
  • a dispersant and, if desired, a solubilizer may be blended into unground acetaminophen, and pulverized and sized using a pulverizing and sizing machine. It has been found that by dispersing and adhering solubilizers, the chargeability and fluidity of acetaminophen are improved, and it can be produced as a premix drug substance with excellent manufacturability. Based on these findings, the present inventors have advanced further research and completed the present invention.
  • the present invention relates to the following (1) to (20).
  • (1) A method for producing a preparation using acetaminophen having a particle size distribution in which d10 is 5 to 300 ⁇ m and d90 is 200 to 900 ⁇ m.
  • (2) The production method according to the above (1), wherein the particle size distribution of acetaminophen is d10 of 10 to 200 ⁇ m and d90 of 250 to 800 ⁇ m.
  • the production method according to the above (1) or (2) comprising a step including a step of blending a lubricant, wherein the preparation is a tablet obtained by a dry direct compression method.
  • the method according to (3) further comprising a step of pulverizing and sizing and dispersing and adhering the additive to the surface of the acetaminophen particles once after at least one of the steps a) to c).
  • Production method (5)
  • the production method according to (3) or (4), wherein the blending ratio of acetaminophen is 75 to 95% by weight with respect to 100% by weight of the preparation.
  • (6) The production method according to any one of (3) to (5) above, wherein the dispersant is hydrous silicon dioxide or light anhydrous silicic acid.
  • the above step b) includes the step of adding water after adding b-1) an insoluble additive, and the step of adding a water-soluble additive, if necessary, b-2) 3) The production method according to any one of (11) to (11).
  • the production method according to the above (12), wherein the addition ratio of water is 0.3 to 2.5% by weight with respect to 100% by weight of the preparation.
  • the sustained-release base is one or more selected from hypromellose, carboxyvinyl polymer, and sodium carboxymethylcellulose.
  • the sustained-release base is two or more selected from hypromellose, carboxyvinyl polymer, and sodium carboxymethylcellulose.
  • the blending ratio of the sustained release base is 1 to 15% by weight with respect to 100% by weight of the preparation.
  • FIG. 1 is a graph showing the results of a dissolution test (up to 30 minutes after the start of dissolution) of the preparation (acetaminophen content 300 mg / tablet) according to the production method of the present invention shown in Example 1.
  • the present invention relates to a method for producing a preparation using acetaminophen which is not pulverized, that is, has a predetermined particle size distribution described later.
  • the preparation produced by the production method of the present invention is not particularly limited, and includes tablets, capsules, powders, granules, solutions, syrups, injections, suppositories, inhalants, premixed drug substances, and the like.
  • the preparation of the present invention is preferably a tablet and a premixed drug substance, more preferably a tablet.
  • the “tablet” means a solid preparation having a certain shape for oral administration unless otherwise specified.
  • These include ordinary tablets, orally disintegrating tablets, chewable tablets, troche tablets, Sublingual tablets, foamed tablets, dispersible tablets, dissolved tablets, and sustained-release tablets are included, with ordinary tablets and sustained-release tablets being preferred, and ordinary tablets being more preferred.
  • the tablets targeted by the present invention include single-layer tablets having a single-layer structure and multilayer tablets having a plurality of layer structures of two or more layers, preferably single-layer tablets.
  • the tablets of the present invention include uncoated uncoated tablets (bare tablets), sugar-coated tablets, gelatin-encapsulated tablets, and film-coated tablets (including enteric tablets and gastric tablets) (for uncoated tablets). These are also collectively referred to as “coated tablets”).
  • the “premix drug substance” is not limited to those mixed with the drug substance and additives and sold as a mixed raw material product for pharmaceutical production, and may be a mixture of drug substances and additives. Any are included.
  • the premix drug substance produced by the production method of the present invention contains acetaminophen at a high content rate, and is improved in fluidity and the like and has high manufacturability. Since the kind and amount of the additive can be reduced and the granulation step can be omitted, it is possible to produce a small, high-content tablet or the like and reduce the production cost. In addition, it is also possible to manufacture a formulation such as a tablet by the present manufacturing method using the present premixed drug substance.
  • the mixture is pulverized and sized using a pulverizing and sizing machine so that an additive such as a dispersant is uniformly applied to the surface of the acetaminophen particles. Disperse and adhere.
  • an additive such as a dispersant is uniformly applied to the surface of the acetaminophen particles. Disperse and adhere.
  • 0.3 to 2.5% by weight, preferably 0.8 to 2.0% by weight, relative to 100% by weight of the tablet More preferably, 1.0 to 1.8% by weight of water is added using a sprayer or the like to adjust the moisture of the powder.
  • the water content may be adjusted by using a solution in which a solubilizing agent such as liquid polysorbate is dissolved in water.
  • tablet hardness can be raised by adjusting water
  • Examples of the insoluble additive in the production method of the present invention include crystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone and the like, and examples of the water-soluble additive include trehalose, hypromellose, carboxyvinyl polymer, carboxymethylcellulose, carboxymethylethylcellulose, Examples thereof include hydroxypropylcellulose, sodium alginate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, gelatin, sodium hydrogencarbonate and the like.
  • (B) Premixed drug substance [1] A dispersant (hydrous silicon dioxide, light anhydrous silicic acid, etc.) and, if desired, a solubilizer (macrogol powder, etc.) are blended in the unground product of acetaminophen. [2] The powder of [1] is pulverized and sized using a pulverizing and sizing machine, and an additive such as a dispersant is uniformly dispersed and adhered to the surface of the acetaminophen particles. In addition, it is also possible to utilize this premix drug substance as [1] of the manufacturing process of said tablet.
  • a dispersant (hydrous silicon dioxide, light anhydrous silicic acid, etc.) and, if desired, a solubilizer (macrogol powder, etc.) are blended into the unmilled product of acetaminophen.
  • a dispersant (hydrous silicon dioxide, light anhydrous silicic acid, etc.) and, if desired, a solubilizer (macrogol powder, etc.) are blended into the unmilled product of acetaminophen.
  • the powder of [1] is pulverized and sized using a pulverizing and sizing machine, and an additive such as a dispersant is uniformly dispersed and adhered to the surface of the acetaminophen particles.
  • Insoluble additives crystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, etc.
  • Insoluble additives crystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, etc.
  • a small amount of water is added to the powder of [3] using a spray bottle and mixed.
  • a lubricant magnesium stearate, etc. is blended into the powder of [4] above and tableted.
  • A-2) Sustained release tablets [1] Acetaminophen unground product selected from dispersants (hydrous silicon dioxide, light anhydrous silicic acid, etc.), sustained release bases (hypromellose, carboxyvinyl polymer, sodium carboxymethylcellulose, etc.) At least two types) and other additives (such as crystalline cellulose). [2] The powder of [1] is pulverized and sized using a pulverizing and sizing machine, and a dispersing agent, sustained-release base and other additives are uniformly dispersed and adhered to the surface of acetaminophen particles. Let [3] A lubricant (magnesium stearate, etc.) is blended with the powder of [2].
  • the powder of [3] is pulverized and sized using a pulverizing and sizing machine, and all the additives are uniformly dispersed and adhered to the surface of the acetaminophen particles, and then tableted. .
  • acetaminophen used is an unground product.
  • acetaminophen is prepared by crushing large crystals produced in the manufacturing process or coarse particles due to secondary aggregation using a pin mill or hammer mill, etc.
  • "acetaminophen ground product” or simply “ground product” is sold.
  • acetaminophen produced by omitting the above pulverization step in the present invention, “unground acetoaminophen”, “acetaminophen unground product” or simply “unground product”
  • the unmilled product is used for formulation. Since the pulverization process is omitted for the unpulverized product, it can be purchased at a lower cost than the pulverized product, and manufacturing using this can lead to a reduction in manufacturing cost.
  • the acetaminophen unground product has a larger particle size than the acetaminophen ground product (d50 of unground product: about 120 to about 500 ⁇ m, d50 of ground product: about 20 to 60 ⁇ m), static electricity Generation is suppressed, fluidity is relatively good, and operability is high. Therefore, it has the advantage that it can be formulated even in the dry direct hitting method, which is often difficult with a pulverized product.
  • the particle size of the drug is large, as in the case of acetaminophen unground product, the total surface area of the entire drug becomes small, and the dissolution rate may decrease. This can improve the elution rate.
  • d10 is usually 5 to 300 ⁇ m, preferably 10 to 200 ⁇ m, more preferably 15 to 100 ⁇ m, and d90 is Usually, the thickness is 200 to 900 ⁇ m, preferably 250 to 800 ⁇ m, more preferably 300 to 700 ⁇ m.
  • unmilled acetaminophen usually has a particle size distribution as defined above.
  • the particle size distribution of the acetaminophen pulverized product differs depending on the drug substance manufacturer and production lot, but d10 is usually 3 to 10 ⁇ m and d90 is 100 to 250 ⁇ m, compared with the present acetaminophen.
  • the particle size is small.
  • the particle size distribution in the present invention is determined by volume distribution evaluation using a laser diffraction scattering method (Mastersizer 2000: Malvern). D10, d50, and d90 are each 10% of the cumulative volume from the smaller diameter side of the particle size distribution. , 50% and 90% particle diameter.
  • the mixing ratio of acetaminophen in the present invention is not particularly limited, but is 90 to 99.9% by weight with respect to 100% by weight of the premixed drug substance of the present invention, preferably 95 to 99. 7 to 9% by weight, more preferably 98 to 99.5% by weight, and 75 to 95% by weight, preferably 85 to 95% by weight, more preferably 100% to 100% by weight of the final preparation such as a tablet. Is 87 to 93% by weight. It is preferable to increase the amount of the drug in order to reduce the size of the tablet and improve the dosage, but the amount of the additive is limited because it is too large so that there is no inconvenience in the formulation design. is important. In the production method of the present invention, acetaminophen may be used alone, but other pharmaceutically active ingredients may be used in any combination depending on the target disease.
  • the apparatus used for crushing and sizing is not particularly limited. However, the apparatus is used to crush the particles by a rod-like rotating body (rotation speed: about 800 rpm to 3000 rpm). A granulator is suitable. For example, the charged raw material powder is crushed by being pressed against a cylindrical screen by centrifugal force with a rotating impeller (rotating blade), and sized on the impeller.
  • the screen diameter (diameter of the opening of the screen) of the pulverizing and granulating machine is preferably about 1 mm to 4 mm.
  • acetaminophen coarse crystals and lumps are selectively loosened and finely dispersed, and particles in the fine powder region are uniformly dispersed without over-pulverization, It is important to uniformly add additives such as a dispersant to the particle surface, that is, to perform pulverization and sizing.
  • additives such as a dispersant to the particle surface, that is, to perform pulverization and sizing.
  • long and narrow needle-like crystals can be dispersed more uniformly by adjusting the particle size by crushing and sizing so that the major axis / minor axis ratio is 3 or less. it can.
  • the acetaminophen unground product used in the present invention includes large crystals generated in the crystallization process in the manufacturing process, lumps due to secondary aggregation, and the like, and the particle size is more uneven than the pulverized product. Therefore, crushing and sizing treatment that can selectively fine the large particle size acetaminophen and adjust the particle size so that secondary agglomeration is not caused by further grinding the small particle size acetaminophen preferable.
  • hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium magnesium hydroxide, magnesium aluminate metasilicate, calcium hydrogen phosphate granulated product Etc. preferably hydrous silicon dioxide or light anhydrous silicic acid, more preferably hydrous silicon dioxide.
  • These dispersing agents may be used alone or in any combination of two or more.
  • the blending ratio of the dispersant in the present invention is not particularly limited, but is 0.1 to 3% by weight, preferably 0.3 to 1.5% by weight with respect to 100% by weight of the preparation.
  • a powdered solubilizer in the production method of the present invention, basically, a powdered solubilizer can be blended together with a dispersant.
  • Liquid lysosorbate 80 or the like can be dissolved in water and added simultaneously with moisture adjustment.
  • the solubilizer used in the production method of the present invention include, for example, macrogol 4000, macrogol 6000 or macrogol 20000, macrogol powder, sodium lauryl sulfate, etc. , Macrogoal 6000.
  • the liquid solubilizer include polysorbate 20, polysorbate 40, polysorbate 80, macrogol 200, macrogol 400, and the like, and polysorbate 80 is preferable.
  • solubilizers may be used alone or in any combination of two or more.
  • the blending ratio of the solubilizer in the present invention is not particularly limited, but is 0 to 0.8% by weight, preferably 0 to 0.6% by weight with respect to 100% by weight of the preparation.
  • excipients used in the production method of the present invention include sugars (lactose, glucose, fructose, sucrose, etc.), sugar alcohols (D-mannitol), crystalline cellulose, powdered cellulose, corn starch, potato starch, partially pregelatinized.
  • Starch sodium carboxymethyl starch, dextrin, ⁇ -cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, Examples thereof include magnesium aluminate metasilicate, synthetic hydrotalcite, talc, kaolin and the like, and preferred is crystalline cellulose.
  • excipients may be used alone or in any combination of two or more.
  • the blending ratio of the excipient, particularly crystalline cellulose in the present invention is not particularly limited, but is 1 to 10% by weight, preferably 2 to 8% with respect to 100% by weight of the preparation other than the premix drug substance. % By weight, more preferably 2.5 to 6% by weight.
  • Examples of the disintegrant used in the production method of the present invention include carboxymethylcelluloses (for example, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crystalline cellulose / carmellose sodium, etc.), carboxymethyl starches (for example, , Carboxymethyl starch, sodium carboxymethyl starch (sodium starch glycolate), crospovidone, low-substituted hydroxypropyl cellulose, low-substituted hydroxymethyl starch sodium, starches (partially pregelatinized starch, corn starch, potato starch, etc.) ), Alginic acid, bentonite and the like.
  • carboxymethylcelluloses for example, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crystalline / carmellose sodium, etc.
  • carboxymethyl starches for example, Carboxymethyl starch, sodium carboxymethyl starch (sodium starch glycolate), crospovidone, low-substi
  • crospovidone low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, partially pregelatinized starch, more preferably crospovid or low-substituted hydroxypropyl cellulose, particularly preferably low-substituted hydroxypropyl Cellulose.
  • These disintegrating agents may be used alone or in any combination of two or more.
  • the mixing ratio of the disintegrant in the present invention is not particularly limited, but is 0 to 10% by weight, preferably 1 to 10% by weight, based on 100% by weight of the preparation other than the premixed drug substance.
  • the amount is preferably 2 to 8% by weight, more preferably 3 to 6% by weight.
  • sustained-release base used in the production method of the present invention for example, those capable of controlling the release of a drug by forming a hydrogel upon contact with water are preferable.
  • Hydroxypropylcellulose high viscosity grade
  • methylcellulose high viscosity grade
  • hypromellose Hydropropylmethylcellulose
  • carboxymethylcellulose carboxymethylcellulose sodium
  • cellulose derivatives such as carboxymethylethylcellulose, carboxyvinyl polymer, sodium alginate and the like, preferably hypromellose, carboxymethylcellulose sodium or carboxyvinyl polymer, more preferably Hypromellose or carboxyvinyl polymer.
  • sustained-release bases may be used singly or in combination of two or more, and are preferably used so that the preparation exhibits a desired sustained-release property.
  • the compounding amount of the sustained-release base is not particularly limited, but is 0 to 15% by weight, preferably 1 to 15% by weight, based on 100% by weight of the preparation other than the premix drug substance.
  • the content is preferably 2 to 10% by weight, more preferably 3 to 8% by weight, and still more preferably 4 to 6% by weight.
  • Examples of the lubricant used in the production method of the present invention include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, polyethylene glycol, dimethylpolysiloxane, carnauba wax, lauryl sulfate. Examples thereof include sodium, beeswax, and white beeswax. Magnesium stearate is preferable. These lubricants may be used alone or in any combination of two or more.
  • the blending ratio of the lubricant in the present invention is not particularly limited, but is 0.05 to 1% by weight, preferably 0.1 to 0.5% by weight with respect to 100% by weight of the preparation. .
  • additives used for the production of general preparations can be appropriately blended depending on the purpose, as long as the purpose of the effect of the present invention is not impaired.
  • examples include binders, antioxidants, preservatives, surfactants, plasticizers, pH adjusters (such as sodium hydrogen carbonate), colorants, flavoring agents, sweeteners, foaming agents, and fragrances.
  • binder for example, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (example: POVACOAT [registered trademark: the same applies hereinafter]), hydroxypropyl cellulose (low viscosity grade), gelatin, hydroxypropyl methylcellulose, polyvinyl Examples include pyrrolidone, polyvinyl alcohol / polyethylene glycol / graft copolymer, ethyl acrylate / methyl methacrylate copolymer, and corn starch. Among these binders, those having a high molecular weight can be used as a solubilizer.
  • the pulverizing and sizing machine was Comil QC-197S (manufactured by Paulek), and the tableting machine was a rotary tableting machine VEL5 (manufactured by Kikusui Seisakusho).
  • Example 1 455.0 g of acetaminophen unground product and 2.5 g of hydrous silicon dioxide (Carplex [registered trademark: the same applies to the following]) are mixed and pulverized and uniformly dispersed with a pulverizing and sizing machine (screen diameter: 1 mm). 16.0 g of crystalline cellulose (Theolas [registered trademark: the same applies below] KG-1000) and 25.0 g of low-substituted hydroxypropylcellulose (L-HPC NBD-021) were added to the powder and mixed. About 1% by weight of water (about 5 g) with respect to the total amount of the powder was added to this and mixed.
  • magnesium stearate 1.5 g was added and tableted with a tableting machine (tablet pressure 10 kN) to obtain tablets with a hardness of 60N.
  • Tablet pressure 10 kN tablette pressure 10 kN
  • Moisture adjustment Magnesium stearate (1.5 g) 0.3% Total 500.0g, moisture 1.0%
  • Example 2 455.0 g of acetaminophen unground product and 2.5 g of hydrous silicon dioxide (Carplex [registered trademark: the same applies to the following]) are mixed and pulverized and uniformly dispersed with a pulverizing and sizing machine (screen diameter: 1 mm). 16.0 g of crystalline cellulose (Theolas [registered trademark: same as below] KG-1000) and 25.0 g of crospovidone (Ultra-10) were added to the powder and mixed. About 1% by weight of water (about 5 g) with respect to the total amount of the powder was added to this and mixed.
  • magnesium stearate 1.5 g was added and tableted with a tableting machine (tablet pressure 10 kN) to obtain tablets with a hardness of 50N.
  • Tablet pressure 10 kN tablette pressure 10 kN
  • Moisture adjustment Magnesium stearate (1.5 g) 0.3% Total 500.0g, moisture 1.0%
  • Example 3 Crystalline cellulose (Ceolus) was added to 300.0 g of acetaminophen pulverized product, 1.5 g of hydrous silicon dioxide (Carplex) and 1.5 g of Macrogol 6000 powder by pulverization and uniform dispersion using a pulverization and sizing machine. (KG-1000) 25.0 g and low-substituted hydroxypropylcellulose 15.0 g were added and mixed. To this, about 1.5% by weight of water was added to the total amount of powder using a spray, and the water content was adjusted. Then 6.5 g of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT) and D-mannitol were added.
  • POVACOAT polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer
  • Example 4 Crystalline cellulose (Ceolus KG) was added to a powder obtained by pulverizing and uniformly dispersing 300.0 g of acetaminophen unground product and 1.5 g of light anhydrous silicic acid (Aerosil [registered trademark]) in a pulverizing and sizing machine. -1000) 25.0 g was added and mixed. To this, about 1.5% by weight of water was added to the total amount of powder using a spray, and the water content was adjusted. Then, 15.0 g of D-mannitol (Partec M) was added, and pulverized sized and uniformly dispersed.
  • Example 5 300.0 g of acetaminophen unground product and 1.5 g of hydrous silicon dioxide (Carplex) were pulverized and uniformly dispersed using a pulverizer and pulverized powder, and 25.0 g of crystalline cellulose (Theolas KG-1000) was added to the powder. Added and mixed. To this, about 1.5% by weight of water was added to the total amount of powder using a mist spray to adjust the water content, and then 13.0 g of D-mannitol (Partec M) was added, and pulverized sized and uniformly dispersed.
  • Carplex hydrous silicon dioxide
  • magnesium stearate was added and tableted with a tableting machine (tablet pressure 14 kN) to obtain a tablet with a hardness of 69 N.
  • Tablet pressure 14 kN tablet pressure 14 kN
  • Tablet rate % by weight
  • Acetaminophen (300.0 g) 87.8% Hydrous silicon dioxide (1.5g) 0.4% Crystalline cellulose (25.0 g) 7.3%
  • Moisture control D-mannitol 13.0 g) 3.8%
  • Magnesium stearate 2.0 g) 0.6% Total 341.5g, moisture 1.5%
  • Example 6 Crystalline cellulose (Ceolus) was added to 300.0 g of acetaminophen pulverized product, 1.5 g of hydrous silicon dioxide (Carplex) and 1.5 g of Macrogol 6000 powder by pulverization and uniform dispersion using a pulverization and sizing machine. (KG-1000) 35.0 g was added and mixed. To this, about 1.5% by weight of water was added to the total amount of powder using a mist spray to adjust the water content, and then 30.0 g of trehalose was added, and pulverized sized and uniformly dispersed.
  • KG-1000 35.0 g was added and mixed.
  • about 1.5% by weight of water was added to the total amount of powder using a mist spray to adjust the water content, and then 30.0 g of trehalose was added, and pulverized sized and uniformly dispersed.
  • Example 7 300.0 g of acetaminophen unground product and 1.5 g of hydrous silicon dioxide (Carplex) were pulverized and uniformly dispersed with a pulverizer and pulverized powder, and 35.0 g of crystalline cellulose (Theolas KG-1000) was added. Added and mixed. To this, about 2.0% by weight of water was added to the total amount of powder using a spray, and the water content was adjusted. Then, 25.0 g of D-mannitol (Mannit P) was added, and pulverized sized and uniformly dispersed.
  • Carplex hydrous silicon dioxide
  • Example 8 A powder of 300.0 g of acetaminophen unground product and 1.6 g of hydrous silicon dioxide (Carplex) pulverized and uniformly dispersed with a pulverizing and sizing machine, and 22.0 g of crystalline cellulose (Theorus KG-1000) Substitution degree Hydroxypropylcellulose 5.0g was added and mixed. About 1.5% by weight of water was added to this and mixed with a sprayer. To this, 2.0 g of magnesium stearate was added and tableted with a tableting machine (tablet pressure 14 kN) to obtain a tablet with a hardness of 55N.
  • a tableting machine tablette pressure 14 kN
  • Example 9 To a powder in which 300.0 g of acetaminophen unground product and 1.6 g of hydrous silicon dioxide (Carplex) were pulverized and uniformly dispersed by a pulverizing and sizing machine, 22.0 g of crystalline cellulose (Theolas KG-1000) and 6.0 g of low-substituted hydroxypropylcellulose was added and mixed. To this, about 2.0% by weight of water was added to the total amount of powder using a spray, and the water content was adjusted. Then, 25.0 g of D-mannitol (Mannit P) was added, and pulverized sized and uniformly dispersed.
  • Carplex hydrous silicon dioxide
  • Example 10 450.0 g of acetaminophen unground product, 5.0 g of hydrous silicon dioxide (Carplex), 15.0 g of hypromellose (Metroise 90SH1000000 SR), 10.0 g of carboxyvinyl polymer (Carbopol 971 PNF) and crystalline cellulose (Theolas KG- 1000) 25.0 g was added and mixed, and pulverized and sized and uniformly dispersed by a pulverizing and sizing machine (screen diameter: 2 mm).
  • a pulverizing and sizing machine screen diameter: 2 mm
  • Example 11 Acetaminophen unground product 398.0g and light anhydrous silicic acid (Aerosil) 2.0g was pulverized and uniformly dispersed with a pulverizer and pulverized powder, and 50.0g of crystalline cellulose (Theorus KG-1000) was added. Added and mixed. To this, about 1.8% by weight of water was added to the total amount of powder using a spray, and the water content was adjusted. Then, 80.0 g of carboxyvinyl polymer was added and pulverized, sized and uniformly dispersed. To this, 2.5 g of magnesium stearate was added and tableted with a tableting machine (tablet pressure 14 kN) to obtain a tablet with a hardness of 71 N.
  • a tableting machine tablette pressure 14 kN
  • Example 12 300.0 g of acetaminophen unground product and 1.5 g of hydrous silicon dioxide (Carplex) were pulverized and uniformly dispersed with a pulverizing and sizing machine, and 32.0 g of crystalline cellulose (Theolas KG-1000) was added. Added and mixed. After adding water of about 1.8% by weight to the total amount of powder using a spray bottle and adjusting the water content, 25.0 g of carboxyvinyl polymer, 7.0 g of hydroxypropyl cellulose (SSL) and 15.0 g of trehalose were added. In addition, pulverized sized and uniformly dispersed.
  • Carplex hydrous silicon dioxide
  • Example 13 An acetaminophen unground product 300.0g and light anhydrous silicic acid (Aerosil) 1.5g were pulverized and uniformly dispersed with a pulverizer and granulated powder, 55.0g of carboxyvinyl polymer, crystalline cellulose (Theolas KG) -1000) 5.0 g and trehalose 5.0 g were added and crushed and sized and dispersed uniformly. To this, 8.5 g of magnesium stearate was added and tableted with a tableting machine (tablet pressure 10 kN) to obtain tablets with a hardness of 43N.
  • a tableting machine tablette pressure 10 kN
  • Example 14 A pulverized sized particle is obtained by adding 50.0 g of carboxyvinyl polymer to a powder obtained by pulverizing and uniformly dispersing 300.0 g of acetaminophen unground product and 1.5 g of light anhydrous silicic acid (Aerosil) with a pulverizing and sizing machine -Uniformly dispersed, and 7.0 g of crystalline cellulose (Theolas KG-1000) and 8.0 g of trehalose were further added and dispersed uniformly. To this was added 8.5 g of magnesium stearate and tableted with a tableting machine (tablet pressure 10 kN) to obtain a tablet with a hardness of 46N.
  • Tablet pressure 10 kN tablette pressure
  • Example 15 Add 45.0 g of carboxyvinyl polymer to the powder obtained by crushing and uniformly dispersing 300.0 g of acetaminophen unground product and 1.5 g of hydrous silicon dioxide (Carplex) with a crushing and sizing machine. -Uniformly dispersed, and further 17.0 g of crystalline cellulose (Theorus KG-1000) was added to uniformly disperse. To this was added 8.5 g of magnesium stearate and tableted with a tableting machine (tablet pressure 10 kN) to obtain a tablet with a hardness of 47N.
  • Carplex hydrous silicon dioxide
  • Example 16 A powder of 300.0 g of acetaminophen unground product and 1.5 g of hydrous silicon dioxide (Carplex) pulverized and uniformly dispersed with a pulverizing and sizing machine was added with 40.0 g of carboxyvinyl polymer and pulverized and sized. -Uniformly dispersed, and further 15.0 g of hydroxypropylcellulose (SSL) and 10.0 g of trehalose were added to uniformly disperse. To this was added 8.5 g of magnesium stearate and tableted with a tableting machine (tablet pressure 10 kN) to obtain a tablet with a hardness of 49N.
  • Carplex hydrous silicon dioxide
  • SSL hydroxypropylcellulose
  • trehalose trehalose
  • Example 17 Add 35.0 g of carboxyvinyl polymer to the powder obtained by crushing and uniformly dispersing 300.0 g of acetaminophen unground product and 1.5 g of hydrous silicon dioxide (Carplex) with a crushing and sizing machine. -Uniformly dispersed, and further dispersed by adding 15.0 g of crystalline cellulose (Theorus KG-1000) and 15.0 g of D-mannitol. To this was added 8.5 g of magnesium stearate and tableted with a tableting machine (tablet pressure 10 kN) to obtain a tablet with a hardness of 46N.
  • Carplex hydrous silicon dioxide
  • Example 19 After adding 398.0 g of acetaminophen unground product, 2.0 g of hydrous silicon dioxide (Carplex) and 2.0 g of Macrogol 6000 powder, crushing and pulverizing with a crushing and sizing machine (screen diameter: 1.99 mm) Granules and uniformly dispersed powder were obtained as a premix drug substance.
  • the angle of repose of the premixed drug substance obtained in the same manner as in Example 18 was measured and found to be 36 degrees. Moreover, the adhesion of powder to the inner surface of the apparatus could be greatly reduced, and the recovery rate was 98%.
  • Comparative Example 1 Only 300.0 g of the acetaminophen pulverized product was put into a low-tap particle size distribution measuring instrument and an attempt was made to measure it. However, the screen was immediately clogged due to electrostatic charging caused by vibration, and measurement was not possible.
  • Comparative Example 2 15.0 g of crystalline cellulose (Theolas KG-1000) was added to 300.0 g of the acetaminophen pulverized product, and a mixed powder that was uniformly dispersed by a rotary drum mixer was obtained. The angle of repose of the premixed drug substance obtained in the same manner as in Example 18 was measured and found to be 45 degrees. In addition, the powder was often attached to the inner surface of the apparatus, and the fine powder was scattered during the operation of recovering the adhesion. The recovery rate was 95%, and it was difficult to recover each time. [Ingredients in blended powder (blending amount)] [Content (% by weight)] Acetaminophen ground product (300.0 g) 95.2% Crystalline cellulose (15.0 g) 4.8%
  • Comparative Example 3 60.0 g of crystalline cellulose (UF702: Asahi Kasei Chemicals) and 8.5 g of magnesium stearate are added to a powder in which 300.0 g of acetaminophen pulverized product and 1.5 g of light anhydrous silicic acid (Aerosil) are uniformly dispersed. Although tableting was performed at a tableting pressure of 10 kN and 12 kN, the tablet hardness was low (12 N) and capping occurred, making evaluation difficult and packaging impossible.
  • a tableting pressure 10 kN and 12 kN
  • Test Example 1 Measurement of particle size distribution of acetaminophen
  • acetaminophen unpulverized products (lots A to D) and pulverized products (lot P)
  • the particle size was measured by laser diffraction particle measurement (dry measurement). Distribution measurements were taken.
  • the apparatus used was a dry automatic dispersion unit microtray (Mastersizer 2000, manufactured by Malvern), the dispersion compression air pressure was 2 Bar, and the particle size distribution analysis was performed by the volume conversion method.
  • Table 1 An example of the results is shown in Table 1. Note that the results of lots E, F, Q, and R are data of other companies implemented using different measurement devices under measurement conditions different from the main test. As shown in the results of Table 1, in the measurement of the particle size distribution, a difference may occur depending on the measurement conditions and the measurement apparatus.
  • Test Example 2 Dissolution Test About the acetaminophen tablet (acetaminophen content 300 mg / tablet) produced in Example 1 above, Japanese Pharmacopoeia (hereinafter abbreviated as “Japan Pharmacopoeia”), General Test Method, Dissolution Test Method The dissolution test was performed by a method according to the second method (paddle method). In addition, the water of the JP General Test Method / Disintegration Test Method was used as the test solution.
  • HPLC high performance liquid chromatography
  • the preparation according to the production method of the present invention exhibits excellent dissolution behavior, and the dissolution of 80% or more in 15 minutes, which is the official dissolution test standard described in the Japanese Pharmacopoeia Part 3 It showed 87.6% which met the standard of rate.
  • the fluidity of acetaminophen can be improved and the additives for formulation can be minimized.
  • This makes it possible to reduce the QOL and compliance of tablets such as acetaminophen tablets that have been downsized and improved in dosage, and acetaminophen sustained-release tablets in which the number of daily doses is reduced compared to conventional preparations. Since it can be manufactured by the simplest dry direct hitting method, the manufacturing efficiency can be improved by reducing the manufacturing time and the manufacturing cost can be reduced. Therefore, it is very useful and practical.

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JP2018177800A (ja) * 2017-04-19 2018-11-15 日本臓器製薬株式会社 プレミックス原薬の製造方法
WO2020004393A1 (ja) * 2018-06-26 2020-01-02 日本臓器製薬株式会社 粒子サイズが不揃いな原薬粒子の処理方法
JPWO2020246120A1 (OSRAM) * 2019-06-07 2020-12-10
JP2022512510A (ja) * 2018-12-18 2022-02-04 ディディピー スペシャルティ エレクトロニック マテリアルズ ユーエス，エルエルシー ヒドロキシアルキルメチルセルロースを含む徐放性組成物

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111920774B (zh) * 2020-08-06 2022-08-12 河北君临药业有限公司 一种对乙酰氨基酚片及其制备方法
CN114432256A (zh) * 2021-12-31 2022-05-06 陕西必康制药集团控股有限公司 对乙酰氨基酚包衣片及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61145111A (ja) * 1984-12-20 1986-07-02 Lion Corp アセトアミノフェン含有錠剤の製造方法
JP2003509368A (ja) * 1999-09-16 2003-03-11 ローディア・インコーポレイテッド 直接圧縮可能な超微粒アセトアミノフェン組成物及びその製造方法
JP2012144520A (ja) * 2010-12-24 2012-08-02 Lion Corp 錠剤

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5733578A (en) 1995-11-15 1998-03-31 Edward Mendell Co., Inc. Directly compressible high load acetaminophen formulations
EP1161941A4 (en) 1999-03-15 2002-08-28 Kaken Pharma Co Ltd QUICKLY DISMANTLING TABLETS AND METHOD FOR THE PRODUCTION THEREOF
JP4925526B2 (ja) 2001-09-10 2012-04-25 旭化成ケミカルズ株式会社 薬物の混合方法
WO2010081722A2 (en) * 2009-01-16 2010-07-22 Add Technologies Ltd. Orally disintegrating tablets for the treatment of pain
EP2460523B1 (en) 2009-07-28 2017-01-04 Takeda Pharmaceutical Company Limited Tablet

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61145111A (ja) * 1984-12-20 1986-07-02 Lion Corp アセトアミノフェン含有錠剤の製造方法
JP2003509368A (ja) * 1999-09-16 2003-03-11 ローディア・インコーポレイテッド 直接圧縮可能な超微粒アセトアミノフェン組成物及びその製造方法
JP2012144520A (ja) * 2010-12-24 2012-08-02 Lion Corp 錠剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Passages", JAPANESE PHARMACEUTICAL EXCIPIENTS DIRECTORY, 25 July 2007 (2007-07-25), pages 65, 67, 68 - 101, 181, , XP009516644, ISBN: 978-4-8408-0986-3 *
See also references of EP3456324A4 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7105473B2 (ja) 2017-04-19 2022-07-25 日本臓器製薬株式会社 プレミックス原薬の製造方法
JP2018177800A (ja) * 2017-04-19 2018-11-15 日本臓器製薬株式会社 プレミックス原薬の製造方法
CN112351772B (zh) * 2018-06-26 2023-05-16 日本脏器制药株式会社 颗粒尺寸不一致的原料药颗粒的处理方法
CN112351772A (zh) * 2018-06-26 2021-02-09 日本脏器制药株式会社 颗粒尺寸不一致的原料药颗粒的处理方法
JPWO2020004393A1 (ja) * 2018-06-26 2021-07-15 日本臓器製薬株式会社 粒子サイズが不揃いな原薬粒子の処理方法
US20210267900A1 (en) * 2018-06-26 2021-09-02 Nippon Zoki Pharmaceutical Co., Ltd. Processing method for drug substance particles of non-uniform particle size
JP7106161B2 (ja) 2018-06-26 2022-07-26 日本臓器製薬株式会社 粒子サイズが不揃いな原薬粒子の処理方法
WO2020004393A1 (ja) * 2018-06-26 2020-01-02 日本臓器製薬株式会社 粒子サイズが不揃いな原薬粒子の処理方法
JP2022512510A (ja) * 2018-12-18 2022-02-04 ディディピー スペシャルティ エレクトロニック マテリアルズ ユーエス，エルエルシー ヒドロキシアルキルメチルセルロースを含む徐放性組成物
JP2024088749A (ja) * 2018-12-18 2024-07-02 ニュートリション アンド バイオサイエンシズ ユーエスエー １，リミティド ライアビリティ カンパニー ヒドロキシアルキルメチルセルロースを含む徐放性組成物
JP7526727B2 (ja) 2018-12-18 2024-08-01 ニュートリション アンド バイオサイエンシズ ユーエスエー １，リミティド ライアビリティ カンパニー ヒドロキシアルキルメチルセルロースを含む徐放性組成物
JPWO2020246120A1 (OSRAM) * 2019-06-07 2020-12-10
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CA3023478A1 (en) 2017-11-16
KR102408085B1 (ko) 2022-06-13
CN109069455A (zh) 2018-12-21
JP2018090638A (ja) 2018-06-14
US20190142754A1 (en) 2019-05-16
JPWO2017195796A1 (ja) 2018-05-24
US11433031B2 (en) 2022-09-06
JP6310164B1 (ja) 2018-04-11
CA3023478C (en) 2024-02-06
EP3456324A1 (en) 2019-03-20
US11033501B2 (en) 2021-06-15
KR20190005939A (ko) 2019-01-16
TW201808272A (zh) 2018-03-16
TWI742078B (zh) 2021-10-11
US20210220283A1 (en) 2021-07-22
SG11201809835UA (en) 2018-12-28

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