WO2017064814A1 - Comprimé contenant du diénogest - Google Patents

Comprimé contenant du diénogest Download PDF

Info

Publication number
WO2017064814A1
WO2017064814A1 PCT/JP2015/079346 JP2015079346W WO2017064814A1 WO 2017064814 A1 WO2017064814 A1 WO 2017064814A1 JP 2015079346 W JP2015079346 W JP 2015079346W WO 2017064814 A1 WO2017064814 A1 WO 2017064814A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
dienogest
particles
direct compression
parts
Prior art date
Application number
PCT/JP2015/079346
Other languages
English (en)
Japanese (ja)
Inventor
前田　泰弘
Original Assignee
持田製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 持田製薬株式会社 filed Critical 持田製薬株式会社
Priority to PCT/JP2015/079346 priority Critical patent/WO2017064814A1/fr
Priority to JP2016519891A priority patent/JP6002869B1/ja
Publication of WO2017064814A1 publication Critical patent/WO2017064814A1/fr

Links

Images

Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; 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
    • A61K47/06—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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K47/06—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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the present invention relates to an oral pharmaceutical tablet produced by a direct tableting method containing dienogest as an active ingredient and a method for producing the same.
  • Dienogest is a kind of hormone-like substance and has already been used as an active ingredient in pharmaceutical preparations.
  • a pharmaceutical preparation containing dienogest as an active ingredient is marketed as a therapeutic agent for endometriosis “Dinagest Tablets 1 mg”. Since dienogest is a physiologically active ingredient that exhibits physiological activity in a trace amount, for example, the content of dienogest in one tablet is as small as 1 mg.
  • direct tableting is used in the manufacture of tablets for oral use, granulation and drying steps are unnecessary, and production efficiency is better than wet granulation. This is a great advantage from the viewpoint of industrial production. It is also said that there are advantages in the stability and dissolution of the preparation.
  • Patent Document 1 prepares 15-50 ⁇ m dienogest particles known as finely divided dienogest and a binder solution as a method for obtaining a rapidly dissolving dienogest oral pharmaceutical preparation, and the dienogest particles are filled.
  • Patent Document 2 discloses a dienogest solid preparation comprising a dienogest, a filler, a disintegrant, a lubricant, and an adhesive component. A 50% ethanol solution of hypromellose is used as an adhesive component, and it is produced by a production method through granulation and drying processes.
  • dienogest corresponding to 1 mg per tablet
  • D-mannitol Partec M100: Merck
  • D 50 70 ⁇ m
  • crystalline cellulose Theorus PH-101: Asahi Kasei Chemicals
  • crospovidone crospovidone
  • talc magnesium stearate
  • An object of the present invention is to provide a direct tablet for oral medicine that suppresses segregation of the content of dienogest despite containing a low content (a trace amount) of dienogest.
  • the present invention also provides a direct tableting method for oral medicine in which a dienogest drug substance is microparticulated and a tablet with a low content of dienogest in one tablet can be efficiently produced by a direct tableting method with fewer steps and good production efficiency. It aims at providing the manufacturing method of a tablet.
  • the finely divided dienogest drug substance and various excipient particles were mixed so as to be 0.5% dienogest, respectively, and a mixing uniformity test and a segregation test were performed on the mixed powder.
  • This is based on the knowledge that a direct-acting tablet can be produced by using single particles of an excipient having a median diameter of 80 to 300 ⁇ m. That is, this invention has the following aspects which achieve the said objective.
  • (1-1) (A) finely divided dienogest, and (B) at least one excipient particle selected from the group consisting of D-mannitol single particles, lactose single particles, and crystalline cellulose single particles.
  • the direct compression tablet according to (1-1) which contains 0.1 mg to 5 mg of dienogest per tablet, and the weight of the tablet is 50 mg to 500 mg.
  • (1-4) The direct compression tablet according to any one of (1-1) to (1-3), wherein the dienogest contains 95% by mass or more of particles having a particle size of 25 ⁇ m or less.
  • (1-5) Directly containing any one of (1-1) to (1-4), wherein 70 parts by weight to 99 parts by weight of the excipient particles of component (B) are contained per 100 parts by weight of the uncoated tablet. Tablets.
  • (1-6) The direct compression tablet according to any one of (1-1) to (1-5), wherein the lactose single particles are anhydrous lactose single particles, lactose hydrate single particles or a mixture thereof.
  • the binder is at least one selected from the group consisting of low-substituted hydroxypropylcellulose, carboxyvinyl polymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, partially pregelatinized starch, and polyvinylpyrrolidone. -8) direct compression tablet.
  • the disintegrant is at least one selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, carmellose calcium, carmellose and sodium carboxymethyl starch.
  • the fluidizing agent is at least one selected from the group consisting of light anhydrous silicic acid, calcium hydrogen phosphate granules, magnesium aluminate metasilicate, talc, hydrous silicon dioxide, and titanium oxide.
  • the direct compression tablet of any one of (1-8) to (1-10).
  • the lubricant is at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, calcium stearate, sucrose fatty acid ester and stearic acid, (1-8) to (1 -11) (1-13) Component (A) 0.1 to 5 parts by mass, Component (B) 70 to 99 parts by mass, Component (C) 0.1 to 100 parts by mass with respect to 100 parts by mass of the uncoated tablet 5 parts by weight of a lubricant, and at least one additive selected from the group consisting of component (D) 0 parts by weight to 29.8 parts by weight of a binder, a disintegrant, and a fluidizing agent (1- A direct compression tablet of any one of 1) to (1-12). (1-14) The direct compression tablet of any one of (1-1) to (1-13), which is an orally disintegrating tablet. (1-15) An oral pharmaceutical coated tablet having a coating layer on the outside of the direct compression tablet of any one of (1-1) to (1-14).
  • (2-1) (A) at least one excipient particle selected from the group consisting of finely divided dienogest and (B) D-mannitol single particles, lactose single particles and crystalline cellulose single particles, A first dry mixing step of dry mixing excipient particles having a median diameter of 80 ⁇ m to 300 ⁇ m.
  • a second dry mixing step in which the obtained dry mixture may be dry mixed with at least one additive selected from the group consisting of a binder, a disintegrant, and a fluidizing agent;
  • a third dry mixing step in which a lubricant is dry mixed with the obtained dry mixture, and a tableting step in which the obtained dry mixture is directly tableted, (1-1) to (1-14)
  • the direct-action tablet for oral medicine of the present invention can function as an orally disintegrating tablet depending on the selection of additives.
  • the dienogest drug substance is microparticulated, and a tablet with a low content of dienogest in one tablet has a lower production process, resulting in better production efficiency.
  • it can manufacture by the direct tableting method which can reduce the production
  • the dienogest used as a pharmaceutically active ingredient in the present invention is 17-hydroxy-3-oxo-19-nor-17 ⁇ -pregna-4,9-diene-21-nitrile (17-hydroxy-3-oxo-19-nor- 17 ⁇ -pregna-4,9-diene-21-nitrile).
  • Dienogest is marketed in Japan under the product name “Dinagest Tablets 1 mg” and the indication is “endometriosis”.
  • the preferred average particle size of dienogest used in the present invention is 0.5 ⁇ m to 20 ⁇ m, more preferably 1 ⁇ m to 15 ⁇ m, and even more preferably 1 ⁇ m to 10 ⁇ m.
  • the dienogest used in the present invention preferably contains 95% by mass or more of particles having a particle size of 25 ⁇ m or less, and more preferably 99% by mass or more of particles having a particle size of 25 ⁇ m or less.
  • numerical ranges indicated by using “to” indicate ranges including numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • the step of making powder fine particles is carried out by a conventional method, and for example, an atomizer, a pin mill, a jet mill, a ball mill, or the like can be used.
  • the particle diameter measurement method is not particularly limited, and for example, a laser diffraction method, an image imaging method, or the like can be used.
  • a measuring device for example, a laser diffraction / scattering type particle size / particle size distribution measuring device (for example, Microtrack MT3100II (Nikkiso Co., Ltd.), a laser diffraction type particle size distribution measuring device (dry / wet) (for example, Mastersizer 3000 (Malvern )), Wet flow type particle size / shape analyzer (eg FPIA-3000 (Malvern)), static automatic image analyzer (eg Morphologi G3 (Malvern)) etc.
  • a laser diffraction / scattering type particle size / particle size distribution measuring device for example, Microtrack MT3100II (Nikkiso Co., Ltd.
  • a laser diffraction type particle size distribution measuring device dry / wet
  • Wet flow type particle size / shape analyzer eg FPIA-3000 (Malvern)
  • static automatic image analyzer eg Morphologi G3 (Malvern)
  • the active ingredient dieno When measuring the strike in dry, measurement range is preferably performed in 0.5 [mu] m ⁇ 175 .mu.m.
  • the finely divided dienogest which is the component (A)
  • Excipient particles which have a median diameter of 80 ⁇ m to 300 ⁇ m, are used.
  • the “single particle” means a particle composed of a single additive as an additive component, and is obtained by granulating two or more additives (for example, crystalline cellulose and light anhydrous Silica premix products, lactose hydrate and hydroxypropyl cellulose premix products, lactose and corn starch premix products, etc.) are not included.
  • the excipient particles may be prepared by mixing two or three kinds of D-mannitol single particles, lactose single particles and crystalline cellulose single particles (for example, D-mannitol single particles and lactose single particles). Etc.). Further, for example, in the case of D-mannitol single particles, a plurality of D-mannitol single particles having different median diameters may be mixed.
  • the median diameter of the excipient particles used in the present invention is preferably 80 ⁇ m to 300 ⁇ m, more preferably 85 ⁇ m to 250 ⁇ m, still more preferably 90 ⁇ m to 200 ⁇ m. In the present specification, the median diameter of the particles may be described as “D 50 ”.
  • the D-mannitol single particles are ⁇ -type crystals, Granutol (registered trademark) S (manufactured by Freund Sangyo Co., Ltd.) having a median diameter D 50 of 83 ⁇ m, and Pertec (registered trademark) M200 having a D 50 of 150 ⁇ m.
  • Granutol (registered trademark) S manufactured by Freund Sangyo Co., Ltd.
  • Pertec (registered trademark) M200 having a D 50 of 150 ⁇ m.
  • Mannit S having a D 50 of 144 ⁇ m
  • PEARITOL registered trademark 300DC having a D 50 of 250 ⁇ m
  • ROQUETTE rocket
  • the median diameter of the D-mannitol single particles used in the present invention is preferably 80 ⁇ m to 300 ⁇ m, more preferably 85 ⁇ m to 250 ⁇ m, still more preferably 100 ⁇ m to 250 ⁇ m, and particularly preferably 120 ⁇ m to 200 ⁇ m.
  • Super Tab (registered trademark) 21AN having D 50 of 150 ⁇ m which is anhydrous lactose
  • Super Tab 22AN having D 50 of 180 ⁇ m
  • Super Tab 24AN having D 50 of 128 ⁇ m (all of which are manufactured by DFE pharma)
  • lactose hydrate D 50 is 94 ⁇ m Dilactos (registered trademark) S
  • D 50 is 171 ⁇ m Dilactos R (both manufactured by Freund Corporation)
  • D 50 is 191 ⁇ m Tablettose (registered trademark) 70
  • D 50 is 145 ⁇ m.
  • FlowLac 100 (manufactured by Meggle Pharma both of these) of 126 .mu.m, D 50 of 110 [mu] m SuperTab11SD and D 50 Super Tab GR (both manufactured by DFE Pharma) or the like can be used.
  • the crystalline cellulose alone particles D 50 is 90 [mu] m Ceolus (TM) UF-702, D 50 is Ceolus PH-102 of 90 [mu] m, D 50 of 170 ⁇ m Ceolus PH-200 (manufactured by either of which Asahi Kasei Chemicals Corporation ), VIVAPUR (registered trademark) 12 having a D 50 of 180 ⁇ m, VIVAPUR 14 (both manufactured by JRS Pharma) having a D 50 of 170 ⁇ m, and the like can be used.
  • crystalline cellulose and light anhydrous silicic acid (premix product) cannot be used as the component (B) in the present invention because they are not single crystalline cellulose particles.
  • the direct compression tablet of the present invention contains 0.1 mg to 5 mg of dienogest per tablet, and preferably has a tablet weight of 50 mg to 500 mg, more preferably 0.25 mg to 2 mg per tablet. It contains dienogest and the tablet weight is 50 mg to 200 mg. Further, it is preferable to contain 0.1 to 5 parts by mass of dienogest, more preferably 0.25 to 2 parts by mass of dienogest, based on 100 parts by mass of the uncoated tablet. .
  • component (A) and component (B) are first dry mixed. At this time, it is preferable to dry-mix so that the component (A) uniformly adheres to the surface of the component (B) particles.
  • the mixture of the component (A) and the component (B) can be used as an uncoated tablet powder of a direct compression tablet, but the shaping of the component (B) with respect to 100 parts by mass of the uncoated tablet It is preferable to use 70 parts by weight to 99 parts by weight of the agent particles, and use at least one additive selected from the group consisting of a binder, a disintegrant, a fluidizing agent and a lubricant as the balance.
  • additives such as antioxidants, colorants, surfactants, plasticizers, flavoring agents, and the like other than the component (B) may be added within a range that does not interfere with the effects of the present invention. it can.
  • one of the blending purposes of the additive is shown (for example, a binder in the case of low-substituted hydroxypropyl cellulose), but the additive usually has a plurality of blending purposes.
  • each additive can be used for blending purposes known in the field of pharmaceutics.
  • the binder is not particularly limited, and for example, at least one selected from the group consisting of low-substituted hydroxypropylcellulose, carboxyvinyl polymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, partially pregelatinized starch, and polyvinylpyrrolidone is used. Is preferred.
  • the disintegrant is not particularly limited, and for example, at least one selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, carmellose calcium, carmellose, and sodium carboxymethyl starch is used. preferable.
  • a fluidizing agent For example, at least 1 selected from the group which consists of a light anhydrous silicic acid, calcium hydrogenphosphate granule, a magnesium aluminate metasilicate, a talc, a hydrous silicon dioxide, and a titanium oxide. It is preferred to use seeds.
  • the lubricant is not particularly limited, but for example, it is preferable to use at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, calcium stearate, sucrose fatty acid ester, and stearic acid.
  • component (A) 0.1 to 5 parts by mass
  • component (C) 0.1 to 5 parts by mass with respect to 100 parts by mass of the uncoated tablet. It is preferable to contain at least one additive selected from the group consisting of a lubricant part by weight, and 0 part by weight to 29.8 parts by weight of a binder, a disintegrant and a fluidizing agent.
  • the direct compression tablet of the present invention is (1) at least one excipient particle selected from the group consisting of (A) finely divided dienogest and (B) D-mannitol single particles, lactose single particles and crystalline cellulose single particles, A first dry mixing step of dry mixing excipient particles having a median diameter of 80 ⁇ m to 300 ⁇ m, (2) A second dry mixing step (optional step) in which at least one additive selected from the group consisting of a binder, a disintegrant, and a fluidizing agent may be dry mixed with the obtained dry mixture.
  • a third dry mixing step in which a lubricant is dry-mixed with the obtained dry mixture, and (4) the resulting dry mixture is manufactured by a manufacturing method having a tableting step for directly tableting.
  • the second dry mixing step is an optional step
  • the third dry mixing step is an essential step, but in one of several preferred embodiments of the present invention, both are optional. It can also be an optional step.
  • the second dry mixing step and the third dry mixing step can be made essential steps.
  • the dry mixing step is preferably performed at room temperature using a dry powder mixer such as a V-type mixer, a W-type mixer, a tumbler mixer, a container mixer, a stirring mixer, and the like.
  • the direct tableting process is preferably carried out at room temperature using a tableting machine such as a single-shot tableting machine or a rotary tableting machine. When a single-shot tableting machine, a rotary tableting machine or the like is used, it is usually preferable to employ a tableting pressure of 1 kN to 30 kN, preferably 3 kN to 20 kN.
  • the obtained tablets have a hardness of about 30N to 150N.
  • the hardness of a tablet can be easily measured by a conventional method using, for example, a tablet hardness meter (8M: Dr. Schleuniger Pharmatron AG).
  • the sieving process is performed in the first dry mixing step.
  • (B) excipient particles are preferably sieved prior to mixing with (A) micronized dienogest.
  • the sieving treatment is performed after mixing (A) and (B).
  • the sieving treatment can be expected to improve the mixing uniformity such as crushing the aggregated particles of the excipient.
  • the sieve used for the sieving process is not particularly limited, for example, a 16 mesh sieve (aperture 1000 ⁇ m), a 20 mesh sieve (aperture 850 ⁇ m), a 32 mesh sieve (aperture 500 ⁇ m), or the like can be used.
  • the direct compression tablet of the present invention preferably exhibits rapid dissolution, preferably within 15 minutes in the dissolution test method described in the Japanese Pharmacopoeia. It is an immediate release preparation that elutes on average 85% or more.
  • the content of dienogest per tablet is in the range of 90.0% to 110.0% of the specified amount, more preferably It is in the range of 95.0% to 105.0%.
  • the direct compression tablet of the present invention may be an orally disintegrating tablet as defined in the 16th revised Japanese Pharmacopoeia General Rules for Preparations 1.1.1.
  • An orally disintegrating tablet is a tablet that can be rapidly dissolved or disintegrated in the oral cavity with saliva or a small amount of water in the oral cavity.
  • An orally disintegrating tablet can be produced according to the above-described method for producing a direct compression tablet by selecting an additive with reference to Formulation Examples 1 and 3 to 5 described in Table 2 of Experimental Example 3.
  • the direct compression tablet of the present invention may be a coated tablet having a coating layer on the outside of the direct compression tablet.
  • the coating layer include film coating and sugar coating.
  • a coating agent and, if necessary, a coating additive plasticizer, colorant, light-shielding agent, fluidizing agent, etc.
  • a direct compression tablet plain tablet
  • Examples of the coating agent used for film coating include polyvinyl alcohol, polyvinyl alcohol copolymer, droxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydroxyethyl cellulose, ethyl cellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, and hydroxypropyl.
  • Natural polymers such as methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, shellac, polysaccharides such as pullulan, etc. Can be mentioned.
  • the plasticizer include polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, glycerin, glycerin fatty acid ester, triacetin and the like.
  • Other coating additives include titanium oxide, yellow iron sesquioxide, iron sesquioxide, talc, and light anhydrous silicic acid.
  • the sugar coating can be formed on the outside of a direct compression tablet (plain tablet) by mixing a sugar coating agent and a coating additive (coloring agent, light-shielding agent, etc.).
  • sugar coating agents include sugar alcohols and sugars, and specific examples include D-mannitol, trehalose, erythritol, xylitol, sucrose, and the like.
  • the coating layer when the direct compression tablet is an orally disintegrating tablet is, for example, a coating layer as disclosed in WO2012 / 147873, WO2013 / 161103, for example, trehalose and / or erythritol, and an average particle size of 0.1 to 100 ⁇ m containing at least one water-insoluble inorganic compound selected from the group consisting of 50 ⁇ m water-insoluble inorganic salts, silicic acid compounds, aluminum hydroxide, magnesium oxide and zinc oxide and / or water-insoluble fatty acids, salts thereof or esters thereof Examples thereof include a film having the following thickness.
  • component (a) containing at least one selected from titanium oxide, (b) crystalline cellulose, crospovidone and albumin and (c) a saccharide or sugar alcohol, and with respect to 100 parts by weight of component (a),
  • coating layer of the fast disintegrating tablet characterized in that the ratio of the component (b) is 50 parts by mass or more include a film having a thickness of 100 ⁇ m or less.
  • the direct compression tablet of the present invention is a tablet containing 1 mg of dienogest, for example, for endometriosis, 2 mg per day is divided into two doses, and the oral cycle from the 2nd to 5th day of the menstrual cycle Administration is preferred.
  • Example 1 Evaluation of mixing uniformity of dienogest and excipient particles
  • the mixing uniformity of the dienogest drug substance and various excipient particles was examined by the following method.
  • the dienogest drug substance was finely divided (micronized), and particles having a particle size of 25 ⁇ m or less were 99% by mass or more.
  • the particle size was measured using a dry laser diffraction particle size distribution analyzer (HELOS & LODOS) (manufactured by Sympatec) with a measurement range of 0.5 ⁇ m to 175 ⁇ m.
  • HELOS & LODOS dry laser diffraction particle size distribution analyzer
  • D-mannitol single particles As excipient particles, two types of D-mannitol single particles, two types of lactose single particles, one type of crystalline cellulose single particles, and two types of crystalline cellulose and light anhydrous silicic acid (premix product) were used.
  • D-mannitol single particles ⁇ -type crystals with a median diameter of D 50 of 83 ⁇ m (Granitol (registered trademark) S) (Freund Sangyo Co., Ltd.) and D 50 of 150 ⁇ m (Partec (registered trademark) M200) (Merck shares) Company).
  • D 50 of 90 ⁇ m (Ceolus (registered trademark) UF-702) was used.
  • As crystalline cellulose light anhydrous silicic acid (premix products), D 50 is 65 .mu.m (PROSOLV (TM) SMCC50) and, D 50 is 125 [mu] m (PROSOLV (TM) SMCC 90) (or, JRS Pharma) were used.
  • the raw materials were weighed according to the formulations in Table 1, and each was placed in a plastic bag and mixed manually.
  • the dienogest drug substance and excipient particles were mixed so that the concentration of dienogest was 0.5% (containing 0.5 mg of dienogest in 100 mg of the mixed powder).
  • Example 3 (Production of dienogest-containing direct compression tablet)
  • direct compression containing dienogest can be produced by the direct compression method.
  • the excipient single particles subjected to the sieving treatment are dry-mixed with dienogest (the drug substance: particles having a particle size of 25 ⁇ m or less are 99% by mass or more).
  • the mixed powder may be sieved.
  • a binder, a disintegrant and a fluidizing agent are added and dry mixed. Add a lubricant and dry mix.
  • Direct compression is obtained by tableting the obtained mixture using a rotary tableting machine.
  • Formulation examples 1, 3, 4, and 5 can also be used as orally disintegrating tablets.
  • Example 4 (Production of coated tablet having a film coating layer) According to the formulation examples in Table 3, each component is dissolved and dispersed in water and / or alcohol to form a coating solution, and the coating device is provided on the outside of the direct compression tablets (plain tablets) based on formulation examples 1 to 7 manufactured in Example 3. By spray coating, a direct compression tablet having a film coating layer can be obtained.
  • Table 3 Formulation example of film coating layer

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un comprimé directement compressé pour médicaments oraux, ledit comprimé comprenant (A) de fines particules de diénogest et (B) au moins un type de particules d'excipient choisies dans le groupe constitué de particules de D-mannitol, de particules de lactose et de particules de cellulose cristalline, dans lequel le diamètre médian des particules d'excipient varie de 80 à 300 μm. Ce comprimé directement compressé pour médicaments oraux contient uniquement une petite quantité de diénogest (traces), mais permet pourtant de réguler la ségrégation du contenu en diénogest.
PCT/JP2015/079346 2015-10-16 2015-10-16 Comprimé contenant du diénogest WO2017064814A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP2015/079346 WO2017064814A1 (fr) 2015-10-16 2015-10-16 Comprimé contenant du diénogest
JP2016519891A JP6002869B1 (ja) 2015-10-16 2015-10-16 ジエノゲスト含有錠剤

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2015/079346 WO2017064814A1 (fr) 2015-10-16 2015-10-16 Comprimé contenant du diénogest

Publications (1)

Publication Number Publication Date
WO2017064814A1 true WO2017064814A1 (fr) 2017-04-20

Family

ID=57048591

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2015/079346 WO2017064814A1 (fr) 2015-10-16 2015-10-16 Comprimé contenant du diénogest

Country Status (2)

Country Link
JP (1) JP6002869B1 (fr)
WO (1) WO2017064814A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000119175A (ja) * 1998-10-13 2000-04-25 Taisho Yakuhin Kogyo Kk 口腔内速崩壊性固形製剤
WO2007018057A1 (fr) * 2005-08-05 2007-02-15 Freund Corporation Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication
JP2009518377A (ja) * 2005-12-05 2009-05-07 リヒター ゲデオン ニュルト 高純度な１７α−シアノメチル−１７β−ヒドロキシ−エストラ−４，９−ジエン−３−オン及びその合成方法
WO2013161103A1 (fr) * 2012-04-26 2013-10-31 持田製薬株式会社 Composition comportant de l'oxyde de titane empêché de changer de couleur

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000119175A (ja) * 1998-10-13 2000-04-25 Taisho Yakuhin Kogyo Kk 口腔内速崩壊性固形製剤
WO2007018057A1 (fr) * 2005-08-05 2007-02-15 Freund Corporation Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication
JP2009518377A (ja) * 2005-12-05 2009-05-07 リヒター ゲデオン ニュルト 高純度な１７α−シアノメチル−１７β−ヒドロキシ−エストラ−４，９−ジエン−３−オン及びその合成方法
WO2013161103A1 (fr) * 2012-04-26 2013-10-31 持田製薬株式会社 Composition comportant de l'oxyde de titane empêché de changer de couleur

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D. N. ANURADHA ET AL.: "Design and evaluation of fast dissolving tablets of ketorolac tromethamine using natural disintegrants", INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES, vol. 2, no. 4, 2013, pages 462 - 473, XP055375539 *
S. M. SHAHIDULLA ET AL.: "Formulation and evaluation of fast disintegrating tablets of domperidone by using plantago ovata mucilage", INTERNATIONAL JOURNAL OF CHEMICAL SCIENCES, vol. 10, no. 3, 2012, pages 1521 - 1528, XP055375537 *
YASUYUKI ASAI: "Chokusetsu Dajoho ni yoru Jozai no Seizo ni Kansuru Kenkyu", FINE CHEMICAL, vol. 35, no. 2, 2006, pages 40 - 46 *

Also Published As

Publication number Publication date
JP6002869B1 (ja) 2016-10-05
JPWO2017064814A1 (ja) 2017-10-19

Similar Documents

Publication Publication Date Title
JP5401327B2 (ja) 溶出性の改善された錠剤
MX2011009440A (es) Tableta y polvo granulado que contiene 6-fluoro-3-hidroxi-2-pirazi ncarboxamida.
WO2014030656A1 (fr) Particule creuse contenant un médicament
WO2010111264A2 (fr) Préparations de rasagiline
CA3029543C (fr) Composition pharmaceutique a liberation immediate d'agents chelateurs du fer
JP5511663B2 (ja) タムスロシン塩酸塩を含有する球形微粒子の製造方法
JP2017075139A (ja) 低用量薬物を含有する口腔内崩壊錠
JP2011246428A (ja) 口腔内崩壊型医薬品及びその製造方法
EP2696857A1 (fr) Composition pharmaceutique comprenant du bosentan
US20100172982A1 (en) Sustained release formulations of divalproex sodium
JP2017075138A (ja) ジエノゲスト含有錠剤
JP6002869B1 (ja) ジエノゲスト含有錠剤
JP5275815B2 (ja) リスペリドンを含有する口腔内崩壊錠剤および苦味抑制製剤
US20180344648A1 (en) Clobazam tablet formulation and process for its preparation
JP2002012540A (ja) 水易溶性薬物含有錠剤
JP6297930B2 (ja) イブプロフェン含有錠剤およびその製造方法
JP4494712B2 (ja) マルチプルユニット型徐放性製剤
JP6002870B1 (ja) 低用量薬物を含有する口腔内崩壊錠
WO2022042646A1 (fr) Composition de chlorhydrate de lurasidone et son procédé de préparation
JP5900702B2 (ja) 経口投与用医薬組成物
WO2022210829A1 (fr) Comprimé contenant de l'acétate d'abiratérone
JP7047236B2 (ja) 微粒子化トルカポンを含む徐放性錠剤
JP2024003789A (ja) 時限放出型顆粒およびその用途
WO2023182332A1 (fr) Composition d'additifs pour comprimés orodispersible
JP2021181434A (ja) 水不溶性ポリマーコーティング顆粒、それを含む製剤及びその製造方法

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2016519891

Country of ref document: JP

Kind code of ref document: A

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15906278

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15906278

Country of ref document: EP

Kind code of ref document: A1