WO2022003980A1 - Solid formulation - Google Patents

Solid formulation Download PDF

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Publication number
WO2022003980A1
WO2022003980A1 PCT/JP2020/026275 JP2020026275W WO2022003980A1 WO 2022003980 A1 WO2022003980 A1 WO 2022003980A1 JP 2020026275 W JP2020026275 W JP 2020026275W WO 2022003980 A1 WO2022003980 A1 WO 2022003980A1
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Prior art keywords
mass
solid preparation
parts
water
preparation according
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PCT/JP2020/026275
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French (fr)
Japanese (ja)
Inventor
俊行 稲田
隆弘 清水
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富士製薬工業株式会社
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Priority to JP2020571900A priority Critical patent/JP6920564B1/en
Priority to PCT/JP2020/026275 priority patent/WO2022003980A1/en
Publication of WO2022003980A1 publication Critical patent/WO2022003980A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K47/30—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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a solid preparation containing avilateron acetate as a drug substance, which is effective as a therapeutic agent for prostate cancer and the like, and a method for producing the same.
  • Patent Document 1 It is known from Patent Document 1 and the like that avilateron acetate is effective as a therapeutic agent for prostate cancer and the like.
  • Patent Document 2 to solve the problem of miniaturization of tablets, for example, in Patent Document 2, by changing polyethylene glycol contained in a commercially available pranlukast preparation to hydroxypropylmethyl cellulose, it adheres even if the content of saccharides is reduced.
  • a small-sized pharmaceutical product is disclosed in which the quality of the pharmaceutical product is stable and the patient's compliance with the drug is improved because the sex can be reduced.
  • Patent Document 3 in the core portion composed of nifedipine and a hydrophilic gel-forming polymer substance, the amount of the hydrophilic gel-forming polymer substance is reduced, and at the same time, a disintegration inhibitor is blended to form nifedipine.
  • the core is miniaturized without affecting elution
  • the outer shell which is composed of nifedipine, a hydrophilic gel-forming polymer substance, and a disintegration inhibitor, is compression-coated and miniaturized once a day. Nucleated tablets containing type nifedipine are disclosed.
  • an object of the present invention is to provide a solid preparation containing abiraterone acetate as a drug substance and a method for producing the same, which enables miniaturization of tablets.
  • the present inventor has studied various miniaturization of abiraterone tablets, and found that if the powder of abiraterone acetate is used as it is, the manufacturability (powder fluidity) is poor and it is difficult to manufacture the miniaturized tablets. However, it has been found that miniaturization is possible by modifying the surface of the powder with a coating agent in advance.
  • a solid preparation containing a coating product obtained by treating an avilateron acetate with a water-soluble coating agent [2] The solid preparation according to the above [1], wherein the bulk density of the coated product is 0.150 to 1.000 g / mL. [3]
  • the water-soluble coating agent is at least one selected from the group consisting of water-soluble cellulose derivatives, polyalkylene glycols, polysaccharides and their derivatives, and copolymers of polyvinyl alcohol and (meth) acrylic acid-based compounds.
  • the solid preparation of the present invention can be miniaturized as compared with the conventional avilateron preparation, and can improve the patient's dosing compliance.
  • the solid preparation of the present invention is characterized in that the avilateron acetate contains a coated product treated with a water-soluble coating agent.
  • Avilaterone acetate powder which is a fine powder of the raw material of Avilateron acetate, tends to be bulky, that is, low bulk density, and these powders have a large angle of repose and poor fluidity, resulting in poor manufacturability. ..
  • an excipient sufficient to counteract the poor fluidity of the drug substance is added, and the tablet of the abiraterone acetate preparation is also relatively large.
  • the bulkiness of the avilateron acetate is overcome by coating the powder of the avilateron acetate with a water-soluble coating agent (that is, the drug substance coating), and the amount of the drug substance is the same as that of the conventional avilateron preparation. Even so, it was possible to obtain a solid preparation capable of miniaturizing the tablet.
  • the coated product is obtained by treating with a water-soluble coating agent, and the powder surface of avilateron acetate is coated with the water-soluble coating agent, or the coated drug substance is aggregated. It is presumed that it is.
  • the average particle size of the avilateron acetate to be subjected to the coating treatment is preferably 0.1 ⁇ m or more from the viewpoint of manufacturability, and preferably 200 ⁇ m or less from the viewpoint of absorbability and elution. From these viewpoints, the average particle size of the avilateron acetate is preferably 0.1 to 200 ⁇ m, more preferably 0.5 to 100 ⁇ m, and even more preferably 1 to 50 ⁇ m.
  • the average particle size of the avilateron acetate is measured by a laser diffraction method (measurement method: wet, solvent: water, stirring and ultrasonic treatment) using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris).
  • the volume is medium particle size (D 50 ).
  • the volume median particle size (D 50 ) means a particle size in which the cumulative volume frequency calculated by the volume fraction is 50% calculated from the smaller particle size.
  • the avilateron acetate is modified from the viewpoint of increasing the bulk density of the coated product and increasing the production efficiency. It is preferable to coat with a water-soluble coating agent together with the agent and / or the disintegrant. By increasing the bulk density of the coated product, the thickness can be reduced and a higher effect on miniaturization can be obtained when compression molding is performed using the same tableting pestle and the same tableting pressure.
  • water-soluble coating agent at least one selected from the group consisting of water-soluble cellulose derivatives, polyalkylene glycols, polysaccharides and their derivatives, and copolymers of polyvinyl alcohol and (meth) acrylic acid-based compounds is used. preferable.
  • the water-soluble cellulose derivative in the present invention forms a hydrogen bond by substituting a part of the hydrogen atom of the hydroxyl group of cellulose with a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or the like. It is a water-soluble polymer that has disappeared. Specific examples include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcellulose acetate succinate, and the like, among which methylcellulose. , Hydroxypropyl cellulose, and hydroxypropylmethyl cellulose are preferred.
  • water-soluble coating agents include SM-4 (manufactured by Shin-Etsu Chemical Co., Ltd., methylcellulose), TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose), HPC-SL (Nippon Soda Co., Ltd.). ), Hydroxypropyl cellulose) grades and counts are different.
  • polyalkylene glycol examples include polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene glycol and the like.
  • polysaccharides and derivatives thereof examples include gelatin, gum arabic, carrageenan, guar gum and the like.
  • examples of the (meth) acrylic acid-based compound include (meth) acrylic acid and alkyl esters of (meth) acrylic acid, among these. , (Meta) acrylic acid and alkyl esters of (meth) acrylic acid are preferred.
  • (meth) acrylic acid means acrylic acid and / or methacrylic acid, and the number of carbon atoms of the alkyl group is preferably 1 to 20.
  • polyvinyl alcohol polyvinyl alcohol, acrylic acid, and methyl methacrylate copolymer are preferable.
  • Examples of commercially available products of copolymers of polyvinyl alcohol and (meth) acrylic acid-based compounds include POVACOAT (polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer manufactured by Nissin Kasei Co., Ltd.).
  • polyvinyl alcohol examples include Gosenol EG (manufactured by Mitsubishi Chemical Corporation, polyvinyl alcohol) grade and different counts.
  • a water-soluble coating agent is used as the coating agent, but a coating agent that is not water-soluble may be contained.
  • the content of the water-soluble coating agent in the total amount of the coating agent is 80% by mass or more. Is preferable, more preferably 90% by mass or more, still more preferably 95% by mass or more, still more preferably 98% by mass or more.
  • the content (coating amount) of the water-soluble coating agent is preferably 0.5 parts by mass or more, preferably 0.5 parts by mass or more, with respect to 100 parts by mass of the avilateron acetate from the viewpoint of improving the powder fluidity by surface modification of the original material. From the viewpoint of suppressing deterioration of elution and absorbability due to excessive amount, 50 parts by mass or less is preferable. From these viewpoints, the content of the water-soluble coating agent is preferably 0.5 to 50 parts by mass, more preferably 1 to 30 parts by mass, still more preferably 1 to 20 parts by mass, still more preferably 3 to 15 parts by mass. Is.
  • the content of the water-soluble coating agent in the coated product is preferably 0.5 to 30% by mass, more preferably 1 to 20% by mass, and further preferably 1.5 to 10% by mass.
  • the excipient preferably contains at least one of wax and light anhydrous silicic acid.
  • various excipients such as lactose hydrate, crystalline cellulose, and starch, which are widely used for producing solid preparations, may be optionally used.
  • the wax examples include hardened rapeseed oil and hardened castor oil, but in the present invention, the hardened powdered oil is preferable from the viewpoint of increasing the amount of powder recovered from the fluidized layer granulator. Hardened rapeseed oil is more preferred.
  • the average particle size of the wax used for the coating treatment is preferably 10 ⁇ m or more from the viewpoint of powder fluidity during the fluidized bed granulation step, and is 200 ⁇ m or less so that the difference from the particle size of the avilateron acetic acid ester does not open too much. preferable. From these viewpoints, the average particle size of the wax is preferably 10 to 200 ⁇ m, more preferably 20 to 100 ⁇ m, and even more preferably 40 to 80 ⁇ m.
  • the average particle size of the wax is a volume medium particle size (D 50 ), and is measured by a laser diffraction method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris).
  • the melting point of the wax is preferably 50 ° C. or higher, which does not melt during the fluidized bed granulation step, and is generally preferably 90 ° C. or lower, which is a temperature that does not reach during the manufacturing step. From these viewpoints, the melting point of the wax is preferably 50 to 90 ° C, more preferably 55 to 80 ° C, still more preferably 60 to 75 ° C.
  • the melting point of the wax is measured by a melting point measuring device (for example, a melting point measuring device (MP-21) manufactured by Yamato Scientific Co., Ltd.).
  • the wax content is preferably 0.25 parts by mass or more with respect to 100 parts by mass of the avilateron acetate ester from the viewpoint of the smoothing effect, and from the viewpoint of not impairing the fluidity of the powder during the fluidized bed granulation process. , 20 parts by mass or less is preferable. From these viewpoints, the wax content is preferably 0.25 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, and further preferably 1 to 10 parts by mass.
  • Light anhydrous silicic acid is also known as colloidal anhydrous silica or colloidal silicon dioxide.
  • the average particle size of the light anhydrous silicic acid to be subjected to the coating treatment is preferably 0.5 ⁇ m or more from the viewpoint of reducing the loss of the light anhydrous silicic acid from the system during the fluidized bed granulation step, and the fluidized bed granulation. From the viewpoint of improving the fluidity of the powder during the process, 50 ⁇ m or less is preferable. From these viewpoints, the average particle size of the light anhydrous silicic acid is preferably 0.5 to 50 ⁇ m, more preferably 1 to 20 ⁇ m, still more preferably 2 to 10 ⁇ m.
  • the average particle size of the light anhydrous silicic acid is a volume medium particle size (D 50 ), and is measured by a laser diffraction method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris).
  • the content of the light anhydrous silicic acid is preferably 0.25 parts by mass or more with respect to 100 parts by mass of the avilateron acetic acid ester from the viewpoint of the fluidity of the powder in the fluidized layer, and the bulk density due to addition in an excessive amount is preferable. From the viewpoint of preventing reduction, 20 parts by mass or less is preferable. From these viewpoints, the content of the light anhydrous silicic acid is preferably 0.25 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, and further preferably 1 to 10 parts by mass.
  • disintegrant examples include crospovidone such as polyvinylpyrrolidone-based (PVP-based) crospovidone, cellulose-based carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crystalline cellulose, powdered cellulose, and starch-based corn.
  • crospovidone such as polyvinylpyrrolidone-based (PVP-based) crospovidone
  • cellulose-based carmellose carmellose calcium
  • croscarmellose sodium low-substituted hydroxypropyl cellulose
  • crystalline cellulose crystalline cellulose
  • powdered cellulose and starch-based corn.
  • starch-based corn examples include starch, partially pregelatinized starch, sodium starch glycolate, pregelatinized starch and the like, and among these, crospovidone is preferable from the viewpoint of elution of the coated product.
  • the average particle size of the disintegrant to be subjected to the coating treatment is preferably 0.5 ⁇ m or more from the viewpoint of powder fluidity during the fluidized bed granulation step, and the difference from the particle size of the avilateron acetate is not too large. From the viewpoint, 200 ⁇ m or less is preferable. From these viewpoints, the average particle size of the disintegrant is preferably 0.5 to 200 ⁇ m, more preferably 5 to 150 ⁇ m, and even more preferably 10 to 130 ⁇ m.
  • the average particle size of the disintegrant is a volume medium particle size (D 50 ), and is measured by a laser diffraction method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris).
  • the content of the disintegrant is preferably 0.25 parts by mass or more with respect to 100 parts by mass of the avilateron acetate from the viewpoint of ensuring the dissolution of the drug substance from the coated product, and it depends on the water absorption during storage of the obtained tablet. From the viewpoint of preventing changes in appearance, 20 parts by mass or less is preferable. From these viewpoints, the content of the disintegrant is preferably 0.25 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, and further preferably 1 to 10 parts by mass.
  • the solid preparation of the present invention can be produced by a method including a step of coating the avilateron acetate with a water-soluble coating agent and a step of formulating the obtained coated product.
  • a water-soluble coating agent is dissolved in a solvent such as purified water in a mixture of avilateron acetate or a mixture of avilateron acetate with an excipient and / or a disintegrant.
  • the prepared coating liquid can be sprayed using a fluidized bed granulator, a stirring granulator or the like.
  • the avilateron acetate may be suspended in the prepared coating liquid and spray-dried using a spray dryer.
  • the solvent is preferably volatilized during the coating treatment. It is also possible to mix an excipient and a water-soluble coating agent with the avilateron acetate, coat the avilateron acetate, and then use a dry granulator to obtain granulated products.
  • the concentration of the water-soluble coating agent in the coating liquid is preferably about 0.1 to 10% by mass, and more preferably 0.15 to 3% by mass from the viewpoint of elution.
  • the coating liquid may contain a plasticizer or the like, but in the present invention, it is preferable that the coating liquid contains a plasticizer from the viewpoint of the spreadability of the water-soluble coating agent to the drug substance.
  • plasticizer examples include polyethylene glycol, glycerin, sorbitol, acetyltributyl citrate, dibutyl phthalate, liquid paraffin and the like.
  • the content of the plasticizer is preferably about 5 to 50 parts by mass with respect to 100 parts by mass of the water-soluble coating agent.
  • the bulk density of avilateron acetate (drug substance) is 0.143 g / mL, but the bulk density is increased by the coating treatment.
  • the bulk density of the coated product is preferably 0.150 g / mL or more from the viewpoint of powder manufacturability (fluidity), and from the viewpoint of suppressing deterioration of manufacturability due to the enlargement of the powder particle size, 1. It is preferably 000 g / mL or less. From these viewpoints, the bulk density of the coated product is preferably 0.150 to 1.000 g / mL, more preferably 0.150 to 0.350 g / mL, and further preferably 0.160 to 0.300 g / mL.
  • the bulk density of the coated product is measured using a powder tester (registered trademark) PT-R (manufactured by Hosokawa Micron Co., Ltd.). Specifically, the nuclear particle mixture is uniformly supplied from above to a cylindrical container of the same size as the measurement container of the bulk density and tap density measurement method 3 described in the 17th revised Japanese Pharmacopoeia through a sieve. The bulk density (loose bulk density) in the loosely filled state is measured by scraping the upper surface and weighing.
  • the formulation using the coated product can be performed by a conventional method.
  • the coated product is mixed with additives such as an excipient (binder), a disintegrant, a solubilizing agent, a fluidizing agent, and a lubricant to obtain a tableting powder, and the obtained tableting powder is obtained.
  • additives such as an excipient (binder), a disintegrant, a solubilizing agent, a fluidizing agent, and a lubricant to obtain a tableting powder, and the obtained tableting powder is obtained.
  • the solid preparation of the present invention can be tableted and molded into a tablet.
  • the additive to be mixed with the coated product in the step of formulating may be mixed in advance or may be divided into multiple stages and mixed.
  • the lubricant may cause a decrease in tablet hardness and a delay in disintegration, it is preferable to mix other additives and then separately mix them.
  • the coated product having a high bulk density is contained, a solid preparation having a high drug substance ratio can be obtained, and the same amount of the avilateron acetic acid ester (250 mg) as that of the conventional avilateron preparation is contained.
  • the solid formulation can be made smaller than the conventional formulation.
  • the drug substance ratio in the solid preparation of the present invention that is, the ratio of the content of abiraterone acetate in one preparation is preferably 60% by mass or more from the viewpoint of tablet miniaturization, and from the viewpoint of facilitating tableting. 90% by mass or less is preferable. From these viewpoints, the content of avilateron acetate is preferably 60 to 90% by mass, more preferably 70 to 87% by mass, and further preferably 75 to 85% by mass.
  • Example 1 The water-soluble coating agent and the plasticizer shown in Table 1 were dissolved in purified water to prepare a coating liquid adjusted to a total amount of 1000 g. Using a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.), 143 g of the obtained coating liquid was sprayed onto 100 g of avilateron acetate (average particle size (D 50): 6.0 ⁇ m). Then, a coated product was obtained. At this point, the purified water was almost volatilized, and the water content of the coated product was about 0.3% by mass.
  • FD-MP-01D fluidized bed granulator
  • a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.) was added to the obtained coated product by adding 2.56 g of an excipient, 2.40 g of a disintegrant, and 7.20 g of a solubilizing agent. After mixing with the above, 1.60 g of a lubricant was further added and mixed to obtain a tableted powder.
  • the obtained tableting powder was put into a rotary tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.) and locked so that the amount of the drug substance per tablet was 250 mg to obtain an uncoated tablet.
  • Example 2 100 g of avilateron acetate (average particle size (D 50 ): 6.0 ⁇ m) was mixed with the cured rapeseed oil shown in Table 1, and the obtained mixture was sprayed with a coating solution in the same manner as in Example 1. , I got an uncoated tablet.
  • Example 3 The same as in Example 1 except that 100 g of avilateron acetic acid ester (average particle size (D 50 ): 6.0 ⁇ m) was mixed with the light anhydrous silicic acid shown in Table 1 and a coating solution was sprayed on the obtained mixture. I got an uncoated tablet.
  • 100 g of avilateron acetic acid ester average particle size (D 50 ): 6.0 ⁇ m
  • Examples 4 to 15 Except for mixing 100 g of avilateron acetate (average particle size (D 50 ): 6.0 ⁇ m) with the cured rapeseed oil and light anhydrous silicic acid shown in Tables 1 and 2 and spraying the coating solution onto the resulting mixture. An uncoated tablet was obtained in the same manner as in Example 1.
  • avilateron acetate average particle size (D 50 ): 6.0 ⁇ m
  • Example 16 100 g of avilateron acetate (average particle size (D 50 ): 6.0 ⁇ m) was mixed with the light anhydrous silicic acid and disintegrant shown in Table 2, and the obtained mixture was sprayed with a coating liquid to obtain a coated product. rice field. To the obtained coated product, 5.20 g of an excipient and 7.20 g of a solubilizing agent were added, mixed using a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.), and then mixed. Further, 2.00 g of a lubricant was added and mixed to obtain a tableted powder.
  • FD-MP-01D fluidized bed granulator
  • the obtained tableting powder was put into a rotary tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.) and locked so that the amount of the drug substance per tablet was 250 mg to obtain an uncoated tablet.
  • VIRGO 0512SS2AY manufactured by Kikusui Seisakusho Co., Ltd.
  • Comparative Example 1 To 100 g of avilateron acetate, 2.56 g of excipient, 2.40 g of disintegrant, and 7.20 g of lysis aid are added, and a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.) is used. After mixing, 1.60 g of a lubricant was further added and mixed to obtain a tableted powder. The obtained tableting powder was tableted using a rotary tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.), but could not be molded into a tablet.
  • a rotary tableting machine VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.
  • Comparative Example 2 In Comparative Example 1, it was not possible to mold into a tablet, but this was considered to be due to the poor fluidity of the drug substance, and the fluidity was improved and the amount of the excipient was increased until tableting became possible. As a result, by increasing the amount of the excipient to 172.55 g, it was possible to mold without sticking for the first time. That is, 172.55 g of an excipient, 2.40 g of a disintegrant, and 7.20 g of a solubilizing agent were added to 100 g of avilateron acetate, and a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.) was added.
  • FD-MP-01D fluidized bed granulator
  • Adsolider 101 manufactured by Freund Sangyo Co., Ltd., average particle size (D 50 ) 3.2 ⁇ m ⁇ Coating agent ⁇
  • MC Methylcellulose
  • SM-4 HPMC manufactured by Shin-Etsu Chemical Co., Ltd .: Hydroxypropylmethylcellulose, TC-5E
  • HPC Hydroxypropylcellulose manufactured by Shin-Etsu Chemical Co., Ltd.
  • HPC-SL PVA manufactured by Nippon Soda Co., Ltd.
  • AA / MMA Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, POVACOAT, manufactured by Nissin Kasei Co., Ltd.
  • Example 3 [Measurement of tablet thickness]
  • the API content per tablet was adjusted to 125 mg and the tableting pressure was adjusted to 50 kgf to 70 kgf using a ⁇ 10 mm, 2-stage R pestle. It was made into tablets.
  • the thickness of the obtained tablet was measured, the thickness of the tablet of Example 3 was small, which reflected the high rate of API.
  • the ester density can be increased, even if the mass per tablet is the same, a smaller uncoated tablet can be obtained when compression molding is performed at the same tableting pressure.
  • the mass of one commercially available avilatelon preparation containing 250 mg of avilateron acetate is 736 mg, the drug substance ratio is calculated to be about 34% by mass. be able to.
  • the mass of one tablet of Examples 1 to 16 having a drug substance ratio of about 75 to 85% by mass is about 290 to 330 mg, which is sufficiently smaller than the commercially available preparation, and the tablet is miniaturized. There is.
  • the solid preparation of the present invention containing avilateron acetate as a drug substance is an effective pharmaceutical preparation as a therapeutic drug for prostate cancer and the like.

Abstract

Provided are: a solid formulation comprising a coating-treated article obtained by treating abiraterone acetate with a water-soluble coating agent; and a method for producing the solid formulation according to any one of claims 1-12, the method comprising a step for coating-treating abiraterone acetate with a water-soluble coating agent and a step for formulating the obtained coating-treated article. A solid formulation according to the present invention, which contains abiraterone acetate as a drug substance, is a pharmaceutical formulation effective as a therapeutic agent for prostate cancer or the like.

Description

固形製剤Solid product
　本発明は、前立腺癌等の治療薬として有効なアビラテロン酢酸エステルを原薬として含有する固形製剤及びその製造方法に関する。 The present invention relates to a solid preparation containing avilateron acetate as a drug substance, which is effective as a therapeutic agent for prostate cancer and the like, and a method for producing the same.
　アビラテロン酢酸エステルは、前立腺癌等の治療薬として有効であることが特許文献１等により知られている。 It is known from Patent Document 1 and the like that avilateron acetate is effective as a therapeutic agent for prostate cancer and the like.
　一方、錠剤の小型化の課題に対しては、例えば、特許文献２に、市販のプランルカスト製剤に含まれるポリエチレングリコールをヒドロキシプロピルメチルセルロースに変更することにより、糖類の含量を少なくしても付着性を低減できるため、製剤の品質が安定し、かつ患者の服用コンプライアンスが向上した小型製剤が開示されている。 On the other hand, to solve the problem of miniaturization of tablets, for example, in Patent Document 2, by changing polyethylene glycol contained in a commercially available pranlukast preparation to hydroxypropylmethyl cellulose, it adheres even if the content of saccharides is reduced. A small-sized pharmaceutical product is disclosed in which the quality of the pharmaceutical product is stable and the patient's compliance with the drug is improved because the sex can be reduced.
　また、特許文献３には、ニフェジピン及び親水性ゲル形成性高分子物質からなる芯部において、親水性ゲル形成性高分子物質の量を減らすと同時に崩壊抑制作用物質を配合することにより、ニフェジピンの溶出に影響を与えることなく芯部を小型化し、これにニフェジピン、親水性ゲル形成性高分子物質及び崩壊抑制作用物質からなる外殻部を圧縮被覆して、小型化された１日１回投与型ニフェジピン含有有核錠剤が開示されている。 Further, in Patent Document 3, in the core portion composed of nifedipine and a hydrophilic gel-forming polymer substance, the amount of the hydrophilic gel-forming polymer substance is reduced, and at the same time, a disintegration inhibitor is blended to form nifedipine. The core is miniaturized without affecting elution, and the outer shell, which is composed of nifedipine, a hydrophilic gel-forming polymer substance, and a disintegration inhibitor, is compression-coated and miniaturized once a day. Nucleated tablets containing type nifedipine are disclosed.
特表２０１６－５１４７０７号公報Special Table 2016-514707 Gazette 特開２００６－８６７６号公報Japanese Unexamined Patent Publication No. 2006-8676 特開２００４－２３４８号公報Japanese Unexamined Patent Publication No. 2004-2348
　アビラテロン製剤は、固形製剤として流通しているが、服薬コンプライアンスを向上するために、錠剤の小型化が望まれる。従って、本発明の課題は、錠剤の小型化が可能な、アビラテロン酢酸エステルを原薬として含有する固形製剤及びその製造方法を提供することにある。 The avilatelon preparation is distributed as a solid preparation, but it is desired to reduce the size of the tablet in order to improve the medication compliance. Therefore, an object of the present invention is to provide a solid preparation containing abiraterone acetate as a drug substance and a method for producing the same, which enables miniaturization of tablets.
　本発明者は、アビラテロン錠剤の小型化を種々検討したところ、アビラテロン酢酸エステルの粉体をそのまま用いたのでは製造性（粉体の流動性）が悪く、小型化した錠剤の製造が困難であるが、予めコーティング剤で粉体の表面改質を行うことで小型化が可能になることを見出した。 The present inventor has studied various miniaturization of abiraterone tablets, and found that if the powder of abiraterone acetate is used as it is, the manufacturability (powder fluidity) is poor and it is difficult to manufacture the miniaturized tablets. However, it has been found that miniaturization is possible by modifying the surface of the powder with a coating agent in advance.
　従って、本発明は、
〔１〕　アビラテロン酢酸エステルが、水溶性コーティング剤により処理されてなる被覆処理物を含む、固形製剤、
〔２〕　被覆処理物のかさ密度が、０．１５０～１．０００ｇ／ｍＬである、前記〔１〕記載の固形製剤、
〔３〕　水溶性コーティング剤が、水溶性セルロース誘導体、ポリアルキレングリコール、多糖類及びそれらの誘導体、並びにポリビニルアルコールと（メタ）アクリル酸系化合物との共重合体からなる群より選ばれた少なくとも１種である、前記〔１〕又は〔２〕記載の固形製剤、
〔４〕　アビラテロン酢酸エステルが、賦形剤及び／又は崩壊剤とともに、水溶性コーティング剤により処理されてなる、前記〔１〕～〔３〕いずれか記載の固形製剤、
〔５〕　賦形剤が、ワックス及び軽質無水ケイ酸の少なくともいずれかを含有する、前記〔４〕記載の固形製剤、
〔６〕　ワックスの含有量が、アビラテロン酢酸エステル１００質量部に対して、１～１０質量部である、前記〔５〕記載の固形製剤、
〔７〕　軽質無水ケイ酸の含有量が、アビラテロン酢酸エステル１００質量部に対して、１～１０質量部である、前記〔５〕又は〔６〕記載の固形製剤、
〔８〕　崩壊剤が、クロスポビドンを含む、前記〔４〕～〔７〕いずれか記載の固形製剤、
〔９〕　崩壊剤の含有量が、アビラテロン酢酸エステル１００質量部に対して、１～１０質量部である、前記〔４〕～〔８〕いずれか記載の固形製剤、
〔１０〕　水溶性コーティング剤の含有量が、アビラテロン酢酸エステル１００質量部に対して、１～２０質量部である、前記〔１〕～〔９〕いずれか記載の固形製剤、
〔１１〕　アビラテロン酢酸エステルの含有量が６０～９０質量％である、前記〔１〕～〔１０〕いずれか記載の固形製剤、
〔１２〕　固形製剤が錠剤である、前記〔１〕～〔１１〕いずれか記載の固形製剤、
〔１３〕　アビラテロン酢酸エステルに対し、水溶性コーティング剤により被覆処理する工程、及び得られた被覆処理物を用いて、製剤化する工程を含む、前記〔１〕～〔１２〕いずれか記載の固形製剤の製造方法、並びに
〔１４〕　被覆処理する工程において、アビラテロン酢酸エステルを賦形剤及び／又は崩壊剤と混合して被覆処理に供する、前記〔１３〕記載の製造方法
に関する。 Therefore, the present invention
[1] A solid preparation containing a coating product obtained by treating an avilateron acetate with a water-soluble coating agent.
[2] The solid preparation according to the above [1], wherein the bulk density of the coated product is 0.150 to 1.000 g / mL.
[3] The water-soluble coating agent is at least one selected from the group consisting of water-soluble cellulose derivatives, polyalkylene glycols, polysaccharides and their derivatives, and copolymers of polyvinyl alcohol and (meth) acrylic acid-based compounds. The solid preparation according to the above [1] or [2], which is a seed,
[4] The solid preparation according to any one of [1] to [3] above, wherein the avilateron acetate is treated with a water-soluble coating agent together with an excipient and / or a disintegrant.
[5] The solid preparation according to [4] above, wherein the excipient contains at least one of wax and light anhydrous silicic acid.
[6] The solid preparation according to [5] above, wherein the wax content is 1 to 10 parts by mass with respect to 100 parts by mass of the avilateron acetate.
[7] The solid preparation according to the above [5] or [6], wherein the content of the light anhydrous silicic acid is 1 to 10 parts by mass with respect to 100 parts by mass of the avilateron acetate.
[8] The solid preparation according to any one of [4] to [7] above, wherein the disintegrant contains crospovidone.
[9] The solid preparation according to any one of [4] to [8] above, wherein the content of the disintegrant is 1 to 10 parts by mass with respect to 100 parts by mass of avilateron acetate.
[10] The solid preparation according to any one of [1] to [9] above, wherein the content of the water-soluble coating agent is 1 to 20 parts by mass with respect to 100 parts by mass of avilateron acetate.
[11] The solid preparation according to any one of [1] to [10] above, wherein the content of avilateron acetate is 60 to 90% by mass.
[12] The solid preparation according to any one of [1] to [11] above, wherein the solid preparation is a tablet.
[13] The solid according to any one of [1] to [12] above, which comprises a step of coating the avilateron acetic acid ester with a water-soluble coating agent and a step of formulating the avilateron acetic acid ester using the obtained coated product. [14] The production method according to the above [13], wherein the avilateron acetic acid ester is mixed with an excipient and / or a disintegrant and subjected to the coating treatment in the step of manufacturing the pharmaceutical product and the coating treatment.
　本発明の固形製剤は、従来のアビラテロン製剤に比べて小型化が可能であり、患者の服用コンプライアンスを向上させることができる。 The solid preparation of the present invention can be miniaturized as compared with the conventional avilateron preparation, and can improve the patient's dosing compliance.
実施例８の素錠とアビラテロン製剤の市販製剤の溶出量を測定したグラフである。It is a graph which measured the elution amount of the uncoated tablet of Example 8 and the commercial preparation of an avilateron preparation.
　本発明の固形製剤は、アビラテロン酢酸エステルが、水溶性コーティング剤により処理された被覆処理物を含む点に大きな特徴を有している。
　アビラテロン酢酸エステルの原体を微粉化したアビラテロン酢酸エステルの粉末は、かさ高い、即ちかさ密度が低い傾向にあり、それらの粉体は安息角が大きく流動性の悪い粉体となり、製造性が悪い。製剤化するためには、原体流動性の悪さを打ち消すほどの賦形剤を添加することとなり、アビラテロン酢酸エステル製剤の錠剤も比較的大きいものとなる。しかしながら、本発明では、アビラテロン酢酸エステルの粉末を水溶性コーティング剤で被覆（即ち、原薬コーティング）することにより、アビラテロン酢酸エステルのかさ高さを克服し、従来のアビラテロン製剤と原薬量は同一であっても、錠剤の小型化が可能な固形製剤を得ることができた。本発明において被覆処理物は、水溶性コーティング剤の処理により得られる物であって、アビラテロン酢酸エステルの粉体表面が水溶性コーティング剤によってコーティングされた状態、あるいはコーティングされた原薬が凝集した状態になっているものと推定される。 The solid preparation of the present invention is characterized in that the avilateron acetate contains a coated product treated with a water-soluble coating agent.
Avilaterone acetate powder, which is a fine powder of the raw material of Avilateron acetate, tends to be bulky, that is, low bulk density, and these powders have a large angle of repose and poor fluidity, resulting in poor manufacturability. .. In order to formulate the product, an excipient sufficient to counteract the poor fluidity of the drug substance is added, and the tablet of the abiraterone acetate preparation is also relatively large. However, in the present invention, the bulkiness of the avilateron acetate is overcome by coating the powder of the avilateron acetate with a water-soluble coating agent (that is, the drug substance coating), and the amount of the drug substance is the same as that of the conventional avilateron preparation. Even so, it was possible to obtain a solid preparation capable of miniaturizing the tablet. In the present invention, the coated product is obtained by treating with a water-soluble coating agent, and the powder surface of avilateron acetate is coated with the water-soluble coating agent, or the coated drug substance is aggregated. It is presumed that it is.
　被覆処理に供するアビラテロン酢酸エステルの平均粒子径は、製造性の観点から、０．１μｍ以上が好ましく、吸収性及び溶出性の観点から、２００μｍ以下が好ましい。これらの観点から、アビラテロン酢酸エステルの平均粒子径は、好ましくは０．１～２００μｍ、より好ましくは０．５～１００μｍ、さらに好ましくは１～５０μｍである。
　ここで、アビラテロン酢酸エステルの平均粒子径は、粒度分布測定装置（Ｍａｓｔｅｒｓｉｚｅｒ３０００、Ｓｐｅｃｔｒｉｓ製）を用いて、レーザー回折法（測定方法：湿式、溶媒：水、撹拌及び超音波処理を実施する）により測定した体積中位粒径（Ｄ５０）である。なお、体積中位粒径（Ｄ５０）は、体積分率で計算した累積体積頻度が粒径の小さい方から計算して５０％になる粒径を意味する。 The average particle size of the avilateron acetate to be subjected to the coating treatment is preferably 0.1 μm or more from the viewpoint of manufacturability, and preferably 200 μm or less from the viewpoint of absorbability and elution. From these viewpoints, the average particle size of the avilateron acetate is preferably 0.1 to 200 μm, more preferably 0.5 to 100 μm, and even more preferably 1 to 50 μm.
Here, the average particle size of the avilateron acetate is measured by a laser diffraction method (measurement method: wet, solvent: water, stirring and ultrasonic treatment) using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris). The volume is medium particle size (D 50 ). The volume median particle size (D 50 ) means a particle size in which the cumulative volume frequency calculated by the volume fraction is 50% calculated from the smaller particle size.
　アビラテロン酢酸エステルを水溶性コーティング剤により処理して被覆処理物を得るにあたって、本発明においては、被覆処理物のかさ密度を高くし、また、生産効率を高める観点から、アビラテロン酢酸エステルを、賦形剤及び／又は崩壊剤とともに、水溶性コーティング剤により被覆処理することが好ましい。被覆処理物のかさ密度を高くすることで、同じ打錠用杵臼を用い、同じ打錠圧で圧縮成形した場合、厚みを薄くすることができ、小型化に対してより高い効果が得られる。 In treating the avilateron acetate with a water-soluble coating agent to obtain a coated product, in the present invention, the avilateron acetate is modified from the viewpoint of increasing the bulk density of the coated product and increasing the production efficiency. It is preferable to coat with a water-soluble coating agent together with the agent and / or the disintegrant. By increasing the bulk density of the coated product, the thickness can be reduced and a higher effect on miniaturization can be obtained when compression molding is performed using the same tableting pestle and the same tableting pressure.
　水溶性コーティング剤としては、水溶性セルロース誘導体、ポリアルキレングリコール、多糖類及びそれらの誘導体、並びにポリビニルアルコールと（メタ）アクリル酸系化合物との共重合体からなる群より選ばれた少なくとも１種が好ましい。 As the water-soluble coating agent, at least one selected from the group consisting of water-soluble cellulose derivatives, polyalkylene glycols, polysaccharides and their derivatives, and copolymers of polyvinyl alcohol and (meth) acrylic acid-based compounds is used. preferable.
　本発明における水溶性セルロース誘導体とは、セルロースの水酸基の水素原子の一部をメチル基、エチル基、プロピル基、ヒドロキシメチル基、ヒドロキシエチル基、ヒドロキシプロピル基等で置換することにより、水素結合を消失させた水溶性高分子である。具体例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシメチルエチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートスクシネート等が挙げられ、これらの中では、メチルセルロース、ヒドロキシプロピルセルロース、及びヒドロキシプロピルメチルセルロースが好ましい。 The water-soluble cellulose derivative in the present invention forms a hydrogen bond by substituting a part of the hydrogen atom of the hydroxyl group of cellulose with a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or the like. It is a water-soluble polymer that has disappeared. Specific examples include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcellulose acetate succinate, and the like, among which methylcellulose. , Hydroxypropyl cellulose, and hydroxypropylmethyl cellulose are preferred.
　水溶性コーティング剤の市販品としては、ＳＭ－４（信越化学工業（株）製、メチルセルロース）、ＴＣ－５Ｅ（信越化学工業（株）製、ヒドロキシプロピルメチルセルロース）、ＨＰＣ－ＳＬ（日本曹達（株）製、ヒドロキシプロピルセルロース）のグレード・番手違い等が挙げられる。 Commercially available water-soluble coating agents include SM-4 (manufactured by Shin-Etsu Chemical Co., Ltd., methylcellulose), TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose), HPC-SL (Nippon Soda Co., Ltd.). ), Hydroxypropyl cellulose) grades and counts are different.
　ポリアルキレングリコールとしては、ポリエチレングリコール、ポリプロピレングリコール、ポリオキシエチレンポリオキシプロピレングリコール等が挙げられる。 Examples of polyalkylene glycol include polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene glycol and the like.
　多糖類及びその誘導体としては、ゼラチン、アラビアガム、カラギナン、グアーガム等が挙げられる。 Examples of polysaccharides and derivatives thereof include gelatin, gum arabic, carrageenan, guar gum and the like.
　ポリビニルアルコールと（メタ）アクリル酸系化合物との共重合体において、（メタ）アクリル酸系化合物としては、（メタ）アクリル酸、（メタ）アクリル酸のアルキルエステル等が挙げられ、これらの中では、（メタ）アクリル酸及び（メタ）アクリル酸のアルキルエステルが好ましい。ここで、「（メタ）アクリル酸」とは、アクリル酸及び／又はメタクリル酸を意味し、アルキル基の炭素数は、1～２０が好ましい。 In the copolymer of polyvinyl alcohol and (meth) acrylic acid-based compound, examples of the (meth) acrylic acid-based compound include (meth) acrylic acid and alkyl esters of (meth) acrylic acid, among these. , (Meta) acrylic acid and alkyl esters of (meth) acrylic acid are preferred. Here, "(meth) acrylic acid" means acrylic acid and / or methacrylic acid, and the number of carbon atoms of the alkyl group is preferably 1 to 20.
　ポリビニルアルコールと（メタ）アクリル酸系化合物との共重合体としては、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体が好ましい。 As the copolymer of polyvinyl alcohol and the (meth) acrylic acid-based compound, polyvinyl alcohol, acrylic acid, and methyl methacrylate copolymer are preferable.
　ポリビニルアルコールと（メタ）アクリル酸系化合物との共重合体の市販品としては、ＰＯＶＡＣＯＡＴ（日新化成（株）製、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体）等が挙げられる。 Examples of commercially available products of copolymers of polyvinyl alcohol and (meth) acrylic acid-based compounds include POVACOAT (polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer manufactured by Nissin Kasei Co., Ltd.).
　ポリビニルアルコールの市販品としては、ゴーセノールＥＧ（三菱ケミカル（株）製、ポリビニルアルコール）グレード・番手違い等が挙げられる。 Examples of commercially available polyvinyl alcohol include Gosenol EG (manufactured by Mitsubishi Chemical Corporation, polyvinyl alcohol) grade and different counts.
　本発明では、コーティング剤として水溶性コーティング剤を用いるが、水溶性ではないコーティング剤が含まれていてもよく、その場合、コーティング剤総量中の水溶性コーティング剤の含有量は、８０質量％以上が好ましく、より好ましくは９０質量％以上、さらに好ましくは９５質量％以上、さらに好ましくは９８質量％以上である。 In the present invention, a water-soluble coating agent is used as the coating agent, but a coating agent that is not water-soluble may be contained. In that case, the content of the water-soluble coating agent in the total amount of the coating agent is 80% by mass or more. Is preferable, more preferably 90% by mass or more, still more preferably 95% by mass or more, still more preferably 98% by mass or more.
　水溶性コーティング剤の含有量（被覆量）は、アビラテロン酢酸エステル１００質量部に対して、原体の表面改質による粉体流動性向上の観点から、０．５質量部以上が好ましく、被覆量過多による溶出性及び吸収性の低下を抑制する観点から、５０質量部以下が好ましい。これらの観点から、水溶性コーティング剤の含有量は、好ましくは０．５～５０質量部、より好ましくは１～３０質量部、さらに好ましくは１～２０質量部、さらに好ましくは３～１５質量部である。 The content (coating amount) of the water-soluble coating agent is preferably 0.5 parts by mass or more, preferably 0.5 parts by mass or more, with respect to 100 parts by mass of the avilateron acetate from the viewpoint of improving the powder fluidity by surface modification of the original material. From the viewpoint of suppressing deterioration of elution and absorbability due to excessive amount, 50 parts by mass or less is preferable. From these viewpoints, the content of the water-soluble coating agent is preferably 0.5 to 50 parts by mass, more preferably 1 to 30 parts by mass, still more preferably 1 to 20 parts by mass, still more preferably 3 to 15 parts by mass. Is.
　また、被覆処理物中の水溶性コーティング剤の含有量は、好ましくは０．５～３０質量％、より好ましくは１～２０質量％、さらに好ましくは１．５～１０質量％である。 The content of the water-soluble coating agent in the coated product is preferably 0.5 to 30% by mass, more preferably 1 to 20% by mass, and further preferably 1.5 to 10% by mass.
　賦形剤は、ワックス及び軽質無水ケイ酸の少なくともいずれかを含有することが好ましい。この他にも、固形製剤の製造に汎用される乳糖水和物、結晶セルロース、デンプン等の各種賦形剤を任意に用いてもよい。 The excipient preferably contains at least one of wax and light anhydrous silicic acid. In addition, various excipients such as lactose hydrate, crystalline cellulose, and starch, which are widely used for producing solid preparations, may be optionally used.
　ワックスとしては、粉末の硬化ナタネ油、硬化ヒマシ油等が挙げられるが、本発明においては、流動層造粒機からの粉体回収量を増加させる観点から、粉末の硬化油が好ましく、粉末の硬化ナタネ油がより好ましい。 Examples of the wax include hardened rapeseed oil and hardened castor oil, but in the present invention, the hardened powdered oil is preferable from the viewpoint of increasing the amount of powder recovered from the fluidized layer granulator. Hardened rapeseed oil is more preferred.
　被覆処理に供するワックスの平均粒子径は、流動層造粒の工程中の粉体流動性の観点から、１０μｍ以上が好ましく、アビラテロン酢酸エステルの粒子径との差が開きすぎない程度の２００μｍ以下が好ましい。これらの観点から、ワックスの平均粒子径は、好ましくは１０～２００μｍ、より好ましくは２０～１００μｍ、さらに好ましくは４０～８０μｍである。
　ここで、ワックスの平均粒子径は、体積中位粒径（Ｄ５０）であり、粒度分布測定装置（Ｍａｓｔｅｒｓｉｚｅｒ３０００、Ｓｐｅｃｔｒｉｓ製）を用いて、レーザー回折法により測定する。 The average particle size of the wax used for the coating treatment is preferably 10 μm or more from the viewpoint of powder fluidity during the fluidized bed granulation step, and is 200 μm or less so that the difference from the particle size of the avilateron acetic acid ester does not open too much. preferable. From these viewpoints, the average particle size of the wax is preferably 10 to 200 μm, more preferably 20 to 100 μm, and even more preferably 40 to 80 μm.
Here, the average particle size of the wax is a volume medium particle size (D 50 ), and is measured by a laser diffraction method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris).
　ワックスの融点は、流動層造粒の工程中に溶融しない５０℃以上が好ましく、一般的に製造工程中に達することのない温度である９０℃以下が好ましい。これらの観点から、ワックスの融点は、好ましくは５０～９０℃、より好ましくは５５～８０℃、さらに好ましくは６０～７５℃である。
　ここで、ワックスの融点は、融点測定装置（例えば、融点測定器（ＭＰ－２１）ヤマト科学（株）製）により測定する。 The melting point of the wax is preferably 50 ° C. or higher, which does not melt during the fluidized bed granulation step, and is generally preferably 90 ° C. or lower, which is a temperature that does not reach during the manufacturing step. From these viewpoints, the melting point of the wax is preferably 50 to 90 ° C, more preferably 55 to 80 ° C, still more preferably 60 to 75 ° C.
Here, the melting point of the wax is measured by a melting point measuring device (for example, a melting point measuring device (MP-21) manufactured by Yamato Scientific Co., Ltd.).
　ワックスの含有量は、アビラテロン酢酸エステル１００質量部に対して、滑沢効果の観点から、０．２５質量部以上が好ましく、流動層造粒の工程中に粉体の流動性を損なわない観点から、２０質量部以下が好ましい。これらの観点から、ワックスの含有量は、好ましくは０．２５～２０質量部、より好ましくは０．５～１５質量部、さらに好ましくは１～１０質量部である。 The wax content is preferably 0.25 parts by mass or more with respect to 100 parts by mass of the avilateron acetate ester from the viewpoint of the smoothing effect, and from the viewpoint of not impairing the fluidity of the powder during the fluidized bed granulation process. , 20 parts by mass or less is preferable. From these viewpoints, the wax content is preferably 0.25 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, and further preferably 1 to 10 parts by mass.
　軽質無水ケイ酸は、コロイド無水シリカ又はコロイド二酸化ケイ素としても知られている。 Light anhydrous silicic acid is also known as colloidal anhydrous silica or colloidal silicon dioxide.
　被覆処理に供する軽質無水ケイ酸の平均粒子径は、流動層造粒の工程中に系内からの軽質無水ケイ酸のロスを軽減させる観点から、０．５μｍ以上が好ましく、流動層造粒の工程中に粉体の流動性を向上させる観点から、５０μｍ以下が好ましい。これらの観点から、軽質無水ケイ酸の平均粒子径は、好ましくは０．５～５０μｍ、より好ましくは１～２０μｍ、さらに好ましくは２～１０μｍである。
　ここで、軽質無水ケイ酸の平均粒子径は、体積中位粒径（Ｄ５０）であり、粒度分布測定装置（Ｍａｓｔｅｒｓｉｚｅｒ３０００、Ｓｐｅｃｔｒｉｓ製）を用いて、レーザー回折法により測定する。 The average particle size of the light anhydrous silicic acid to be subjected to the coating treatment is preferably 0.5 μm or more from the viewpoint of reducing the loss of the light anhydrous silicic acid from the system during the fluidized bed granulation step, and the fluidized bed granulation. From the viewpoint of improving the fluidity of the powder during the process, 50 μm or less is preferable. From these viewpoints, the average particle size of the light anhydrous silicic acid is preferably 0.5 to 50 μm, more preferably 1 to 20 μm, still more preferably 2 to 10 μm.
Here, the average particle size of the light anhydrous silicic acid is a volume medium particle size (D 50 ), and is measured by a laser diffraction method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris).
　軽質無水ケイ酸の含有量は、アビラテロン酢酸エステル１００質量部に対して、流動層中の粉体の流動性の観点から、０．２５質量部以上が好ましく、過量に添加することによるかさ密度の低減を防止する観点から、２０質量部以下が好ましい。これらの観点から、軽質無水ケイ酸の含有量は、好ましくは０．２５～２０質量部、より好ましくは０．５～１５質量部、さらに好ましくは１～１０質量部である。 The content of the light anhydrous silicic acid is preferably 0.25 parts by mass or more with respect to 100 parts by mass of the avilateron acetic acid ester from the viewpoint of the fluidity of the powder in the fluidized layer, and the bulk density due to addition in an excessive amount is preferable. From the viewpoint of preventing reduction, 20 parts by mass or less is preferable. From these viewpoints, the content of the light anhydrous silicic acid is preferably 0.25 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, and further preferably 1 to 10 parts by mass.
　崩壊剤としては、ポリビニルピロリドン系（ＰＶＰ系）クロスポビドン等のクロスポビドン、セルロース系のカルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、結晶セルロース、粉末セルロース、デンプン系のトウモロコシデンプン、部分アルファー化デンプン、デンプングリコール酸ナトリウム、アルファー化デンプン等が挙げられ、これらの中では、被覆処理物の溶出性の観点から、クロスポビドンが好ましい。 Examples of the disintegrant include crospovidone such as polyvinylpyrrolidone-based (PVP-based) crospovidone, cellulose-based carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crystalline cellulose, powdered cellulose, and starch-based corn. Examples thereof include starch, partially pregelatinized starch, sodium starch glycolate, pregelatinized starch and the like, and among these, crospovidone is preferable from the viewpoint of elution of the coated product.
　被覆処理に供する崩壊剤の平均粒子径は、流動層造粒の工程中における粉体流動性の観点から、０．５μｍ以上が好ましく、アビラテロン酢酸エステルの粒子径との差が開きすぎない程度の観点から、２００μｍ以下が好ましい。これらの観点から、崩壊剤の平均粒子径は、好ましくは０．５～２００μｍ、より好ましくは５～１５０μｍ、さらに好ましく１０～１３０μｍである。
　ここで、崩壊剤の平均粒子径は、体積中位粒径（Ｄ５０）であり、粒度分布測定装置（Ｍａｓｔｅｒｓｉｚｅｒ３０００、Ｓｐｅｃｔｒｉｓ製）を用いて、レーザー回折法により測定する。 The average particle size of the disintegrant to be subjected to the coating treatment is preferably 0.5 μm or more from the viewpoint of powder fluidity during the fluidized bed granulation step, and the difference from the particle size of the avilateron acetate is not too large. From the viewpoint, 200 μm or less is preferable. From these viewpoints, the average particle size of the disintegrant is preferably 0.5 to 200 μm, more preferably 5 to 150 μm, and even more preferably 10 to 130 μm.
Here, the average particle size of the disintegrant is a volume medium particle size (D 50 ), and is measured by a laser diffraction method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Spectris).
　崩壊剤の含有量は、アビラテロン酢酸エステル１００質量部に対して、被覆処理物からの原体溶出性を確保する観点から、０．２５質量部以上が好ましく、得られる錠剤の保管時水分吸収による外観変化防止の観点から、２０質量部以下が好ましい。これらの観点から、崩壊剤の含有量は、好ましくは０．２５～２０質量部、より好ましくは０．５～１５質量部、さらに好ましくは１～１０質量部である。 The content of the disintegrant is preferably 0.25 parts by mass or more with respect to 100 parts by mass of the avilateron acetate from the viewpoint of ensuring the dissolution of the drug substance from the coated product, and it depends on the water absorption during storage of the obtained tablet. From the viewpoint of preventing changes in appearance, 20 parts by mass or less is preferable. From these viewpoints, the content of the disintegrant is preferably 0.25 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, and further preferably 1 to 10 parts by mass.
　本発明の固形製剤は、アビラテロン酢酸エステルに対し、水溶性コーティング剤により被覆処理する工程、及び得られた被覆処理物を用いて、製剤化する工程を含む方法により製造することができる。 The solid preparation of the present invention can be produced by a method including a step of coating the avilateron acetate with a water-soluble coating agent and a step of formulating the obtained coated product.
　アビラテロン酢酸エステルの被覆処理は、例えば、アビラテロン酢酸エステルに対し、又はアビラテロン酢酸エステルを賦形剤及び／又は崩壊剤と混合した混合物に対し、水溶性コーティング剤を精製水等の溶剤に溶解させて調製したコーティング液を、流動層造粒機、撹拌造粒機等を用いて、噴霧して行うことができる。また、調製したコーティング液にアビラテロン酢酸エステルを懸濁し、スプレードライヤーを用いて噴霧乾燥して行うこともできる。なお、溶剤は被覆処理中に揮発させることが好ましい。また、アビラテロン酢酸エステルに賦形剤と水溶性コーティング剤を混合し、アビラテロン酢酸エステルを被覆処理した後、さらに、乾式造粒機を用いて造粒物を得ることも可能である。 In the coating treatment of avilateron acetate, for example, a water-soluble coating agent is dissolved in a solvent such as purified water in a mixture of avilateron acetate or a mixture of avilateron acetate with an excipient and / or a disintegrant. The prepared coating liquid can be sprayed using a fluidized bed granulator, a stirring granulator or the like. Alternatively, the avilateron acetate may be suspended in the prepared coating liquid and spray-dried using a spray dryer. The solvent is preferably volatilized during the coating treatment. It is also possible to mix an excipient and a water-soluble coating agent with the avilateron acetate, coat the avilateron acetate, and then use a dry granulator to obtain granulated products.
　コーティング液中の水溶性コーティング剤の濃度は、０．１～１０質量％程度が好ましく、溶出性の観点から、より好ましくは０．１５～３質量％である。 The concentration of the water-soluble coating agent in the coating liquid is preferably about 0.1 to 10% by mass, and more preferably 0.15 to 3% by mass from the viewpoint of elution.
　コーティング液には、可塑剤等が含まれていてもよいが、本発明においては、水溶性コーティング剤の原体への展延性の観点から、可塑剤が含まれていることが好ましい。 The coating liquid may contain a plasticizer or the like, but in the present invention, it is preferable that the coating liquid contains a plasticizer from the viewpoint of the spreadability of the water-soluble coating agent to the drug substance.
　可塑剤としては、ポリエチレングリコール、グリセリン、ソルビトール、クエン酸アセチルトリブチル、フタル酸ジブチル、流動パラフィン等が挙げられる。可塑剤の含有量は、水溶性コーティング剤１００質量部に対して、５～５０質量部程度が好ましい。 Examples of the plasticizer include polyethylene glycol, glycerin, sorbitol, acetyltributyl citrate, dibutyl phthalate, liquid paraffin and the like. The content of the plasticizer is preferably about 5 to 50 parts by mass with respect to 100 parts by mass of the water-soluble coating agent.
　アビラテロン酢酸エステル（原薬）のかさ密度は０．１４３ｇ／ｍＬであるが、被覆処理によりかさ密度が高くなる。被覆処理物のかさ密度は、粉体の製造性（流動性）の観点から、０．１５０ｇ／ｍＬ以上が好ましく、粉体粒子径の肥大化による製造性の低下を抑制する観点から、１．０００ｇ／ｍＬ以下が好ましい。これらの観点から、被覆処理物のかさ密度は、好ましくは０．１５０～１．０００ｇ／ｍＬ、より好ましくは０．１５０～０．３５０ｇ／ｍＬ、さらに好ましくは０．１６０～０．３００ｇ／ｍＬ、さらに好ましくは０．１８０～０．２５０ｇ／ｍＬである。
　ここで、被覆処理物のかさ密度は、パウダテスタ（登録商標）ＰＴ－Ｒ（ホソカワミクロン（株）製）を用いて測定する。具体的には、第１７改正日本薬局方に記載されている、かさ密度及びタップ密度測定法第３法の測定用容器と同サイズの円筒容器に核粒子混合物を篩いを通して上方から均一に供給し、上面をすり切って秤量することによって疎充填の状態のかさ密度（ゆるみかさ密度）を測定する。 The bulk density of avilateron acetate (drug substance) is 0.143 g / mL, but the bulk density is increased by the coating treatment. The bulk density of the coated product is preferably 0.150 g / mL or more from the viewpoint of powder manufacturability (fluidity), and from the viewpoint of suppressing deterioration of manufacturability due to the enlargement of the powder particle size, 1. It is preferably 000 g / mL or less. From these viewpoints, the bulk density of the coated product is preferably 0.150 to 1.000 g / mL, more preferably 0.150 to 0.350 g / mL, and further preferably 0.160 to 0.300 g / mL. , More preferably 0.180 to 0.250 g / mL.
Here, the bulk density of the coated product is measured using a powder tester (registered trademark) PT-R (manufactured by Hosokawa Micron Co., Ltd.). Specifically, the nuclear particle mixture is uniformly supplied from above to a cylindrical container of the same size as the measurement container of the bulk density and tap density measurement method 3 described in the 17th revised Japanese Pharmacopoeia through a sieve. The bulk density (loose bulk density) in the loosely filled state is measured by scraping the upper surface and weighing.
　被覆処理物を用いた製剤化は、常法により行うことができる。例えば、被覆処理物を、賦形剤（結合剤）、崩壊剤、溶解補助剤、流動化剤、滑沢剤等の添加剤と混合して打錠末を得、得られた打錠末を打錠し、本発明の固形製剤を錠剤に成型することができる。 The formulation using the coated product can be performed by a conventional method. For example, the coated product is mixed with additives such as an excipient (binder), a disintegrant, a solubilizing agent, a fluidizing agent, and a lubricant to obtain a tableting powder, and the obtained tableting powder is obtained. The solid preparation of the present invention can be tableted and molded into a tablet.
　製剤化する工程において被覆処理物と混合する添加剤は、予め混合して用いてもよく、多段階に分割して混合してもよい。例えば、滑沢剤は、錠剤硬度の低下、崩壊遅延の原因となる可能性があるため、他の添加剤を混合した後に、別途混合することが好ましい。 The additive to be mixed with the coated product in the step of formulating may be mixed in advance or may be divided into multiple stages and mixed. For example, since the lubricant may cause a decrease in tablet hardness and a delay in disintegration, it is preferable to mix other additives and then separately mix them.
　本発明においては、前記したように、かさ密度の高い被覆処理物を含むため、原薬率の高い固形製剤を得ることができ、従来のアビラテロン製剤と同量のアビラテロン酢酸エステル（２５０ｍｇ）を含む固形製剤を、従来の製剤よりも小型化することができる。 In the present invention, as described above, since the coated product having a high bulk density is contained, a solid preparation having a high drug substance ratio can be obtained, and the same amount of the avilateron acetic acid ester (250 mg) as that of the conventional avilateron preparation is contained. The solid formulation can be made smaller than the conventional formulation.
　本発明の固形製剤における原薬率、即ち、１製剤中のアビラテロン酢酸エステルの含有量の割合は、錠剤の小型化の観点から、６０質量％以上が好ましく、錠剤化を容易にする観点から、９０質量％以下が好ましい。これらの観点から、アビラテロン酢酸エステルの含有量は、好ましくは６０～９０質量％、より好ましくは７０～８７質量％、さらに好ましくは７５～８５質量％である。 The drug substance ratio in the solid preparation of the present invention, that is, the ratio of the content of abiraterone acetate in one preparation is preferably 60% by mass or more from the viewpoint of tablet miniaturization, and from the viewpoint of facilitating tableting. 90% by mass or less is preferable. From these viewpoints, the content of avilateron acetate is preferably 60 to 90% by mass, more preferably 70 to 87% by mass, and further preferably 75 to 85% by mass.
　以下に、実施例により本発明を具体的に説明するが、本発明はこれらの実施例によってなんら限定されるものではない。樹脂等の物性は、以下の方法により測定した。 Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples. The physical properties of the resin and the like were measured by the following methods.
実施例１
　表１に示す水溶性コーティング剤と可塑剤を精製水に溶解させ、総量１０００ｇに調整したコーティング液を調製した。
　アビラテロン酢酸エステル（平均粒子径（Ｄ５０）：６．０μｍ）１００ｇに対し、流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、（株）パウレック製）を用いて、得られたコーティング液１４３ｇを噴霧し、被覆処理物を得た。なお、この時点で精製水はほぼ揮発し、被覆処理物の水分量は約０．３質量％であった。
　得られた被覆処理物に、賦形剤２.５６ｇ、崩壊剤２．４０ｇ、及び溶解補助剤７．２０ｇを添加し、流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、（株）パウレック製）を用いて混合した後、さらに、滑沢剤１．６０ｇを添加して混合し、打錠末を得た。
　得られた打錠末を、ロータリー打錠機（ＶＩＲＧＯ　０５１２ＳＳ２ＡＹ、菊水製作所（株）製）に投入し、１錠あたりの原薬量が２５０ｍｇとなるように打錠し、素錠を得た。 Example 1
The water-soluble coating agent and the plasticizer shown in Table 1 were dissolved in purified water to prepare a coating liquid adjusted to a total amount of 1000 g.
Using a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.), 143 g of the obtained coating liquid was sprayed onto 100 g of avilateron acetate (average particle size (D 50): 6.0 μm). Then, a coated product was obtained. At this point, the purified water was almost volatilized, and the water content of the coated product was about 0.3% by mass.
A fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.) was added to the obtained coated product by adding 2.56 g of an excipient, 2.40 g of a disintegrant, and 7.20 g of a solubilizing agent. After mixing with the above, 1.60 g of a lubricant was further added and mixed to obtain a tableted powder.
The obtained tableting powder was put into a rotary tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.) and locked so that the amount of the drug substance per tablet was 250 mg to obtain an uncoated tablet.
実施例２
　アビラテロン酢酸エステル（平均粒子径（Ｄ５０）：６．０μｍ）１００ｇを、表１に示す硬化ナタネ油と混合し、得られた混合物にコーティング液を噴霧した以外は、実施例１と同様にして、素錠を得た。 Example 2
100 g of avilateron acetate (average particle size (D 50 ): 6.0 μm) was mixed with the cured rapeseed oil shown in Table 1, and the obtained mixture was sprayed with a coating solution in the same manner as in Example 1. , I got an uncoated tablet.
実施例３
　アビラテロン酢酸エステル（平均粒子径（Ｄ５０）：６．０μｍ）１００ｇを、表１に示す軽質無水ケイ酸と混合し、得られた混合物にコーティング液を噴霧した以外は、実施例１と同様にして、素錠を得た。 Example 3
The same as in Example 1 except that 100 g of avilateron acetic acid ester (average particle size (D 50 ): 6.0 μm) was mixed with the light anhydrous silicic acid shown in Table 1 and a coating solution was sprayed on the obtained mixture. I got an uncoated tablet.
実施例４～１５
　アビラテロン酢酸エステル（平均粒子径（Ｄ５０）：６．０μｍ）１００ｇを、表１、２に示す硬化ナタネ油及び軽質無水ケイ酸と混合し、得られた混合物にコーティング液を噴霧した以外は、実施例１と同様にして、素錠を得た。 Examples 4 to 15
Except for mixing 100 g of avilateron acetate (average particle size (D 50 ): 6.0 μm) with the cured rapeseed oil and light anhydrous silicic acid shown in Tables 1 and 2 and spraying the coating solution onto the resulting mixture. An uncoated tablet was obtained in the same manner as in Example 1.
実施例１６
　アビラテロン酢酸エステル（平均粒子径（Ｄ５０）：６．０μｍ）１００ｇを、表２に示す軽質無水ケイ酸及び崩壊剤と混合し、得られた混合物にコーティング液を噴霧し、被覆処理物を得た。
　得られた被覆処理物に、賦形剤５．２０ｇ及び溶解補助剤７．２０ｇを添加し、流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、（株）パウレック製）を用いて混合した後、さらに、滑沢剤２．００ｇを添加して混合し、打錠末を得た。
　得られた打錠末を、ロータリー打錠機（ＶＩＲＧＯ　０５１２ＳＳ２ＡＹ、菊水製作所（株）製）に投入し、１錠あたりの原薬量が２５０ｍｇとなるように打錠し、素錠を得た。 Example 16
100 g of avilateron acetate (average particle size (D 50 ): 6.0 μm) was mixed with the light anhydrous silicic acid and disintegrant shown in Table 2, and the obtained mixture was sprayed with a coating liquid to obtain a coated product. rice field.
To the obtained coated product, 5.20 g of an excipient and 7.20 g of a solubilizing agent were added, mixed using a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.), and then mixed. Further, 2.00 g of a lubricant was added and mixed to obtain a tableted powder.
The obtained tableting powder was put into a rotary tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.) and locked so that the amount of the drug substance per tablet was 250 mg to obtain an uncoated tablet.
比較例１
　アビラテロン酢酸エステル１００ｇに、賦形剤２.５６ｇ、崩壊剤２．４０ｇ、及び溶解補助剤７．２０ｇを添加し、流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、（株）パウレック製）を用いて混合した後、さらに、滑沢剤１．６０ｇを添加して混合し、打錠末を得た。
　得られた打錠末を、ロータリー打錠機（ＶＩＲＧＯ　０５１２ＳＳ２ＡＹ、菊水製作所（株）製）を用いて打錠したが、錠剤に成型できなかった。 Comparative Example 1
To 100 g of avilateron acetate, 2.56 g of excipient, 2.40 g of disintegrant, and 7.20 g of lysis aid are added, and a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.) is used. After mixing, 1.60 g of a lubricant was further added and mixed to obtain a tableted powder.
The obtained tableting powder was tableted using a rotary tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.), but could not be molded into a tablet.
比較例２
　比較例１では錠剤に成型できなかったが、これは原薬の流動性の悪さが原因と考え、流動性を改善して、錠剤化が可能になるまで賦形剤の量を増量した。その結果、賦形剤を１７２．５５ｇまで増量することで、初めてスティッキングが発生することなく成型することができた。
　即ち、アビラテロン酢酸エステル１００ｇに、賦形剤１７２．５５ｇ、崩壊剤２．４０ｇ、及び溶解補助剤７．２０ｇを添加し、流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、（株）パウレック製）を用いて混合した後、さらに、滑沢剤１．６０ｇを添加して混合し、打錠末を得た。
　得られた打錠末を、ロータリー打錠機（ＶＩＲＧＯ　０５１２ＳＳ２ＡＹ、菊水製作所（株）製）を用いて打錠し、素錠を得た。 Comparative Example 2
In Comparative Example 1, it was not possible to mold into a tablet, but this was considered to be due to the poor fluidity of the drug substance, and the fluidity was improved and the amount of the excipient was increased until tableting became possible. As a result, by increasing the amount of the excipient to 172.55 g, it was possible to mold without sticking for the first time.
That is, 172.55 g of an excipient, 2.40 g of a disintegrant, and 7.20 g of a solubilizing agent were added to 100 g of avilateron acetate, and a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.) was added. After mixing with the above, 1.60 g of a lubricant was further added and mixed to obtain a tableted powder.
The obtained tableting powder was locked using a rotary locking machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain an uncoated tablet.
　実施例及び比較例で使用した原料の詳細は下記の通り。
〔硬化ナタネ油〕
ラブリワックス－１０３、フロイント産業（株）製、平均粒子径（Ｄ５０）６９μｍ、融点６９℃
〔軽質無水ケイ酸〕
アドソリダー１０１、フロイント産業（株）製、平均粒子径（Ｄ５０）３．２μｍ
〔コーティング剤〕
ＭＣ：メチルセルロース、ＳＭ－４、信越化学工業（株）製
ＨＰＭＣ：ヒドロキシプロピルメチルセルロース、ＴＣ－５Ｅ、信越化学工業（株）製
ＨＰＣ：ヒドロキシプロピルセルロース、ＨＰＣ－ＳＬ、日本曹達（株）製
ＰＶＡ・ＡＡ・ＭＭＡ：ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ＰＯＶＡＣＯＡＴ、日新化成（株）製
〔可塑剤〕
ポリエチレングリコール、マクロゴール６０００、三洋化成工業（株）製
〔賦形剤〕
グランフィラーＤ、（株）ダイセル製
〔崩壊剤〕
ＰＶＰ系クロスポビドン、Ｋｏｌｌｉｄｏｎ－ＣＬ、ＢＡＳＦ製、平均粒子径（Ｄ５０）１２０μｍ
〔溶解補助剤〕
ラウリル硫酸ナトリウム、ｋｏｌｌｉｐｈｏｒ　ＳＬＳ　ｆｉｎｅ、ＢＡＳＦ製
〔滑沢剤〕
ステアリン酸マグネシウム、日油（株）製 Details of the raw materials used in the examples and comparative examples are as follows.
[Hardened rapeseed oil]
Loveliwax-103, manufactured by Freund Sangyo Co., Ltd., average particle size (D 50 ) 69 μm, melting point 69 ° C.
[Light anhydrous silicic acid]
Adsolider 101, manufactured by Freund Sangyo Co., Ltd., average particle size (D 50 ) 3.2 μm
〔Coating agent〕
MC: Methylcellulose, SM-4, HPMC manufactured by Shin-Etsu Chemical Co., Ltd .: Hydroxypropylmethylcellulose, TC-5E, HPC: Hydroxypropylcellulose manufactured by Shin-Etsu Chemical Co., Ltd., HPC-SL, PVA manufactured by Nippon Soda Co., Ltd. AA / MMA: Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, POVACOAT, manufactured by Nissin Kasei Co., Ltd. [Plastic agent]
Polyethylene glycol, Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd. [Excipient]
Granfiller D, manufactured by Daicel Co., Ltd. [Disintegrant]
PVP-based crospovidone, Kollidon-CL, manufactured by BASF, average particle size (D 50 ) 120 μm
[Dissolution aid]
Sodium lauryl sulfate, kolliphor SLS fine, made by BASF [lubricating agent]
Magnesium stearate, manufactured by NOF CORPORATION
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
〔かさ密度の測定〕
　原薬と実施例１～４、６、７、９～１６の被覆処理物のかさ密度を測定した。
　その結果、表１、２に示すように、実施例１～４、６、７、９～１６の被覆処理物のかさ密度は、原薬のみのかさ密度と比較して、十分に高いものであった。 [Measurement of bulk density]
The bulk densities of the API and the coated products of Examples 1 to 4, 6, 7, 9 to 16 were measured.
As a result, as shown in Tables 1 and 2, the bulk density of the coated products of Examples 1 to 4, 6, 7, 9 to 16 is sufficiently higher than the bulk density of the drug substance alone. there were.
〔錠剤の厚みの測定〕
　実施例３と比較例２において、打錠により錠剤化する際に、φ１０ｍｍ、２段Ｒの杵臼を用いて、1錠当たりの原薬含量を１２５ｍｇとし、打圧を５０ｋｇｆ～７０ｋｇｆに調整して錠剤化した。得られた錠剤の厚みを計測したところ、実施例３の錠剤の厚みは小さく、原薬率の高さが反映された結果であった。 [Measurement of tablet thickness]
In Example 3 and Comparative Example 2, when tableting by tableting, the API content per tablet was adjusted to 125 mg and the tableting pressure was adjusted to 50 kgf to 70 kgf using a φ10 mm, 2-stage R pestle. It was made into tablets. When the thickness of the obtained tablet was measured, the thickness of the tablet of Example 3 was small, which reflected the high rate of API.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　以上の結果から、実施例１～１６と比較例１、２の対比から、アビラテロン酢酸エステルをコーティング剤で被覆処理することにより、アビラテロン酢酸エステルをそのまま用いるよりも、かさ密度を高くすることができ、また、高い原薬率での錠剤化が可能であることが分かる。原薬率を高くすることで、原薬量が同量であってもかさ低い小型の錠剤を得ることができる。
　なかでも、実施例１と実施例２～４の対比から、アビラテロン酢酸エステルを、賦形剤とともに水溶性コーティング剤により処理することにより、原薬率が高いことに加えて、さらに被覆処理物のかさ密度を高めることができるため、１錠当たりの質量は同じであっても、同じ打錠圧で圧縮成形した場合に、より小さな素錠を得ることができる。
　なお、アビラテロン酢酸エステルを２５０ｍｇ含有するアビラテロン製剤の市販製剤（ザイティガ錠２５０ｍｇ、ヤンセンファーマ（株）製）の１錠の質量は７３６ｍｇであることから、その原薬率は約３４質量％と算出することができる。これに対し、原薬率が約７５～８５質量％の実施例１～１６の１錠の質量は、約２９０～３３０ｍｇであり、市販製剤と比べても十分に小さく、錠剤は小型化されている。 From the above results, from the comparison between Examples 1 to 16 and Comparative Examples 1 and 2, by coating the avilateron acetate with a coating agent, the bulk density can be increased as compared with using the avilateron acetate as it is. Also, it can be seen that tableting with a high drug substance rate is possible. By increasing the drug substance rate, it is possible to obtain a small tablet having a low bulk even if the drug substance amount is the same.
Among them, from the comparison between Examples 1 and 2 to 4, by treating the avilateron acetate with a water-soluble coating agent together with the excipient, in addition to the high drug substance ratio, it is a coated product. Since the ester density can be increased, even if the mass per tablet is the same, a smaller uncoated tablet can be obtained when compression molding is performed at the same tableting pressure.
Since the mass of one commercially available avilatelon preparation containing 250 mg of avilateron acetate (Zytiga tablet 250 mg, manufactured by Janssen Pharma Co., Ltd.) is 736 mg, the drug substance ratio is calculated to be about 34% by mass. be able to. On the other hand, the mass of one tablet of Examples 1 to 16 having a drug substance ratio of about 75 to 85% by mass is about 290 to 330 mg, which is sufficiently smaller than the commercially available preparation, and the tablet is miniaturized. There is.
〔溶出性〕
　実施例８の素錠とアビラテロン製剤の市販製剤（ザイティガ錠２５０ｍｇ、ヤンセンファーマ（株）製、アビラテロン酢酸エステル２５０ｍｇ含有）の溶出量を以下の条件で試験した。その結果、図１に示すように、実施例８の素錠が市販製剤と同程度の溶出性を有することを確認した。
＜試験条件＞
試験液：０．１％ＳＤＳ ＭｃＩｌｖｉｎｅ緩衝液（ｐＨ４．０）９００ｍＬ
採取時間：５，１０，１５，３０，４５，６０，９０，１２０ｍｉn
回転数：５０ｒｐｍ [Elution]
The elution amount of the uncoated tablet of Example 8 and the commercially available pharmaceutical product of Avilateron (containing 250 mg of Zytiga tablet, manufactured by Janssen Pharma Co., Ltd., and 250 mg of Avilateron acetate) was tested under the following conditions. As a result, as shown in FIG. 1, it was confirmed that the uncoated tablet of Example 8 had the same degree of dissolution as the commercially available pharmaceutical product.
<Test conditions>
Test solution: 0.1% SDS McIlvine buffer (pH 4.0) 900 mL
Collection time: 5,10,15,30,45,60,90,120min
Rotation speed: 50 rpm
　アビラテロン酢酸エステルを原薬として含有する本発明の固形製剤は、前立腺癌等の治療薬として有効な医薬製剤である。 The solid preparation of the present invention containing avilateron acetate as a drug substance is an effective pharmaceutical preparation as a therapeutic drug for prostate cancer and the like.

Claims (14)

  1. 　アビラテロン酢酸エステルが、水溶性コーティング剤により処理されてなる被覆処理物を含む、固形製剤。 A solid preparation containing a coating product in which avilateron acetate is treated with a water-soluble coating agent.
  2. 　被覆処理物のかさ密度が、０．１５０～１．０００ｇ／ｍＬである、請求項１記載の固形製剤。 The solid preparation according to claim 1, wherein the bulk density of the coated product is 0.150 to 1.000 g / mL.
  3. 　水溶性コーティング剤が、水溶性セルロース誘導体、ポリアルキレングリコール、多糖類及びそれらの誘導体、並びにポリビニルアルコールと（メタ）アクリル酸系化合物との共重合体からなる群より選ばれた少なくとも１種である、請求項１又は２記載の固形製剤。 The water-soluble coating agent is at least one selected from the group consisting of water-soluble cellulose derivatives, polyalkylene glycols, polysaccharides and their derivatives, and copolymers of polyvinyl alcohol and (meth) acrylic acid-based compounds. , The solid preparation according to claim 1 or 2.
  4. 　アビラテロン酢酸エステルが、賦形剤及び／又は崩壊剤とともに、水溶性コーティング剤により処理されてなる、請求項１～３いずれか記載の固形製剤。 The solid preparation according to any one of claims 1 to 3, wherein the avilateron acetate is treated with a water-soluble coating agent together with an excipient and / or a disintegrant.
  5. 　賦形剤が、ワックス及び軽質無水ケイ酸の少なくともいずれかを含有する、請求項４記載の固形製剤。 The solid preparation according to claim 4, wherein the excipient contains at least one of wax and light anhydrous silicic acid.
  6. 　ワックスの含有量が、アビラテロン酢酸エステル１００質量部に対して、１～１０質量部である、請求項５記載の固形製剤。 The solid preparation according to claim 5, wherein the wax content is 1 to 10 parts by mass with respect to 100 parts by mass of avilateron acetate.
  7. 　軽質無水ケイ酸の含有量が、アビラテロン酢酸エステル１００質量部に対して、１～１０質量部である、請求項５又は６記載の固形製剤。 The solid preparation according to claim 5 or 6, wherein the content of light anhydrous silicic acid is 1 to 10 parts by mass with respect to 100 parts by mass of avilateron acetate.
  8. 　崩壊剤が、クロスポビドンを含む、請求項４～７いずれか記載の固形製剤。 The solid preparation according to any one of claims 4 to 7, wherein the disintegrant contains crospovidone.
  9. 　崩壊剤の含有量が、アビラテロン酢酸エステル１００質量部に対して、１～１０質量部である、請求項４～８いずれか記載の固形製剤。 The solid preparation according to any one of claims 4 to 8, wherein the content of the disintegrant is 1 to 10 parts by mass with respect to 100 parts by mass of avilateron acetate.
  10. 　水溶性コーティング剤の含有量が、アビラテロン酢酸エステル１００質量部に対して、１～２０質量部である、請求項１～９いずれか記載の固形製剤。 The solid preparation according to any one of claims 1 to 9, wherein the content of the water-soluble coating agent is 1 to 20 parts by mass with respect to 100 parts by mass of avilateron acetate.
  11. 　アビラテロン酢酸エステルの含有量が６０～９０質量％である、請求項１～１０いずれか記載の固形製剤。 The solid preparation according to any one of claims 1 to 10, wherein the content of avilateron acetate is 60 to 90% by mass.
  12. 　固形製剤が錠剤である、請求項１～１１いずれか記載の固形製剤。 The solid preparation according to any one of claims 1 to 11, wherein the solid preparation is a tablet.
  13. 　アビラテロン酢酸エステルに対し、水溶性コーティング剤により被覆処理する工程、及び得られた被覆処理物を用いて、製剤化する工程を含む、請求項１～１２いずれか記載の固形製剤の製造方法。 The method for producing a solid preparation according to any one of claims 1 to 12, which comprises a step of coating the avilateron acetate with a water-soluble coating agent and a step of formulating the avilateron acetate using the obtained coated product.
  14. 　被覆処理する工程において、アビラテロン酢酸エステルを賦形剤及び／又は崩壊剤と混合して被覆処理に供する、請求項１３記載の製造方法。 The production method according to claim 13, wherein in the coating treatment step, the avilateron acetate is mixed with an excipient and / or a disintegrant and subjected to the coating treatment.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054752A1 (en) * 1999-03-15 2000-09-21 Kaken Pharmaceutical Co., Ltd. Quickly disintegrating tablets and process for producing the same
JP2002167327A (en) * 2000-09-22 2002-06-11 Takeda Chem Ind Ltd Solid formulation
JP2006008676A (en) * 2004-05-27 2006-01-12 Ono Pharmaceut Co Ltd Composition for solid preparation
JP2006507036A (en) * 2002-08-14 2006-03-02 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー Method for coating drug particles
WO2014009436A1 (en) * 2012-07-11 2014-01-16 Sandoz Ag Nanosuspension of abiraterone acetate
WO2019208725A1 (en) * 2018-04-25 2019-10-31 富士フイルム株式会社 Pharmaceutical composition, and method for producing pharmaceutical composition

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021024865A (en) * 2019-08-07 2021-02-22 沢井製薬株式会社 Abiraterone acetate-containing preparation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054752A1 (en) * 1999-03-15 2000-09-21 Kaken Pharmaceutical Co., Ltd. Quickly disintegrating tablets and process for producing the same
JP2002167327A (en) * 2000-09-22 2002-06-11 Takeda Chem Ind Ltd Solid formulation
JP2006507036A (en) * 2002-08-14 2006-03-02 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー Method for coating drug particles
JP2006008676A (en) * 2004-05-27 2006-01-12 Ono Pharmaceut Co Ltd Composition for solid preparation
WO2014009436A1 (en) * 2012-07-11 2014-01-16 Sandoz Ag Nanosuspension of abiraterone acetate
WO2019208725A1 (en) * 2018-04-25 2019-10-31 富士フイルム株式会社 Pharmaceutical composition, and method for producing pharmaceutical composition

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