WO2010126168A2 - Préparation solide - Google Patents

Préparation solide Download PDF

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Publication number
WO2010126168A2
WO2010126168A2 PCT/JP2010/057923 JP2010057923W WO2010126168A2 WO 2010126168 A2 WO2010126168 A2 WO 2010126168A2 JP 2010057923 W JP2010057923 W JP 2010057923W WO 2010126168 A2 WO2010126168 A2 WO 2010126168A2
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WO
WIPO (PCT)
Prior art keywords
give
salt
granule
solid preparation
mixed
Prior art date
Application number
PCT/JP2010/057923
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English (en)
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WO2010126168A3 (fr
Inventor
Wataru Hoshina
Makoto Fukuta
Shigeyuki Marunaka
Original Assignee
Takeda Pharmaceutical Company Limited
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=43032637&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010126168(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to MA34358A priority Critical patent/MA33280B1/fr
Priority to BRPI1014388A priority patent/BRPI1014388A2/pt
Priority to KR1020117027421A priority patent/KR101797776B1/ko
Priority to AU2010242308A priority patent/AU2010242308A1/en
Priority to MX2011011011A priority patent/MX2011011011A/es
Priority to CA2760073A priority patent/CA2760073A1/fr
Priority to US13/138,950 priority patent/US20120115837A1/en
Priority to SG2011078391A priority patent/SG175794A1/en
Priority to NZ596395A priority patent/NZ596395A/xx
Priority to EA201171329A priority patent/EA201171329A1/ru
Priority to EP10719654A priority patent/EP2424501A2/fr
Priority to JP2011545129A priority patent/JP5666471B2/ja
Priority to CN2010800289702A priority patent/CN102481248B/zh
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2010126168A2 publication Critical patent/WO2010126168A2/fr
Publication of WO2010126168A3 publication Critical patent/WO2010126168A3/fr
Priority to TNP2011000538A priority patent/TN2011000538A1/en
Priority to IL215962A priority patent/IL215962A0/en
Priority to ZA2011/08375A priority patent/ZA201108375B/en

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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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a solid preparation showing improved dissolution property of a drug from a preparation.
  • BACKGROUND OF INVENTION [0002] Hypertension is one of the diseases most frequently found in adults. According to the 2000 circulatory disease basic research by the Ministry of Health, Labour and Welfare, the number of hypertension patients in Japan (those with systolic blood pressure of not less than 140 mmHg or diastolic blood pressure of not less than 90 mmHg, or depressor recipients) reaches about 31 million to 38 million. Hypertension is a strong risk factor for any circulatory diseases including cerebrovascular diseases and myocardial infarction. Thus, an appropriate control of the blood pressure is important for both improved prognosis of patients, and mitigation of personal and social burdens. [0003]
  • R 1 is a monocyclic nitrogen-containing heterocyclic group having a deprotonatable hydrogen atom
  • R 2 is an optionally esterified carboxyl group
  • R 3 is an optionally substituted lower alkyl group, or a salt thereof, is known as an angiotensin II receptor antagonist showing a superior hypotensive effect and an organ-protective action.
  • JP-B- 2514282 discloses 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy- 1- [ [2 r - (lH-tetrazol-5-yl) biphenyl-4-yl] methyl]benzimidazole-7- carboxylate (candesartan cilexetil) as examples of the representative medicament. [0006]
  • WO01/15674 discloses a combined use of a rennin- angiotensin inhibitor and other depressor, cholesterol- lowering drug, diuretic or the like.
  • WO02/43807 discloses a combined use of an angiotensin II receptor antagonist and other depressor or statin.
  • a combined use of plural medicaments for different timings of ingestion may adversely affect the drug compliance of patients, where a failure to control the blood pressure due to forgetfulness is feared.
  • a combination preparation containing various depressors in one medicament is strongly desired in clinical practice, since it is an ideal medicament that exhibits a strong hypotensive effect and maintains drug compliance of patients .
  • a combination preparation containing an angiotensin II receptor antagonist and a calcium antagonist has been suggested.
  • WO92/10097 discloses a combination preparation containing an angiotensin II receptor antagonist and other medicament such as diuretic, calcium antagonist and the like.
  • JP-A-2006-290899 discloses a combination preparation containing an imidazolecarboxylate type angiotensin II receptor antagonist such as olmesartan medoxomil and the like and a calcium antagonist.
  • JP-B-2930252 discloses a combination preparation containing 2-butyl-4- chloro-l-[ (2'-(lH-tetrazol-5-yl)biphenyl-4- yl) methyl] imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof, each of which is an angiotensin II receptor antagonist, and diltiazem, which is a calcium antagonist.
  • JP-B-3057471 discloses a combination preparation containing a benzimidazole derivative, which is an angiotensin receptor antagonist, and a diuretic or calcium antagonist.
  • a preparation containing a benzimidazole derivative, which is an angiotensin II receptor antagonist, and a calcium antagonist is expected to simultaneously show, in clinical practice, efficacy of the benzimidazole derivative, which is an angiotensin II receptor antagonist with a high organ- protective effect, and efficacy of the calcium antagonist with a strong hypotensive effect.
  • its clinical usefulness is extremely high, since the action can be enhanced and the side effects can be reduced depending on the manner of combination.
  • the present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems, and found a solid preparation comprising (i) a compound represented by the formula (I) or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist, and the preparation shows appropriately controlled dissolution property in the human gastrointestinal tract. Specifically, they have taken note of excipients and found that the dissolution property of a drug from a solid preparation can be improved by using a highly water-soluble sugar alcohol, which resulted in the completion of the present invention. [0014] Accordingly, the present invention relates to
  • R 1 is a monocyclic nitrogen-containing heterocyclic group having a deprotonatable hydrogen atom
  • R 2 is an optionally esterified carboxyl group
  • R 3 is an optionally substituted lower alkyl group, or a salt thereof, (ii) a sugar alcohol, and (iii) a calcium antagonist;
  • [IA] the solid preparation of the above-mentioned [1], wherein R 2 is a carboxyl group optionally esterified by a lower alkyl group having a carbon number of 1 to 4, which is optionally substituted by 1 to 3 substituents selected from a hydroxyl group, an amino group, a halogen atom, a lower alkanoyloxy group having a carbon number of 2 to 6, a lower cycloalkanoyloxy group having a carbon number of 4 to 7, a carbonyloxy group having a lower alkoxy group having a carbon number of 1 to 6, a carbonyloxy group having a lower cycloalkoxy group having a carbon number of 3 to 7, and a lower alkoxy group having a carbon number of 1 to 4; [IB] the solid preparation of the above-mentioned [1], wherein R 2 is a 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group or a carboxyl group;
  • (I) or a salt thereof is 2-ethoxy-l- [ [2' - (4, 5-dihydro-5-oxo- 1,2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -lH-benzimidazole-7- carboxylic acid or a salt thereof;
  • a solid preparation wherein the dissolution of a compound represented by the above-mentioned formula (I) or a salt thereof, and a calcium antagonist from the preparation in the gastrointestinal tract is appropriately controlled, and the stability thereof in the preparation is finely maintained can be obtained. That is, the solid preparation of the present invention is superior in the dissolution property of a compound represented by the above- mentioned formula (I) or a salt thereof and a calcium antagonist from a preparation and the stability thereof.
  • the solid preparation of the present invention is a solid preparation comprising (i) a compound represented by the following formula (I) : [0019]
  • R 1 is a monocyclic nitrogen-containing heterocyclic group having a deprotonatable hydrogen atom
  • R 2 is an optionally esterified carboxyl group
  • R 3 is an optionally- substituted lower alkyl group, or a salt thereof, (ii) sugar alcohol, and (iii) a calcium antagonist (hereinafter to be also referred to as the solid preparation of the present invention) .
  • a tetrazolyl group 4, 5-dihydro-5-oxo-l, 2, 4-oxadiazol-3-yl group and the like can be mentioned.
  • the 4, 5-dihydro-5-oxo-l, 2, 4-oxadiazol-3-yl group includes all of the above-mentioned a' , b' and c' .
  • examples of the optionally esterified carboxyl group for R 2 include a carboxyl group optionally esterified by a lower alkyl group having a carbon number of 1 to 4.
  • the aforementioned lower alkyl group is optionally substituted by 1 to 5 (preferably 1 to 3) substituent (s) selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, a lower alkanoyloxy group having a carbon number of 2 to 6 (e.g., acetyloxy group, pivaloyloxy group and the like) , a lower cycloalkanoyloxy group having a carbon number of 4 to 7, a carbonyloxy group having a lower alkoxy group having a carbon number of 1 to 6 (e.g., methoxycarbonyloxy group, ethoxycarbonyloxy group and the like) , a carbonyloxy group having a lower cycloalkoxy group having a carbon number of 1 to 6 (e.g
  • a lower alkyl group having a carbon number of 1 to 5, which is optionally substituted by 1 to 5 (preferably 1 to 3) substituent (s) selected from the group consisting of a hydroxyl group, an amino group, a halogen atom and a lower alkoxy group having a carbon number of 1 to 4, can be mentioned.
  • substituent (s) selected from the group consisting of a hydroxyl group, an amino group, a halogen atom and a lower alkoxy group having a carbon number of 1 to 4
  • particularly preferred is an ethyl group.
  • the salt of the compound represented by the above- identified formula (I) only needs to be a pharmaceutically acceptable salt and, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid and the like of a compound represented by the formula (I) can be mentioned.
  • a salt with an inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt, ammonium salt and the like.
  • Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N f -dibenzylethylenediamine and the like.
  • Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like.
  • Preferable examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • the compound represented by the above-mentioned formula (I) or a salt thereof may be a hydrate or a non-hydrate, and a solvate or a nonsolvate.
  • the compound represented by the above-mentioned formula (I) or a salt thereof is preferably crystalline, and the melting point is 100 to 250 0 C, preferably 120 to 200 0 C, particularly 130 to 180 0 C.
  • a compound represented by the above-mentioned formula (I) or a salt thereof is used.
  • the compound or a salt thereof include 1- (cyclohexyloxycarbonyloxy) ethyl 2- ethoxy-l-[ [2' - (lH-tetrazol-5-yl) biphenyl-4- yl]methyl] benzimidazole-7-carboxylate, 2-ethoxy-l- [ [2' - (IH- tetrazol-5-yl) biphenyl-4-yl] methyl] -lH-benzimidazole-7- carboxylic acid, pivaloyloxymethyl 2-ethoxy-l- [ [2' - (IH- tetrazol-5-yl) biphenyl-4-yl] methyl] -lH-benzimidazole-7- carboxylate, 2-ethoxy-l- [ [2' - (4, 5-dihydro
  • the compound represented by the above-mentioned formula (I) or a salt thereof is contained in the solid preparation of the present invention in a proportion of 0.1 to 60 wt%, preferably 1 to 40 wt%, more preferably 3 to 30 wt% based on a free form.
  • any sugar alcohols can be used as long as it simultaneously establishes the stability of the compound represented by the above-mentioned formula (I) or a salt thereof in a preparation, and the dissolution property thereof from a preparation and can be applied to pharmaceutical products.
  • sugar alcohol to be used in the present invention examples include monosaccharide sugar alcohols such as tetritol (e.g., erythritol, D-threitol, L-threitol and the like) , pentitol (e.g., D-arabinitol, xylitol and the like), hexitol (e.g., D- iditol, galactitol (dulcitol) , D-glucitol (sorbitol) , mannitol and the like), cyclitol (e.g., inositol and the like) and the like; disaccharide sugar alcohols such as maltitol, lactitol, reduced paratinose (isomalt) and the like; oligosaccharide sugar alcohols such as pentaerythritol, hydrogenated maltose starch syrup and the like; and the like.
  • tetritol
  • monosaccharide sugar alcohols are preferable. More preferable are mannitol, sorbitol and erythritol. Particularly, mannitol is preferable, and D-mannitol is especially preferable.
  • the sugar alcohol may be used alone or two or more kinds thereof may be used in combination. In addition, the sugar alcohol simultaneously achieves the stability of a calcium antagonist in a preparation and dissolution property thereof from the preparation.
  • the sugar alcohol is contained in the solid preparation of the present invention in a proportion of 15 to 85 wt%, preferably 20 to 80 wt%, more preferably 25 to 75 wt%.
  • Examples of the calcium antagonist to be used in the present invention include dihydropyridine compounds such as azelnidipine, amlodipine, aranidipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, barnidipine, felodipine, benidipine, manidipine and the like; benzodiazepine compounds such as diltiazem and the like; and the like.
  • the calcium antagonist to be used in the present invention also includes salts of the compounds recited as the aforementioned calcium antagonist.
  • dihydropyridine compounds particularly amlodipine or a salt thereof is preferable.
  • a salt of amlodipine is more preferable, and amlodipine besylate is particularly preferable.
  • a calcium antagonist is contained in the solid preparation of the present invention in a proportion of generally 0.05 to 60 wt%, preferably 0.1 to 40 wt%, more preferably 0.5 to 20 wt%, based on a free form.
  • amlodipine is contained in a proportion of generally 0.05 to 60 wt%, preferably 0.1 to 40 wt%, more preferably 0.5 to 20 wt%, based on a free form.
  • the solid preparation of the present invention may further contain an alkylene oxide polymer.
  • the alkylene oxide polymer include a polymer of ethylene oxide, propylene oxide, trimethylene oxide, tetrahydrofuran or the like (preferably, ethylene oxide) .
  • the molecular weight of the alkylene oxide polymer is preferably 1,000 to 10,000, more preferably 3,000 to 10,000.
  • the alkylene oxide polymer may be a copolymer of alkylene oxide, and examples of the copolymer of alkylene oxide include copolymer of two or more kinds of the above-mentioned alkylene oxide, which has a molecular weight of 1,000 to 10,000 (preferably 3,000 to 10,000).
  • the alkylene oxide polymer may be used alone or two or more kinds thereof may be used in combination. [0039]
  • polyethylene glycol is preferable, polyethylene glycol having a molecular weight of 1,000 to 10,000 is more preferable, and polyethylene glycol (e.g., polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 10000) having a molecular weight of 3,000 to 10,000 is particularly preferable.
  • polyethylene glycol e.g., polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 10000 having a molecular weight of 3,000 to 10,000 is particularly preferable.
  • the alkylene oxide polymer is contained in the solid preparation of the present invention in a proportion of preferably 1 to 5 wt%, more preferably 1 to 3 wt%.
  • a preferable embodiment of the solid preparation of the present invention includes a solid preparation wherein the compound represented by the above-mentioned formula (I) or a salt thereof is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-l- [ [2' - (IH-tetrazol- 5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (hereinafter sometimes referred to as "compound A”) or a salt thereof, and the calcium antagonist is amlodipine besylate; a solid preparation wherein the compound represented by the above-mentioned formula (I) or a salt thereof is 2-ethoxy-l- [ [2' - (4, 5-dihydro-5-oxo-l, 2, 4-oxadiazol-3-yl) biphenyl-4- yl] methyl] -lH-benzimidazole-7-carboxylic acid (hereinafter sometimes referred to as "compound B”)
  • a solid preparation suitable for oral administration such as tablet, granule, fine granule, capsule, pill and the like can be mentioned, with preference given to tablet and more preference given to single-layer tablet.
  • the form of the tablet is any of round, oval, oblong and the like. While the size of the tablet varies depending on the form of the tablet (round, caplet, oblong etc.), any size is possible as long as patients can take the tablet with ease.
  • the solid preparation of the present invention is a single-layer tablet, it is easily taken due to its small tablet size.
  • the embodiment of the solid preparation of the present invention includes (1) one group granulated preparation a solid preparation obtained by granulating a mixture comprising a compound represented by the formula (I) or a salt thereof, sugar alcohol, and a calcium antagonist (preferably, a compound represented by the formula (I) or a salt thereof, sugar alcohol, a calcium antagonist, and a polyethylene glycol) , and compression molding the obtained granulated material (e.g., one group granulated single-layer tablet); (2) two group granulated preparation (a) a solid preparation obtained by mixing and compression molding the following first part and the second part obtained by individual granulation (e.g., two group granulated single- layer tablet) ;
  • first part a part comprising a compound represented by the formula (I) or a salt thereof (preferably, a compound represented by the formula (I) or a salt thereof, and a polyethylene glycol)
  • second part a part comprising sugar alcohol and a calcium antagonist and the like.
  • the preferable embodiment of the solid preparation of the present invention is one group granulated preparation (e.g., one group granulated single-layer tablet) .
  • the solid preparation of the present invention may contain additives conventionally used in the pharmaceutical field.
  • the additive include excipient, disintegrant, binder, lubricant, pH adjuster, colorant, surfactant, stabilizer, acidulant, flavor, glidant and the like. These additives are used in amounts conventionally employed in the pharmaceutical field. In addition, these additives may be used in a mixture of two or more kinds thereof at an appropriate ratio. [0045]
  • excipient examples include starches such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like, saccharides such as lactose, fructose, glucose, sucrose and the like, anhydrous calcium phosphate, crystalline cellulose, microcrystalline cellulose, Glycyrrhiza uralensis, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium silicate and the like.
  • starches such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like
  • saccharides such as lactose, fructose, glucose, sucrose and the like, anhydrous calcium phosphate, crystalline cellulose, microcrystalline cellulose, Glycyrrhiza uralensis, sodium hydrogen carbonate, calcium phosphate, calcium sulfate
  • disintegrant examples include amino acid, starch, corn starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylstarch and the like.
  • a disintegrant is contained in a proportion of preferably 0.1 to 30 wt%, more preferably 1 to 10 wt%, of the solid preparation of the present invention.
  • binder examples include crystalline cellulose (e.g., microcrystalline cellulose), hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, tragacanth, carboxymethylcellulose, sodium alginate, pullulan, glycerol and the like.
  • a binder is contained in a proportion of preferably 0.1 to 40 wt%, more preferably 1 to 10 wt%, of the solid preparation of the present invention.
  • the lubricant include magnesium stearate, stearic acid, calcium stearate, talc (purified talc) , sucrose esters of fatty acids, sodium stearyl fumarate and the like.
  • Examples of the pH adjuster include citric acid and a salt thereof, phosphoric acid and a salt thereof, carbonic acid and a salt thereof, tartaric acid and a salt thereof, fumaric acid and a salt thereof, acetic acid and a salt thereof, amino acid and a salt thereof and the like.
  • Examples of the colorant include food colors such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No.
  • iron oxide pigments such as red ferric oxide (colcothar) , yellow ferric oxide, triiron tetraoxide (iron oxide black) and the like; and so on.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol and the like.
  • stabilizer examples include tocopherol, tetrasodium edetate, nicotinamide, cyclodextrins and the like.
  • Examples of the acidulant include ascorbic acid, citric acid, tartaric acid, malic acid and the like.
  • Examples of the flavor include menthol, peppermint oil, lemon oil, vanillin and the like.
  • Examples of the glidant include light anhydrous silicic acid, hydrated silicon dioxide and the like.
  • the solid preparation of the present invention can also be processed into a film-coated preparation by applying a film coating such as a coating base, a coating additive and the like.
  • a film coating such as a coating base, a coating additive and the like.
  • the film-coated preparation include a sugar- coated preparation, sustained-release preparation, enteric preparation and the like.
  • the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a sustained-release film coating base and the like.
  • sucrose is used.
  • talc precipitated calcium carbonate
  • gelatin gum arabic, pullulan, Carnauba wax and the like
  • water-soluble film coating base examples include cellulose polymers such as hydroxypropylcellulose [e.g., NISSO HPC (grades: L, SL, SL-T, SSL) (trade name); Nippon Soda Co., Ltd.], hypromellose [e.g., TC-5 (grades: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.], hydroxyethylcellulose, methylhydroxyethylcellulose and the like, synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name) ; manufactured by ROHM AND HAAS JAPAN KK.], poly
  • enteric film coating base examples include cellulose polymers such as hypromellose phthalic acid ester, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like, acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name) ] , methacrylic acid copolymer LD [Eudragit L-30D55 (trade name) ; manufactured by ROHM AND HAAS JAPAN KK.], methacrylic acid copolymer S [Eudragit S (trade name); manufactured by ROHM AND HAAS JAPAN KK.] and the like, natural polymers such as shellac and the like; and so on. [0061]
  • sustained-release film coating base examples include cellulose polymers such as ethylcellulose and the like, acrylic acid polymers such as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name); manufactured by ROHM AND HAAS JAPAN KK.], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name) ; manufactured by ROHM AND HAAS JAPAN KK.] and the like; and so on. [ 0062 ]
  • the coating additives include light protecting agents such as titanium dioxide and the like, glidants such as talc and the like, colorants such as red ferric oxide, yellow ferric oxide and the like, plasticizers such as polyethylene glycol [e.g., macrogol 6000 (trade name); manufactured by Sanyo Chemical Industries, Ltd.], triethyl citrate, castor oil, polysorbates and the like, organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid and the like; and so on. [0063]
  • the solid preparation of the present invention can be produced by a method known per se (e.g., the method described in the Japanese Pharmacopoeia 15th Edition, General Principles) .
  • Examples of the method include operations such as mixing, kneading, granulation, compression molding, film coating and the like, and an appropriate combination of these operations.
  • Mixing is performed using, for example, a mixer such as a horizontal cylindrical mixer, a V-type mixer, a tumbler mixer and the like, and kneading is performed using a rotary vessel- type kneader such as a ball mill and the like, a fixed vessel- type kneader such as a screw-type kneader, a Henschel mixer and the like, a rolling kneader such as a rolling mill, a taper rolling mill and the like, and the like.
  • a mixer such as a horizontal cylindrical mixer, a V-type mixer, a tumbler mixer and the like
  • kneading is performed using a rotary vessel- type kneader such as a ball mill and the like, a fixed vessel- type kneader such as a screw-type kneader, a Henschel mixer and the like, a rolling kneader such as a rolling mill,
  • Granulation is performed by a stirring granulation method using a high-speed stirring granulator, a rolling granulation method using a container of a pan type, conical drum type, multi-stage conical drum type, stirring blade-equipped drum type, vibration type or the like, a fluidized bed granulation and drying method, a spray drying granulation method, an extrusion-granulation method, a method using a granulator such as a Roller-compactor and the like, and the like.
  • Compression molding is performed, for example, by molding by an extrusion molding machine, or tableting using a single punch tableting machine, a rotary tableting machine and the like.
  • Film coating is performed, for example, by using a pan coating machine of a horizontal type, an inclination type and the like, a fluid coating machine of a horizontal rotating- disc type, an inclined plate type and the like, a fluid coating machine of a fluidized bed type, a spouted bed type, a tumbling fluidized bed type and the like, and the like.
  • the solid preparation of the present invention can be produced, for example, by the following production steps.
  • a mixture comprising a compound represented by the above- mentioned formula (I) or a salt thereof, sugar alcohol, and a calcium antagonist (preferably, a compound represented by the formula (I) or a salt thereof, sugar alcohol, a calcium antagonist, and a polyethylene glycol) is granulated, and the obtained granulated material is compression molded to give the solid preparation of the present invention (one group granulated single-layer tablet) .
  • a calcium antagonist preferably, a compound represented by the formula (I) or a salt thereof, sugar alcohol, a calcium antagonist, and a polyethylene glycol
  • a compound represented by the above- mentioned formula (I) or a salt thereof, a calcium antagonist and an additive such as excipient, sugar alcohol (e.g., D- mannitol) and the like are mixed, and the mixture is granulated while spraying a liquid obtained by dispersing or dissolving polyethylene glycol and an additive such as a binder and the like in a solvent (e.g., water).
  • a solvent e.g., water
  • An additive such as disintegrant, lubricant and the like is added to the thus-obtained granulated material and, after mixing, the mixture is compression molded to give a tablet.
  • the tablet is coated with a film solution containing a coating base and the like, whereby the solid preparation of the present invention (one group granulated single-layer tablet) is produced.
  • a compound represented by the above-mentioned formula (I) or a salt thereof and an additive such as excipient and the like are mixed, and the mixture is granulated while spraying a liquid obtained by dispersing or dissolving polyethylene glycol and an additive such as a binder and the like in a solvent (e.g., water).
  • a calcium antagonist and an additive such as excipient, sugar alcohol (e.g., D-mannitol) and the like are mixed, and the mixture is granulated while spraying a liquid obtained by dispersing or dissolving an additive such as a binder and the like in a solvent (e.g., water).
  • An additive such as disintegrant, lubricant and the like is added to the thus-obtained granulated material containing a compound represented by the above-mentioned formula (I) or a salt thereof and the thus-obtained granulated material containing the calcium antagonist and, after mixing, the mixtures are compression molded to give the solid preparation of the present invention (two group granulated single-layer tablet) .
  • a compound represented by the above-mentioned formula (I) or a salt thereof and an additive such as excipient and the like are mixed, and the mixture is granulated while spraying a liquid obtained by dispersing or dissolving polyethylene glycol and an additive such as a binder and the like in a solvent (e.g., water).
  • a solvent e.g., water
  • An additive such as disintegrant, lubricant and the like is added to the thus-obtained granulated material to give a mixed granule.
  • a calcium antagonist and an additive such as excipient, sugar alcohol (e.g., D-mannitol) and the like are mixed, and the mixture is granulated while spraying a liquid obtained by dispersing or dissolving an additive such as a binder and the like in a solvent (e.g., water).
  • An additive such as disintegrant, lubricant and the like is added to the thus-obtained granulated material to give a mixed granule.
  • a calcium antagonist and an additive such as excipient, sugar alcohol (e.g., D-mannitol) and the like are mixed, and the mixture is granulated while spraying a liquid obtained by dispersing or dissolving an additive such as a binder and the like in a solvent (e.g., water).
  • An additive such as disintegrant, lubricant and the like is added to the obtained granulated material and, after mixing, the mixture is compression molded to give a tablet.
  • the tablet is coated with a film solution containing a coating base and the like to give an inner core tablet.
  • a compound represented by the above- mentioned formula (I) or a salt thereof and an additive such as excipient and the like are mixed, and the mixture is granulated while spraying a liquid obtained by dispersing or dissolving polyethylene glycol and an additive such as a binder and the like in a solvent (e.g., water) .
  • An additive such as disintegrant, lubricant and the like is added to the obtained granulated material to give a mixed granule.
  • the mixed granule is added as an outer layer to the above-mentioned inner core tablet and they are compression molded to give the solid preparation of the present invention (dry coated tablet) .
  • the solid preparation of the present invention is granules or fine granules, they can be produced by a method similar to the above-mentioned methods.
  • the solid preparation of the present invention is a capsule
  • it can be produced by filling the above-mentioned granules or fine granules in a capsule containing gelatin, hypromellose and the like.
  • a hard capsule can be produced by filling a compound represented by the above- mentioned formula (I) or a salt thereof and a calcium antagonist together with a sugar alcohol and other excipient etc. in a capsule containing gelatin, hypromellose and the like.
  • a soft capsule can be produced by encapsulation molding a compound represented by the above- mentioned formula (I) or a salt thereof and a calcium antagonist into a given shape with a base containing gelatin and a plasticizer such as glycerol and the like.
  • the solid preparation of the present invention may have a punch mark for identification or print on the surface. In addition, it may have a score line for partition.
  • the solid preparation of the present invention is low toxic and can be safely administered orally or parenterally as a medicament for a mammal (e.g., human, monkey, cat, swine, horse, bovine, mouse, rat, guinea pig, dog, rabbit and the like) .
  • a mammal e.g., human, monkey, cat, swine, horse, bovine, mouse, rat, guinea pig, dog, rabbit and the like.
  • a compound represented by the formula (I) or a salt thereof has a strong angiotensin II receptor antagonistic action, and therefore, the solid preparation of the present invention is useful as a prophylactic or therapeutic drug for (1) a disease developed (or promoted to be developed) by coarctation or growth of blood vessel or an organ disorder expressed via angiotensin II receptor, (2) a disease developed (or promoted to be developed) by the presence of angiotensin II, or (3) a disease developed (or promoted to be developed) by a factor induced by the presence of angiotensin II in the aforementioned mammals.
  • Examples of the diseases of the above-mentioned (1) to (3) include hypertension, blood pressure circadian rhythm abnormality, heart diseases (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including cardiac failure, failure of expansion, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiac infraction etc.), cerebrovascular disorders (e.g., asymptomatic cerebrovascular disorder, transient cerebral ischemia, apoplexy, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction etc.), cerebral edema, cerebral circulatory disorder, recurrence and sequela of cerebrovascular disorders (e.g., neurotic symptom, psychic symptom, subjective symptom, disorder in daily living activities etc.), ischemic peripheral circulation disorder, myocardial ischemia, venous insufficiency, progression of cardiac insufficiency after myocardial infarction, renal diseases (e.g., nep
  • vascular hypertrophy vascular hypertrophy or obliteration and organ damages after intervention
  • intervention e.g., percutaneous transluminal coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, dounce thrombolytic therapy etc.
  • vascular re- obliteration and restenosis after bypass polycythemia, hypertension, organ damage and vascular hypertrophy after transplantation, rejection after transplantation, ocular diseases (e.g., glaucoma, ocular hypertension etc.), thrombosis, multiple organ disorder, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (e.g., deep vein thrombosis, obstructive peripheral circulatory disorder, arteriosclerosis obliterans, thromboangiitis obliterans, ischemic cerebral circulatory disorder, Raynaud's disease, Berger disease etc.), metabolic and/or nutritional disorders (e.g., obesity, hyperlipidemia,
  • myelopoietic diseases e.g., erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelopathy etc.
  • bone diseases e.g., fracture, refracture, osteoporosis, osteomalacia, bone Paget' s disease, sclerosing myelitis, rheumatoid arthritis, joint tissue dysfunction and the like caused by osteoarthritis of the knee and diseases similar to these
  • solid tumor tumors (e.g., malignant melanoma, malignant lymphoma, cancer of digestive organs (e.g., stomach, intestine etc.) etc.), cancer and cachexia following cancer, metastasis cancer, endocrinopathy (e.g., Addison' s disease, Cushing' s syndrome, pheochromocytoma, hyperaldosteronism, primary aldosteronism etc.
  • Creutzfeldt-Jakob disease urinary organ and/or male genital diseases (e.g., cystitis, prostatic hypertrophy, prostatic cancer, sex infectious disease etc. ) , female disorders (e.g., climacteric disorder, gestosis, endometriosis, hysteromyoma, ovarian disease, breast disease, sex infectious disease etc.), disease relating to environment and occupational factors (e.g., radiation hazard, hazard by ultraviolet, infrared or laser beam, altitude sickness etc.), respiratory diseases (e.g., cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary- embolism etc.) / infectious diseases (e.g., viral infectious diseases with cytomegalovirus, influenza virus, herpes virus etc., rickettsiosis, bacterial infectious disease etc.), toxemias (e.g., sepsis, septic shock, endo
  • the solid preparation of the present invention comprising a combination of a compound represented by the formula (I) or a salt thereof and a calcium antagonist is useful as a prophylactic or therapeutic drug for the above-mentioned diseases (preferably, a prophylactic or therapeutic drug for hypertension, cardiac failure, diabetic nephropathy or arteriosclerosis, more preferably, a prophylactic or therapeutic drug for hypertension) .
  • the solid preparation of the present invention can reduce the doses of a compound represented by the formula (I) or a salt thereof and a calcium antagonist as compared to single use thereof.
  • the daily dose for a human adult (body weight 60 kg) based on a free form is about 0.05 to 500 mg, preferably 0.1 to 100 mg, more preferably 1 to 100 mg, still more preferably 2 to 40 mg.
  • the daily dose of compound A for human adult (body weight 60 kg) is about 1 to 80 mg, preferably 2 to 32 mg
  • the daily dose of compound B for human adult (body weight 60 kg) is about 1 to 50 mg, preferably 10 to 40 mg.
  • the daily dose of a calcium antagonist varies depending on the subject of administration, administration route, target disease, symptom and the like, the daily dose of, for example, amlodipine or a salt thereof for a human adult (body weight 60 kg) based on a free form is about 1 to 50 mg, preferably 2.5 to 10 mg.
  • the administration frequency of the solid preparation of the present invention to the aforementioned mammals is preferably 1 to 3 times per day, more preferably once per day.
  • a single-layer tablet comprising 8 mg of compound A and 6.93 mg of amlodipine besylate (5 mg as amlodipine) per tablet ⁇ a single-layer tablet comprising 8 mg of compound A and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) per tablet”;
  • ⁇ X a single-layer tablet comprising 4 mg of compound A and 3.47 mg of amlodipine besylate (2.5 mg as amlodipine) per tablet";
  • the solid preparation of the present invention can be used in combination with one or more different kinds of medicaments (hereinafter sometimes to be abbreviated as "concomitant drug”) .
  • the "concomitant drug” include therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, antiobestic agents, diuretics, antithrombotic agents and the like.
  • insulin preparations e.g., animal insulin preparations extracted from the pancreas of bovine or swine; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-I), oral insulin preparation
  • insulin sensitizers e.g., pioglitazone or a salt thereof (preferably, hydrochloride) , rosiglitazone or a salt thereof (preferably, maleate) , Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, compounds described in WO2007/013694, WO2007/018314, WO2008/093639 or WO2008/099794) , ⁇ -glucos
  • GIP Glucose-dependent insulinotropic peptide
  • GPR119 agonists e.g., PSN821
  • FGF21 FGF analogue and the like
  • aldose reductase inhibitors e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201) , lidorestat
  • neurotrophic factor and increasing agents thereof e.g., NGF, NT-3, BDNF, neurotrophic production/secretion promoting agent described in WO01/14372 (e.g., 4- (4- chlorophenyl) -2- (2-methyl-l-imidazolyl) -5- [3- (2- methylphenoxy) propyl] oxazole) , compounds described in WO2004/039365
  • PKC inhibitors e.g., ruboxistaurin mesylate
  • AGE inhibitors e.g., ALT946, N-phenacylthiazolium bromide (ALT766) , EXO-226, Pyridorin, pyridoxamine
  • HMG-CoA reductase inhibitors e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)
  • squalene synthase inhibitors e.g., compounds described in WO97/10224, for example, N- [ [ (3R, 5S) -1- (3- acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2, 3-dimethoxyphenyl ) - 2-oxo-l, 2, 3, 5-tetrahydro-4, l-benzoxazepin-3- yl] acetyl] piperidin-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate) , anion exchange resin
  • angiotensin converting enzyme inhibitors e.g., captopril, enalapril, delapril and the like
  • angiotensin II antagonists e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesart, olmesartan medoxomil, azilsartan and the like
  • a calcium antagonists e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, amlodipine, cilnidipine and the like
  • ⁇ blockers e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol and
  • monoamine uptake inhibitors e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine
  • serotonin 2C receptor agonists e.g., lorcaserin
  • serotonin 6 receptor antagonists histamine H3 receptor
  • GABA-regulating drugs e.g., topiramate
  • neuropeptide Y antagonists e.g., velneperit
  • cannabinoid receptor antagonists e.g., rimonabant, taranabant
  • opioid receptor antagonists e.g., GSK-1521498
  • orexin receptor antagonists melanocortin 4 receptor agonists, ll ⁇ -hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017)
  • panocortin 4 receptor agonists e.g., ll ⁇ -hydroxysteroid dehydrogenase inhibitors
  • panocortin 4 receptor agonists e.g
  • Escherichia coli or yeast fragment or derivative of GLP-I (e.g., exenatide, liraglutide) ) , amylin preparations (e.g., pramlintide, AC-2307) , neuropeptide Y agonists (e.g., PYY3-36, derivative of PYY3-36, obinepitide, TM-30339, TM-30335) , oxyntomodulin preparations; FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragment or derivative of FGF21) ) , feeding deterrents (e.g., P-57) and the like can be mentioned.
  • GLP-I e.g., exenatide, liraglutide
  • amylin preparations e.g., pramlintide
  • xanthine derivatives e.g., theobromine sodium salicylate, theobromine calcium salicylate and the like
  • thiazide preparations e.g., ethiazide, cyclopenthiazide, trichloromethyazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, poly ⁇ thiazide, methyclothiazide and the like
  • antialdosterone preparations e.g., spironolactone, triamterene and the like
  • carbonic anhydrase inhibitors e.g., acetazolamide and the like
  • chlorobenzenesulfonamide agents e.g., chlortalidone, mefruside, indapamide and the like
  • azosemide isosorbide, ethacrynic acid
  • heparin e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium
  • warfarin e.g., warfarin potassium
  • anti-thrombin drugs e.g., aragatroban, dabigatran
  • FXa inhibitors e.g., rivaroxaban, apixaban, edoxaban, YM150, compounds described in WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823 or WO2005/113504
  • thrombolytic agents e.g., urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase
  • platelet aggregation inhibitors e.g., ticlopidine hydrochloride, clopidogrel, prasugrel
  • the administration period thereof is not limited, and they may be administered simultaneously or in a staggered manner to the administration subject.
  • the solid preparation of the present invention and a concomitant drug may be administered as separate preparations, or as a single preparation containing the solid preparation of the present invention and a concomitant drug.
  • the dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations of each drug.
  • the mixing ratio of the solid preparation of the present invention and a concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • a concomitant drug can be used in 0.01 to 100 parts by weight relative to 1 part by weight of the solid preparation of the present invention.
  • the present invention also provides a method of improving the dissolution property of and a method of stabilizing a compound represented by the formula (I) or a salt thereof, and/or a calcium antagonist, contained in a solid preparation, which comprises adding sugar alcohol. According to the present invention, the dissolution property of a compound represented by the formula (I) or a salt thereof in the solid preparation are significantly improved.
  • binding solution I Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9000 g) to give binding solution I. Red ferric oxide (2.880 g) was dispersed in purified water (2880 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (720.0 g) to give binding solution II.
  • Amlodipine besylate (1253 g) , compound A (1449 g) , D-mannitol (14880 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill(P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • Example 2 To the obtained milled granule (40760 g (2 batches) ) were added croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) , and they were mixed in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to give a mixed granule. (3) The mixed granule obtained above was tableted by a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) with a diameter of 7.0 mm punch (tableting pressure 10 kN, weight per tablet: 130 mg) to give plain tablets of the composition shown in Table 1. [0096] Example 2
  • Amlodipine besylate (1253 g) , compound A (1449 g) , D-mannitol (14870 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • binding solution II (1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to give binding solution I. Yellow ferric oxide (11.70 g) was dispersed in purified water (1800 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (540.0 g) to give binding solution II.
  • Amlodipine besylate (627.7 g) , compound A (1449 g) , D-mannitol (15550 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • Example 4 To the obtained milled granule (40760 g (2 batches) ) were added croscarmellose sodium (1848 g) and magnesium stearate (297.0 g) , and they were mixed in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to give a mixed granule. (3) The mixed granule obtained above was tableted by a rotary tableting machine (AQUARIUS-36K, Kikusui Seisakusho) with a long diameter of 8.5 mm and short diameter of 5.0 mm punch (tableting pressure 8 kN, weight per tablet: 130 mg) to give plain tablets of the composition shown in Table 3. [0100] Example 4
  • binding solution II (1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to give binding solution I. Red ferric oxide (11.70 g) was dispersed in purified water (1800 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (540.0 g) to give binding solution II.
  • Amlodipine besylate (1253 g) , compound A (724.3 g) , D-mannitol (15600 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • binding solution I Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to give binding solution I. Yellow ferric oxide (11.70 g) was dispersed in purified water (1800 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (540.0 g) to give binding solution II.
  • Amlodipine besylate (627.7 g) , compound A (724.3 g) , D-mannitol (16220 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • binding solution II (1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to give binding solution I. Red ferric oxide (18.72 g) was dispersed in purified water (1800 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (540.0 g) to give binding solution II.
  • Amlodipine besylate (1248 g) , compound A (1446 g) , D-mannitol (14870 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • binding solution II (1) Hydroxypropylcellulose (720.0 g) and macrogol 6000 (324.0 g) were dissolved in purified water (9900 g) to give binding solution I. Yellow ferric oxide (18.72 g) was dispersed in purified water (1800 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (540.0 g) to give binding solution II.
  • Amlodipine besylate (625.2 g) , compound A (1446 g) , D-mannitol (15500 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mmcp punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • binding solution I was mixed with dispersion I and purified water (108.0 g) to give binding solution II.
  • Macrogol 6000 (14.04 g) was dissolved in binding solution II
  • binding solution II (1) Hydroxypropylcellulose (144.0 g) was dissolved in purified water (1980 g) to give binding solution I. Red ferric oxide (3.744 g) was dispersed in purified water (360.0 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (108.0 g) to give binding solution II. Macrogol 6000 (23.40 g) was dissolved in binding solution II (259.6 g) to give binding solution III.
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 280.7 g
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 280.7 g
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 280.7 g
  • microcrystalline cellulose 72.00 g
  • a part of the obtained granule was sieved with a sieve (16 mesh) to give a milled granule.
  • binding solution II (1) Hydroxypropylcellulose (144.0 g) was dissolved in purified water (1980 g) to give binding solution I. Red ferric oxide (3.744 g) was dispersed in purified water (360.0 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (108.0 g) to give binding solution II. Macrogol 6000 (37.44 g) was dissolved in binding solution II (259.6 g) to give binding solution III.
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 266.6 g
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 266.6 g
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 266.6 g
  • microcrystalline cellulose 72.00 g
  • a part of the obtained granule was sieved with a sieve (16 mesh) to give a milled granule.
  • Premix I 240.0 g was dissolved in purified water (2160.0 g) to give a film coating solution.
  • a film coating was formed by uniformly spraying the film coating solution on the core tablets (3120.0 g) in a film coating machine (DRC-500, POWREX Co., Ltd.) to give film-coated tablets of the composition shown in Table 12 (weight per tablet: 135 mg) .
  • the premix I is a premixed powder.
  • the composition of the premix I is shown in Table 12a.
  • a film coating was formed by uniformly spraying the film coating solution on the core tablets (200.0 g) in a film coating machine (DRC-200, POWREX Co., Ltd.) to give film-coated tablets of the composition shown in Table 13 (weight per tablet: 135 mg) .
  • the premix I is a premixed powder.
  • the composition of the premix I is shown in Table 13a.
  • Premix I (40.00 g) was dissolved in purified water (360.0 g) to give a film coating solution.
  • a film coating was formed by uniformly spraying the film coating solution on the core tablets (200.0 g) in a film coating machine (DRC-200, POWREX Co., Ltd.) to give film-coated tablets of the composition shown in Table 14 (weight per tablet: 135 mg) .
  • the premix I is a premixed powder.
  • the composition of the premix I is shown in Table 14a.
  • Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to give a binding solution.
  • Amlodipine besylate (10.40 g) , compound B (30.00 g) , D-mannitol (250.6 g) and microcrystalline cellulose (39.00 g) were uniformly mixed in a fluid bed granulator (Lab- 1, POWREX Co., Ltd.), and the mixture was granulated while spraying the binding solution, and then dried to give a granule. A part of the obtained granule was sieved with a sieve (16 mesh) to give a milled granule.
  • Hypromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to give film coating solution I.
  • Titanium dioxide (7.680 g) , red ferric oxide (0.1650 g) and yellow ferric oxide (0.5100 g) were dispersed in purified water (330.0 g) to give a dispersion I.
  • Film coating solution I, dispersion I and purified water (68.25 g) were mixed to give film coating solution II.
  • a film coating was formed by uniformly spraying film coating solution II on the core tablets (120.0 g) in a film coating machine (DRC-200, POWREX Co., Ltd.) to give film-coated tablets of the composition shown in Table 15 (weight per tablet: 135.154 mg) .
  • Hypromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to give film coating solution I.
  • Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to give a binding solution.
  • Amlodipine besylate (10.40 g) , compound B (60.00 g) , D-mannitol (220.6 g) and microcrystalline cellulose (39.00 g) were uniformly mixed in a fluid bed granulator (Lab- 1, POWREX Co., Ltd.), and the mixture was granulated while spraying the binding solution, and then dried to give a granule. A part of the obtained granule was sieved with a sieve (16 mesh) to give a milled granule.
  • Hypromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to give film coating solution I.
  • film coating solution II was formed by uniformly spraying film coating solution II on the core tablets (120.0 g) in a film coating machine (DRC-200, POWREX Co., Ltd.) to give film- coated tablets of the composition shown in Table 17 (weight per tablet: 135.119 mg) .
  • Hypromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to give film coating solution I.
  • Titanium dioxide (7.680 g) and red ferric oxide (0.1500 g) were dispersed in purified water (330.0 g) to give a dispersion I.
  • Film coating solution I, dispersion I and purified water (68.25 g) were mixed to give film coating solution II.
  • a film coating was formed by uniformly spraying film coating solution II on the core tablets (120.0 g) in a film coating machine (DRC-200, POWREX Co., Ltd.) to give film- coated tablets of the composition shown in Table 18 (weight per tablet: 135.119 mg) .
  • Hydroxypropylcellulose (35.10 g) and macrogol 6000 (16.20 g) were dissolved in purified water (403.7 g) to give a binding solution.
  • Amlodipine besylate (10.40 g) , compound B (120.0 g) , D-mannitol (160.6 g) and microcrystalline cellulose (39.00 g) were uniformly mixed in a fluid bed granulator (Lab- 1, POWREX Co., Ltd.), and the mixture was granulated while spraying the binding solution, and then dried to give a granule. A part of the obtained granule was sieved with a sieve (16 mesh) to give a milled granule.
  • Hypromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to give film coating solution I.
  • Hypromellose (57.44 g) and macrogol 6000 (11.52 g) were dissolved in purified water (375.0 g) to give film coating solution I.
  • Titanium dioxide (7.680 g) and yellow ferric oxide (0.6900 g) were dispersed in purified water (330.0 g) to give a dispersion I.
  • Film coating solution I, dispersion I and purified water (68.25 g) were mixed to give film coating solution II.
  • a film coating was formed by uniformly spraying film coating solution II on the core tablets (120.0 g) in a film coating machine (DRC-200, POWREX Co., Ltd.) to give film- coated tablets of the composition shown in Table 20 (weight per tablet: 135.155 mg) .
  • Hypromellose 720.0 g was dissolved in purified water (9000 g) to give binding solution I.
  • Red ferric oxide (2.880 g) was dispersed in purified water (2880 g) to give dispersion I.
  • Dispersion I and purified water (720.0 g) were mixed in binding solution I to give binding solution II.
  • Amlodipine besylate (1249 g) , D-mannitol (16660 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give milled granule I.
  • Hypromellose 720.0 g was dissolved in purified water (9000 g) to give binding solution I.
  • Red ferric oxide (2.880 g) was dispersed in purified water (2880 g) to give dispersion I.
  • Binding solution I was mixed with dispersion I and purified water (720.0 g) to give binding solution II.
  • Amlodipine besylate (1249 g) , D-mannitol (16660 g) and microcrystalline cellulose (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give milled granule I.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule of the amlodipine besylate layer.
  • Premix I 252.0 g was dissolved in purified water (2268.0 g) to give a film coating solution.
  • a film coating was formed by uniformly spraying the film coating solution on the core tablets (3120.0 g) in a film coating machine (DRC-500, POWREX Co., Ltd.) to give film-coated tablets of the composition shown in Table 23 (weight per tablet: 239 mg) .
  • the premix I is a premixed powder.
  • the composition of the premix I is shown in Table 23a.
  • binding solution II (1) Hydroxypropylcellulose (80.00 g) and macrogol 4000 (36.00 g) were dissolved in purified water (1100 g) to give binding solution I. Red ferric oxide (2.080 g) was dispersed in purified water (200.1 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (60.00 g) to give binding solution II.
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol (297.6 g)
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol (297.6 g)
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 297.6 g
  • microcrystalline cellulose 72.00 g
  • a part of the obtained granule was sieved with a sieve (16 mesh) to give a milled granule.
  • binding solution II (1) Hydroxypropylcellulose (80.00 g) and macrogol 10000 (36.00 g) were dissolved in purified water (1100 g) to give binding solution I. Red ferric oxide (2.080 g) was dispersed in purified water (200.1 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (60.10 g) to give binding solution II.
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol (297.6 g)
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol (297.6 g)
  • microcrystalline cellulose 72.00 g
  • Amlodipine besylate 24.95 g
  • compound A 28.80 g
  • D-mannitol 297.6 g
  • microcrystalline cellulose 72.00 g
  • a part of the obtained granule was sieved with a sieve (16 mesh) to give a milled granule.
  • binding solution I Hydroxypropylcellulose (720.0 g) and macrogol 6000 (468.0 g) were dissolved in purified water (9000 g) to give binding solution I. Red ferric oxide (2.880 g) was dispersed in purified water (2880 g) to give dispersion I. Binding solution I was mixed with dispersion I and purified water (720.0 g) to give binding solution II.
  • Amlodipine besylate (1253 g) , compound A (1449 g) , lactose hydrate (14830 g) and corn starch (3600 g) were uniformly mixed in a fluid bed granulator (FD-S2, POWREX Co., Ltd.), and the mixture was granulated while spraying binding solution II, and then dried to give a granule.
  • a part of the obtained granule was milled with a 1.5 mm ⁇ punching screen in a screening mill (P-3, Showa Kagakukikai Co., Ltd.) to give a milled granule.
  • the dissolution property of the active ingredient (compound A) from the plain tablets obtained in Examples 1 to 11, 24, 25 and Comparative Example 1 was evaluated by a dissolution test (1.0(w/w)% polysorbate 20 solution, 900 mL, 37°C, Paddle Method, number of rotation 50 rpm) .
  • the dissolution test was performed according to the Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method). The results are shown in Table 27.
  • Table 27 shows average values, maximum values and minimum values of the dissolution rate after 15 min from the start of the dissolution.
  • Examples 1, 4, 5, 8 to 11, 24, 25 and Comparative Example 1 show average values, maximum values and minimum values of the dissolution rates of 6 tablets, and Examples 2, 3, 6 and 7 show average values, maximum values and minimum values of the dissolution rates of 12 tablets. [0147]
  • Table 27 shows average values, maximum values and minimum values of the dissolution rates after 15 min from the start of the dissolution.
  • Example 20 B) from the film-coated tablet obtained in Example 20 was evaluated by a dissolution test (the Japanese Pharmacopoeia, 15th Edition, 2nd fluid for dissolution test, 900 itiL, 37°C, Paddle Method, number of rotation 50 rpm) .
  • the dissolution test was performed according to the Japanese Pharmacopoeia, 15th Edition, Dissolution Test, Apparatus 2 (Paddle Method) .
  • Table 28 shows average values, maximum values and minimum values of the dissolution rate of 6 tablets at each time point after 5 to 60 min from the start of the dissolution. [0150] Table 28
  • the present invention provides a solid preparation comprising a compound represented by the formula (I) or a salt thereof, sugar alcohol, and a calcium antagonist, which appropriately controls dissolution of the compound represented by the formula (I) or a salt thereof and the calcium antagonist from the solid preparation in the gastrointestinal tract, and maintains good stability thereof in the solid preparation.

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Abstract

La présente invention a pour objet une préparation solide comprenant (i) un composé représenté par la formule (I), chaque symbole étant tel que défini dans la description, ou un sel de celui-ci, (ii) un alcool de sucre, et (iii) un antagoniste du calcium, qui est supérieur du point de vue de la propriété de dissolution et de la stabilité.
PCT/JP2010/057923 2009-04-30 2010-04-28 Préparation solide WO2010126168A2 (fr)

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BRPI1014388A BRPI1014388A2 (pt) 2009-04-30 2010-04-28 preparação de sólido.
EA201171329A EA201171329A1 (ru) 2009-04-30 2010-04-28 Твердый препарат
NZ596395A NZ596395A (en) 2009-04-30 2010-04-28 Stable solid benzimidazole derivative preparation having optimized dissolution property
AU2010242308A AU2010242308A1 (en) 2009-04-30 2010-04-28 Solid preparation
MX2011011011A MX2011011011A (es) 2009-04-30 2010-04-28 Preparacion solida.
CA2760073A CA2760073A1 (fr) 2009-04-30 2010-04-28 Preparation solide
US13/138,950 US20120115837A1 (en) 2009-04-30 2010-04-28 Solid Preparation
SG2011078391A SG175794A1 (en) 2009-04-30 2010-04-28 Solid preparation
KR1020117027421A KR101797776B1 (ko) 2009-04-30 2010-04-28 고형 제제
MA34358A MA33280B1 (fr) 2009-04-30 2010-04-28 Preparation solide
JP2011545129A JP5666471B2 (ja) 2009-04-30 2010-04-28 固形製剤
EP10719654A EP2424501A2 (fr) 2009-04-30 2010-04-28 Préparation solide
CN2010800289702A CN102481248B (zh) 2009-04-30 2010-04-28 固体制剂
TNP2011000538A TN2011000538A1 (en) 2009-04-30 2011-10-24 Solid preparation
IL215962A IL215962A0 (en) 2009-04-30 2011-10-26 Soilid preparation
ZA2011/08375A ZA201108375B (en) 2009-04-30 2011-11-15 Solid preparation

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JP2019059706A (ja) * 2017-09-28 2019-04-18 エルメッド エーザイ株式会社 アジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤の品質向上方法、並びにアジルサルタン又はその塩及びアムロジピン又はその塩含有錠剤及びその製造方法
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WO2010126168A3 (fr) 2011-03-03
MX2011011011A (es) 2011-11-02
MY158158A (en) 2016-09-15
EA201171329A1 (ru) 2012-05-30
ZA201108375B (en) 2013-01-30
AU2010242308A1 (en) 2011-12-01
CA2760073A1 (fr) 2010-11-04

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