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WO2013081044A1 - Pilule comprenant un hydrate de méthanesulfonate de 1-cyclopropyle-8-(difluorométhoxy)-7-[(1r)-1-méthyle-2,3-dihydro-1h-isoindol-5-yle]-4-oxo-1,4-dihydroquinoléine-3-acide carboxylique - Google Patents

Pilule comprenant un hydrate de méthanesulfonate de 1-cyclopropyle-8-(difluorométhoxy)-7-[(1r)-1-méthyle-2,3-dihydro-1h-isoindol-5-yle]-4-oxo-1,4-dihydroquinoléine-3-acide carboxylique Download PDF

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Publication number
WO2013081044A1
WO2013081044A1 PCT/JP2012/080887 JP2012080887W WO2013081044A1 WO 2013081044 A1 WO2013081044 A1 WO 2013081044A1 JP 2012080887 W JP2012080887 W JP 2012080887W WO 2013081044 A1 WO2013081044 A1 WO 2013081044A1
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WO
WIPO (PCT)
Prior art keywords
tablet
mixed
manufactured
uncoated
sieve
Prior art date
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Ceased
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PCT/JP2012/080887
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English (en)
Japanese (ja)
Inventor
佐保枝 角田
務 宮崎
康太郎 岡田
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Toyama Chemical Co Ltd
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Toyama Chemical Co Ltd
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Priority to SG11201402597WA priority Critical patent/SG11201402597WA/en
Priority to BR112014012994A priority patent/BR112014012994A2/pt
Priority to RU2014126094A priority patent/RU2633477C2/ru
Priority to CN201280066321.0A priority patent/CN104039322A/zh
Priority to JP2013547208A priority patent/JP6117112B2/ja
Application filed by Toyama Chemical Co Ltd filed Critical Toyama Chemical Co Ltd
Priority to MX2014006378A priority patent/MX350659B/es
Publication of WO2013081044A1 publication Critical patent/WO2013081044A1/fr
Priority to ZA2014/03942A priority patent/ZA201403942B/en
Priority to PH12014501224A priority patent/PH12014501224B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to miniaturized 1-cyclopropyl-8- (difluoromethoxy) -7-[(1R) -1-methyl-2,3-dihydro-1H-isoindol-5-yl] -4-oxo
  • the present invention relates to a tablet containing methanesulfonate hydrate of 1,4-dihydroquinoline-3-carboxylic acid.
  • Compound A 1-cyclopropyl-8- (difluoromethoxy) -7-[(1R) -1-methyl-2,3-dihydro-1H-isoindol-5-yl] -4-oxo-1,4-dihydroquinoline- Methanesulfonate hydrate of 3-carboxylic acid (hereinafter referred to as Compound A) has a strong antibacterial action against Gram-positive and Gram-negative bacteria, especially MRSA, and is useful as a therapeutic agent for various infectious diseases [Patent Document 1].
  • Tablets containing Compound A methanesulfonate hydrate are commercially available as film-coated tablets (Geninac Tablets 200 mg, manufactured by Toyama Chemical Co., Ltd.), and each tablet contains Compound A 200 mg, weight: about 357 mg, major axis: About 11.8mm, short axis: about 7.1mm, thickness: about 4.7mm.
  • the content of methanesulfonate hydrate of Compound A in this tablet is about 72% of the tablet weight (mass percentage: hereinafter,% used in the present specification means mass percentage unless otherwise specified. means.).
  • two tablets are orally administered once a day. Such relatively large tablets have a sense of resistance and pressure even in adult patients, and in patients with difficulty in swallowing, such as children and the elderly, it is not easy to take drugs, resulting in decreased compliance. May cause.
  • Non-patent Document 1 the size of a round tablet easy to drink is 7 to 8 mm in diameter, and the size of an elliptical tablet easy to drink is 9 mm in long diameter.
  • a tablet smaller than 200 mg of commercially available Geninac tablets is desired.
  • An object of the present invention is to provide a tablet of methanesulfonate hydrate of Compound A that is smaller than 200 mg of commercially available Geninac tablets.
  • a tablet having a methanesulfonate hydrate content of Compound A of 80 to 97.5% by mass is a commercially available Geninac tablet 200 mg. It was found to be a smaller tablet, having excellent dissolution properties and excellent hardness and friability.
  • the tablet of the present invention has the following characteristics. (1) The content of methanesulfonate hydrate of Compound A per formulation is 80-97.5% by mass. (2) The tablet size is smaller than 200 mg of commercially available Geninac tablets. (3) As a result, medication compliance is improved. (4) Elution is excellent. (5) Excellent hardness and friability. (6) As a result, it withstands film coating and transfer.
  • the tablet of the present invention is useful as a tablet of Compound A methanesulfonate hydrate.
  • the methanesulfonate hydrate of Compound A used in the present invention can be produced, for example, by the method described in WO99 / 21849.
  • the tablet of the present invention contains methanesulfonate hydrate of Compound A.
  • the methanesulfonate hydrate content of Compound A may be 80-97.5% by mass, preferably 80-95% by mass, based on the mass of the uncoated tablet.
  • the tablet of this invention can add a disintegrating agent as needed.
  • a fluidizing agent, a lubricant and / or a coating agent can be added as necessary.
  • the tablet of the present invention can be obtained by producing a granulated powder containing the methanesulfonate hydrate of Compound A, adding an additive if desired, and compression molding. Moreover, it can be film-coated as necessary.
  • the disintegrant and other additives used in the present invention can be blended in and / or outside the granulated powder.
  • Disintegrants used in the present invention include, for example, cellulose derivatives such as croscarmellose sodium, carmellose calcium, low substituted hydroxypropylcellulose and carmellose; starch derivatives such as sodium starch glycolate and partially pregelatinized starch; and And polyvinylpyrrolidone derivatives such as crospovidone.
  • Preferred disintegrants include crospovidone, croscarmellose sodium and carmellose calcium, more preferably croscarmellose sodium and carmellose calcium. These disintegrants may be used alone or in combination of two or more.
  • the content of the disintegrant may be 0.5 to 20%, preferably 1.0 to 15%, more preferably 1.5 to 7.5% of the uncoated tablet mass.
  • the fluidizing agent used in the present invention includes, for example, silicon dioxide.
  • the fluidizing agent can be blended in and / or outside the granulated powder.
  • silicon dioxide examples include light silicic acid anhydrides such as Adsolider 101 (Freund Sangyo), Erojil 200 (Nippon Aerosil) and Sirisia 350 (Way-Kay F); and AdSolider 102 (Freund Sangyo) and Carplex # 67. , # 80, # 100, # 1120 (Shionogi Pharmaceutical Co., Ltd.) and the like.
  • Preferred silicon dioxide includes Erogil 200 and Carplex 80.
  • the content of silicon dioxide is 0.1 to 15%, preferably 0.25 to 7.5%, more preferably 0.5 to 5% of the mass of the tablet or granulated powder.
  • the methanesulfonate hydrate content of Compound A is a small tablet having a mass of 80% by mass or more, and has excellent dissolution properties, and has high hardness and friability. The effect is excellent.
  • Examples of the coating agent used in the present invention include hypromellose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer and polyvinyl alcohol / polyethylene glycol / graft copolymer. Preferably, hypromellose is more preferable. These coating agents may be used alone or in combination of two or more.
  • a lubricant can be blended in and / or outside the granulated powder.
  • a method of blending outside the granulated powder more preferably, a method of blending inside and outside the granulated powder can be mentioned.
  • the lubricant include sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, talc and sucrose fatty acid ester.
  • Preferable lubricants include magnesium stearate and talc, and more preferably magnesium stearate.
  • the content of the lubricant is from 0.1 to 5%, preferably from 0.2 to 4%, more preferably from 0.5 to 3% of the mass of the tablet or granulated powder.
  • excipients used as desired in the present invention include, for example, sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; ⁇ -cyclodextrin, ⁇ - And cyclodextrins such as cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin and sulfobutyl ether ⁇ -cyclodextrin sodium; and celluloses such as powdered cellulose and crystalline cellulose. These excipients may be used alone or in combination of two or more. The addition amount of the excipient is not particularly limited, and a necessary amount may be appropriately blended depending on the purpose.
  • Preferred excipients include crystalline cellulose.
  • Crystalline cellulose includes microcrystalline cellulose. Crystalline cellulose of various grades can be used. Preferred examples include those having an average degree of polymerization of 100 to 350, an average particle size of 20 to 170 ⁇ m, a loss on drying of 1.0 to 7.0%, and a bulk density of 0.10 to 0.46 g / cm 3 , and more preferably an average degree of polymerization of 100 to 350, Examples include those having an average particle size of 50 ⁇ m, loss on drying of 2.0 to 6.0%, and bulk density of 0.10 to 0.31 g / cm 3 .
  • additives usually used for drugs can be used within a range not impairing the effects of the present invention.
  • Additives that are usually used in medicines include flavoring agents, coloring agents, flavoring agents, surfactants, plasticizers and antifoaming agents.
  • Examples of the corrigent include aspartame, saccharin, stevia, thaumatin, and acesulfame potassium.
  • Examples of the colorant include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible red No. 102, edible yellow No. 4, and edible yellow No. 5.
  • flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, And powder fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
  • the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbates, and polyoxyethylene hydrogenated castor oil.
  • plasticizer include triethyl citrate, dibutyl phthalate, triacetin and propylene glycol, and triacetin is preferable.
  • antifoaming agent examples include a silicon antifoaming agent and a silicon resin emulsion. These additives may be used singly or in combination of two or more, and the blending amount is not particularly limited, and may be appropriately blended so that the effect is sufficiently exhibited according to each purpose. .
  • the administration method, the dosage and the number of administration can be appropriately selected according to the age, weight and symptoms of the patient, but usually the amount capable of exerting the drug effect is several times a day. In general, for adults, 100 to 2000 mg of Compound A is administered once a day.
  • a granulated powder is produced by a dry granulation method, and if desired, one or more excipients, disintegrants, lubricants and the like are further added to obtain a mixed powder for tableting, An uncoated tablet can be obtained by tableting, and a film coating method can be used.
  • Examples of the dry granulation method include a compacting method, a slugging method, and a briquetting method, and the compacting method is preferable.
  • Examples of the compacting method include a method of producing a compression molded product using a roller compactor and crushing it to obtain granulated particles. The pressure of the roller compactor varies depending on the model used, but when using TF-LABO (manufactured by Freund Industries), 3 to 9 MPa is preferable.
  • a method for adding the disintegrant (1) a method of adding a disintegrant to the mixed powder of methanesulfonate hydrate of compound A and other additives to produce a compression molded product, (2) from a compression molded product
  • examples thereof include a method of adding a disintegrant together with other additives to the obtained granulated particles and a method of using the methods (3), (1) and (2) in combination.
  • a method of adding a fluidizing agent (1) a method of producing a compression molded product by adding silicon dioxide to a mixed powder of methanesulfonate hydrate of compound A and a disintegrant, (2) obtained from the compression molded product
  • Examples include a method of adding silicon dioxide together with other additives to the obtained granulated particles, and a method of using the methods (3), (1) and (2) in combination, and any method may be used.
  • the tablet of the present invention is preferably a round tablet.
  • the size of the round tablet is preferably 7 to 9 mm in diameter and 3 to 5 mm in thickness.
  • the hardness of the uncoated tablet is preferably 50 to 200N, more preferably 60 to 200N.
  • the friability of the uncoated tablet is preferably as small as possible, but is preferably 0 to 4% and more preferably 0 to 2% under the condition of 750 revolutions (30 minutes) at 25 rpm using a tablet friability tester.
  • the tablets of the present invention are the 16th revised Japanese Pharmacopoeia Dissolution Test Method (Paddle Method), and the 85% dissolution time in a dissolution test where the first solution of the Japanese Pharmacopoeia Dissolution Test is the test solution and the rotation speed is 50 times / min. May be 30 minutes or less, but is preferably 15 minutes or less.
  • the test liquid No. 1 in the Japanese Pharmacopoeia dissolution test method is a test liquid prepared by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to make 1000 mL.
  • the 85% dissolution time is the time for 85% by weight of Compound A out of Compound A contained in the tablet.
  • Test example 1 As samples, the film-coated tablets of Examples 1 to 4, 9 to 10 and Reference Examples 1 to 2 were used.
  • the dissolution test was conducted by the Japanese Pharmacopoeia dissolution test (paddle method). The rotation speed of the paddle was 50 rpm. A sample was put into 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test, and after 30 minutes, the test solution was collected, and the dissolution rate (%) of Compound A was determined by the absorbance method.
  • the first dissolution test solution was prepared as 1000 mL by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid (JIS K 8180, special grade) and water. The results are shown in Table 1.
  • Film-coated tablets using corn starch (Reference Example 1) and hydroxypropyl starch (Reference Example 2) as disintegrants had an elution rate of less than 85% after 30 minutes and exhibited low elution properties.
  • a film-coated tablet using Example 9) and partially pregelatinized starch (Example 10) had a high content of 85% of the methanesulfonate hydrate of Compound A in the uncoated tablet. The elution rate after a minute was 85% or more, and an excellent elution property was shown.
  • Test example 2 As samples, the film-coated tablets and uncoated tablets of Examples 1 to 8 were used. The dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1. The hardness of the uncoated tablet was determined by measuring three times using a tablet hardness meter (tablet hardness meter 8M, manufactured by Schleunigel). The friability of the uncoated tablets is 750 rotations (30 minutes) at 25 rpm for 22 tablets using a tablet friability tester (PTF1ER, manufactured by PHARMATE) according to the Japanese Pharmacopoeia reference information “Table friability test method”. Obtained according to conditions. The results are shown in Table 2.
  • the hardness of uncoated tablets containing no light anhydrous silicic acid is 58 to 86 N, while the hardness of uncoated tablets containing light anhydrous silicic acid (Examples 5 to 8) is 88 to 86 N. It was greatly improved to 132N.
  • the uncoated tablet containing light anhydrous silicic acid (Examples 5 to 8) has a friability of 1.1 to 1.7% compared to the uncoated tablet containing light anhydrous silicic acid (Examples 1 to 4). The degree was 0.4-0.7%.
  • the uncoated tablets of Examples 1 to 4 were excellent as tablets having necessary hardness and friability, and the uncoated tablets of Examples 5 to 8 were excellent as tablets having further improved hardness and friability. Both the film-coated tablets not containing light anhydrous silicic acid (Examples 1 to 4) and the film-coated tablets containing light anhydrous silicic acid (Examples 5 to 8) had an elution rate of 85% or more after 30 minutes, Excellent elution was exhibited.
  • Test example 3 The film-coated tablets and uncoated tablets of Examples 11 and 12 were used as samples.
  • the dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1.
  • the hardness of the uncoated tablet and the friability of the uncoated tablet were the same as in Test Example 2.
  • the hardness of the uncoated tablet was determined by measuring 10 times. The results are shown in Table 3.
  • Film coated tablets having a 90% content of methanesulfonate hydrate of Compound A in the uncoated tablets have an dissolution rate of 85% or more after 30 minutes, and exhibit excellent dissolution properties. It was.
  • the uncoated tablet containing light anhydrous silicic acid (Example 12) has a hardness approximately twice that of the uncoated tablet not containing light anhydrous silicic acid (Example 11), and the friability is about Reduced to 1/2.
  • Test example 4 The film-coated tablets and uncoated tablets of Examples 6, 13 and 14 were used as samples.
  • the dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1.
  • the hardness of the uncoated tablet and the friability of the uncoated tablet were the same as in Test Example 2.
  • the hardness of the uncoated tablet was determined by measuring 3 times in Example 6, 6 times in Example 13, and 10 times in Example 14. The results are shown in Table 4.
  • the dissolution rate after a minute was 85% or more, showing excellent dissolution, and the uncoated tablet was excellent as a tablet having the required hardness and friability.
  • the film-coated tablet containing light anhydrous silicic acid (Example 13) and the film-coated tablet containing hydrous silicon dioxide (Example 14) had an elution rate of 85% or more after 30 minutes regardless of the type of silicon dioxide. And showed excellent dissolution properties, and the uncoated tablet was excellent as a tablet having the required hardness and friability.
  • Test Example 5 The film-coated tablets and uncoated tablets of Examples 15 to 29 were used as samples.
  • the dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1.
  • the hardness of the uncoated tablet and the friability of the uncoated tablet were the same as in Test Example 2.
  • the hardness of the uncoated tablet was determined by measuring 10 times. The results are shown in Table 5.
  • Film coated tablets (Examples 15 to 23) with 95% content of methanesulfonate hydrate of Compound A in the uncoated tablets have an elution rate of 85% or more after 30 minutes and show excellent dissolution properties. It was. Moreover, those uncoated tablets had sufficient hardness. In particular, the uncoated tablet containing light anhydrous silicic acid and / or hydrous silicon dioxide (Examples 15, 17, 19-22) had an excellent friability of 1-2%. In addition, the content of methanesulfonate hydrate of Compound A in the uncoated tablet is as high as 97.5%, and the film-coated tablets (Examples 24 to 29) also have an excellent dissolution rate of 85% or more after 30 minutes. Showed sex. Those uncoated tablets were excellent as tablets having the required hardness and friability.
  • Example 1 122.91 g of methanesulfonate hydrate of Compound A, 13.81 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and 7.1 g of low-substituted hydroxypropylcellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical) Sieve twice with an open 850 ⁇ m sieve.
  • crystalline cellulose Theolas PH101, manufactured by Asahi Kasei Chemicals
  • L-HPC LH-11 low-substituted hydroxypropylcellulose
  • magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 2 122.92 g of methanesulfonate hydrate of Compound A, 13.81 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals Co., Ltd.) and 7.1 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) are mixed and mixed with a sieve having an opening of 850 ⁇ m. Sifted through. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • magnesium stearate magnesium stearate
  • magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 10 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 3 122.92 g of methanesulfonate hydrate of Compound A, 13.81 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and 7.1 g of croscarmellose sodium (Primellose, manufactured by DMV) are mixed and sieved twice with a sieve having an opening of 850 ⁇ m I had. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • magnesium stearate magnesium stearate
  • magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 4 122.92g of methanesulfonate hydrate of Compound A, 13.81g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and 7.11g of sodium starch glycolate (Primogel, manufactured by DMV) were mixed and twice with a sieve having an opening of 850 ⁇ m Sifted. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • magnesium stearate magnesium stearate
  • magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 5 122.9 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 12.4 g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and low-substituted hydroxypropylcellulose (L-HPC) (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) 7.11 g was mixed and sieved twice with a sieve having an opening of 850 ⁇ m.
  • crystalline cellulose Theolas PH101, manufactured by Asahi Kasei Chemicals
  • Erogyl 200 light anhydrous silicic acid
  • L-HPC low-substituted hydroxypropylcellulose
  • magnesium stearate magnesium stearate, manufactured by Taihei Chemical Industry
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.7 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 6 122.9 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 12.4 g, 1.4 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and carmellose calcium (ECG-505, Nichirin Chemical) 7.1 g) was mixed and sieved twice with a sieve having an opening of 850 ⁇ m. To this mixed powder, 1.3 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m, and mixed for 30 minutes.
  • crystalline cellulose Theolas PH101, manufactured by Asahi Kasei Chemicals
  • Erogyl 200 manufactured by Nippon Aerosil
  • ECG-505, Nichirin Chemical 7.1 g
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.7 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 7 122.91 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 12.4 g, 1.4 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and croscarmellose sodium (Primelose, manufactured by DMV) 7.1 g was mixed and sieved twice with a sieve having an opening of 850 ⁇ m. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m, and mixed for 30 minutes.
  • magnesium stearate magnesium stearate
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 8 122.91 g of methanesulfonate hydrate of Compound A, 12.4 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals), 1.4 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and sodium starch glycolate (Primogel, manufactured by DMV) ) 7.1 g was mixed and sieved twice with a sieve having an opening of 850 ⁇ m. To this mixed powder, 1.3 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m, and mixed for 30 minutes.
  • magnesium stearate magnesium stearate
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 9 44.07 g of methane sulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 4.44 g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) 0.5 g, carmellose (NS-300, manufactured by Nichirin Chemical) 0.44 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having 2.54 g and an opening of 500 ⁇ m was mixed, and sieved twice with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes.
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets.
  • the coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
  • Example 10 44.07 g of methane sulfonate hydrate of Compound A, 4.43 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals), 0.49 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil), partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals) ) 0.44 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having 2.54 g and an opening of 500 ⁇ m was mixed and sieved twice with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes.
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets.
  • a coating agent a material obtained by adding a small amount of a silicon antifoaming agent (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) to Opadry 00K43069 was used.
  • Example 11 Methanesulfonate hydrate 47.32g of compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 2.43g, carmellose calcium (ECG-505, manufactured by Nichirin Chemical) 1.89g, and stearic acid passed through a sieve with an opening of 500 ⁇ m
  • Magnesium (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) (0.35 g) was mixed and sieved twice with a sieve having an aperture of 850 ⁇ m. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • Example 12 47.31g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 1.91g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) 0.52g, carmellose calcium (ECG-505, Nichirin Chemical) (Manufactured) 1.9 g and 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having an opening of 500 ⁇ m were mixed, and sieved twice with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes.
  • crystalline cellulose Theolas PH101, manufactured by Asahi Kasei Chemicals
  • Erogyl 200 manufactured by Nippon Aerosil
  • carmellose calcium ECG-505, Nichirin Chemical
  • Manufactured 1.9 g and 0.35 g of
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.9 mg per tablet to obtain film-coated tablets.
  • Example 13 59.83 g of methanesulfonate hydrate of Compound A and 2.14 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) were mixed and sieved with a granulator (Comil, screen diameter 1.143 mm). The sieved powder was placed in a mixing container. Next, 3.56 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) and 3.9 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals Co., Ltd.) are sifted with a granulator (Comil, screen diameter 1.143 mm).
  • ECG-505 manufactured by Nichirin Chemical Co., Ltd.
  • 3.9 g of crystalline cellulose Theolas PH101, manufactured by Asahi Kasei Chemicals Co., Ltd.
  • the finished powder was placed in a mixing container. After sieving, 0.65 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 11 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.8 mg per tablet to obtain film-coated tablets.
  • magnesium stearate magnesium stearate, manufactured by Taihei Chemical Industry
  • Example 14 44.42 g of methanesulfonate hydrate of Compound A, 2.89 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals), 1.58 g of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan), carmellose calcium (ECG-505, Nichirin) Chemical) (2.63 g) and 0.47 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Sangyo) passed through a sieve with an opening of 500 ⁇ m were mixed, and sieved twice with an sieve of an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes.
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.9 mg per tablet to obtain film-coated tablets.
  • Example 15 49.97g of methane sulfonate hydrate of Compound A, 0.53g of light anhydrous silicic acid (Erogil 200, manufactured by Nippon Aerosil) and 1.17g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) are mixed and sieved with 850 ⁇ m mesh And sieved. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • Erogil 200 light anhydrous silicic acid
  • ECG-505 carmellose calcium
  • Example 16 49.95 g of methanesulfonate hydrate of Compound A and 1.69 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) were mixed and sieved with a sieve having an opening of 850 ⁇ m.
  • ECG-505 manufactured by Nichirin Chemical
  • 0.35 g of magnesium stearate magnesium stearate, manufactured by Taihei Chemical Industry
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
  • Example 17 49.94 g of methanesulfonate hydrate of Compound A, 0.53 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) and 1.17 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals Co., Ltd.) are mixed. And sieved with a sieve. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • Erogyl 200 manufactured by Nippon Aerosil Co., Ltd.
  • croscarmellose sodium Karlolate ND-2HS, manufactured by Asahi Kasei Chemicals Co., Ltd.
  • Example 18 49.99 g of methanesulfonate hydrate of Compound A and 1.70 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 ⁇ m. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • magnesium stearate magnesium stearate
  • Example 19 Mix methanesulfonate hydrate 50.22g of compound A, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) 0.26g and carmellose calcium (ECG-505, manufactured by Nichirin Chemical) 1.18g sieve And sieved.
  • ECG-505, manufactured by Nichirin Chemical 1.18g sieve And sieved.
  • 0.35 g of magnesium stearate magnesium stearate, manufactured by Taihei Chemical Industry
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • Example 20 Compound A 50.20 g of methanesulfonate hydrate, 0.26 g of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 1.18 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) were mixed, and the mesh opening was 850 ⁇ m. Sieving with a sieve. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • magnesium stearate magnesium stearate
  • Example 21 50.48 g of methanesulfonate hydrate of Compound A and 1.19 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) were mixed and sieved with a sieve having an opening of 850 ⁇ m. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • ECG-505 manufactured by Nichirin Chemical Co., Ltd.
  • Example 22 49.96 g of methanesulfonate hydrate of Compound A, 0.53 g of light anhydrous silicic acid (Erogil 200, manufactured by Nippon Aerosil), 0.60 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) and crospovidone (Polyplastone XL- (10, ISP Japan) 0.60 g was mixed and sieved with a sieve having an opening of 850 ⁇ m. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • Erogil 200 light anhydrous silicic acid
  • ECG-505 carmellose calcium
  • crospovidone Polyplastone XL- (10, ISP Japan
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 1.1% of magnesium stearate equivalent to the weight of the uncoated tablet was added through a 500 ⁇ m sieve and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
  • Example 23 49.96g of Compound A methanesulfonate hydrate, 0.85g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) and 0.85g of crospovidone (Polyplastidone XL-10, ISP Japan) were mixed, and the mesh opening was 850 ⁇ m. Sieving with a sieve. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • ECG-505, manufactured by Nichirin Chemical Co., Ltd. 0.85g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) and 0.85g of crospovidone (Polyplastidone XL-10, ISP Japan) were mixed, and the mesh opening was 850 ⁇ m. Sieving with
  • magnesium stearate equivalent to the weight of the uncoated tablet was added through a 500 ⁇ m sieve and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
  • Example 24 48.99g of Compound A methanesulfonate hydrate, 0.25g of light anhydrous silicic acid (Erogil 200, manufactured by Nippon Aerosil Co., Ltd.) and 0.75g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals Co., Ltd.) are mixed. And sieved with a sieve. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • Erogil 200 manufactured by Nippon Aerosil Co., Ltd.
  • croscarmellose sodium Karl-molded with a dry granulator
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
  • Example 25 48.99 g of methanesulfonate hydrate of Compound A, 0.25 g of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 0.75 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) are mixed. Sieving with an 850 ⁇ m sieve. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
  • Example 26 49.24 g of methanesulfonate hydrate of Compound A and 0.76 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.5% equivalent amount of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) and 0.5% equivalent amount of magnesium stearate passed through a 500 ⁇ m sieve were added. Mixed for minutes.
  • Erogyl 200 manufactured by Nippon Aerosil Co., Ltd.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
  • Example 27 49.24 g of methanesulfonate hydrate of Compound A and 0.76 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.5% equivalent amount of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 0.5% equivalent amount of magnesium stearate passed through a 500 ⁇ m sieve are added to the uncoated tablet weight, Mix for 30 minutes.
  • Hydrous silicon dioxide Carplex # 80, manufactured by DSL Japan
  • magnesium stearate passed through a 500 ⁇ m sieve are added to the uncoated tablet weight, Mix for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
  • Example 28 48.99 g of methanesulfonate hydrate of Compound A and 1.01 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) were mixed and sieved with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a 500 ⁇ m sieve and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
  • ECG-505 carmellose calcium
  • Example 29 48.99 g of methanesulfonate hydrate of Compound A and 1.01 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a 500 ⁇ m sieve and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
  • Reference example 1 44.05g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 4.43g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) 0.49g, corn starch (eclipse corn starch W, Japanese food) (Kako) (2.53 g) and 0.46 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having an opening of 500 ⁇ m were mixed, and sieved twice with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes.
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets.
  • a coating agent a material obtained by adding a small amount of a silicon antifoaming agent (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) to Opadry 00K43069 was used.
  • Reference example 2 44.07 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 4.45 g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) 0.49 g, hydroxypropyl starch (HPS101, manufactured by Nissho Chemical Co., Ltd.) ) 0.46 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having 2.53 g and an opening of 500 ⁇ m was mixed and sieved twice with a sieve having an opening of 850 ⁇ m. This mixed powder was mixed for 30 minutes.
  • This mixed powder was compression-molded with a dry granulator, and the formed solid was sized.
  • 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 ⁇ m and mixed for 30 minutes.
  • This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet.
  • the uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets.
  • a coating agent a material obtained by adding a small amount of a silicon antifoaming agent (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) to Opadry 00K43069 was used.
  • the content of methanesulfonate hydrate of Compound A is 80 to 97.5% by mass
  • the tablet size is smaller than 200 mg of commercially available Geninac tablets
  • medication compliance was improved, (4) excellent elution, (5) excellent hardness and friability, (6) as a result, withstand film coating and transfer, etc., and hydrated compound A with methanesulfonate It is useful as a product tablet.

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Abstract

(1) La pilule de l'invention présente une teneur de 80 à 97,5% en masse d'un hydrate de méthanesulfonate de 1-cyclopropyle-8-(difluorométhoxy)-7-[(1R)-1-méthyle-2,3-dihydro-1H-isoindol-5-yle]-4-oxo-1,4-dihydroquinoléine-3-acide carboxylique. (2) La taille de la pilule est inférieure à celle de la pilule Geninax 200mg disponible dans le commerce. (3) Ainsi, l'observance est améliorée. (4) Ses propriétés d'élution sont excellentes. (5) Sa dureté et sa friabilité sont excellentes. (6) Ainsi, cette pilule est utile en tant que pilule d'hydrate de méthanesulfonate, composé (A), et résiste au pelliculage, au transport, ou similaire.
PCT/JP2012/080887 2011-11-30 2012-11-29 Pilule comprenant un hydrate de méthanesulfonate de 1-cyclopropyle-8-(difluorométhoxy)-7-[(1r)-1-méthyle-2,3-dihydro-1h-isoindol-5-yle]-4-oxo-1,4-dihydroquinoléine-3-acide carboxylique Ceased WO2013081044A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
MX2014006378A MX350659B (es) 2011-11-30 2012-11-29 Tableta que contiene hidrato de metansulfonato del acido 1-ciclopropil- 8 - (difluorometoxi) -7- [ (1r) -1-metil-2,3-dihidro-1h-isoindol-5-il] -4-oxo-1,4-dihidroquinolin- 3-carboxilico.
BR112014012994A BR112014012994A2 (pt) 2011-11-30 2012-11-29 tablete contendo hidrato de metanossulfonato do ácido 1-ciclopropil-8-(difluorometóxi)-7-[(1r)-1-metil-2,3-diidro-1h-isoindol-5-il]-4-oxo-1, 4-diidroquinolina-3-carboxílico
RU2014126094A RU2633477C2 (ru) 2011-11-30 2012-11-29 Таблетка, содержащая гидрат метансульфоната 1-циклопропил-8-(дифторметокси)-7-[(1r)-1-метил-2, 3-дигидро-1н-изоиндол-5-ил]-4-оксо-1, 4-дигидрохинолин-3-карбоновой кислоты
CN201280066321.0A CN104039322A (zh) 2011-11-30 2012-11-29 含有1-环丙基-8-(二氟甲氧基)-7-[(1r)-1-甲基-2,3-二氢-1h-异吲哚-5-基]-4-氧代-1,4-二氢喹啉-3-羧酸的甲磺酸盐水合物的片剂
JP2013547208A JP6117112B2 (ja) 2011-11-30 2012-11-29 １−シクロプロピル−８−（ジフルオロメトキシ）−７−［（１ｒ）−１−メチル−２，３−ジヒドロ−１ｈ−イソインドール−５−イル］−４−オキソ−１，４−ジヒドロキノリン−３−カルボン酸のメタンスルホン酸塩水和物含有錠剤
SG11201402597WA SG11201402597WA (en) 2011-11-30 2012-11-29 Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate
ZA2014/03942A ZA201403942B (en) 2011-11-30 2014-05-29 Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindol-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonate hydrate
PH12014501224A PH12014501224B1 (en) 2011-11-30 2014-05-30 Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonate hydrate

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PCT/JP2012/080887 Ceased WO2013081044A1 (fr) 2011-11-30 2012-11-29 Pilule comprenant un hydrate de méthanesulfonate de 1-cyclopropyle-8-(difluorométhoxy)-7-[(1r)-1-méthyle-2,3-dihydro-1h-isoindol-5-yle]-4-oxo-1,4-dihydroquinoléine-3-acide carboxylique

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SG (1) SG11201402597WA (fr)
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WO2017188362A1 (fr) * 2016-04-27 2017-11-02 富山化学工業株式会社 Comprimé contenant de la tosufloxacine tosilate, un désintégrateur et un acide aminé acide
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WO2017073738A1 (fr) * 2015-10-29 2017-05-04 日本臓器製薬株式会社 Comprimé ayant comme principe actif la fexofénadine
WO2017188362A1 (fr) * 2016-04-27 2017-11-02 富山化学工業株式会社 Comprimé contenant de la tosufloxacine tosilate, un désintégrateur et un acide aminé acide
JPWO2017188362A1 (ja) * 2016-04-27 2019-02-28 富士フイルム富山化学株式会社 トスフロキサシントシル酸塩、崩壊剤および酸性アミノ酸を含む錠剤
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JP7058104B2 (ja) 2017-10-19 2022-04-21 日本化薬株式会社 アプレピタントを有効成分とする医薬錠剤

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CN104039322A (zh) 2014-09-10
BR112014012994A2 (pt) 2017-06-13
CN109662952A (zh) 2019-04-23
MY169750A (en) 2019-05-15
SG11201402597WA (en) 2014-09-26
JPWO2013081044A1 (ja) 2015-04-27
MX350659B (es) 2017-09-13
ZA201403942B (en) 2015-08-26
JP6117112B2 (ja) 2017-04-19
MX2014006378A (es) 2014-10-13
PH12014501224B1 (en) 2014-09-08
RU2633477C2 (ru) 2017-10-12
RU2014126094A (ru) 2016-01-27

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