WO2006036007A2 - Modified-release preparation - Google Patents

Modified-release preparation Download PDF

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Publication number
WO2006036007A2
WO2006036007A2 PCT/JP2005/018486 JP2005018486W WO2006036007A2 WO 2006036007 A2 WO2006036007 A2 WO 2006036007A2 JP 2005018486 W JP2005018486 W JP 2005018486W WO 2006036007 A2 WO2006036007 A2 WO 2006036007A2
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WO
WIPO (PCT)
Prior art keywords
granules
substituted
compound
pharmaceutical agent
group
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PCT/JP2005/018486
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French (fr)
Other versions
WO2006036007A3 (en
Inventor
Akihiko Ono
Shuji Yoneyama
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Takeda Pharmaceutical Company Limited
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Publication of WO2006036007A2 publication Critical patent/WO2006036007A2/en
Publication of WO2006036007A3 publication Critical patent/WO2006036007A3/en

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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
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to a pharmaceutical agent comprising a nitrogen containing 5-membered heterocyclic compound useful as an agent for the prophylaxis or treatment of diabetes melLitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like, which has improved sustainability of an effective blood concentration of the compound.
  • R 1 represents a hydrocarbon group which may be substituted or a. heterocyclic group which may be substituted
  • X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -CO-, -CS-, -CR 4 (OR 5 )- or -NR 6 - wherein each of R 4 and R 6 represents a hydrogen atom or a hydrocarbon group which may be substituted, and R 5 represents a hydrogen atom or a protective group for a hydroxyl group; in represents an integer of 0 to 3;
  • Y represents an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO 2 -, -NR 7 -, -CONR 7 - or -NR 7 CO- wherein R 7 represents a hydrogen atom or a hydrocarbon group which may be substituted; ring A represents an aromatic ring which may further have 1 to
  • n represents an integer of 1 to 8;
  • ring B represents a nitrogen-containing 5-membered hetero ring which may further be substituted by an alkyl group;
  • X I represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO 2 -, -0-SO 2 - or -NR 16 - wherein R 16 represents a hydrogen atom ox a hydrocarbon group which may be substituted;
  • R 2 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
  • W represents a bond or a divalent hydrocarbon residue having 1 to 20 carbon atoms;
  • R 3 represents a group of the formula: -OR 8 (R 8 represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR 9 R 10 (each of R 9 and R 10 , whether identical or not, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted; R 9 and R 10 may bind together to form a ring) ; provided that R 1 is a heterocyclic group which may be substituted or R 2 is an aromatic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, when ring A is a benzene ring which may be substituted, and Y is an oxygen atom, a sulfur atom, -NH- or -CONH-; and a salt thereof [in the present description, these are sometimes to be abbreviated as compound (I) or a nitrogen containing 5- membered heterocyclic compound] have been reported to be useful as agents
  • the present inventors have conducted intensive studies in an attempt to achieve the aforementioned objects and found that a combination of two or more parts having mutually different release rates of a nitrogen containing 5-membered heterocyclic compound can decrease the maximum blood concentration of the compound when administered to a living organism, and improve sustainability of: an effective blood concentration of the compound.
  • the present inventors have further studied based on these findings, which resulted in the completion of the present invention. Accordingly, the present invent ⁇ on provides the following.
  • a pharmaceutical agent comprising a combination of two or more parts comprising a compound of the formula:
  • R 1 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted
  • X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -CO-, -CS-, -CR 4 (OR 5 )- or -NR 6 - wherein each of R 4 and R 6 represents a hydrogen atom orr a hydrocarbon group which may be substituted, and R 5 represents a hydrogen atom or a protective group for a hydroxyl group
  • m represents an integer of 0 to 3;
  • Y represents an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO 2 -, -NR 7 -, -CONR 7 - or -NR 7 CO- wherein R 7 represents a hydrogen atom or a hydrocarbon group which may be substituted; ring A represents an aromatic ring which may further have 1 to 3 substituents; n represents an integer of 1 to 8; ring B represents a nitrogen-containing 5-membered hetero ring which may further be substituted by an alkyl group; X 1 represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO 2 -, -0-SO 2 - or -NR 16 - wherein R 16 represents a hydrogen atom or a hydrocarbon group whdLch may be substituted; R 2 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a di
  • R 3 represents a group of the formula: -OR 8 (R 8 represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR 9 R 10 (each of R 9 and R 10 , whether identical or not, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted; R 9 and R 10 may bind together to form a ring) ; provided that R 1 is a heterocyclic group which may be substituted or R 2 is an aromatic hydrocarbon group wliich may be substituted or a heterocyclic group which may be substituted, when ring A is a benzene ring which may be substituted, and Y is an oxygen atom, a sulfur atom, -NH- or -CONH-; orr a salt thereof, said two or more parts have mutually different release rates of the compound or a salt thereof.
  • the pharmaceutical agent of the aforementioned [7] which is a single preparation wherein the modified-release part is coated with the immediate-release part.
  • the pharmaceutical agent of the aforementioned [1] which is a granule obtained by coating a sucrose-starch sphere with a coating layer comprising a compound represented by the formula (I) or a salt thereof, an excipient, a binder and a disintegrant to give granules (A) , coating granules (A) with a coating layer comprising a mixture of a methacrylic acid copolymer L and a methacrylic acid copolymer S, a plasticizer and a lubricant to give granules (B) , and coating granules (B) with a coating layer comprising the compound represented by the formula (I) or a salt thereof, an excipient, a binder
  • the pharmaceutical agent of the present invention shows a suppressed maximum blood concentration of compound (I) when administered to a living organism, and improved sustainability of an effective blood concentration of compound (I) .
  • the pharmaceutical agent of the present invention reduces the side effects of compound (I) and potentiates the efficacy of compound (I) .
  • the pharmaceutical agent of the present invention can reduce the administration frequency of compound (I) to patients as compared to conventional preparations (immediate-release preparations) comprising compound (I) , and the compliance is improved and a high treatment effect can be afforded. Therefore, the pharmaceutical agent of the present invention is extremely useful as an agent for the prophylaxis or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like.
  • Fig. 1 shows the results of the dissolution test of the pharmaceutical agent of the present invention.
  • Fig. 2 shows changes with time of a plasma concentration of compound (I) when the pharmaceutical agent of the present invention and comparative preparation were orally administered to cynomolgus monkeys.
  • the compound (I) to be used for the pharmaceutical agent of the present invention is described in WO01/38325, and as a preferable examples thereof, the following compounds A-G and the like can be mentioned.
  • Compound (I) can be produced by, for example, the methods described in WO01/38325, WO03/042183 and the like. (Compound A)
  • R 1 is a 5- or ⁇ -membered aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl) which may be condensed with a benzene ring, and which may have 1 or 2 substituents selected from 1) furyl, thienyl, pyridyl, pyrazinyl, phenyl or naphthyl, each of which may have 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, alkoxy groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, halogen atoms, nitro, hydroxy, and amino; and
  • X is a bond or -NR 6 - wherein R 6 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; m is 1 or 2;
  • Y is an oxygen atom, a sulfur atom, -NH- or -NHCO-;
  • ring A is benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene, etc.) or a 5- or ⁇ -membered aromatic hetero ring (preferably pyridine, isoxazole, etc.), each of which ring may further have 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, hydroxy group, alkoxy groups having 1 to 4 carbon atoms, aralkyloxy groups having 7 to 10 carbon atoms and halogen atoms;
  • n is an integer of 1 to 3;
  • ring B is a "5-membered aromatic hetero ring which contains at least 1 nitrogen atom, in addition to carbon atoms, as ring constituent atoms, and which may further contain 1 hetero atom selected from oxygen atom, sulfur atom and nitrogen atom" (e.g
  • X I is a bond
  • R 2 is an aliphatic hydrocarbon group having 1 to 8 carbon atoms (preferably an alkyl group) , an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, etc.) or a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl, etc.), each of which may have 1 to 3 substituents selected from the group consisting of 1) halogen atoms, 2) alkyl groups having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms, 3) alkoxy groups having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms, 4) aralkyloxy groups having 7 to 10 carbon atoms (e.g., benzyloxy) , 5) aryloxy groups having 6 to 14 carbon atoms (e.g., phenoxy) and 6)
  • W is a Ci-8 alkylene, a C2-8 alkenylene or a C2-8 alkynylene;
  • R 3 is -OR 8 (R 8 is a hydrogen atom, an "alkyl group having
  • R 1 is a 5- or 6-membered aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl) which may be condensed with a benzene ring, and which may have 1 or
  • substituents selected from the group consisting of alkoxy groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, halogen atoms, nitro, hydroxy, and amino;
  • X is a bond or -NR 6 - wherein R 6 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; m is 1 or 2;
  • Y is an oxygen atom, a sulfur atom, -NH- or -NHCO-;
  • ring A is benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene, etc.) or a 5- or ⁇ -membered aromatic hetero ring (preferably pyridine, isoxazole, etc.), each of which ring may further have 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, hydroxy group, alkoxy groups having 1 to 4 carbon atoms, aralkyloxy groups having 7 to 10 carbon atoms and halogen atoms;
  • n is an integer of 1 to 3;
  • ring B is a ⁇ 5-membered aromatic hetero ring which contains at least 1 nitrogen atom, in addition to carbon atoms, as ring constituent atoms, and which may further contain 1 hetero atom selected from oxygen atom, sulfur atom and nitrogen atom" (e.g
  • X I is an oxygen atom
  • R 2 is an aliphatic hydrocarbon group having 1 to 8 carbon atoms (preferably an alkyl group) , an aromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms (preferably an aralkyl group (e.g., benzyl)) or a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl, etc.), each of which may have 1 to 3 substituents selected from the group consisting of 1) halogen atoms, 2) alkyl groups having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms, 3) aralkyloxy groups having 7 to 10 carbon atoms (e.g., benzyloxy) , 4) [5- or 6-membered aromatic heterocyclic groups (e.g., pyridyl, oxazolyl, thiazolyl, triazolyl) which may have 1 or- 2 substituents selected from alkyl groups
  • W is a Ci-8 alkylene, a C2-8 alkenylene or a C2-8 alkynylene;
  • R 3 is -OR 8 (R 8 is a hydrogen atom, an "alkyl group having 1 to 4 carbon atoms” or an "aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents selected from alkyl gromps having 1 to 4 carbon atoms and halogen atoms”) or -NR 9 R 10 (each of R 9 and R 10 , whether identical or not, is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) .
  • R 9 and R 10 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • the salt of compound (I) is preferably a pharmacologically acceptable salt, and is exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
  • salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts.
  • salts with organic bases include salts w ⁇ th trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N / N-dibenzylethylenediamine, etc.
  • salts with inorganic acids include salts w ⁇ th hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • salts with organic acids 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, etc.
  • salts with basic amino acids include salts with arginine, lysine, ornithine, etc.
  • Examples of preferred salts with acidic amino acids include salts w ⁇ th aspartic acid, glutamic acid, etc.
  • the pharmaceutical agent of the present invention comprises a combination of two or more parts comprising compound (I), said two or more parts have mutually different release rates of compound (I) .
  • the part may be a preparation (e.g., fine granules, granules, tablets) by itself, or may be a part (e.g., core or coating layer of coated preparation; each layer constituting multilayer tablets) constituting a preparation.
  • a preparation e.g., fine granules, granules, tablets
  • a part e.g., core or coating layer of coated preparation; each layer constituting multilayer tablets
  • the mechanism for controlling the release of compound (I) from the above-mentioned part is not particularly limited, and may be any of 1) a preparation wherein compound (I) is released by passive diffusion from the preparation, 2) a preparation wherein compound (I) is released along with the erosion of the preparation, 3) a preparation wherein compound (I) is released in response to the changes in environmental pH, 4) a preparation wherein compound (I) is released due to the inner pressure caused t>y the swelling of the inside of the preparation by the absorption of the environmental moisture, 5) a preparation wherein compound (I) is immediately released by the disintegration or dissolution of the preparation and the like.
  • sustained-release preparations [preferably matrix tablet using a hydrophilic polymer (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide) ] ; matrix tablet containing a liposoluble base (e.g., carnauba wax, hydrogenated castor oil, hydrogenated rapeseed oil, polyglycerol fatty acid ester) ; tablets and granules coated with sustained-release base (e.g., cellulose polymers such as ethylcellulose and the like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name, manufactured by Rohm Pharma) ] , an ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name, manufactured by Rohm Pharma) ] and the like) and the like) and the like) and the like can be mentioned.
  • a hydrophilic polymer e.g., hydroxypropylcellulose, hydroxy
  • the mixing and molding is performed according to a method conventionally used in the technical field of pharmaceutical preparations.
  • pharmaceutically acceptable carrier various organic or inorganic carrier substances in common use as materials for pharmaceutical preparations, for example, excipients, lubricants, binders, disintegrants and the like, can be mentioned.
  • other additives for pharmaceutical preparations such as antiseptics, antioxidants, coloring agents, and sweetening agents, may also be used as necessary.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starcti (e.g., corn starch), gelatinized starch, dextrin, crystalline cellulose, low- substituted hydroxypropylcellulose, caxboxymethylcellulose sodium, gum arabic, pullulan, light antiydrous silicic acid, synthetic aluminum silicate, and magnesium metasilicate aluminate.
  • Preferred examples of the lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • Preferred examples of the binders include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.
  • Preferred examples of the disintegrants include lactose, sucrose, starch (e.g., corn starch), carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, Light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.
  • Preferred examples of the antiseptics include p- oxybenzoic acid esters, chlorobutanol, benzyl alcohoL , phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Preferred examples of the antioxidants include sulfites and ascorbates.
  • Preferred examples of the coloring agents incl_ude water-soluble tar colors for food e.g., Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blme Nos. 1 and 2
  • water-insoluble lake colors e.g., aluminum salts of the aforementioned water-soluble tar colors for food
  • natural colors e.g., ⁇ -carotene, chlorophyll, red ferric oxide, yellow ferric oxide
  • sweetening agents include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • the release control mechanisms of compound (I) from the "two or more parts" constituting the pharmaceutical agent of the present invention may be the same or different.
  • control mechanisms are preferably different from each other, and as a combination of the different control mechanisms, a combination of "preparation wherein compound (I) is released in response to the changes in environmental pH” and "preparation wherein compound (I) is immediately released by the disintegration or dissolution of the preparation” is preferable.
  • the "two or more parts” may form a single preparation or may be present as mutually independent multiple preparations.
  • a preparation wherein "one part” is coated with “other part” e.g., dry coated granules
  • a preparation wherein "one part” and “other part” are laminated in layers e.g., multilayer tablets
  • a capsule comprising a preparation comprising "one part” (e.g., fine granules, granules) and a preparation comprising "other part” (e.g., fine granules, granules); and the like
  • a preparation comprising "one part” e.g., fine granules, granules
  • other part e.g., fine granules, granules
  • a preparation comprising "one part” e.g., fine granules, granules, tablet
  • a preparation comprising "other part” e.g., fine granules, granules, tablet
  • "two or more parts” preferably form a single preparation.
  • the content of compound (I) in each part constituting the “two or more parts” varies depending on the kind of compound (I) , the size of the preparation and the like, it is, for example, 1-90 wt%, preferably 5-80 wt%.
  • the pharmaceutical agent of the present invention preferably comprises a combination of a modified-release part comprising compound (I) and an immediate-release part comprising compound (I) , and by employing such combination, an effective blood concentration of compound (I) can be sustained. for a long term from immediately after administration to a living organism.
  • immediate-release means a "drug dissolution rate from a composition at 30 min after the start of the test" of not less than 75% (preferably not less than 80%) when The Japanese Pharmacopoeia, Dissolution Test, Method 2 (Paddle Method) is performed using a suitable dissolution medium (900 mL) at a paddle rotation of 50 rpm, or a "drug dissolution rate from a composition at 30 min after the start of the test” of not less than 75% (preferably not less than 80%) when The Japanese Pharmacopoeia, Dissolution Test, Method 1 (Rotary Basket Method) is performed using a suitable dissolution medium (900 mL) at a paddle rotation of 75 rpm.
  • dissolution medium one conventionally employed in the technical field of pharmaceutical preparations, such as water, buffer and the like, is used. Particularly, phosphate buffer used in the below-mentioned Experimental Example 1 is preferable.
  • At least one of the "two or more parts" preferably comprises a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5.
  • hydroxypropylmethylcellulose phthalate (trade name: HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.), cellulose acetate phthalate, carboxymethylethylcellulose (trade name: CMEC, manufactured by Freund Corporation) , methyl methacrylate-methacrylic acid copolymer [methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) , methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma) ] , methacrylic acid-ethyl acrylate copolymer [dried methacrylic acid copolymer LD (trade name: Eudragit L100-55, manufactured by Rohm Pharma) , methacrylic acid copolymer LD (trade name: Eudragit L30D-55, manufactured by Rohm Pharma)], methacrylic acid-methyl acrylate-methyl methacrylate copolymer (trade name: HP-55
  • the polymer substance is preferably a methyl methacrylate-methacrylic acid copolymer, more preferably a mixture of methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) and methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma) .
  • a mixing ratio (weight ratio) of methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) and methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma) is preferably 1:0.5 to 1:7, more preferably 1:0.5 to 1:5, and particularly preferably about 1:3.
  • the pharmaceutical agent of the present invention preferably comprises a combination of a modified-release part wherein a core comprising compound (I) is coated with a coating layer comprising a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5, and an immediate-release part comprising the compound.
  • a coating layer comprising a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5, and an immediate-release part comprising the compound.
  • particles obtained by coating an inert carrier such as sucrose-starch spheres (trade name: Nonpareil-101 (particle size: 850 to 710 ⁇ m, 710 to 500 ⁇ m or 500 to 355 ⁇ m) manufactured by Freund Corporation) , purified sucrose spheres (trade name: Nonpareil-103 (particle size: 850 to 710 ⁇ m, 710 to 500 ⁇ tn or 500 to 355 ⁇ m) manufactured by Freund Corporation) , lactose-crystalline cellulose spheres (trade name: Nonpareil-105 (particle size: 710 to 500 ⁇ m, 500 to 355 ⁇ m or 300 to 180 ⁇ m) manufactured by Freund Corporation) , crystalline cellulose spheres (trade name: Celphere CP-507 (particle size: 500 to 710 ⁇ m) , Celphere CP-305 (particle size: 300 to 500 ⁇ m) , Celp
  • the sucrose-starch spheres are spherical granules containing 65-85 wt% of sucrose (preferably purified sucrose) and 15-35 wt% of starch (preferably corn starch) .
  • the sucrose- starch spheres preferably have a particle size within the range of 850-355 ⁇ m.
  • the particle size of particulate inert carriers such as sucrose-starch spheres, purified sucrose spheres, lactose- crystalline cellulose spheres, crystalline cellulose spheres and the like is preferably 850 to 150 ⁇ m, more preferably 850 to 710 ⁇ m.
  • the average particles diameter of the "core comprising compound (I)" is preferably 50 to 2000 ⁇ m, more preferably 100 to 1400 ⁇ m.
  • the aforementioned polymer substances are used.
  • the “coating layer” may further contain a plasticizer such as polyethylene glycol, dibutyl sebacate, diethyl phthalate, triacetin, triethyl citrate and the like; a lubricant such as talc, titanium dioxide, magnesium stearate, calcium stearate, light anhydrous silicic acid and the like; and the like.
  • the amount of the "coating layer” is generally 5 to 200 wtl, preferably 20 to 100 wt%, more preferably 20 to 50 wt%, relative to the "core comprising compound (I)".
  • the "core comprising compound (I)" can be coated with the “coating layer” by a method known per se.
  • the immediate-release part comprising compound (I) can be produced by mixing compound (I) and the aforementioned "pharmacologically acceptable carrier” and molding (preferably granulating) the mixture.
  • modified-release part and the “immediate-release part” may form a single preparation, or may be present as mutually independent multiple preparations.
  • the "single preparation” a preparation wherein "modified-release part” is coated with “immediate-release part” (e.g., dry coated granules); a preparation wherein "modified-release part” and “immediate- release part” are laminated in layers (e.g., multilayer tablets) ; a capsule comprising a preparation comprising "modified-release part” (e.g., fine granules, granules) and a preparation comprising "immediate-release part” (e.g., fine granules, granules) ; and the like can be mentioned.
  • a preparation comprising "modified- release part” e.g., fine granules, granules, tablet
  • a preparation comprising "immediate-release part” e.g., fine granules, granules, tablet
  • the "modified-release part” and the “immediate-release part” preferably form a single preparation.
  • a single preparation wherein a modified-release part is coated with an immediate-release part a “capsule comprising a modified- release part and an immediate-release part as independent preparations” and the like are preferable.
  • granules (C) obtained by coating sucrose-starch spheres (preferably Nonpareil-101 (trade name) having a particle size of 850 to 710 ⁇ jn (preferably average particle size 750 ⁇ m) ) with a coating layer comprising compound (I) , an excipient (preferably sucrose (e.g., purified sucrose), corn starch, crystalline cellulose) , a binder (preferably hydroxypropylcellulose) and a disintegrant (preferably low- substituted hydroxypropylcellulose) to give granules (A) , coating granules (A) with a coating layer comprising a mixture of methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) and methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma)
  • sucrose-starch spheres preferably Nonpareil-101 (trade name) having a particle size of 850 to 710
  • a plasticizer preferably triethyl citrate
  • a lubricant preferably talc
  • the low-substituted hydroxypropylcellulose to be used in the present invention refers to one having a hydroxypropoxyl group content of 5.0 to 16.0%.
  • hydroxypropylcellulose one having a hydroxypropoxyl group content of 53.4 to 77.5% can be mentioned.
  • hydroxypropylmethylcellulose 2910 (methoxyl group content 28.0 to 30.0%, hydroxypropoxyl group content 7.0 to 12.0%), hydroxypropylmethylcellulose 2906 (methoxyl group content 27.0 to 30.0%, hydroxypropoxyl group content 4.0 to 7.5%), hydroxypropylmethylcellulose 2208 (methoxyl group content 19.0 to 24.0%, hydroxypropoxyl group content 4.0 to 12.0%) and the like can be mentioned.
  • the content of the excipient in granules (A) is preferably 5 to 90 wt%.
  • the content of the binder in granules (A) is preferably 0.1 to 1.0 wt%, more preferably 0.3 to 0.7 wt%.
  • the content of the disintegrant in granules (A) is preferably 2 to 20 wt%.
  • the content of the mixture of methacrylic acid copolymer L and methacrylic acid copolymer S in granules (B) is preferably 10 to 70 wt%, more preferably 10 to 50 wt%, particularly preferably 10 to 25 wt%.
  • the content of the plasticizer in granules (B) is preferably 1 to 5 wt%.
  • the content of the lubricant in granules (B) is preferably 5 to 20 wt%.
  • the content of the excipient in the coating layer covering granules (B) is preferably 5 to 90 wt%.
  • the content of the binder in the coating layer covering granules (B) is preferably 20 to 60 wt%.
  • the content of the disintegrant in the coating layer covering granules (B) is preferably 3 to 15 wt%.
  • oral preparations such as tablet, capsule (including microcapsule) , granule, powder and the like; and parenteral preparations such as suppositories (e.g., rectal suppository, vaginal suppository) and the like can be mentioned. Each of these can be safely administered orally or parenterally. Of these, oral preparations such as tablet, capsule, granule and the like are preferable.
  • the pharmaceutical agent of the present invention shows low toxicity and a few side effects, and can be used as an agent for the prophylaxis or treatment of diabetes mellitus (e.g., type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, obesity diabetes mellitus) ; an agent for the prophylaxis or treatment of hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-high- density-lipoparoteinemia, postprandial hyperlipemia) ; an insulin resistance improving agent; an insulin sensitizer; an agent for the prophylaxis or treatment of IGT (Impaired Glucose Tolerance) or IFG (Impaired Fasting Glucose or Impaired Fasting Glycaemia) ; an agent for the prophylaxis or treatment of syndrome X; an agent for the prophylaxis or treatment of dysmetabolic syndrome; an agent for the prophylaxis or treatment of metabolic syndrome (a condition
  • the pharmaceutical agent of the present invention can be used as an agent for preventing progress from impaired glucose tolerance or IFG (Impaired Fasting Glucose or Impaired Fasting Glycaemia) to diabetes mellitus.
  • IFG Impaired Fasting Glucose or Impaired Fasting Glycaemia
  • the administration mode of the pharmaceutical agent of the present invention is not particularly limited, and "two or more parts" only need to be combined on administration.
  • administration mode for example, 1) administration of "two or more parts” as a single preparation, 2) simultaneous administration of ⁇ two or more parts” as multiple preparations (administration route may be the same or different) , 3) administration of "two or more parts” as multiple preparations at staggered times (administration route may be the same or different) arxd the like can be mentioned.
  • administration of "two or more parts" as a single preparation is preferable .
  • the dose of the pharmaceutical agent of the present invention varies depending on administration subject, administration route, target disease, clinical condition, etc., it is desirable that the active ingredient, i.e., compound (I) r be administered at a usual dosage per administration of about 0.01 to 100 mg/kg body weight, preferably 0.05 to 10 mcj/kg body weight, more preferably 0.1 to 2 mg/kg body weight, 1 or 2 times a day, for oral administration to an admit diabetic patient, for instance.
  • the pharmaceutical agent of the present invention can be used in combination with a drug such as a therapeutic agent for diabetes mellitus, a. therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antiinflammatory agent, an antithrombotic agent, a therapeutic agent for osteoporosis, a vitamin, an antidementia agent, a therapeutic agent for urinary incontinence or pollakiuria, a therapeutic agent for dysuria and the like (hereinafter, sometimes abbreviated as drug X) .
  • a drug such as a therapeutic agent for diabetes mellitus, a. therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antiinflammatory agent, an antithrombotic agent,
  • insulin preparations e.g., animal insulin preparations extracted from the bovine or swine pancreas; human insulin preparations synthesized by a genetic engineering technique using Escherichia coli or a yeast, insulin zinc; zinc insulin protamine; fragment or derivative of insulin (e.g., INS-I) ; oral insulin preparations
  • insulin sensitizers e.g., pioglLitazone or its salt (preferably hydrochloride) , rosiglitazone or its salt (preferably maleate) , Reglixane (JTT-501) , Netoglitazone (MCC-555) , FK- 614, Rivoglitazone (CS-OIl), Muraglitazar (BMS-298585) , compounds described in " WO99/58510 (e.g., (E) -4- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy)benzyloxyi
  • WO99/58510 e
  • glucokinase activators e.g., Ro-28-1675 and the like.
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat, ranirestat (AS-3201) , minalrestat, CT-112) , neurotrophic factors and its increasing agents (e.g., NGF, NT-3, BDNF, neurotrophin production secretion promoters described in WO01/14372 (e.g., 4- (4-chlorophenyl) -2- (2-methyl-l- imidazolyl) -5- [3- (2-methylphenoxy) propyl]oxazole) ) , protein kinase C (PKC) inhibitors (e.g., ruboxistaurin mesylate (LY- 333531)), AGE inhibitors (e.g., ALT-945, pimagedine, N- phenacylthiazolium bromide (ALT-766), EXO-226, ALT
  • antihyperlipidemic agent examples include HMG- CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin or their salts (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97/10224, such as N- [ [ (3R,5S)—1- (3-acetoxy-2,2- dimethylpropyl) -7-chloro-5- (2, 3-dimethoxyphenyl) -2-oxo-
  • HMG- CoA reductase inhibitors e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin or their salts (e.g., sodium salt, calcium salt)
  • squalene synthase inhibitors
  • fibrate compounds e.g., bezafibrate, clofibrate, simfibrate, clinofibrate
  • antioxidants e.g., lipoic acid, probucol
  • ACAT inhibitors e.g., Avasimibe, Eflucimibe
  • anion exchange resins e.g., cholestylamine
  • probucol e.g., nicotinic pharmaceutical agents
  • ethyl icosapentate e.g., phytosterol (e.g., soysterol, ⁇ -oryzanol) and the like.
  • hypotensive agent examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril) , angiotensin II antagonists (e.g., losartan, candesartan cilexetil, eprosartan, valsartan , termisartan, irbesartan, olmesartan medoxomil, tasosartan , l-[[2'-(2,5- dihydro-5-oxo-4H-l,2, 4-oxadiazol-3-yl)biphenyl-4-yl]methyl] -2- ethoxy-lH-benzimidazole-7-carboxylic acid) , calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (e.g., levcromakalim,
  • antiobesity agent examples include antiobesity drugs acting on the central nervous system (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP- 7941; compounds described in WO01/82925 and WO01/87834) ; neuropeptide Y antagonists (e.g., CP-422935) ; cannabinoid receptor antagonists (e.g., SR-141716, SR-147778) ; ghrelin antagonists; ll ⁇ -hydroxysteroid dehydrogenase inhibitors (e .g., BVT-3498)), pancreatic lipase inhibitors (e.g., orlistat, /VIL- 962), ⁇ 3 agonists (e.g.
  • diuretic agent examples include xanthine derivatives (e.g., theobromine and sodium salicylate, theobromine and calcium salicylate) , thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide) , antialdosterone preparations (e.g., spironolactone, triamterene) , carbonate dehydratase inhibitors (e.g., acetazolamide) , chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefruside, indapamide) , azosemide, isosorbide, ethacrynic acid, piretanide, bumet
  • chemotherapeutic agent examples include alkylating agents (e.g., cyclophosphamide, ifosamide) , metabolic antagonists (e.g., methotrexate, 5-fluorouracil or derivative thereof (Furtulon, Neo-Furtulon) ) , antitumor antibiotics (e.g., mitomycin, adriamycin) , plant-derived antitumor agents (e.g., vincristine, vindesine, Taxol) , cisplatin, carboplatin, etoposide and the like.
  • alkylating agents e.g., cyclophosphamide, ifosamide
  • metabolic antagonists e.g., methotrexate, 5-fluorouracil or derivative thereof (Furtulon, Neo-Furtulon)
  • antitumor antibiotics e.g., mitomycin, adriamycin
  • plant-derived antitumor agents
  • immunotherapeutic agent examples include microorganism- or bacterium-derived components (e.g., murarnyl dipeptide derivatives, Picibanil) , immunopotentiator polysaccharides (e.g., lentinan, schizophyllan, krestin) , genetically engineered cytokines (e.g., interferons, interleukins (e.g., IL-I, IL-2, IL-12) ) , colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin) and the like.
  • microorganism- or bacterium-derived components e.g., murarnyl dipeptide derivatives, Picibanil
  • immunopotentiator polysaccharides e.g., lentinan, schizophyllan, krestin
  • genetically engineered cytokines e.g., interferons, interleukins (e.g
  • antiinflammatory agent examples include non- steroidal antiinflammatory drugs (e.g., aspirin, acetaminophen, indomethacin) and the like.
  • non- steroidal antiinflammatory drugs e.g., aspirin, acetaminophen, indomethacin
  • antithrombotic agent examples include heparin (e.g., heparin sodium, heparin calcium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin agents (e.g., argatroban) , thrombolytic agents (e.g., urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase) , platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.
  • heparin e.g., heparin sodium, heparin calcium, dalteparin sodium
  • warfarin e.g., warfarin potassium
  • antithrombin agents e.g., argatroban
  • Examples of the therapeutic agents for osteoporosis include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, risedronate disodium, pamidronate disodium, alendronate sodium hydrate, reminderonate disodium and the like.
  • Examples of vitamins include vitamin Bi , vitamin B 3 . 2 and the like.
  • antidementia agent examples include tacrine, donepezil, rivastigmine, galanthamine and the like.
  • Examples of the therapeutic agents for urinary incontinence or pollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
  • Examples of the therapeutic agents for dysuria include acetylcholine esterase inhibitors (e.g., distigmine) and the like.
  • drugs confirmed to exhibit a cachexia ameliorating effect in animal models and clinical applications namely, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone) , metoclopramide pharmaceuticals, tetrahydrocannabinol pharmaceuticals, fat metabolism ameliorating agents (e.g., eicosapentanoic acid) , growth hormones, IGF-I, and antibodies to the cachexia-inducing factor TNF- ⁇ , LIF, IL-6 or oncostatin M and the like, can be also used in combination with the pharmaceutical agent of the present invention.
  • cyclooxygenase inhibitors e.g., indomethacin
  • progesterone derivatives e.g., megestrol acetate
  • glucocorticoids e.g., dexamethasone
  • glycation inhibitors e.g., ALT-711
  • nerve regeneration promoters e.g., Y-128, VX853, prosaptide
  • antidepressants e.g., desipramine, amitriptyline, imipramine
  • antiepileptics e.g., lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine
  • antiarrhythmics e.g., mexiletine
  • acetylcholine receptor ligands e.g., ABT-594
  • endothelin receptor antagonists e.g., ABT-627
  • monoamine uptake inhibitors e.g., tramadol
  • narcotic analgesics e.g., morphine
  • GABA receptor agonists e.g., gabapentin, gabapentin MR agents
  • ⁇ 2 receptor agonists e
  • the above drug X can be used as a mixture of two or more species in an appropriate ratio.
  • the pharmaceutical agent of the present invention and drug X By combining the pharmaceutical agent of the present invention and drug X, superior effects, for example, (1) the dose of the pharmaceutical agent of the present invention and/or drug X can be reduced, (2) side effects of the pharmaceutical agent of the present invention and/or drug X can be reduced, (3) effects (action) of the pharmaceutical agent of the present invention and/or drug X can be potentiated, and the like can be obtained as compared to single administration of the pharmaceutical agent of the present invention or drug X.
  • the administration time of the pharmaceutical agent of the present invention and drug X is not restricted, and the pharmaceutical agent of the present invention and drug X can be administered to an administration subject simultaneously, or may be administered at staggered times.
  • the dosage of drug X can be determined according to the administration amount clinically used, and appropriately selected depending on an administration 'Subject, administration route, disease, combination and the like.
  • the administration mode of the pharmaceutical agent of the present invention and drug X is not particularly limited, and the pharmaceutical agent of the present invention and drug X only need to be combined on administration.
  • administration mode for example, (1) administration of a single preparation obtained by simultaneously producing the pharmaceutical agent of the present invention and drug X, (2) simultaneous administration by the same administration route of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X, (3) administration by the same administration route at staggered times of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X, (4) simultaneous administration by different administration routes of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X, (5) administration by different administration routes at staggered times of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X (for example, the pharmaceutical agent of the present invention and drug X are administered in this order, or in the reverse order) and the like can be mentioned.
  • Examples for example, the pharmaceutical agent of the present invention and drug X are administered in this order,
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) , and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules are vacuum dried at 40 0 C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ m - 1400 ⁇ m) having the following composition.
  • Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) .
  • Talc (783.0 g) is dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules (2656 g) obtained in Reference Example 1 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44 0 C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 44°C to give enteric coated granules having the following composition.
  • the granules are passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ m) .
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules are vacuum dried at 4O 0 C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ m - 1400 ⁇ m) having the following composition.
  • Example 3 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 45°C, inlet air volume: 1.2 m 2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 45 0 C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (600 ⁇ m - 1400 ⁇ m) .
  • MP-10 fluidized bed coating machine
  • Compound D (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose (166.0 g) and crystalline cellulose (143.3 g) are mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder.
  • an agitation granulator type FG-VG-10, manufactured by POWREX CORPORATION
  • Nonpareil-lOl (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) , and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules are vacuum dried at 40 0 C for 16 hr and passed through a round sieve, to give immediate-release granules (600 ⁇ m - 1400 ⁇ rn) having the following composition.
  • Methacrylic acid copolymer S (1175 g) , itiethacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) .
  • Talc (783.0 g) is dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules obtained in Reference Example 5 are coated wzLth the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44°C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 44 0 C to give enteric coated granules having the following composition.
  • the granules are passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ m) .
  • Reference Example 7 Compound D (827.3 g) , purified sucrose (614.7 g) and low-substituted hydroscypropylcellulose (339.9 g) are thoroughly mixed to give a dusting powder.
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the abo ⁇ e-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules are vacuum dried at 40 0 C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ tn - 1400 ⁇ m) having the following composition.
  • Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) are dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) .
  • Talc (216.0 g) is dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules (990.6 g) obtained in Reference Example 7 are coated with the above—mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 45°C, inlet air volume: 1.2 m 2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 45 0 C to give enteric coated granules having the following composition.
  • the granules are passed through a round sieve to give granules (600 ⁇ m - 1400 ⁇ m) .
  • Reference Example 9 Compound E (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose (166.0 g) and crystalline cellulose (143.3 g) were mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder.
  • an agitation granulator type FG-VG-10, manufactured by POWREX CORPORATION
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (780.0 g) were fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above—mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules were vacuum dried at 40 0 C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ m - 1400 ⁇ m) having the following composition.
  • composition of immediate-release granules pea: 189.7 mg
  • Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) were dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) .
  • Talc (783.0 g) was dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules (2656 g) obtained in Reference Example 9 were coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44°C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized becd dried at inlet air temperature: 44°C to give enteric coated granules having the following composition.
  • the granules were passed through a round sieve to give granules (850 ⁇ m - 17 OO ⁇ m) ⁇
  • Nonpareil-101 16.0 mg Compound E 16.0 mg purified sucrose 12.0 mg low-substituted hydroxypropylcellulose 6.6 mg hydroxypropylcellulose 0.2 mg total 50.8 mg
  • Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) were dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) .
  • Talc (216.0 g) was dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules obtained in Reference Example 11 were coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 45 0 C, inlet air volume: 1.2 m 2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 45°C to give enteric coated granules having the following composition.
  • the granules were passed through a round sieve to give granules (600 ⁇ m - 1400 ⁇ m) .
  • Reference Example 13 Compound F (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose (166.0 g) and crystalline cellulose (143.3 g) are mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder.
  • an agitation granulator type FG-VG-10, manufactured by POWREX CORPORATION
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules are vacuum dried at 40 0 C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ m - 1400 ⁇ m) having the following composition.
  • Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) .
  • Talc (783.0 g) is dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules obtained in Reference Example 13 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44 0 C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 44 0 C to give enteric coated granules having the following composition.
  • the granules are passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ m) .
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules are vacuum dried at 40°C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ m - 1400 ⁇ m) having the following composition.
  • Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) are dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) .
  • Talc (216.0 g) is dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules (990.6 g) obtained in Reference Example 15 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 45 0 C, inlet air volume: 1.2 m 2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 45°C to give enteric coated granules having the following composition.
  • the granules are passed through a round sieve to give granules (600 ⁇ m - 1400 ⁇ m) •
  • Compound E (2480 g) , purified sucrose (1852 g) , corn starch (1129 g) , low-substituted hydroxypropylcellulose (640.2 g) and crystalline cellulose (551.1 g) were mixed in a vertical granulator (type FM-VG-50P, manufactured by POWREX CORPORATION) at 300 rpm for 3 min to give a dusting powder.
  • a vertical granulator type FM-VG-50P, manufactured by POWREX CORPORATION
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (2720 g) were fed into a centrifugal tumbling granulator (CF-600S, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.22 w/w%) to give spherical granules.
  • the granules were vacuum dried at 4O 0 C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ m - 1400 ⁇ m) having the following composition.
  • Methacrylic acid copolymer S 3541 g
  • methacrylic acid copolymer L 1180 g
  • triethyl citrate 471.1 g
  • Talc 2356 g was dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules obtained in Reference Example 17 were coated with the above-mentioned coating solution in a fluidized bed coating machine (FD-S2, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 52 0 C, inlet air volume: 6.5 m 2 /min, coating solution spray rate: 150 g/min, spray air pressure: 0.55 MP and spray air volume: 290 NL/min, and fluidized bed dried at inlet air temperature: 52°C to give enteric coated granules having the following composition.
  • the granules were passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ m) •
  • Nonpareil-101 (trade name, particle size: 850 to 710 ⁇ m, manufacti ⁇ red by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxyprropylcellulose (2.44 w/w%) to give spherical granules.
  • the granules are vacuum dried at 40 0 C for 16 hr and passed through a. round sieve to give immediate-release granules (600 ⁇ m - 140O ⁇ m) having the following composition.
  • Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) .
  • Talc (783.0 g) is dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules obtained in Reference Example 19 (2656 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44°C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet a ⁇ _r temperature: 44°C to give enteric coated granules having the following composition.
  • the granules are passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ rn) .
  • Nonpareil-101 (trade name, part ⁇ cle size: 850 to 710 ⁇ m, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcelli ⁇ lose (2.44 w/w%) to give spherical granules, The granules are -vacuum dried at 40 0 C for 16 hr and passed through a round sieve to give immediate-release granules (600 ⁇ jn - 1400 ⁇ in) having the following composition.
  • Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) are dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) .
  • Talc (216.0 g) is dispersed in the obtained solution to give a coating solution.
  • the immediate-release granules (990.6 g) obtained in Reference Example 21 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 45 0 C, inlet air volume: 1.2 m 2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air tem.peratu.re: 45°C to give enteric coated granules having the following composition.
  • the granules are passed through a round sieve to give granules (600 ⁇ m - 1400 ⁇ m) .
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound C (256.5 g) are dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules (1271 g) obtained in Reference Example 2 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 7O 0 C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume:. 90 NL/min, and flixidized bed dried at inlet air temperature: 7O 0 C to give two-stage release granules having the following composition.
  • the gxanules are passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ m) . Then, the granules are vacuum dried at 40 0 C for 16 hr.
  • composition of two-stage release granules per 315.7 mg enteric coated granules obtained in Reference Example 2 282.5 mg Compound C 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 12.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 315.7 mg
  • the two-stage release granules (3631 g) obtained in Example 1 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound C per capsule.
  • TM- 15 manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO
  • ZANASI type 6F manufactured by IMA
  • Example 4 The mixed granules (158.0 mg) obtained in Example 2 are filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound C per capsule.
  • ZANASI type 6F manufactured by IMA
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound D (256.5 g) are dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules obtained in Reference Example 6 (1271 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 70 0 C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 70 0 C to give two-stage release granules having the following composition.
  • the granules are passed through a round sieve (850 ⁇ m - 1700 ⁇ m) to give granxiles. Then the granules are vacuum dried at 40 0 C for 16 hr.
  • the two-stage release granules (3631 g) obtained in Example 5 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound D per capsule.
  • TM- 15 manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO
  • ZANASI type 6F manufactured by IMA
  • Example 6 The mixed granules (158.0 mg) obtained in Example 6 aire filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound D per capsule.
  • ZANASI type 6F manufactured by IMA
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW " ) (192.0 g) and purified sucrose (41.1 g) were dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound E (256.5 g) were dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules obtained in Reference Example 10 (1271 g) were coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 70 0 C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 7O 0 C to give two-stage release granules having the following composition.
  • the granules were passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ m) .
  • the two-stage release granules (3631 g) obtained in Example 9 and talc (3.45 g) were mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO), and the obtained mixed granules (316.0 mg) were filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound E per capsule.
  • TM- 15 manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO
  • ZANASI type 6F manufactured by IMA
  • Example 11 The mixed granules (158.0 mg) obtained in Example 10 were filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound E per capsule.
  • ZANASI type 6F manufactured by IMA
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (11.78 g) and purified sucrose (2.55 g) were dissolved in purified water (141.36 g) . Low-substituted hydroxypropylcellulose (2.55 g) and Compound E (15.71. g) were dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules obtained in Reference Example 12 were coated with the above-mentioned coating solution in a tumbling fluidized bed glanulator (SPIR-A-FLOW, manufactured by Freund Corporation) under the conditions of inlet air temperature: 55 0 C, rotor revolution speed: 150 rpm, coating solution spray rate: 3.0 g/min and spray air pressure: 1.0 kg/cm 2 to give two-stage release granules having the following composition.
  • the granules were vacuum dried at 40 0 C for 16 hr and passed through a round sieve to give granules (1180 ⁇ m - 1400 ⁇ m) .
  • Example 13 The two-stage release granules (262.4 mg) obtained in Example 13 were filled in one No. 2 capsule to give a capsule containing 64 mg of Compound E.
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5RW) (14.73 g) and purified sucrose (2.55 g) were dissolved in purified water (294.50 g) . Low-substituted hydroxypropylcellulose (2.55 g) and Compound E (15.71 g) were dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules obtained in Reference Example 12 were coated with the above-mentioned coating solution in a tumbling fluidized bed granulator (SPIR-A-FLOW, manufactured by Freund Corporation) under the conditions of inlet air temperature: 55 0 C, rotor revolution speed: 150 rpm, coating solution spray rate: 3.15 g/min and spray air pressure: 1.0 kg/cm 2 to give two-stage release granules having the following composition.
  • the granules were vacuum dried at 40 0 C for 16 hr and passed through a round sieve to give granules (710 ⁇ m - 1400 ⁇ m) .
  • Example 15 The two-stage release granules (262.4 mg) obtained in Example 15 were filled in one No. 2 capsule to give a capsule containing 64 mg of Compound E.
  • Hydroxypropylcellulose (1.024 g) and purified sucrose (2.56 g) were dissolved in purified water (157.9 g) .
  • Low- substituted hydroxypropylcellulose (2.56 g) and Compound E (16.0 g) were dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules obtained in Reference Example 12 (210 g) were coated with the above- mentioned coating solution in a tumbling fluidized bed granulator (SPIR-A-FLOW, manufactured by Freund Corporation) under the conditions of inlet air temperature: 55 0 C, rotor revolution speed: 100 rpm, coating solution spray rate: 3.0 g/min and spray air pressure: 1.0 kg/cm 2 to give two-stage release granules having the following composition.
  • the granules were vacuum dried at 40°C for 16 hr and passed through a round sieve to give granules (710 ⁇ m - 1400 ⁇ m) .
  • composition of two-stage release granules (per 252.144 mg) enteric coated granules obtained in Reference Example 12 230.00 mg
  • Compound E 16.00 mg purified sucrose 2.56 mg hydroxypropylcellulose 1.024 mg low-substituted hydroxypropylcellulose 2.56 mg total 252.144 mg
  • Example 17 The two-stage release granules (252.144 mg) obtained in Example 17 were filled in one No. 2 capsule to give a capsule containing 64 mg of Compound E.
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound F (256.5 g) are dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules obtained in Reference Example 14 (1271 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 70 0 C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 70 0 C to give two-stage release granules having the following composition.
  • the granules are passed through a round sieve (850 ⁇ jn - 1700 ⁇ m) to give granules. Then, the granules are vacuum dried at 40 0 C for 16 hr.
  • Example 20 The two-stage release granules (3631 g) obtained in
  • Example 19 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound F per capsule.
  • TM- 15 manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO
  • ZANASI type 6F manufactured by IMA
  • Example 22 The mixed granules (158.0 mg) obtained in Example 20 are filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound F per capsule.
  • ZANASI type 6F manufactured by IMA
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (188Og) and purified sucrose (401.0 g) were dissolved in purified water (22520 g) .
  • the enteric coated granules obtained in Reference Example 18 (19170 g) were coated with the above-mentioned coating solution in a fluidized bed coating machine (FD-S2, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 63°C, inlet air volume: 7.0 m 2 /min, coating solution spray rate: 134 g/min, spray air pressure: 0.50 MPa and spray air volume: 280 NL/min, and fluidized bed dried at inlet air temperature: 63°C to give two-stage release granules having the following composition.
  • the granules were passed through a round sieve to give granules (850 ⁇ m - 1700 ⁇ m) . Then, the granules were vacuum dried at 40 0 C for 16 hr.
  • the two-stage release granules (78960 g) obtained in Example 23 and talc (75.2 g) were mixed in a tumbler mixer (type TM20-0-0, manufactured by SUEHIRO KAKOKI CO., LTD.) and the obtained mixed granules (494.0 mg) were filled in a No. 0 long capsule by a capsule filling machine (ZANASI type 32F, manufactured by IMA) to give a capsule containing 100 mg of Compound E per capsule.
  • ZANASI type 32F manufactured by IMA
  • Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound G (256.5 g) are dispersed in the obtained solution to give a coating solution.
  • the enteric coated granules obtained in Reference Example 20 (1271 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 70 0 C, inlet air volume: 2.0 m 2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 70 0 C to give two-stage release granules having the following composition.
  • the granules are passed through a round sieve (850 ⁇ tn - 1700 ⁇ m) to give granules. Then, the granules are vacuum dried at 40 0 C for 16 hr.
  • the two-stage release granules (3631 g) obtained in Example 25 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound G per capsule.
  • TM- 15 manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO
  • ZANASI type 6F manufactured by IMA
  • Example 26 The mixed granules (158.0 mg) obtained in Example 26 are filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound G per capsule.
  • ZANASI type 6F manufactured by IMA
  • Comparative Example Compound E (769.5 g) , lactose (3522 g) and corn starch (528.0 g) were uniformly mixed in a fluidized bed granulating dryer (FD-5S, POWREX CORPORATION), granulated while spraying an aqueous solution of hydroxypropylcellulose (158.4 g) and then dried in the dryer.
  • the obtained granules were pulverized in a Power Mill grinder (P-3, SHOWA KAGAKU KIKAI KOSAKUSHO) using a 1.5 mm ⁇ punching screen.
  • Croscarmellose sodium (220.0 g) and magnesium stearate (32.0 g) were added to the obtained sized granules (4148 g) and mixed in a tumbler mixer (TM-15, SHOWA KAGAKU KIKAI KOSAKUSHO) .
  • the obtained mixture was tableted with a rotary tablet press (Correct 12HUK, KIKUSUI SEISAKUSHO LTD.) using a 6.5 inm ⁇ punch (tableting pressure: 8.5 KN/punch, weight per tablet: 110 mg) to give plain tablets.
  • Hydroxypropylmethylcellulose 2910 (358.8 g) and macrogol 6000 (72.0 g) were dissolved in purified water (4320 g) and titanium dioxide (48.0 g) and yellow ferric oxide (1.2 g) were dispersed therein to give a coating agent.
  • the coating agent was sprayed on the aforementioned plain tablets in a Driacoater coating machine (DRC-500, manufactured by POWREX CORPORATION) to give film-coated tablet having the following composition (sometimes to be abbreviated as comparative preparation in the present description) .
  • composition of comparative preparation (per 114 mg) Compound E 16.00 mg lactose 73.40 mg corn starch 11.00 mg hydroxypropylcellulose 3.30 mg croscarmellose sodium 5.50 mg magnesium stearate 0.80 mg hydroxypropylmethylcellulose 2910 2.99 mg macrogol 6000 0.60 mg titanium dioxide 0.40 mg yellow ferric oxide 0.01 mg total 114.00 mg
  • the drug dissolution property of the two-stage release granules obtained in Example 9 was evaluated by a dissolution test (phosphate buffer (pH 6.8, 900 mL) containing 0.4 w/w% sodium dodecylsulfate, Paddle Method, 50 rpm, 37 0 C) .
  • the dissolution test was performed according to the Japanese Pharmacopoeia, Fourteenth Edition, Dissolution Test, Method 2 (Paddle Method) .
  • the results are shown in Fig. 1 wherein -o- shows the results of the two-stage release granules of Example 9.
  • the pharmaceutical agent of the present invention showed a step-wise release of compound (I) .
  • the results are shown in Fig. 2 wherein -o- shows the results of the capsule of Example 10 and -•- shows the results of the comparative preparation.
  • the pharmaceutical agent of the present invention suppressed the maximum blood concentration of compound (I) and further, sustainability of blood concentration of compound (I) was achieved.
  • a pharmaceutical agent comprising a nitrogen containing 5-membered heterocyclic compound useful as an agent for the prophylaxis or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like, which has improved sustainability of an effective blood concentration of the compound, can be provided.

Abstract

The present invention relates to a pharmaceutical agent comprising a combination of two or more parts comprising a compound of the formula:wherein R1 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; X represents a bond, or the like; m represents an integer of 0 to 3; Y represents an oxygen atom or the like; ring A represents an aromatic ring which may further have 1 to 3 substituents; n represents an integer of 1 to 8; ring B represents a nitrogen-containing 5-membered hetero ring which may further be substituted by an alkyl group; X1 represents a bond or the like; R2 represents a hydrogen atom or the like; W represents a bond or the like; R3 represents a group of the formula: -OR8 (R8 represents a hydrogen atom or a hydrocarbon group which may be substituted) or the like; or a salt thereof, said two or more parts have mutually different release rates of the compound or a salt thereof. According to the present invention, a pharmaceutical agent comprising a nitrogen containing 5-membered heterocyclic compound useful as an agent for the prophylaxis or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like, which has improved sustainability of an effective blood concentration of the compound, can be provided.

Description

DESCRIPTION
MODIFIED-RELEASE PREPARATION Technical Field
The present invention relates to a pharmaceutical agent comprising a nitrogen containing 5-membered heterocyclic compound useful as an agent for the prophylaxis or treatment of diabetes melLitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like, which has improved sustainability of an effective blood concentration of the compound.
Background Art
A compound of the formula to be used in the present invention:
Figure imgf000002_0001
wherein R1 represents a hydrocarbon group which may be substituted or a. heterocyclic group which may be substituted;
X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -CO-, -CS-, -CR4(OR5)- or -NR6- wherein each of R4 and R6 represents a hydrogen atom or a hydrocarbon group which may be substituted, and R5 represents a hydrogen atom or a protective group for a hydroxyl group; in represents an integer of 0 to 3;
Y represents an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO2-, -NR7-, -CONR7- or -NR7CO- wherein R7 represents a hydrogen atom or a hydrocarbon group which may be substituted; ring A represents an aromatic ring which may further have 1 to
3 substituents; n represents an integer of 1 to 8; ring B represents a nitrogen-containing 5-membered hetero ring which may further be substituted by an alkyl group;
XI represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO2-, -0-SO2- or -NR16- wherein R16 represents a hydrogen atom ox a hydrocarbon group which may be substituted;
R2 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent hydrocarbon residue having 1 to 20 carbon atoms;
R3 represents a group of the formula: -OR8 (R8 represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR9R10 (each of R9 and R10, whether identical or not, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted; R9 and R10 may bind together to form a ring) ; provided that R1 is a heterocyclic group which may be substituted or R2 is an aromatic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, when ring A is a benzene ring which may be substituted, and Y is an oxygen atom, a sulfur atom, -NH- or -CONH-; and a salt thereof [in the present description, these are sometimes to be abbreviated as compound (I) or a nitrogen containing 5- membered heterocyclic compound] have been reported to be useful as agents for the prophylaxis or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis, and the like (WO01/38325) .
However, there is no report on a pharmaceutical agent having improved sustainability of an effective blood concentration of the compound and a salt thereof. Disclosure of the Invention
It is therefore an object of the present invention to provide a pharmaceutical agent comprising a nitrogen containing 5-membered heterocyclic compound useful as an agent for the prophylaxis or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like, which has improved sustainability of an effective blood concentration of the compound. The present inventors have conducted intensive studies in an attempt to achieve the aforementioned objects and found that a combination of two or more parts having mutually different release rates of a nitrogen containing 5-membered heterocyclic compound can decrease the maximum blood concentration of the compound when administered to a living organism, and improve sustainability of: an effective blood concentration of the compound. The present inventors have further studied based on these findings, which resulted in the completion of the present invention. Accordingly, the present invent±on provides the following.
[1] A pharmaceutical agent comprising a combination of two or more parts comprising a compound of the formula:
Figure imgf000004_0001
wherein R1 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -CO-, -CS-, -CR4 (OR5)- or -NR6- wherein each of R4 and R6 represents a hydrogen atom orr a hydrocarbon group which may be substituted, and R5 represents a hydrogen atom or a protective group for a hydroxyl group; m represents an integer of 0 to 3;
Y represents an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO2-, -NR7-, -CONR7- or -NR7CO- wherein R7 represents a hydrogen atom or a hydrocarbon group which may be substituted; ring A represents an aromatic ring which may further have 1 to 3 substituents; n represents an integer of 1 to 8; ring B represents a nitrogen-containing 5-membered hetero ring which may further be substituted by an alkyl group; X1 represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO2-, -0-SO2- or -NR16- wherein R16 represents a hydrogen atom or a hydrocarbon group whdLch may be substituted; R2 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent hydrocarbon residue having 1 to 20 carbon atoms;
R3 represents a group of the formula: -OR8 (R8 represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR9R10 (each of R9 and R10, whether identical or not, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted; R9 and R10 may bind together to form a ring) ; provided that R1 is a heterocyclic group which may be substituted or R2 is an aromatic hydrocarbon group wliich may be substituted or a heterocyclic group which may be substituted, when ring A is a benzene ring which may be substituted, and Y is an oxygen atom, a sulfur atom, -NH- or -CONH-; orr a salt thereof, said two or more parts have mutually different release rates of the compound or a salt thereof. [2] The pharmaceutical agent of the aforementioned [1], wherein at least one of the two or more parts compriLses a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5.
[3] The pharmaceutical agent of the aforementioned C2], wherein the polymer substance is a methyl methacrylate- methacrylic acid copolymer.
[4] The pharmaceutical agent of the aforementioned [3], wherein the polymer substance is a mixture of a methacrylic acid copolymer L and a methacrylic acid copolymer S. [5] The pharmaceutical agent of the aforementioned [4], wherein the weight ratio of the methacrylic acid copolymer L:methacrylic acid copolymer S is 1:0.5 to 1:7.
[6] The pharmaceutical agent of the aforementioned [1], wherein the two or more parts form a single preparation. [7] The pharmaceutical agent of the aforementioned [1], which comprises a combination of a modified-release part wherein a core comprising a compound represented by the formula (I) or a salt thereof is coated with a coating layer comprising a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5, and an immediate-release part comprising the compound or a salt thereof.
[8] The pharmaceutical agent of the aforementioned [7], which is a single preparation wherein the modified-release part is coated with the immediate-release part. [9] The pharmaceutical agent of the aforementioned [7], which is a capsule comprising the modified-release part and the immediate-release part as independent preparations. [10] The pharmaceutical agent of the aforementioned [1] , wherein the compound represented by the formula (I) is ethyl 3- [3-ethoxy-l- [4- (2-phenyl-4-oxazolylmethoxy)benzyl] -IH- pyrazol-4-yl]propionate/ ethyl 3- [3-ethoxy-l- [2- (5-methyl-2-phenyl-4- oxazolylmethoxy)benzyl] -lH-pyrazol-4-yl]propionate; 3- (3-ethoxy-l-{4- [ (2-phenyl-l, 3-thiazol-4-yl)methoxy]benzyl}- lH-pyrazol-4-yl)propanoic acid; 3- [3-ethoxy-l- [4-[2- (2-furyl)-5-methyl-4- oxazolylmethoxy]benzyl] -lH-pyrazol-4-yl]propionic acid; or
3- [3-ethoxy-l-[4-[5-methyl-2- (2-thienyl) -4- oxazolylmethoxy]benzyl] -lH-pyrazol-4-yl]propionic acid. [11] The pharmaceutical agent of the aforementioned [1], which is a granule obtained by coating a sucrose-starch sphere with a coating layer comprising a compound represented by the formula (I) or a salt thereof, an excipient, a binder and a disintegrant to give granules (A) , coating granules (A) with a coating layer comprising a mixture of a methacrylic acid copolymer L and a methacrylic acid copolymer S, a plasticizer and a lubricant to give granules (B) , and coating granules (B) with a coating layer comprising the compound represented by the formula (I) or a salt thereof, an excipient, a binder and a disintegrant.
[12] The pharmaceutical agent of the aforementioned [11], which is a granule obtained by coating a sucrose-starch sphere with a coating layer comprising a compound represented by the formula (I) or a salt thereof, sucrose, corn starch, crystalline cellulose, hydroxypropylcellulose and low- substituted hydroxypropylcellulose to give granules (A) , coating granules (A) with a coating layer comprising a mixture of a methacrylic acid copolymer L and a methacrylic acid copolymer S in a weight ratio of 1:0.5 to 1:7, triethyl citrate and talc to give granules (B) , and coating granules (B) with a coating layer comprising the compound represented by the formula (I) or a salt thereof, sucrose, hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose. As compared with conventional preparation (immediate- release preparation) comprising compound (I) , the pharmaceutical agent of the present invention shows a suppressed maximum blood concentration of compound (I) when administered to a living organism, and improved sustainability of an effective blood concentration of compound (I) .
Therefore, the pharmaceutical agent of the present invention reduces the side effects of compound (I) and potentiates the efficacy of compound (I) . As a result, the pharmaceutical agent of the present invention can reduce the administration frequency of compound (I) to patients as compared to conventional preparations (immediate-release preparations) comprising compound (I) , and the compliance is improved and a high treatment effect can be afforded. Therefore, the pharmaceutical agent of the present invention is extremely useful as an agent for the prophylaxis or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like.
Brief Description of the Drawings Fig. 1 shows the results of the dissolution test of the pharmaceutical agent of the present invention.
Fig. 2 shows changes with time of a plasma concentration of compound (I) when the pharmaceutical agent of the present invention and comparative preparation were orally administered to cynomolgus monkeys.
Best Mode for Embodying the Invention The compound (I) to be used for the pharmaceutical agent of the present invention is described in WO01/38325, and as a preferable examples thereof, the following compounds A-G and the like can be mentioned.
Compound (I) can be produced by, for example, the methods described in WO01/38325, WO03/042183 and the like. (Compound A)
Compounds in which R1 is a 5- or β-membered aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl) which may be condensed with a benzene ring, and which may have 1 or 2 substituents selected from 1) furyl, thienyl, pyridyl, pyrazinyl, phenyl or naphthyl, each of which may have 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, alkoxy groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, halogen atoms, nitro, hydroxy, and amino; and
2) alkyl groups having 1 to 4 carbon atoms or cycloalkyl groups having 3 to 7 carbon atoms, each of which may have 1 to 3 substituents selected from the group consisting of alkoxy groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, halogen atoms, nitro, hydroxy, and amino;
X is a bond or -NR6- wherein R6 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; m is 1 or 2;
Y is an oxygen atom, a sulfur atom, -NH- or -NHCO-; ring A is benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene, etc.) or a 5- or β-membered aromatic hetero ring (preferably pyridine, isoxazole, etc.), each of which ring may further have 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, hydroxy group, alkoxy groups having 1 to 4 carbon atoms, aralkyloxy groups having 7 to 10 carbon atoms and halogen atoms; n is an integer of 1 to 3; ring B is a "5-membered aromatic hetero ring which contains at least 1 nitrogen atom, in addition to carbon atoms, as ring constituent atoms, and which may further contain 1 hetero atom selected from oxygen atom, sulfur atom and nitrogen atom" (e.g., pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole) which may further be substituted by an alkyl group having 1 to 4 carbon atoms;
XI is a bond; R2 is an aliphatic hydrocarbon group having 1 to 8 carbon atoms (preferably an alkyl group) , an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, etc.) or a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl, etc.), each of which may have 1 to 3 substituents selected from the group consisting of 1) halogen atoms, 2) alkyl groups having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms, 3) alkoxy groups having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms, 4) aralkyloxy groups having 7 to 10 carbon atoms (e.g., benzyloxy) , 5) aryloxy groups having 6 to 14 carbon atoms (e.g., phenoxy) and 6) aromatic heterocyclic groups (e.g., furyl, thienyl) ;
W is a Ci-8 alkylene, a C2-8 alkenylene or a C2-8 alkynylene;
R3 is -OR8 (R8 is a hydrogen atom, an "alkyl group having
1 to 4 carbon atoms" or an λΛaryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents selected from alkyl groups having 1 to 4 carbon atoms and halogen atoms") or -NR9R10 (each of R9 and R10, whether identical or not, is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) . (Compound B)
Compounds in which
R1 is a 5- or 6-membered aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl) which may be condensed with a benzene ring, and which may have 1 or
2 substituents selected from
1) furyl, thienyl, pyridyl, pyrazinyl, phenyl or naphthyl, each of which may have 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, alkoxy groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, halogen atoms, nitro, hydroxy, and amino; and
2) alkyl groups having 1 to 4 carbon atoms or cycloalkyl groups having 3 to 7 carbon atoms, each of which may have 1 to
3 substituents selected from the group consisting of alkoxy groups having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms, halogen atoms, nitro, hydroxy, and amino;
X is a bond or -NR6- wherein R6 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; m is 1 or 2;
Y is an oxygen atom, a sulfur atom, -NH- or -NHCO-; ring A is benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene, etc.) or a 5- or β-membered aromatic hetero ring (preferably pyridine, isoxazole, etc.), each of which ring may further have 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, hydroxy group, alkoxy groups having 1 to 4 carbon atoms, aralkyloxy groups having 7 to 10 carbon atoms and halogen atoms; n is an integer of 1 to 3; ring B is a λΛ5-membered aromatic hetero ring which contains at least 1 nitrogen atom, in addition to carbon atoms, as ring constituent atoms, and which may further contain 1 hetero atom selected from oxygen atom, sulfur atom and nitrogen atom" (e.g., pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole) which may further be substituted by an alkyl group having 1 to 4 carbon atoms;
XI is an oxygen atom;
R2 is an aliphatic hydrocarbon group having 1 to 8 carbon atoms (preferably an alkyl group) , an aromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms (preferably an aralkyl group (e.g., benzyl)) or a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl, etc.), each of which may have 1 to 3 substituents selected from the group consisting of 1) halogen atoms, 2) alkyl groups having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms, 3) aralkyloxy groups having 7 to 10 carbon atoms (e.g., benzyloxy) , 4) [5- or 6-membered aromatic heterocyclic groups (e.g., pyridyl, oxazolyl, thiazolyl, triazolyl) which may have 1 or- 2 substituents selected from alkyl groups having 1 to 3 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms (e.g., cyclohexyl) , furyl, thienyl, phenyl and naphthyl]- alkoxy groups having 1 to 6 carbon atoms, 5) aromatic heterocyclic groups (e.g., furyl, thienyl, pyridyl) , 6) aryloxy groups having 6 to 14 carbon atoms (e.g., phenoxy) and 7) alkoxy groups having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms;
W is a Ci-8 alkylene, a C2-8 alkenylene or a C2-8 alkynylene;
R3 is -OR8 (R8 is a hydrogen atom, an "alkyl group having 1 to 4 carbon atoms" or an "aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents selected from alkyl gromps having 1 to 4 carbon atoms and halogen atoms") or -NR9R10 (each of R9 and R10, whether identical or not, is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) . (Compound C) ethyl 3- [3-ethoxy-l- [4- (2-phenyl-4-oxazolylmethoxy)benzyl] -IH- pyra.zol-4-yl]propionate. (Compound D) ethyl 3- [3-ethoxy-l- [2- (5-methyl-2-phenyl-4- oxazolylmethoxy)benzyl] -lH-pyrazol-4-yl]propionate. (Compound E)
3- (3-ethoxy-l-{4- [ (2-phenyl-l, 3-thiazol-4-yl)methoxy]benzyl}- lH-pyrazol-4-yl)propanoic acid . (Compound F)
3- [3-ethoxy-l- [4- [2- (2-furyl) -5-methyl-4- oxazolylmethoxy]benzyl] -lH-pyrazol-4-yl]propionic acid. (Compound G) 3- [3-ethoxy-l- [4- [5-methyl-2- (2-thienyl) -4- oxazolylmethoxy]benzyl] -lH-pyrazol-4-yl]propionic acid.
The salt of compound (I) is preferably a pharmacologically acceptable salt, and is exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
Preferred examples of the salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts.
Preferred examples of the salts with organic bases include salts w±th trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N/N-dibenzylethylenediamine, etc.
Preferred examples of the salts with inorganic acids include salts w±th hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
Preferred examples of the salts with organic acids 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, etc.
Preferred examples of the salts with basic amino acids include salts with arginine, lysine, ornithine, etc.
Examples of preferred salts with acidic amino acids include salts w±th aspartic acid, glutamic acid, etc.
The pharmaceutical agent of the present invention comprises a combination of two or more parts comprising compound (I), said two or more parts have mutually different release rates of compound (I) .
As used herein, the part may be a preparation (e.g., fine granules, granules, tablets) by itself, or may be a part (e.g., core or coating layer of coated preparation; each layer constituting multilayer tablets) constituting a preparation.
The mechanism for controlling the release of compound (I) from the above-mentioned part is not particularly limited, and may be any of 1) a preparation wherein compound (I) is released by passive diffusion from the preparation, 2) a preparation wherein compound (I) is released along with the erosion of the preparation, 3) a preparation wherein compound (I) is released in response to the changes in environmental pH, 4) a preparation wherein compound (I) is released due to the inner pressure caused t>y the swelling of the inside of the preparation by the absorption of the environmental moisture, 5) a preparation wherein compound (I) is immediately released by the disintegration or dissolution of the preparation and the like. Here, as the "preparation wherein compound (I) is released by passive diffusion from the preparation", for example, sustained-release preparations [preferably matrix tablet using a hydrophilic polymer (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide) ] ; matrix tablet containing a liposoluble base (e.g., carnauba wax, hydrogenated castor oil, hydrogenated rapeseed oil, polyglycerol fatty acid ester) ; tablets and granules coated with sustained-release base (e.g., cellulose polymers such as ethylcellulose and the like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name, manufactured by Rohm Pharma) ] , an ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name, manufactured by Rohm Pharma) ] and the like) and the like can be mentioned. As the "preparation wherein compound (I) is released along with the erosion of the preparation", for example, capsule containing polyglycolated glyceride (e.g., Gelucire 50/13 (trade name, manufactured by GATTEFOSSE CO.) and the like can be mentioned. As the "preparation wherein compound (I) is released in response to the changes in environmental pH", for example, tablets and granules each coated with the below-mentioned "polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5" and the like can be mentioned.
As the "preparation wherein compound (I) is released due to the inner pressure caused by the swelling of the inside of the preparation by the absorption off the environmental moisture", for example, OROS system (trrade name, manufactured by ALZA Corporation) and the like can t>e mentioned.
As the "preparation wherein compound (I) is immediately released by the disintegration or dissolution of the preparation", for example, a preparation obtained by mixing compound (I) and a pharmacologically acceptable carrier and molding the mixture can be mentioned.
Here, the mixing and molding is performed according to a method conventionally used in the technical field of pharmaceutical preparations. As the aforementioned "pharmacologically acceptable carrier", various organic or inorganic carrier substances in common use as materials for pharmaceutical preparations, for example, excipients, lubricants, binders, disintegrants and the like, can be mentioned. In addition, during the mixing and molding, other additives for pharmaceutical preparations, such as antiseptics, antioxidants, coloring agents, and sweetening agents, may also be used as necessary.
Preferred examples of the excipients include lactose, sucrose, D-mannitol, D-sorbitol, starcti (e.g., corn starch), gelatinized starch, dextrin, crystalline cellulose, low- substituted hydroxypropylcellulose, caxboxymethylcellulose sodium, gum arabic, pullulan, light antiydrous silicic acid, synthetic aluminum silicate, and magnesium metasilicate aluminate. Preferred examples of the lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.
Preferred examples of the binders include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Preferred examples of the disintegrants include lactose, sucrose, starch (e.g., corn starch), carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, Light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. Preferred examples of the antiseptics include p- oxybenzoic acid esters, chlorobutanol, benzyl alcohoL , phenethyl alcohol, dehydroacetic acid, and sorbic acid.
Preferred examples of the antioxidants include sulfites and ascorbates. Preferred examples of the coloring agents incl_ude water-soluble tar colors for food (e.g., Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blme Nos. 1 and 2), water-insoluble lake colors (e.g., aluminum salts of the aforementioned water-soluble tar colors for food) , and natural colors (e.g., β-carotene, chlorophyll, red ferric oxide, yellow ferric oxide) .
Preferred examples of the sweetening agents include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia. The release control mechanisms of compound (I) from the "two or more parts" constituting the pharmaceutical agent of the present invention may be the same or different.
The control mechanisms are preferably different from each other, and as a combination of the different control mechanisms, a combination of "preparation wherein compound (I) is released in response to the changes in environmental pH" and "preparation wherein compound (I) is immediately released by the disintegration or dissolution of the preparation" is preferable. In addition, the "two or more parts" may form a single preparation or may be present as mutually independent multiple preparations.
Here, as specific examples of the "single preparation", a preparation wherein "one part" is coated with "other part" (e.g., dry coated granules); a preparation wherein "one part" and "other part" are laminated in layers (e.g., multilayer tablets) ; a capsule comprising a preparation comprising "one part" (e.g., fine granules, granules) and a preparation comprising "other part" (e.g., fine granules, granules); and the like can be mentioned.
In addition, as specific examples of the "independent multiple preparations", a preparation comprising "one part" (e.g., fine granules, granules, tablet) and a preparation comprising "other part" (e.g., fine granules, granules, tablet) , which are mutually independently present, can be mentioned.
In the pharmaceutical agent of the present invention, "two or more parts" preferably form a single preparation. In the pharmaceutical agent of the present invention, while the content of compound (I) in each part constituting the "two or more parts" varies depending on the kind of compound (I) , the size of the preparation and the like, it is, for example, 1-90 wt%, preferably 5-80 wt%. The pharmaceutical agent of the present invention preferably comprises a combination of a modified-release part comprising compound (I) and an immediate-release part comprising compound (I) , and by employing such combination, an effective blood concentration of compound (I) can be sustained. for a long term from immediately after administration to a living organism.
In the present description, "immediate-release" means a "drug dissolution rate from a composition at 30 min after the start of the test" of not less than 75% (preferably not less than 80%) when The Japanese Pharmacopoeia, Dissolution Test, Method 2 (Paddle Method) is performed using a suitable dissolution medium (900 mL) at a paddle rotation of 50 rpm, or a "drug dissolution rate from a composition at 30 min after the start of the test" of not less than 75% (preferably not less than 80%) when The Japanese Pharmacopoeia, Dissolution Test, Method 1 (Rotary Basket Method) is performed using a suitable dissolution medium (900 mL) at a paddle rotation of 75 rpm. As the above-mentioned dissolution medium, one conventionally employed in the technical field of pharmaceutical preparations, such as water, buffer and the like, is used. Particularly, phosphate buffer used in the below-mentioned Experimental Example 1 is preferable.
In the pharmaceutical agent of the present invention, at least one of the "two or more parts" preferably comprises a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5.
As the polymer substance, hydroxypropylmethylcellulose phthalate (trade name: HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.), cellulose acetate phthalate, carboxymethylethylcellulose (trade name: CMEC, manufactured by Freund Corporation) , methyl methacrylate-methacrylic acid copolymer [methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) , methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma) ] , methacrylic acid-ethyl acrylate copolymer [dried methacrylic acid copolymer LD (trade name: Eudragit L100-55, manufactured by Rohm Pharma) , methacrylic acid copolymer LD (trade name: Eudragit L30D-55, manufactured by Rohm Pharma)], methacrylic acid-methyl acrylate-methyl methacrylate copolymer (trade name: Eudragit FS30D, manufactured by Rohm Pharma), hydroxypropylcellulose acetate succinate (trade name: HPMCAS, manufactured by Shin-Etsu Chemical Co., Ltd.), polyvinyl acetate phthalate, shellac and the like can be mentioned. Two or more of these polymer substances may be used in a mixture at an appropriate ratio.
The polymer substance is preferably a methyl methacrylate-methacrylic acid copolymer, more preferably a mixture of methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) and methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma) . A mixing ratio (weight ratio) of methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) and methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma) is preferably 1:0.5 to 1:7, more preferably 1:0.5 to 1:5, and particularly preferably about 1:3.
The pharmaceutical agent of the present invention preferably comprises a combination of a modified-release part wherein a core comprising compound (I) is coated with a coating layer comprising a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5, and an immediate-release part comprising the compound. As used herein, as the "core comprising compound (I)", for example,
1) particles (e.g., fine granules, granules) obtained by coating an inert carrier such as sucrose-starch spheres (trade name: Nonpareil-101 (particle size: 850 to 710 μm, 710 to 500 μm or 500 to 355 μm) manufactured by Freund Corporation) , purified sucrose spheres (trade name: Nonpareil-103 (particle size: 850 to 710 μm, 710 to 500 μtn or 500 to 355 μm) manufactured by Freund Corporation) , lactose-crystalline cellulose spheres (trade name: Nonpareil-105 (particle size: 710 to 500 μm, 500 to 355 μm or 300 to 180 μm) manufactured by Freund Corporation) , crystalline cellulose spheres (trade name: Celphere CP-507 (particle size: 500 to 710 μm) , Celphere CP-305 (particle size: 300 to 500 μm) , Celphere CP-203 (particle size: 150 to 300 μm) , Celphere CP-102 (particle size: 106 to 212 μm) , all manufactured by Asahi Kasei Chemical Corporation) , and the like, with compound (I) together with the aforementioned "pharmacologically acceptable carrier"; 2) particles (e.g., fine granules, granules) obtained by mixing compound (I) and the aforementioned "pharmacologically acceptable carrier" and molding (preferably granulating) the mixture; and the like can be mentioned.
The sucrose-starch spheres are spherical granules containing 65-85 wt% of sucrose (preferably purified sucrose) and 15-35 wt% of starch (preferably corn starch) . The sucrose- starch spheres preferably have a particle size within the range of 850-355 μm.
The particle size of particulate inert carriers such as sucrose-starch spheres, purified sucrose spheres, lactose- crystalline cellulose spheres, crystalline cellulose spheres and the like is preferably 850 to 150 μm, more preferably 850 to 710 μm.
The average particles diameter of the "core comprising compound (I)" is preferably 50 to 2000 μm, more preferably 100 to 1400 μm.
In the "coating layer comprising a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5", as the "polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5", the aforementioned polymer substances are used.
The "coating layer" may further contain a plasticizer such as polyethylene glycol, dibutyl sebacate, diethyl phthalate, triacetin, triethyl citrate and the like; a lubricant such as talc, titanium dioxide, magnesium stearate, calcium stearate, light anhydrous silicic acid and the like; and the like. The amount of the "coating layer" is generally 5 to 200 wtl, preferably 20 to 100 wt%, more preferably 20 to 50 wt%, relative to the "core comprising compound (I)".
The "core comprising compound (I)" can be coated with the "coating layer" by a method known per se.
The immediate-release part comprising compound (I) can be produced by mixing compound (I) and the aforementioned "pharmacologically acceptable carrier" and molding (preferably granulating) the mixture.
The aforementioned "modified-release part" and the "immediate-release part" may form a single preparation, or may be present as mutually independent multiple preparations.
As specific examples of the "single preparation", a preparation wherein "modified-release part" is coated with "immediate-release part" (e.g., dry coated granules); a preparation wherein "modified-release part" and "immediate- release part" are laminated in layers (e.g., multilayer tablets) ; a capsule comprising a preparation comprising "modified-release part" (e.g., fine granules, granules) and a preparation comprising "immediate-release part" (e.g., fine granules, granules) ; and the like can be mentioned.
In addition, as specific examples of the "independent multiple preparations", a preparation comprising "modified- release part" (e.g., fine granules, granules, tablet) and a preparation comprising "immediate-release part" (e.g., fine granules, granules, tablet) , which are mutually independently present, can be mentioned.
In the pharmaceutical agent of the present invention, the "modified-release part" and the "immediate-release part" preferably form a single preparation. Moreover, "a single preparation wherein a modified-release part is coated with an immediate-release part", a "capsule comprising a modified- release part and an immediate-release part as independent preparations" and the like are preferable.
As a preferable and specific example of the pharmaceutical agent of the present invention, granules (C) obtained by coating sucrose-starch spheres (preferably Nonpareil-101 (trade name) having a particle size of 850 to 710 μjn (preferably average particle size 750 μm) ) with a coating layer comprising compound (I) , an excipient (preferably sucrose (e.g., purified sucrose), corn starch, crystalline cellulose) , a binder (preferably hydroxypropylcellulose) and a disintegrant (preferably low- substituted hydroxypropylcellulose) to give granules (A) , coating granules (A) with a coating layer comprising a mixture of methacrylic acid copolymer L (trade name: Eudragit LlOO, manufactured by Rohm Pharma) and methacrylic acid copolymer S (trade name: Eudragit SlOO, manufactured by Rohm Pharma)
(preferably a mixture having a mixing ratio (weight ratio) of 1:0.5 to 1:7, more preferably 1:0.5 to 1:5, particularly preferably about 1:3), a plasticizer (preferably triethyl citrate) and a lubricant (preferably talc) to give granules (B) , and coating the obtained granules (B) with a coating layer comprising compound (I) , an excipient (preferably sucrose (e.g., purified sucrose)), a binder (preferably hydroxypropylmethylcellulose) and a disintegrant (preferably low-substituted hydroxypropylcellulose) can be mentioned.
The low-substituted hydroxypropylcellulose to be used in the present invention refers to one having a hydroxypropoxyl group content of 5.0 to 16.0%.
As hydroxypropylcellulose, one having a hydroxypropoxyl group content of 53.4 to 77.5% can be mentioned.
As hydroxypropylmethylcellulose, hydroxypropylmethylcellulose 2910 (methoxyl group content 28.0 to 30.0%, hydroxypropoxyl group content 7.0 to 12.0%), hydroxypropylmethylcellulose 2906 (methoxyl group content 27.0 to 30.0%, hydroxypropoxyl group content 4.0 to 7.5%), hydroxypropylmethylcellulose 2208 (methoxyl group content 19.0 to 24.0%, hydroxypropoxyl group content 4.0 to 12.0%) and the like can be mentioned.
The content of the excipient in granules (A) is preferably 5 to 90 wt%.
The content of the binder in granules (A) is preferably 0.1 to 1.0 wt%, more preferably 0.3 to 0.7 wt%.
The content of the disintegrant in granules (A) is preferably 2 to 20 wt%.
The content of the mixture of methacrylic acid copolymer L and methacrylic acid copolymer S in granules (B) is preferably 10 to 70 wt%, more preferably 10 to 50 wt%, particularly preferably 10 to 25 wt%. The content of the plasticizer in granules (B) is preferably 1 to 5 wt%.
The content of the lubricant in granules (B) is preferably 5 to 20 wt%.
The content of the excipient in the coating layer covering granules (B) is preferably 5 to 90 wt%.
The content of the binder in the coating layer covering granules (B) is preferably 20 to 60 wt%.
The content of the disintegrant in the coating layer covering granules (B) is preferably 3 to 15 wt%. As the dosage form of the pharmaceutical agent of the present invention, for example, oral preparations such as tablet, capsule (including microcapsule) , granule, powder and the like; and parenteral preparations such as suppositories (e.g., rectal suppository, vaginal suppository) and the like can be mentioned. Each of these can be safely administered orally or parenterally. Of these, oral preparations such as tablet, capsule, granule and the like are preferable.
The pharmaceutical agent of the present invention shows low toxicity and a few side effects, and can be used as an agent for the prophylaxis or treatment of diabetes mellitus (e.g., type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, obesity diabetes mellitus) ; an agent for the prophylaxis or treatment of hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-high- density-lipoparoteinemia, postprandial hyperlipemia) ; an insulin resistance improving agent; an insulin sensitizer; an agent for the prophylaxis or treatment of IGT (Impaired Glucose Tolerance) or IFG (Impaired Fasting Glucose or Impaired Fasting Glycaemia) ; an agent for the prophylaxis or treatment of syndrome X; an agent for the prophylaxis or treatment of dysmetabolic syndrome; an agent for the prophylaxis or treatment of metabolic syndrome (a condition associated with three or more from hypertriglyceridemia, hypo- HDL-cholesterolemia, hypertension, abdominal obesity and impaired glucose tolerance) and the like, for mammals (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat) .
Moreover, the pharmaceutical agent of the present invention can be used as an agent for preventing progress from impaired glucose tolerance or IFG (Impaired Fasting Glucose or Impaired Fasting Glycaemia) to diabetes mellitus.
The administration mode of the pharmaceutical agent of the present invention is not particularly limited, and "two or more parts" only need to be combined on administration. As such administxation mode, for example, 1) administration of "two or more parts" as a single preparation, 2) simultaneous administration of λΛtwo or more parts" as multiple preparations (administration route may be the same or different) , 3) administration of "two or more parts" as multiple preparations at staggered times (administration route may be the same or different) arxd the like can be mentioned. Of these, administration of "two or more parts" as a single preparation is preferable .
While the dose of the pharmaceutical agent of the present invention varies depending on administration subject, administration route, target disease, clinical condition, etc., it is desirable that the active ingredient, i.e., compound (I)r be administered at a usual dosage per administration of about 0.01 to 100 mg/kg body weight, preferably 0.05 to 10 mcj/kg body weight, more preferably 0.1 to 2 mg/kg body weight, 1 or 2 times a day, for oral administration to an admit diabetic patient, for instance.
The pharmaceutical agent of the present invention can be used in combination with a drug such as a therapeutic agent for diabetes mellitus, a. therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antiinflammatory agent, an antithrombotic agent, a therapeutic agent for osteoporosis, a vitamin, an antidementia agent, a therapeutic agent for urinary incontinence or pollakiuria, a therapeutic agent for dysuria and the like (hereinafter, sometimes abbreviated as drug X) . Examples of the therapeutic agent for diabetes mellitus include insulin preparations (e.g., animal insulin preparations extracted from the bovine or swine pancreas; human insulin preparations synthesized by a genetic engineering technique using Escherichia coli or a yeast, insulin zinc; zinc insulin protamine; fragment or derivative of insulin (e.g., INS-I) ; oral insulin preparations), insulin sensitizers (e.g., pioglLitazone or its salt (preferably hydrochloride) , rosiglitazone or its salt (preferably maleate) , Reglixane (JTT-501) , Netoglitazone (MCC-555) , FK- 614, Rivoglitazone (CS-OIl), Muraglitazar (BMS-298585) , compounds described in "WO99/58510 (e.g., (E) -4- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy)benzyloxyimino] -4-phenylbutyric acid), Tesaglitazar (AZ-242), Edaglitazone (BM-13-1258) , LM- 4156, Metaglidasen (MBK-102) , Naveglitazar (LY-519818), MX- 6054, LY-510929, Balaglitazone (NN-2344), T-131 or its salt, THR-0921) , α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emlglitate) , biguanides (e.g., phenformin, metformin, buformin or their salts (e.g., hydrochloride, fumarate, succinate)), insulin secretagogues [sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride) , repaglinide, senaglinide, mitiglini_de or its calcium salt hydrate, nateglinide] , GPR40 agonist, GLP-I receptor agonists [e.g., GLP-I, GLP-IMR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib(8,35)hGLP-l(7,37)NH2 , CJC-1131] , dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP-278, PT-100, P32/98, P93/01, NVP-DPP-728, Vildagliptin (LAF237) , TS-021, Sitagliptin phosphate (MK-0431) , Saxagliptin (BMS-477118) , E- 3024, T-6666 (TA-6666) , 823093, 825964, 815541), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140) , amylin agonists (e.g., pramlintide) , phosphothyrosine phosphatase inhibitors (e.g., sodium vanadate), gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase ±nhibitors, glucagon antagonists) , SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095) , llβ-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498), adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), leptin resistance improving drugs, somatostatin receptor agonists (compounds described in
WO01/25228, WO03/42204, WO98/44921, WO98/45285, WO99/22735) , glucokinase activators (e.g., Ro-28-1675) and the like.
Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat, ranirestat (AS-3201) , minalrestat, CT-112) , neurotrophic factors and its increasing agents (e.g., NGF, NT-3, BDNF, neurotrophin production secretion promoters described in WO01/14372 (e.g., 4- (4-chlorophenyl) -2- (2-methyl-l- imidazolyl) -5- [3- (2-methylphenoxy) propyl]oxazole) ) , protein kinase C (PKC) inhibitors (e.g., ruboxistaurin mesylate (LY- 333531)), AGE inhibitors (e.g., ALT-945, pimagedine, N- phenacylthiazolium bromide (ALT-766), EXO-226, ALT-711, Pyridorin, Pyridoxamine) , active oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapuride) , somatostatin receptor agonists (e.g., BIM23190) , apoptosis signal regulating kinase-1 (ASK-I) inhibitors and the like.
Examples of the antihyperlipidemic agent include HMG- CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin or their salts (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97/10224, such as N- [ [ (3R,5S)—1- (3-acetoxy-2,2- dimethylpropyl) -7-chloro-5- (2, 3-dimethoxyphenyl) -2-oxo-
1,2,3, 5-tetrahydro-4, l-benzoxazepin-3-yl]acetyl]piperidine-4- acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate) , antioxidants (e.g., lipoic acid, probucol) , ACAT inhibitors (e.g., Avasimibe, Eflucimibe) , anion exchange resins (e.g., cholestylamine) , probucol, nicotinic pharmaceutical agents (e.g., nicomol, niceritrol) , ethyl icosapentate, phytosterol (e.g., soysterol, γ-oryzanol) and the like.
Examples of the hypotensive agent include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril) , angiotensin II antagonists (e.g., losartan, candesartan cilexetil, eprosartan, valsartan , termisartan, irbesartan, olmesartan medoxomil, tasosartan , l-[[2'-(2,5- dihydro-5-oxo-4H-l,2, 4-oxadiazol-3-yl)biphenyl-4-yl]methyl] -2- ethoxy-lH-benzimidazole-7-carboxylic acid) , calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (e.g., levcromakalim, L-27152, AL 0671, NIP-121), clonidine and the like. Examples of the antiobesity agent include antiobesity drugs acting on the central nervous system (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP- 7941; compounds described in WO01/82925 and WO01/87834) ; neuropeptide Y antagonists (e.g., CP-422935) ; cannabinoid receptor antagonists (e.g., SR-141716, SR-147778) ; ghrelin antagonists; llβ-hydroxysteroid dehydrogenase inhibitors (e .g., BVT-3498)), pancreatic lipase inhibitors (e.g., orlistat, /VIL- 962), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, AJ- 9677, AZ40140), anorectic peptides (e.g., leptin, CNTF (Ciliary Neurotrophic Factor) ) , cholecystokinin agonists (e.g., lintitript, FPL-15849) , feeding deterrent (e.g., P-57) and the like.
Examples of the diuretic agent include xanthine derivatives (e.g., theobromine and sodium salicylate, theobromine and calcium salicylate) , thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide) , antialdosterone preparations (e.g., spironolactone, triamterene) , carbonate dehydratase inhibitors (e.g., acetazolamide) , chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefruside, indapamide) , azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
Examples of the chemotherapeutic agent include alkylating agents (e.g., cyclophosphamide, ifosamide) , metabolic antagonists (e.g., methotrexate, 5-fluorouracil or derivative thereof (Furtulon, Neo-Furtulon) ) , antitumor antibiotics (e.g., mitomycin, adriamycin) , plant-derived antitumor agents (e.g., vincristine, vindesine, Taxol) , cisplatin, carboplatin, etoposide and the like. Examples of the immunotherapeutic agent include microorganism- or bacterium-derived components (e.g., murarnyl dipeptide derivatives, Picibanil) , immunopotentiator polysaccharides (e.g., lentinan, schizophyllan, krestin) , genetically engineered cytokines (e.g., interferons, interleukins (e.g., IL-I, IL-2, IL-12) ) , colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin) and the like.
Examples of the antiinflammatory agent include non- steroidal antiinflammatory drugs (e.g., aspirin, acetaminophen, indomethacin) and the like.
Examples of the antithrombotic agent include heparin (e.g., heparin sodium, heparin calcium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin agents (e.g., argatroban) , thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) , platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like. Examples of the therapeutic agents for osteoporosis include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, risedronate disodium, pamidronate disodium, alendronate sodium hydrate, incadronate disodium and the like. Examples of vitamins include vitamin Bi , vitamin B3.2 and the like.
Examples of the antidementia agent include tacrine, donepezil, rivastigmine, galanthamine and the like.
Examples of the therapeutic agents for urinary incontinence or pollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
Examples of the therapeutic agents for dysuria include acetylcholine esterase inhibitors (e.g., distigmine) and the like.
Furthermore, drugs confirmed to exhibit a cachexia ameliorating effect in animal models and clinical applications, namely, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone) , metoclopramide pharmaceuticals, tetrahydrocannabinol pharmaceuticals, fat metabolism ameliorating agents (e.g., eicosapentanoic acid) , growth hormones, IGF-I, and antibodies to the cachexia-inducing factor TNF-α, LIF, IL-6 or oncostatin M and the like, can be also used in combination with the pharmaceutical agent of the present invention.
Furthermore, glycation inhibitors (e.g., ALT-711), nerve regeneration promoters (e.g., Y-128, VX853, prosaptide) , antidepressants (e.g., desipramine, amitriptyline, imipramine) , antiepileptics (e.g., lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine) , antiarrhythmics (e.g., mexiletine) , acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), monoamine uptake inhibitors (e.g., tramadol), narcotic analgesics (e.g., morphine), GABA receptor agonists (e.g., gabapentin, gabapentin MR agents), α2 receptor agonists (e.g., clonidine) , local analgesics (e.g., capsaicin), antianxiety drugs (e.g., benzodiazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine) and the like can be also used in combination with the pharmaceutical agent of the present invention.
The above drug X can be used as a mixture of two or more species in an appropriate ratio.
By combining the pharmaceutical agent of the present invention and drug X, superior effects, for example, (1) the dose of the pharmaceutical agent of the present invention and/or drug X can be reduced, (2) side effects of the pharmaceutical agent of the present invention and/or drug X can be reduced, (3) effects (action) of the pharmaceutical agent of the present invention and/or drug X can be potentiated, and the like can be obtained as compared to single administration of the pharmaceutical agent of the present invention or drug X. When the pharmaceutical agent of the present invention and drug X are used in combination, the administration time of the pharmaceutical agent of the present invention and drug X is not restricted, and the pharmaceutical agent of the present invention and drug X can be administered to an administration subject simultaneously, or may be administered at staggered times. The dosage of drug X can be determined according to the administration amount clinically used, and appropriately selected depending on an administration 'Subject, administration route, disease, combination and the like.
In addition, the administration mode of the pharmaceutical agent of the present invention and drug X is not particularly limited, and the pharmaceutical agent of the present invention and drug X only need to be combined on administration. As such administration mode, for example, (1) administration of a single preparation obtained by simultaneously producing the pharmaceutical agent of the present invention and drug X, (2) simultaneous administration by the same administration route of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X, (3) administration by the same administration route at staggered times of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X, (4) simultaneous administration by different administration routes of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X, (5) administration by different administration routes at staggered times of two kinds of preparations obtained by separately producing the pharmaceutical agent of the present invention and drug X (for example, the pharmaceutical agent of the present invention and drug X are administered in this order, or in the reverse order) and the like can be mentioned. Examples
The present invention is explained in more detail in the following by referring to Reference Examples, Examples, Comparative Example and Experimental Examples, which are mere exemplifications and do not limit the scope of the present invention in any manner.
In Reference Examples, Examples and Comparative Example, as purified sucrose, hydroxypropylcellulose, corn starch, crystalline cellulose and hydroxypropylmethylcellulose 2910, the Japanese Pharmacopoeia, Fourteenth Edition compatible products were used.
Reference Example 1
Compound C (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose
(166.0 g) and crystalline cellulose (143.3 g) are mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) , and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules are vacuum dried at 400C for 16 hr and passed through a round sieve to give immediate-release granules (600 μm - 1400 μm) having the following composition.
Composition of immediate-release granules (per 189.7 mg) Nonpareil-101 60.0 mg
Compound C 48.0 mg purified sucrose 36.0 mg corn starch 21.9 mg low-substituted hydroxypropylcellulose 12.4 mg crystalline cellulose 10.7 mg hydroxypropylcellulose 0.7 mg total 189.7 mg
Reference Example 2
Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) . Talc (783.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules (2656 g) obtained in Reference Example 1 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 440C, inlet air volume: 2.0 m2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 44°C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (850 μm - 1700 μm) .
Composition of enteric coated granules (per 282.5 mg) immediate-release granules obtained in Reference Example 1 189.7 mg methacrylic acid copolymer S 43.5 mg methacrylic acid copolymer L 14.5 mg talc 29.0 mg triethyl citrate 5.8 mg total 282.5 mg
Reference Example 3
Compound C (827.3 g) , purified sucrose (614.7 g) and low-substituted hydroxypropylcellulose (339.9 g) are thoroughly mixed to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules are vacuum dried at 4O0C for 16 hr and passed through a round sieve to give immediate-release granules (600 μm - 1400 μm) having the following composition.
Composition of immediate-release granules (per 50.8 mg) Nonpareil-101 16.0 mg
Compound C 16.0 mg purified sucrose 12.0 mg low-substituted hydroxypropylcellulose 6.6 mg hydroxypropylcellulose 0.2 mg total 50.8 mg
Reference Example 4 Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) are dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) . Talc (216.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules (990.6 g) obtained in Reference
Example 3 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 45°C, inlet air volume: 1.2 m2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 450C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (600 μm - 1400 μm) . Composition of enteric coated granules (per 229.2 mg) immediate-release granules obtained in Reference Example 3 152.4 mg methacrylic acid copolymer S 36.0 mg methacrylic acid copolymer L 12.0 mg talc 24.0 mg triethyl citrate 4.8 mg total 229.2 mg
Reference Example 5
Compound D (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose (166.0 g) and crystalline cellulose (143.3 g) are mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder. Nonpareil-lOl (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) , and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules are vacuum dried at 400C for 16 hr and passed through a round sieve, to give immediate-release granules (600 μm - 1400 μrn) having the following composition.
Composition of immediate-release granules (per 189.7 mg)
Nonpareil-101 60.0 mg
Compound D 48.0 mg purified sucrose 36.0 mg corn starch 21.9 mg low-substituted hydroxypropylcellulose 12.4 mg crystalline cellulose 10.7 mg hydroxypropylcellulose 0.7 mg total 189.7 mg
Reference Example 6
Methacrylic acid copolymer S (1175 g) , itiethacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) . Talc (783.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules obtained in Reference Example 5 (2656 g) are coated wzLth the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44°C, inlet air volume: 2.0 m2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 440C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (850 μm - 1700 μm) .
Composition of enteric coated granules (per 282.5 mg) immediate-release granules obtained in Reference Example 5 189.7 mg methacrylic acid copolymer S 43.5 mg methacrylic acid copolymer L 14.5 mg talc 29.0 mg triethyl citrate 5.8 mg total 282.5 mg
Reference Example 7 Compound D (827.3 g) , purified sucrose (614.7 g) and low-substituted hydroscypropylcellulose (339.9 g) are thoroughly mixed to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the aboΛ^e-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules are vacuum dried at 400C for 16 hr and passed through a round sieve to give immediate-release granules (600 μtn - 1400 μm) having the following composition.
Composition of immediate-release granules (per 50.8 mg) Nonpareil-101 16.0 mg
Compound D 16.0 mg purified sucrose 12.0 mg low-substituted hydroxypropylcellulose 6.6 mg hydroxypropylcellulose 0.2 mg total 50.8 mg
Reference Example 8
Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) are dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) . Talc (216.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules (990.6 g) obtained in Reference Example 7 are coated with the above—mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 45°C, inlet air volume: 1.2 m2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 450C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (600 μm - 1400 μm) .
Composition of enteric coated granules (per 229.2 mg) immediate-release granules obtained in Reference Example 7 152.4 mg methacrylic acid copolymer S 36.0 mg methacrylic acid copolymer L 12.0 mg talc 24.0 mg triethyl citrate 4.8 mg total 229.2 mg
Reference Example 9 Compound E (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose (166.0 g) and crystalline cellulose (143.3 g) were mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (780.0 g) were fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above—mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules were vacuum dried at 400C for 16 hr and passed through a round sieve to give immediate-release granules (600 μm - 1400 μm) having the following composition.
Composition of immediate-release granules (pea: 189.7 mg)
Nonpareil-101 60.0 mg
Compound E 48.0 mg purified sucrose 36.0 mg corn starch 21.9 mg low-substituted hydroxypropylcellulose 12.4 mg crystalline cellulose 10-7 mg hydroxypropylcellulose 0- 7 mg total 189.7 mg Reference Example 10
Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) were dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) . Talc (783.0 g) was dispersed in the obtained solution to give a coating solution. The immediate-release granules (2656 g) obtained in Reference Example 9 were coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44°C, inlet air volume: 2.0 m2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized becd dried at inlet air temperature: 44°C to give enteric coated granules having the following composition. The granules were passed through a round sieve to give granules (850 μm - 17 OO μm) ■
Composition of enteric coated granules (per 282.5 mg) immediate-release granules obtained in Reference Example 9 189.7 mg methacrylic acid copolymer S 43.5 mg methacrylic acid copolymer L 14.5 mg talc 29.0 mg triethyl citrate 5.8 mg total 282.5 mg
Reference Example 11
Compound E (827.3 g) , purified sucrose (614.7 g) and low-substituted hydroxypropylcellulose (339.9 g) were thoroughly mixed to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured ~bγ Freund Corporation) (800.0 g) were fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules were vacuum dried at 400C for 16 hr and passed through a round sieve to give immediate-release granules (600 μm - 1400 μm) having the following composition.
Composition of immediate-release granules (per 50.8 mg)
Nonpareil-101 16.0 mg Compound E 16.0 mg purified sucrose 12.0 mg low-substituted hydroxypropylcellulose 6.6 mg hydroxypropylcellulose 0.2 mg total 50.8 mg
Reference Example 12
Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) were dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) . Talc (216.0 g) was dispersed in the obtained solution to give a coating solution. The immediate-release granules obtained in Reference Example 11 (990.6 g) were coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 450C, inlet air volume: 1.2 m2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 45°C to give enteric coated granules having the following composition. The granules were passed through a round sieve to give granules (600 μm - 1400 μm) .
Composition of enteric coated granules (per 229.2 mg) immediate-release granules obtained in Reference Example 11 152.4 mg methacrylic acid copolymer S 36.0 mg methacrylic acid copolymer L 12.0 mg talc 24.0 mg triethyl citrate 4.8 mg total 229.2 mg
Reference Example 13 Compound F (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose (166.0 g) and crystalline cellulose (143.3 g) are mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules are vacuum dried at 400C for 16 hr and passed through a round sieve to give immediate-release granules (600 μm - 1400 μm) having the following composition.
Composition of immediate-release granules (per 189.7 mg)
Nonpareil-101 60.0 mg
Compound F 48.0 mg purified sucrose 36.0 mg corn starch 21.9 mg low-substituted hydroxypropylcellulose 12.4 mg crystalline cellulose 10.7 mg hydroxypropylcellulose 0.7 mg total 189.7 mg Reference Example 14
Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) . Talc (783.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules obtained in Reference Example 13 (2656 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 440C, inlet air volume: 2.0 m2 /min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 440C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (850 μm - 1700 μm) .
Composition of enteric coated granules (per 282.5 mg) immediate-release granules obtained in Reference Example 13 189.7 mg methacrylic acid copolymer S 43.5 mg methacrylic acid copolymer L 14.5 mg talc 29.0 mg triethyl citrate 5.8 mg total 282.5 mg
Reference Example 15
Compound F (827.3 g) , purified sucrose (614.7 g) and low-substituted hydroxypropylcellulose (339.9 g) are thoroughly mixed to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.44 w/w%) to give spherical granules. The granules are vacuum dried at 40°C for 16 hr and passed through a round sieve to give immediate-release granules (600 μm - 1400 μm) having the following composition.
Composition of immediate-release granules (per 50.8 mg)
Nonpareil-101 16.0 mg
Compound F 16.0 mg purified sucrose 12.0 mg low-substituted hydroxypropylcellulose 6.6 mg hydroxypropylcellulose 0.2 mg total 50.8 mg
Reference Example 16
Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) are dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) . Talc (216.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules (990.6 g) obtained in Reference Example 15 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 450C, inlet air volume: 1.2 m2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air temperature: 45°C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (600 μm - 1400 μm) •
Composition of enteric coated granules (per 229.2 mg) immediate-release granules obtained in Reference Example 15 152.4 mg methacrylic acid copolymer S 36.0 mg methacrylic acid copolymer L 12.0 mg talc 24.0 mg triethyl citrate 4.8 mg total 229.2 mg
Reference Example 17
Compound E (2480 g) , purified sucrose (1852 g) , corn starch (1129 g) , low-substituted hydroxypropylcellulose (640.2 g) and crystalline cellulose (551.1 g) were mixed in a vertical granulator (type FM-VG-50P, manufactured by POWREX CORPORATION) at 300 rpm for 3 min to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactured by Freund Corporation) (2720 g) were fed into a centrifugal tumbling granulator (CF-600S, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcellulose (2.22 w/w%) to give spherical granules. The granules were vacuum dried at 4O0C for 16 hr and passed through a round sieve to give immediate-release granules (600 μm - 1400 μm) having the following composition.
Composition of immediate-release granules (per 296.45 mg) Nonpareil-101 93.80 mg
Compound E 75.00 mg purified sucrose 56.26 mg corn starch 34.20 mg low-substituted hydroxypropylcellulose 19.40 mg crystalline cellulose 16.70 mg hydroxypropylcellulose 1.09 mg total 296.45 mg Reference Example 18
Methacrylic acid copolymer S (3541 g) , methacrylic acid copolymer L (1180 g) and triethyl citrate (471.1 g) were dissolved in a mixture of purified water (6791 g) and dehydrated ethanol (61140 g) . Talc (2356 g) was dispersed in the obtained solution to give a coating solution. The immediate-release granules obtained in Reference Example 17 (13930 g) were coated with the above-mentioned coating solution in a fluidized bed coating machine (FD-S2, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 520C, inlet air volume: 6.5 m2 /min, coating solution spray rate: 150 g/min, spray air pressure: 0.55 MP and spray air volume: 290 NL/min, and fluidized bed dried at inlet air temperature: 52°C to give enteric coated granules having the following composition. The granules were passed through a round sieve to give granules (850 μm - 1700 μm) •
Composition of enteric coated granules (per 441.61 mg) immediate-release granules obtained in Reference Example 17 296.45 mg methacrylic acid copolymer S 68.10 mg methacrylic acid copolymer L 22.70 mg talc 45.30 mg triethyl citrate 9.06 mg total 441.61 mg
Reference Example 19
Compound G (644.0 g) , purified sucrose (480.7 g) , corn starch (293.2 g) , low-substituted hydroxypropylcellulose
(166.0 g) and crystalline cellulose (143.3 g) are mixed in an agitation granulator (type FG-VG-10, manufactured by POWREX CORPORATION) at 500 rpm for 3 min to give a dusting powder. Nonpareil-101 (trade name, particle size: 850 to 710 μm, manufactiαred by Freund Corporation) (780.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxyprropylcellulose (2.44 w/w%) to give spherical granules. The granules are vacuum dried at 400C for 16 hr and passed through a. round sieve to give immediate-release granules (600 μm - 140O μm) having the following composition.
Composit±on of immediate-release granules (per 189.7 mg)
Nonpareil-101 60.0 mg
Compound G 48.0 mg purified sucrose 36.0 mg corn starch 21.9 mg low-substituted hydroxypropylcellulose 12.4 mg crystalline cellulose 10.7 mg hydroxypxopylcellulose 0.7 mg total 189.7 mg
Reference Example 20
Methacrylic acid copolymer S (1175 g) , methacrylic acid copolymer L (391.5 g) and triethyl citrate (156.6 g) are dissolved in a mixture of purified water (2250 g) and dehydrated ethanol (20296 g) . Talc (783.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules obtained in Reference Example 19 (2656 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 44°C, inlet air volume: 2.0 m2/min, coating solution spray rate: 27 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet aά_r temperature: 44°C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (850 μm - 1700 μrn) .
Composition of enteric coated granules (per 282.5 mg) immediate-release granules obtained in Reference Example 19 189.7 mg methacrylic acid copolymer S 43.5 mg methacrylic acid copolymer L 14.5 mg talc 29.0 mg triethyl citrate 5.8 mg total 282.5 mg
Reference Example 21
Compound G (827.3 g) , purified sucrose (614.7 g) and low-substituted hydroxypropylcellulose (339.9 g) are thoroughly mixed "to give a dusting powder. Nonpareil-101 (trade name, part±cle size: 850 to 710 μm, manufactured by Freund Corporation) (800.0 g) are fed into a centrifugal tumbling granulator (CF-360, manufactured by Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution of hydroxypropylcelliαlose (2.44 w/w%) to give spherical granules, The granules are -vacuum dried at 400C for 16 hr and passed through a round sieve to give immediate-release granules (600 μjn - 1400 μin) having the following composition.
Composition of immediate-release granules (per 50 . 8 mg)
Nonpareil-101 16. 0 mg
Compound G 16. 0 mg purified sucrose 12 . 0 mg low-substituted h.ydroxypropylcellulose 6. 6 mg hydroxypropylceliulose 0. 2 mg total 50 . 8 mg Reference Example 22
Methacrylic acid copolymer S (324.0 g) , methacrylic acid copolymer L (108.0 g) and triethyl citrate (43.20 g) are dissolved in a mixture of purified water (622.1 g) and dehydrated ethanol (5599 g) . Talc (216.0 g) is dispersed in the obtained solution to give a coating solution. The immediate-release granules (990.6 g) obtained in Reference Example 21 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 450C, inlet air volume: 1.2 m2 /min, coating solution spray rate: 15 g/min, spray air pressure: 0.24 MPa and spray air volume: 80 NL/min, and fluidized bed dried at inlet air tem.peratu.re: 45°C to give enteric coated granules having the following composition. The granules are passed through a round sieve to give granules (600 μm - 1400 μm) .
Composition of enteric coated granules (per 229.2 mg) immediate-release granules obtained in Reference Example 21 152.4 mg methacrylic acid copolymer S 36.0 mg methacrylic acid copolymer H1 12.0 mg talc 24.0 mg triethyl citrate 4.8 mg total 229.2 mg
Example 1
Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound C (256.5 g) are dispersed in the obtained solution to give a coating solution. The enteric coated granules (1271 g) obtained in Reference Example 2 are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-IO, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 7O0C, inlet air volume: 2.0 m2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume:. 90 NL/min, and flixidized bed dried at inlet air temperature: 7O0C to give two-stage release granules having the following composition. The gxanules are passed through a round sieve to give granules (850 μm - 1700 μm) . Then, the granules are vacuum dried at 400C for 16 hr.
Composition of two-stage release granules (per 315.7 mg) enteric coated granules obtained in Reference Example 2 282.5 mg Compound C 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 12.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 315.7 mg
Example 2
The two-stage release granules (3631 g) obtained in Example 1 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound C per capsule.
Example 3
The mixed granules (158.0 mg) obtained in Example 2 are filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound C per capsule. Example 4
The immediate-release granules obtained in Reference Example 3 (50.8 mg) and the enteric coated granules obtained in Reference Example 4 (229.2 mg) are filled in one No. 2 capsule to give a capsule containing 64 mg of Compound C.
Example 5
Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound D (256.5 g) are dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 6 (1271 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 700C, inlet air volume: 2.0 m2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 700C to give two-stage release granules having the following composition. The granules are passed through a round sieve (850 μm - 1700 μm) to give granxiles. Then the granules are vacuum dried at 400C for 16 hr.
Composition of two-stage release granules (per 315.7 mg) enteric coated granules obtained in Reference Example 6 282.5 mg
Compound D 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 12.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 315.7 mg Example 6
The two-stage release granules (3631 g) obtained in Example 5 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound D per capsule.
Example 7
The mixed granules (158.0 mg) obtained in Example 6 aire filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound D per capsule.
Example 8
The immediate-release granules obtained in Reference Example 7 (50.8 mg) and the enteric coated granules obtained in Reference Example 8 (229.2 mg) are filled in one No. 2 capsule to give a capsule containing 64 mg of Compound D.
Example 9
Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW" ) (192.0 g) and purified sucrose (41.1 g) were dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound E (256.5 g) were dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 10 (1271 g) were coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 700C, inlet air volume: 2.0 m2/min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 7O0C to give two-stage release granules having the following composition. The granules were passed through a round sieve to give granules (850 μm - 1700 μm) .
Then, the granules were vacuum dried at 4O0C for 16 hr.
Composition of two-stage release granules (per 315.7 mg) enteric coated granules obtained in Reference Example 10 282.5 mg
Compound E 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 12.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 315.7 mg
Example 10
The two-stage release granules (3631 g) obtained in Example 9 and talc (3.45 g) were mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO), and the obtained mixed granules (316.0 mg) were filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound E per capsule.
Example 11 The mixed granules (158.0 mg) obtained in Example 10 were filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound E per capsule.
Example 12
The immediate-release granules obtained in Reference Example 11 (50.8 mg) and the enteric coated granules obtained in Reference Example 12 (229.2 mg) were filled in one No. 2 capsule to give a capsule containing 64 mg of Compound E. Example 13
Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (11.78 g) and purified sucrose (2.55 g) were dissolved in purified water (141.36 g) . Low-substituted hydroxypropylcellulose (2.55 g) and Compound E (15.71. g) were dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 12 (150 g) were coated with the above-mentioned coating solution in a tumbling fluidized bed glanulator (SPIR-A-FLOW, manufactured by Freund Corporation) under the conditions of inlet air temperature: 550C, rotor revolution speed: 150 rpm, coating solution spray rate: 3.0 g/min and spray air pressure: 1.0 kg/cm2 to give two-stage release granules having the following composition. The granules were vacuum dried at 400C for 16 hr and passed through a round sieve to give granules (1180 μm - 1400 μm) .
Composition of two-stage release granules (per 262.4 mg) enteric coated granules obtained in Reference Example 12 229.2 mg
Compound E 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 12.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 262.4 mg
Example 14
The two-stage release granules (262.4 mg) obtained in Example 13 were filled in one No. 2 capsule to give a capsule containing 64 mg of Compound E.
Example 15
Hydroxypropylmethylcellulose 2910 (trade name: TC-5RW) (14.73 g) and purified sucrose (2.55 g) were dissolved in purified water (294.50 g) . Low-substituted hydroxypropylcellulose (2.55 g) and Compound E (15.71 g) were dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 12 (150 g) were coated with the above-mentioned coating solution in a tumbling fluidized bed granulator (SPIR-A-FLOW, manufactured by Freund Corporation) under the conditions of inlet air temperature: 550C, rotor revolution speed: 150 rpm, coating solution spray rate: 3.15 g/min and spray air pressure: 1.0 kg/cm2 to give two-stage release granules having the following composition. The granules were vacuum dried at 400C for 16 hr and passed through a round sieve to give granules (710 μm - 1400 μm) .
Composition of two-stage release granules (per 265.4 mg) enteric coated granules obtained in Reference Example 12 229.2 mg
Compound E 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5RW) 15.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 265.4 mg
Example 16
The two-stage release granules (262.4 mg) obtained in Example 15 were filled in one No. 2 capsule to give a capsule containing 64 mg of Compound E.
Example 17
Hydroxypropylcellulose (1.024 g) and purified sucrose (2.56 g) were dissolved in purified water (157.9 g) . Low- substituted hydroxypropylcellulose (2.56 g) and Compound E (16.0 g) were dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 12 (210 g) were coated with the above- mentioned coating solution in a tumbling fluidized bed granulator (SPIR-A-FLOW, manufactured by Freund Corporation) under the conditions of inlet air temperature: 550C, rotor revolution speed: 100 rpm, coating solution spray rate: 3.0 g/min and spray air pressure: 1.0 kg/cm2 to give two-stage release granules having the following composition. The granules were vacuum dried at 40°C for 16 hr and passed through a round sieve to give granules (710 μm - 1400 μm) .
Composition of two-stage release granules (per 252.144 mg) enteric coated granules obtained in Reference Example 12 230.00 mg Compound E 16.00 mg purified sucrose 2.56 mg hydroxypropylcellulose 1.024 mg low-substituted hydroxypropylcellulose 2.56 mg total 252.144 mg
Example 18
The two-stage release granules (252.144 mg) obtained in Example 17 were filled in one No. 2 capsule to give a capsule containing 64 mg of Compound E.
Example 19
Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound F (256.5 g) are dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 14 (1271 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 700C, inlet air volume: 2.0 m2/min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 700C to give two-stage release granules having the following composition. The granules are passed through a round sieve (850 μjn - 1700 μm) to give granules. Then, the granules are vacuum dried at 400C for 16 hr.
Composition of two-stage release granules (per 315.7 mg) enteric coated granules obtained in Reference Example 14 282.5 mg
Compound F 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 12.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 315.7 mg
Example 20 The two-stage release granules (3631 g) obtained in
Example 19 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound F per capsule.
Example 21
The mixed granules (158.0 mg) obtained in Example 20 are filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound F per capsule. Example 22
The immediate-release granules obtained in Reference Example 15 (50.8 mg) and the enteric coated granules obtained in Reference Example 16 (229.2 mg) are filled in one No. 2 capsule to give a capsule containing 64 mg of Compound F.
Example 23
Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (188Og) and purified sucrose (401.0 g) were dissolved in purified water (22520 g) . Low-substituted hydroxypropylcellulose (406.0 g) and Compound E (2505 g) were dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 18 (19170 g) were coated with the above-mentioned coating solution in a fluidized bed coating machine (FD-S2, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 63°C, inlet air volume: 7.0 m2 /min, coating solution spray rate: 134 g/min, spray air pressure: 0.50 MPa and spray air volume: 280 NL/min, and fluidized bed dried at inlet air temperature: 63°C to give two-stage release granules having the following composition. The granules were passed through a round sieve to give granules (850 μm - 1700 μm) . Then, the granules were vacuum dried at 400C for 16 hr.
Composition of two-stage release granules (per 493.53 mg) enteric coated granules obtained in Reference Example 18 441.61 mg
Compound E 25.00 mg purified sucrose 4.06 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 18.80 mg low-substituted hydroxypropylcellulose 4.06 mg total 493.53 mg Example 24
The two-stage release granules (78960 g) obtained in Example 23 and talc (75.2 g) were mixed in a tumbler mixer (type TM20-0-0, manufactured by SUEHIRO KAKOKI CO., LTD.) and the obtained mixed granules (494.0 mg) were filled in a No. 0 long capsule by a capsule filling machine (ZANASI type 32F, manufactured by IMA) to give a capsule containing 100 mg of Compound E per capsule.
Example 25
Hydroxypropylmethylcellulose 2910 (trade name: TC-5EW) (192.0 g) and purified sucrose (41.1 g) are dissolved in purified water (2304 g) . Low-substituted hydroxypropylcellulose (41.6 g) and Compound G (256.5 g) are dispersed in the obtained solution to give a coating solution. The enteric coated granules obtained in Reference Example 20 (1271 g) are coated with the above-mentioned coating solution in a fluidized bed coating machine (MP-10, manufactured by POWREX CORPORATION) under the conditions of inlet air temperature: 700C, inlet air volume: 2.0 m2 /min, coating solution spray rate: 19 g/min, spray air pressure: 0.30 MPa and spray air volume: 90 NL/min, and fluidized bed dried at inlet air temperature: 700C to give two-stage release granules having the following composition. The granules are passed through a round sieve (850 μtn - 1700 μm) to give granules. Then, the granules are vacuum dried at 400C for 16 hr.
Composition of two-stage release granules (per 315.7 mg) enteric coated granules obtained in Reference Example 20 282.5 mg
Compound G 16.0 mg purified sucrose 2.6 mg hydroxypropylmethylcellulose 2910 (TC-5EW) 12.0 mg low-substituted hydroxypropylcellulose 2.6 mg total 315.7 mg
Example 26
The two-stage release granules (3631 g) obtained in Example 25 and talc (3.45 g) are mixed in a tumbler mixer (TM- 15, manufactured by SHOWA KAGAKU KIKAI KOSAKUSHO) and the obtained mixed granules (316.0 mg) are filled in a No. 1 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 64 mg of Compound G per capsule.
Example 27
The mixed granules (158.0 mg) obtained in Example 26 are filled in a No. 3 capsule by a capsule filling machine (ZANASI type 6F, manufactured by IMA) to give a capsule containing 32 mg of Compound G per capsule.
Example 28
The immediate-release granules obtained in Reference Example 21 (50.8 mg) and the enteric coated granules obtained in Reference Example 22 (229.2 mg) are filled in one No. 2 capsule to give a capsule containing 64 mg of Compound G.
Comparative Example Compound E (769.5 g) , lactose (3522 g) and corn starch (528.0 g) were uniformly mixed in a fluidized bed granulating dryer (FD-5S, POWREX CORPORATION), granulated while spraying an aqueous solution of hydroxypropylcellulose (158.4 g) and then dried in the dryer. The obtained granules were pulverized in a Power Mill grinder (P-3, SHOWA KAGAKU KIKAI KOSAKUSHO) using a 1.5 mmφ punching screen. Croscarmellose sodium (220.0 g) and magnesium stearate (32.0 g) were added to the obtained sized granules (4148 g) and mixed in a tumbler mixer (TM-15, SHOWA KAGAKU KIKAI KOSAKUSHO) . The obtained mixture was tableted with a rotary tablet press (Correct 12HUK, KIKUSUI SEISAKUSHO LTD.) using a 6.5 inmφ punch (tableting pressure: 8.5 KN/punch, weight per tablet: 110 mg) to give plain tablets. Hydroxypropylmethylcellulose 2910 (358.8 g) and macrogol 6000 (72.0 g) were dissolved in purified water (4320 g) and titanium dioxide (48.0 g) and yellow ferric oxide (1.2 g) were dispersed therein to give a coating agent. The coating agent was sprayed on the aforementioned plain tablets in a Driacoater coating machine (DRC-500, manufactured by POWREX CORPORATION) to give film-coated tablet having the following composition (sometimes to be abbreviated as comparative preparation in the present description) .
Composition of comparative preparation (per 114 mg) Compound E 16.00 mg lactose 73.40 mg corn starch 11.00 mg hydroxypropylcellulose 3.30 mg croscarmellose sodium 5.50 mg magnesium stearate 0.80 mg hydroxypropylmethylcellulose 2910 2.99 mg macrogol 6000 0.60 mg titanium dioxide 0.40 mg yellow ferric oxide 0.01 mg total 114.00 mg
Experimental Example 1
The drug dissolution property of the two-stage release granules obtained in Example 9 was evaluated by a dissolution test (phosphate buffer (pH 6.8, 900 mL) containing 0.4 w/w% sodium dodecylsulfate, Paddle Method, 50 rpm, 370C) . The dissolution test was performed according to the Japanese Pharmacopoeia, Fourteenth Edition, Dissolution Test, Method 2 (Paddle Method) . The results are shown in Fig. 1 wherein -o- shows the results of the two-stage release granules of Example 9.
As shown in Fig. 1, the pharmaceutical agent of the present invention showed a step-wise release of compound (I) .
Experimental Example 2
The capsule (dose: 64 mg/body as Compound E) obtained in Example 10 was orally administered with water (60 inL) to cynomolgus monkeys (n= 5) under fasting and time course changes of plasma concentration of compound E were examined. As a control, similarly, the comparative preparation (dose: 64 mg/body as Compound E) obtained in Comparative Example was orally administered with water (60 mL) to cynomolgus monkeys (n= 5) under fasting and time course changes of plasma concentration of compound E were examined. The results are shown in Fig. 2 wherein -o- shows the results of the capsule of Example 10 and -•- shows the results of the comparative preparation.
As shown in Fig. 2, as compared with the comparative preparation, the pharmaceutical agent of the present invention suppressed the maximum blood concentration of compound (I) and further, sustainability of blood concentration of compound (I) was achieved.
Industrial Applicability According to the present invention, a pharmaceutical agent comprising a nitrogen containing 5-membered heterocyclic compound useful as an agent for the prophylaxis or treatment of diabetes mellitus, hyperlipidemia, impaired glucose tolerance, inflammatory diseases, arteriosclerosis and the like, which has improved sustainability of an effective blood concentration of the compound, can be provided.
This application is based on a patent application No. 2004-287244 filed in Japan, the contents of which are hereby incorporated by reference.

Claims

1. A pharmaceutical agent comprising a combination of two or more parts comprising a compound of the formula:
Figure imgf000062_0001
wherein R1 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -CO-, -CS-, -CR4(OR5)- or -NR6- wherein each of R4 and R6 represents a hydrogen atom or a hydrocarbon group which may be substituted, and R5 represents a hydrogen atom or a protective group for a hydroxyl group; m represents an integer of 0 to 3;
Y represents an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO2-, -NR7-, -CONR7- or -NR7CO- wherein R7 represents a hydrogen atom or a hydrocarbon group which may be substituted; ring A represents an aromatic ring which may further have 1 to
3 substituents; n represents an integer of 1 to 8; ring B represents a nitrogen-containing 5-membered hetero ring which may further be substituted by an alkyl group;
XI represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: -SO-, -SO2-, -0-SO2- or -NR16- wherein R16 represents a hydrogen atom or a hydrocarbon group which may be ' substituted;
R2 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent hydrocarbon residue having 1 to 20 carbon atoms; R3 represents a group of the formula: -OR8 (R8 represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR9R10 (each of R9 and R10, whether identical or not, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted; R9 and R10 may bind together to form a ring) ; provided that R1 is a heterocyclic group which may be substituted or R2 is an aromatic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, when ring A is a benzene ring which may be substituted, and Y is an oxygen atom, a sulfur atom, -NH- or -CONH-; or a salt thereof, said two or more parts have mutually different release rates of the compound or a salt thereof.
2. The pharmaceutical agent of claim 1, wherein at least one of the two or more parts comprises a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5.
3. The pharmaceutical agent of claim 2, wherein the polymer substance is a methyl methacrylate-methacrylic acid copolymer.
4. The pharmaceutical agent of claim 3, wherein the polymer substance is a mixture of a methacrylic acid copolymer L and a methacrylic acid copolymer S.
5. The pharmaceutical agent of claim 4, wherein the weight ratio of the methacrylic acid copolymer L:methacrylic acid copolymer S is 1:0.5 to 1:7.
6. The pharmaceutical agent of claim 1, wherein the two or more parts form a single preparation.
7. The pharmaceutical agent of claim 1, which comprises a combination of a modified-release part wherein a core comprising a compound represented by the formula (I) or a salt thereof is coated with a coating layer comprising a polymer substance which is soluble within the range of not less than pH 6.0 and not more than pH 7.5, and an immediate-release part comprising the compound or a salt thereof.
8. The pharmaceutical agent of claim 7, which is a single preparation wherein the modified-release part is coated with the immediate-release part.
9. The pharmaceutical agent of claim 7, which is a capsule comprising the modified-release part and the immediate-release part as independent preparations.
10. The pharmaceutical agent of claim 1, wherein the compound represented by the formula (I) is ethyl 3- [3-ethoxy-l- [4- (2-phenyl-4-oxazolylmethoxy)benzyl] -IH- pyrazol-4-yl]propionate; ethyl 3- [3-ethoxy-l-[2- (5-methyl-2-phenyl-4- oxazolylmethoxy)benzyl] -lH-pyrazol-4-yl]propionate;
3- (3-ethoxy-l-{4- [ (2-phenyl-l, 3-thiazol-4-yl)methoxy]benzyl}- lH-pyrazol-4-yl)propanoic acid;
3- [3-ethoxy-l- [4- [2- (2-furyl) -5-methyl-4- oxazolylmethoxy]benzyl] -lH-pyrazol-4-yl]propionic acid; or 3- [3-ethoxy-l-[4- [5-methyl-2- (2-thienyl) -4- oxazolylmethoxy]benzyl] -lH-pyrazol-4-yl]propionic acid.
11. The pharmaceutical agent of claim 1, which is a granule obtained by coating a sucrose-starch sphere with a coating layer comprising a compound represented by the formula (I) or a salt thereof, an excipient, a binder and a disintegrant to give granules (A) , coating granules (A) with a coating layer comprising a mixture of a methacrylic acid copolymer L and a methacrylic acid copolymer S, a plasticizer and a lubricant to give granules (B) , and coating granules (B) with a coating layer comprising the compound represented by the formula (I) or a salt thereof, an excipient, a binder and a disintegrant.
12. The pharmaceutical agent of claim 11, which is a granule obtained by coating a sucrose-starch sphere with a coating layer comprising a compound represented by the formula (I) or a salt thereof, sucrose, corn starch, crystalline cellulose, hydroxypropylcellulose and low-substituted hydroxypropylcellulose to give granules (A) , coating granules (A) with a coating layer comprising a mixture of a methacrylic acid copolymer L and a methacrylic acid copolymer S in a weight ratio of 1:0.5 to 1:7, triethyl citrate and talc to give granules (B) , and coating granules (B) with a coating layer comprising the compound represented by the formula (I) or a salt thereof, sucrose, hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose.
PCT/JP2005/018486 2004-09-30 2005-09-29 Modified-release preparation WO2006036007A2 (en)

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WO2008081891A1 (en) * 2006-12-28 2008-07-10 Takeda Pharmaceutical Company Limited Orally disintegrating solid preparation
US20100074950A1 (en) * 2008-03-14 2010-03-25 Nectid Inc. Anti-diabetic combinations
WO2011055385A1 (en) * 2009-11-03 2011-05-12 Lupin Limited Modified release formulation of lacosamide
WO2011101863A3 (en) * 2010-02-19 2012-01-19 Cadila Healthcare Limited Extended release pharmaceutical compositions of lacosamide
US9180101B2 (en) 2009-10-09 2015-11-10 Yungjin Pharm Co., Ltd. Pharmaceutical composition simultaneously having rapid-acting property and long-acting property
US10973783B2 (en) 2015-12-30 2021-04-13 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of seizure-related disorders

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EP1541564A1 (en) * 2002-09-10 2005-06-15 Takeda Pharmaceutical Company Limited Five-membered heterocyclic compounds

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008081891A1 (en) * 2006-12-28 2008-07-10 Takeda Pharmaceutical Company Limited Orally disintegrating solid preparation
US9486446B2 (en) 2006-12-28 2016-11-08 Takeda Pharmaceutical Company Limited Orally disintegrating solid preparation
JP5366558B2 (en) * 2006-12-28 2013-12-11 武田薬品工業株式会社 Orally disintegrating solid preparation
US20100074950A1 (en) * 2008-03-14 2010-03-25 Nectid Inc. Anti-diabetic combinations
US8551524B2 (en) * 2008-03-14 2013-10-08 Iycus, Llc Anti-diabetic combinations
US9180101B2 (en) 2009-10-09 2015-11-10 Yungjin Pharm Co., Ltd. Pharmaceutical composition simultaneously having rapid-acting property and long-acting property
US10786464B2 (en) 2009-11-03 2020-09-29 Lupin Limited Modified release formulation of lacosamide
EP2496220B1 (en) 2009-11-03 2019-10-16 Lupin Limited Modified release formulation of lacosamide
WO2011055385A1 (en) * 2009-11-03 2011-05-12 Lupin Limited Modified release formulation of lacosamide
US11278502B2 (en) 2009-11-03 2022-03-22 Lupin Limited Modified release formulation of lacosamide
WO2011101863A3 (en) * 2010-02-19 2012-01-19 Cadila Healthcare Limited Extended release pharmaceutical compositions of lacosamide
US10973783B2 (en) 2015-12-30 2021-04-13 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of seizure-related disorders
US10987324B2 (en) 2015-12-30 2021-04-27 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of seizure-related disorders

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