Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to a solid preparation containing [ (3S) -6- ( ⁇ 2' , 6' -dimethyl- ' - [3-
• compound (A) (methylsulfonyl) propoxy] biphenyl-3-yl Jmethoxy) -2, 3-dihydro-l- benzofuran-3-yl] acetic acid (sometimes to be abbreviated as "compound (A) " in the present specification) or a salt thereof and metformin or a salt thereof and the like. In addition, it relates to . compound (A) or a salt thereof and the like superior in dissolution property.
• Compound (A) is a compound represented by the following formula :
• GPR40 receptor agonist useful as an insulin secretagogue or a prophylactic or therapeutic drug for diabetes and the like (patent document 1) .
• patent document 1 US-A-2010/0004312
• the present inventors have studied a solid preparation containing compound (A) or a salt thereof and metformin or a salt thereof. As a result, they could not obtain preferable disintegration property, and the disintegration property varied among individual preparations.
• compound (A) or a salt thereof in a solid preparation sometimes showed poor dissolution property.
• the present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that a solid preparation containing compound (A) or a salt thereof, metformin or a salt thereof, and crospovidone is superior in disintegration property, shows small variation in the
• the present invention provides the following.
• a solid preparation comprising
• metformin or a salt thereof comprising adding crospovidone to the solid preparation
• metformin or a salt thereof comprising adding crospovidone to the solid preparation
• the solid preparation of the present invention is useful as a therapeutic drug for diabetes and the like, and superior in disintegration property.
• the solid preparation of the present invention shows small variation in disintegration property of respective preparations.
• the solid preparation of the present invention further containing hydroxypropylcellulose is superior in preservation stability. Specifically, in the solid preparation, the production of a decomposition product or analogue of the active ingredient (particularly, compound (A) ) during the steps of a preparation production method and a long-term (e.g., 2 weeks) preservation process is suppressed.
• the dissolution property of a solid preparation containing compound (A) or a salt thereof can be improved, and the amount of the active ingredient absorbed in the body can be increased, whereby the efficacy thereof can be improved.
• Compound (A) or a salt thereof can be produced by a known method, for example, the method described in WO2008/001931 or a method analogous thereto.
• Examples of the salt of compound (A) include a
• pharmacologically acceptable salt such as a salt with
• inorganic acid a salt with organic acid, a salt with basic or acidic amino acid and the like.
• Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• salt with organic acid examples include salts with benzoic acid, formic acid, acetic acid,
• methanesulfonic acid methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
• salt with basic amino acid examples include salts with arginine, lysine, ornithine and the like
• salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
• compound (A) or a salt thereof free form of compound (A) is preferable.
• Compound (A) may be a solvate (e.g., hydrate) or non- solvate (e.g., non-hydrate).
• Compound (A) is preferably a hydrate, more preferably 0.5 hydrate .
• Compound (A) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I) and the like.
• an isotope e.g., 3 H, 14 C, 35 S, 125 I
• a deuterium-converted compound wherein 1 H has been converted to 2 H(D) is also encompassed in the compound (A) .
• the average particle size of compound (A) or a salt thereof is preferably about 5 - about 45 more preferably about 10 - about 40 um, particularly preferably about 15 - about 35 ⁇ . With such average particle size, a solid
• the average particle size of compound (A) or a salt thereof is less than 35
• a solid preparation containing compound (A) or a salt thereof shows superior dissolution property.
• the average particle size of compound (A) may vary due to the coagulation of compound (A) and the like in the process of producing the solid preparation of the present invention, or in the process of preserving the solid preparation after production.
• the average particle size means a particle size at which particles are divided into 50% each of crude particles and fine granules in weight
• the average particle size can be measured using a known measurement device, for example, a laser diffraction particle distribution apparatus (e.g., HELOS&RODOS (trade name) (manufactured by SYMPATEC) ) and the like.
• a laser diffraction particle distribution apparatus e.g., HELOS&RODOS (trade name) (manufactured by SYMPATEC)
• SYMPATEC manufacture of manufacture
• Compound (A) having a desired average particle size can also be produced by pulverizing compound (A) having a large average particle size together with, where necessary, an excipient such as microcrystalline cellulose and the like.
• pulverization is performed according to a known method and using, for example, a cutter mill, a hammer mill, a jet mill and the like.
• Compound (A) having the above-mentioned desired average particle size preferably shows dispersibility of "particles of 0.1 ⁇ or below in not more than 10% of the total amount, and particles of 1000 um or more in not more than 10% of the total amount", wherein the dispersibility is preferably measured by a laser diffraction particle distribution apparatus.
• the content of compound (A) or a salt thereof is generally 0.5 - 90 wt%, preferably 1 - 30 wt%, more preferably 1 - 20 wt%, particularly preferably 1 - 10 wt%.
• the solid preparation of the present invention contains metformin or a salt thereof.
• metformin or a salt thereof is preferably metformin
• the content of metformin or a salt thereof is generally 50 - 95 wt%, preferably 55 - 90 wt%, more preferably 60 - 85 wt%,
• the solid preparation of the present invention contains crospovidone .
• the content of crospovidone and is generally 0.5 - 20 wt%,
• the solid preparation of the present invention may be any suitable solid preparation of the present invention.
• preparation materials can be used. They are appropriately added as, for example, excipient, binder, glidant, lubricant, colorant, pH adjuster, surfactant, stabilizer, acidulant, flavor, coating agent or coating additive in an appropriate amount.
• excipient examples include microcrystalline
• cellulose cellulose, sugar alcohols such as D-mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol and the like; saccharides such as lactose, sucrose, glucose, maltose and the like; starches such as cornstarch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like; light anhydrous silicic acid, dextrin, carboxymethylstarch, gelatin, magnesium oxide, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium
• the content of the excipient in the solid preparation of the present invention is preferably 1 - 90 wt%, more preferably 2 - 80 wt%.
• the binder only needs to be an additive capable of binding particles during dry or wet granulation and direct tableting and, for example, hydroxypropylcellulose [e.g., grade: L, SL, SSL (trade name); Nippon Soda Co., Ltd.],
• hydroxypropylmethylcellulose e.g., hypromellose 2910, TC-5
• the content of the binder is preferably 0.5 - 15 wt%, more
• glidant examples include talc, light anhydrous silicic acid, hydrated silicon dioxide and magnesium
• lubricant examples include stearic acid, magnesium stearate, calcium stearate, sucrose ester of fatty acid, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol 6000 and light anhydrous silicic acid, and magnesium stearate is preferable.
• the colorant include food colors such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 and the like; food lake colors, red ferric oxide, yellow ferric oxide and the like.
• pH adjuster examples include citric acid or a salt thereof, phosphoric acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt
• surfactant examples include sodium lauryl sulfate, polysorbate 80,
• the stabilizer include succinic acid, tartaric acid, citric acid, lactic acid, fumaric acid, malic acid, ascorbic acid, acetic acid, acidic amino acid (e.g., glutamic acid, aspartic acid) , inorganic salts of these acids (e.g., alkali metal salt, alkaline earth metal salt), salts with inorganic bases (e.g., ammonium) of these acids, salts with organic bases (e.g., meglumine) of these acids, salts with basic amino acid (e.g., arginine, lysine, ornithine) of these acids, hydrates thereof, solvates thereof and the like.
• acidic amino acid e.g., glutamic acid, aspartic acid
• inorganic salts of these acids e.g., alkali metal salt, alkaline earth metal salt
• salts with inorganic bases e.g., ammonium
• salts with organic bases e.g.
• the acidulant include ascorbic acid, citric acid, tartaric acid, malic acid and the like.
• flavor examples include menthol, peppermint oil, lemon oil, vanillin and the like.
• the coating agent include sugar coating agent, aqueous film coating agent, enteric film coating agent, sustained-release film coating agent and the like.
• sugar coating agent for example, purification sucrose can be mentioned, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
• aqueous film coating agent examples include
• cellulose polymers such as hydroxypropylcellulose [e.g., grade: L, SL, SSL (trade name); Nippon Soda Co., Ltd.],
• hydroxypropylmethylcellulose e.g., hypromellose 2910, TC-5 (grade: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co.,
• enteric film coating agent examples include
• cellulose polymers such as hydroxypropylmethylcellulose
• acrylic acid polymers such as methacrylic acid
• copolymer LD (Eudragit L-30D55 (trade name) ]
• methacrylic acid copolymer S (trade name) ] and the like; naturally occurring substances such as shellac and the like; and the like.
• sustained-release film coating agent examples include cellulose polymers such as ethylcellulose and the like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name) ] , ethyl acrylate-methacrylic acid methyl copolymer suspension [Eudragit NE (trade name) ] and the like; and the like.
• the coating additive include light shielding agents such as titanium oxide and the like; glidants such as talc and the like; colorants such as red ferric oxide, yellow ferric oxide and the like; plasticizers such as macrogol 6000, triethyl citrate, castor oil, polysorbates and the like; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid- and the like; and the like.
• light shielding agents such as titanium oxide and the like
• glidants such as talc and the like
• colorants such as red ferric oxide, yellow ferric oxide and the like
• plasticizers such as macrogol 6000, triethyl citrate, castor oil, polysorbates and the like
• organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid- and the like; and the like.
• the above-mentioned additive may be a mixture of two or more kinds at an appropriate ratio.
• the solid preparation of the present invention preferably further contains hydroxypropylcellulose to improve preservation stability of the preparation.
• the improvement of the preservation stability of a solid preparation means, for example, the production of a decomposition product or analogue of the active ingredient (particularly, compound (A) ) in the preparation is suppressed when the solid preparation is preserved for a long term (e.g., 2 weeks) .
• the preservation conditions may be severe conditions (40°C, 75%RH) .
• hydroxypropylcellulose for example, those having the following properties: those having the following properties: those having the following properties: those having the following properties: those having the following properties:
• the content of the solid preparation of the present invention contains hydroxypropylcellulose, the content of the
• hydroxypropylcellulose in the solid preparation is generally 1 - 30 wt%, preferably 2 - 25 wt%, more preferably 3 - 20 wt%, particularly preferably 3 - 10 wt%.
• the solid preparation of the present invention preferably further contains microcrystalline cellulose to optimize
• the content of the solid preparation of the present invention contains microcrystalline cellulose, the content of the
• microcrystalline cellulose in the solid preparation is
• the solid preparation...of the present invention nay further contain magnesium stearate to optimize physicochemical property of the preparation (e.g., manufacturability, tablet disintegration property, tablet hardness) .
• the content of the magnesium stearate in the solid preparation is generally 0.01 - 10 wt%, preferably 0.1 - 5 wt%, more preferably 0.15 - 2 wt%.
• the solid preparation of the present invention is
• a solid preparation comprising
• excipient preferably, microcrystalline cellulose
• binder preferably, hydroxypropylcellulose
• lubricant preferably, magnesium stearate
• a solid preparation comprising
• the contents of the components of the solid preparation of the present invention are preferably the following contents.
• the solid preparation of the present invention may contain components other than the following components.
• metformin or a salt thereof 60 - 80 wt%
• crospovidone 1 - 10 wt%
• microcrystalline cellulose 3 - 20 wt%
• magnesium stearate 0.15 - 2 wt%
• the contents of the components of the solid preparation of the present invention are more preferably the following contents.
• the solid preparation of the present invention may contain components other than the following components.
• metformin or a salt thereof 70 - 80 wt%
• microcrystalline cellulose 5 - 15 wt%
• magnesium stearate 0.15 - 2 wt%
• Examples of the dosage form of the solid preparation of the present invention include granule, tablet (e.g., uncoated tablet, film-coated tablet) and the like. Of these, tablet is preferable .
• the solid preparation of the present invention can be produced by a method conventionally used in the pharmaceutical field.
• the solid preparation of the present invention can be specifically produced by appropriately combining operations such as granulation, mixing, tableting (compression molding) , coating and the like.
• a granulation machine such as an agitating granulator, a fluid bed granulator, a dry granulating machine and the like is used.
• a mixer such as a V-type mixer, a umbler mixer and the like is used.
• V-type mixer a mixer
• umbler mixer a mixer
• the like is used for mixing.
• Tableting is performed by punching using, for example, a single punch tableting machine, a rotary tableting machine and the like, at a pressure of generally 0.3- 35 kN/cm 2 .
• Coating is performed using, for example, a film coating apparatus together with the aforementioned coating agent and coating additive.
• the solid preparation of the present invention is
• coating agent and coating additive used for film coating include those similar to the ones used for the aforementioned additive.
• the film coating layer can be formed in a
• Each starting material used in the following production steps is used in such amount as to achieve the aforementioned content per finally obtained solid preparation.
• Compound (A) or a salt thereof and metformin or a salt thereof are mixed together with other additives (e.g., excipient, binder, disintegrant) as necessary in an appropriate mixer, and the mixture is granulated using an aqueous solution of a binder (e.g., hydroxypropylcellulose and the like), and sieved when desired.
• a binder e.g., hydroxypropylcellulose and the like
• crospovidone e.g., hydroxypropylcellulose and the like
• lubricant e.g., magnesium stearate and the like
• a film coating solution is sprayed when desired to give a film- coated tablet.
• Mixing and granulation can be performed using, for example, a fluid bed dryer granulator and the like.
• Molding can be performed by tableting using, for example, a rotary tableting machine.
• a film-coated tablet can be produced by, for example, coating a uncoated tablet obtained by the above-mentioned method, by spraying an aqueous solution of a film coating agent (e.g., a mixture of film coating base such as hypromellose 2910 and the like; plasticizer such as macrogol 6000 and the like; and colorant such as titanium oxide, red ferric oxide, yellow ferric oxide and the like) by a film coating machine and the like .
• a film coating agent e.g., a mixture of film coating base such as hypromellose 2910 and the like; plasticizer such as macrogol 6000 and the like; and colorant such as titanium oxide, red ferric oxide, yellow ferric oxide and the like
• the solid preparation of the present invention is preferably produced by a fluid bed granulation method.
• the solid preparation of the present invention is
• a tablet containing granules e.g., granules obtained by the above-mentioned granulation
• granules e.g., granules obtained by the above-mentioned granulation
• 70 - 100 wt% more preferably 85 - 98 wt%, further preferably 80 - 95 wt% .
• the "granule” here means particles having almost the same size and shape, which are obtained by granulating a starting material in the form of powder, bulk, solution, molten liquid and the like by a wet granulation method, a dry granulation method, a heating granulation method and the like (preferably, dry granulation method) .
• the granules generally have a particle size of not less than 1000 ⁇ for not more than 20%, not more than 150 pm for not more than 65% (on (remaining on sieves) with 16M sieves: not more than 20%; pass (pass through sieves) with 100 sieves: not more than 65%), preferably not less than 1000 ⁇ for not more than 5%, not more than 150 ⁇ for not more than 55% (on with 16M sieves: not more than 5%; pass with 100 M sieves: not more than 55%) .
• the particle size is, for example, a value obtained by measuring the weight of the granules remaining on the
• the granules may have different sizes and shapes during the process of formulation (e.g., tableting step) to give the solid preparation of the present invention.
• invention e.g., the weight per tablet
• the weight per tablet is generally 50 - 2000 mg, preferably 70 - 1800 mg, more preferably 80 - 1500 mg.
• the solid preparation of the present invention has superior effects as a medicament, and shows low toxicity and fewer side effects, it is useful in mammals (e.g., human, bovine, horse, swine, dog, cat, monkey, mouse, rat,
• diabetes e.g., type 1 diabetes, type 2 diabetes, type 1.5 diabetes (LADA (Latent Autoimmune Diabetes in Adults)), gestational diabetes, diabetes with impaired insulin secretion, obese diabetes, IGT (impaired glucose tolerance) , IFG (Impaired Fasting Glucose), IFG (Impaired Fasting Glycaemia)
• diabetes e.g., type 1 diabetes, type 2 diabetes, type 1.5 diabetes (LADA (Latent Autoimmune Diabetes in Adults)
• IGT impaired glucose tolerance
• IFG Impaired Fasting Glucose
• IFG Impaired Fasting Glycaemia
• diabetic complications e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, arteriosclerosis, osteopenia, hyperosmolar diabetic coma
• infections e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infection, inferior limb infection
• diabetic gangrene xerostomia,
• hypercholesterolemia hypoHDL-emia, postprandial hyperlipemia
• arteriosclerosis e.g., atherosclerosis
• hypertension myocardial infarction
• angina pectoris e.g., aortasis
• disorders e.g., cerebral infarction, cerebral apoplexy
• insulin resistance syndrome e.g., glucose resistance syndrome
• syndrome X e.g., dysmetabolic syndrome and the like.
• invention is also useful for secondary prevention (e.g., secondary prevention of cardiovascular event such as myocardial infarction and the like) or suppression of progression [e.g., suppression of progression from impaired glucose tolerance to diabetes; suppression of progression from diabetes to diabetic complications (preferably diabetic neuropathy, diabetic
• the solid preparation of the present invention can be administered orally and safely to a mammal.
• the dose of the solid preparation of the present invention only needs to contain an effective amount of compound (A) or a salt thereof as a pharmaceutically active ingredient.
• the effective amount is generally 1 mg - 500 mg, preferably 1 mg - 400 mg, more preferably 10 mg - 250 mg, further preferably 10 mg - 200 mg (further more preferably 12.5 mg, 25 mg, 50 mg, 100 mg) , once per day, as compound (A) free form (anhydride) .
• the dose of the solid preparation of the present invention only needs to contain an effective amount of metformin or a salt thereof as a pharmaceutically active ingredient.
• an adult body weight 60 kg
• the dose of the solid preparation of the present invention only needs to contain an effective amount of metformin or a salt thereof as a pharmaceutically active ingredient.
• effective amount is generally -300 ng - 20CC-ng, preferably 400 mg - 1500 mg, more preferably 500 - 1000 mg (further more preferably 500 mg, 850 mg, 1000 mg) , once per day, as
• the size of the solid preparation of the present invention varies depending on the shape of the solid preparation (round, caplet, oblong etc.).
• the solid preparation of the present invention can be used in combination with one or more other kinds of medicaments (hereinafter sometimes to be abbreviated as "concomitant drug") .
• the concomitant drug include one or more medicaments selected from a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an
• antiobesity agent a diuretic, an antithrombotic agent and the like.
• insulin preparations e.g., animal insulin preparation extracted from the pancreas of bovine, swine; human insulin preparation synthesized by genetic engineering using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or
• insulin e.g., INS-1
• oral insulin preparation e.g., insulin sensitizers (e.g., pioglitazone or a salt thereof
• metaglidasen (preferably maleate) , metaglidasen, A G-131, balaglitazone, MBX- 2044, rivoglitazone, aleglitazar, chiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, compound described in
• oc-glucosidase inhibitors e.g., voglibose, acarbose, miglitol, emiglitate
• insulin secretagogues e.g., sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide,
• inhibitors e.g., alogliptin or a salt thereof (preferably benzoate) , trelagliptin or a salt thereof (preferably succinate) , vildagliptin, sitagliptin, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP- 104), ⁇ 3 agonists (e.g., N-5984), GLP-1 receptor agonists (e.g., GLP-1, GLP-1MR agent, liraglutide, exenatide, AVE-0010, BIM- 51077, Aib(8,35)hGLP-l(7,37)NH2, CJC-1131, albiglutide) , amylin agonists (e.g., pramlintide) , phosphotyrosine phosphatas
• gluconeogenesis inhibitors e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, FBPase inhibitor
• SGLT2 gluconeogenesis inhibitors
• sodium-glucose cotransporter 2 inhibitors e.g., depagliflozin, AVE2268, TS-033, YM543, TA-7284, remogliflozin, ASP1941
• SGLT1 inhibitors e.g., ⁇ -hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498, INCB-13739), adiponectin or agonist thereof, IKK inhibitors (e.g., AS-2868) , leptin resistance improving drugs, somatostatin receptor agonists, glucokinase activators (e.g., piragliatin, AZD1656, AZD6370, TTP-355, compound described in WO2006/112549, O2007/028135, WO2008/047821 , WO2008/050821 ,
• GPR119 agonists e.g., PSN821
• FGF21 e.g., FGF analogue and the like.
• aldose reductase inhibitors e.g., kaolin
• ranirestat (AS-3201) , lidorestat) , neurotrophic factors and increasing drugs thereof (e.g., NGF, NT-3, BDNF, neurotrophin production/secretion promoting agent described in WOOl/14372 (e.g., 4- (4-chlorophenyl) -2- (2-methyl-l-imidazolyl) -5- [3- (2- methylphenoxy) propyl] oxazole) , compound described in
• PKC inhibitors e.g., ruboxistaurin mesylate
• AGE inhibitors e.g., ALT946, N-phenacylthiazolium bromide
• ALT766 ALT766
• EXO-226, pyridorin, pyridoxamine GABA receptor agonists
• GABA receptor agonists e.g., gabapentin, pregabalin
• serotonin noradrenaline reuptake inhibitors e.g., duloxetine
• inhibitors e.g., lacosamide
• active oxygen scavengers e.g., thioctic acid
• cerebral vasodilators e.g., tiapride
• somatostatin receptor agonists e.g., BIM23190
• ASK-1 apoptosis signal regulating kinase-1
• HMG-CoA reductase inhibitors e.g., pravastatin
• simvastatin simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compound described in
• WO97/10224 for example, N- [ [ (3R, 5S) -1- (3-acetoxy-2, 2- dimethylpropyl) -7-chloro-5- (2, 3-dimethoxyphenyl) -2-oxo-l, 2,3,5- tetrahydro-4, l-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate,
• anion exchange resins e.g., simfibrate, clinofibrate
• colestyramine colestyramine
• probucol nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan) , ethyl icosapentate, phytosterol (e.g., soysterol, ⁇ -oryzanol) , cholesterol absorption inhibitors (e.g., Zetia) , CETP inhibitors (e.g., dalcetrapib, anacetrapib) , ⁇ -3 fatty acid preparations (e.g., ⁇ -3-acid ethyl esters 90) and the like .
• nicotinic acid drugs e.g., nicomol, niceritrol, niaspan
• ethyl icosapentate phytosterol (e.g., soysterol, ⁇ -oryzanol)
• cholesterol absorption inhibitors e.g., Zetia
• CETP inhibitors
• antihypertensive agent examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril,
• angiotensin II antagonists e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil and the like
• calcium antagonists e.g., manidipine, nifedipine,
• ⁇ blockers e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol and the like
• antiobesity agent examples include monoamine uptake inhibitors (e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine) , ⁇ serotonin 2C receptor agonists (e.g., lorcaserin) , serotonin 6 receptor antagonists, histamine H3 receptor
• monoamine uptake inhibitors e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine
• ⁇ serotonin 2C receptor agonists e.g., lorcaserin
• serotonin 6 receptor antagonists histamine H3 receptor
• GABA modulators e.g., topiramate
• neuropeptide Y antagonists e.g., velneperit
• cannabinoid receptor antagonists e.g., rimonabant, taranabant
• ghrelin antagonists e.g., ghrelin receptor antagonists
• ghrelin acylation enzyme inhibitors e.g., opioid receptor antagonists (e.g., GSK-1521498 )
• opioid receptor antagonists e.g., GSK-1521498
• orexin receptor antagonists melanocortin 4 receptor agonists
• 11 ⁇ - hydroxysteroid dehydrogenase inhibitors e.g., AZD-4017
• pancreatic lipase inhibitors e.g., orlistat, cetilistat
• ⁇ 3 agonists e.g., N-5984
• DGAT1 acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918) , sodium-glucose cotransporter inhibitors (e.g., J J-28431754, remogliflozin) ,
• ACC acetyl-CoA carboxylase
• stearoyl-CoA desaturase inhibitors stearoyl-CoA desaturase inhibitors
• microsomal triglyceride transfer protein inhibitors e.g., R-256918
• sodium-glucose cotransporter inhibitors e.g., J J-28431754, remogliflozin
• NF B inhibitors e.g., HE-3286) , PPAR agonists (e.g., GFT-505, DRF-11605) , phosphotyrosine phosphatase inhibitors (e.g., sodium -vanadate, trodusquemine) , GPR119 agonists (e.g., PSN-821) , glucokinase activators (e.g., AZD-1656) , leptin, leptin
• GLP-1 glucagon-like peptide-1
• bovine or swine pancreas bovine or swine pancreas; human GLP-1 preparation synthesized by genetic engineering using Escherichia coli or yeast; fragment or derivative of GLP-1 (e.g., exenatide, liraglutide) , amylin preparation (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obinepitide, TM-30339, TM-30335), oxyntomodulin preparation: FGF21
• GLP-1 synthesized by genetic engineering using Escherichia coli or yeast
• fragment or derivative of GLP-1 e.g., exenatide, liraglutide
• amylin preparation e.g., pramlintide, AC-2307
• neuropeptide Y agonists e.g., PYY3-36, derivatives of PY
• preparations e.g., animal FGF21 preparation extracted from bovine or swine pancreas; human FGF21 preparation synthesized by genetic engineering using Escherichia coli or yeast; fragment or derivative of FGF21
• anorexigenic agents e.g., P-57
• diuretic examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide,
• cyclopenthiazide trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide) , antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase
• inhibitors e.g., acetazolamide
• chlorobenzenesulfonamide agents e.g., chlortalidone, mefruside, indapamide
• azosemide isosorbide
• piretanide bumetanide
• furosemide e.g., piretanide inhibitors
• chlorobenzenesulfonamide agents e.g., chlortalidone, mefruside, indapamide
• azosemide azosemide
• isosorbide ethacrynic acid
• piretanide piretanide
• bumetanide furosemide and the like.
• antithrombotic agent examples include heparins (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarins (e.g., warfarin potassium), anti- thrombin drugs (e.g., argatroban, dabigatran) , FXa inhibitors (e.g., rivaroxaban) , apixaban, edoxaban, YM150, compound
• thrombolytic agents e.g., urokinase, tisokinase, alteplase, nateplase, monteplase,
• pamiteplase a platelet aggregation inhibitor
• platelet aggregation inhibitors e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348,
• sensitizers preferably pioglitazone hydrochloride
• insulin preparation preferably voglibose, acarbose
• sulfonylureas preferably glimepiride
• dipeptidyl peptidase IV inhibitor preferably, alogliptin benzoate
• the administration time of these is not limited, and they may be administered simultaneously to an administration subject, or may be
• the solid preparation of the present invention and the concomitant drug may be administered as separate preparations to an administration subject, or they may be administered to an administration subject as a single preparation containing the solid preparation of the present invention and the concomitant drug.
• the dose of the concomitant drug can be appropriately determined based on the clinically employed dose of each drug.
• the mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately determined according to the administration subject,
• the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the solid preparation of the present invention.
• concomitant drug in this way provides superior effects such as 1) enhanced effect of the action of one or more medicaments selected from compound (A) or a salt thereof, metformin or a salt thereof, and a concomitant drug (synergistic effect of medicament actions) , 2) reduction effect of the doseof_ one-_or_ more-medicaments- -selected- from compound (A) or a salt thereof, metformin or a salt thereof, and a concomitant drug ' (reduction effect of medicament dose as compared to single drug administration) , 3) reduction effect of secondary action of one or more medicaments selected from compound (A) or a salt thereof, metformin or a salt thereof, and a concomitant drug, and the like.
• the present invention also provides a method of
• the preparation can be produced in the same manner as the solid preparation of the present invention, and can be used for the treatment of diabetes and the like.
• the amount of crospovidone to be added is the same as the content of crospovidone in the solid preparation of the present invention.
• the variation in the disintegration property means, for example, variation in the disintegration property per tablet as shown in the below- mentioned Experimental Examples.
• variation in the disintegration property of the solid preparation of in the present invention means variation in the disintegration time by the
• the standard deviation of the disintegration time by the disintegration test method is preferably within 0.3 min.
• the present invention also provides compound (A) or a salt thereof having an average particle size of less than 35 ⁇ , and a (solid) preparation containing compound (A) or a salt thereof having an average particle size of less than 35 ⁇ .
• the (solid) preparation can be produced in the same manner as the solid preparation of the present invention, and can be used for the treatment of diabetes and the like.
• the (solid) preparation may further contain metformin or a salt thereof (preferably metformin
• the (solid) preparation may further contain alogliptin or a salt thereof (preferably alogliptin benzoate) .
• the average particle size of compound (A) or a salt thereof By setting the average particle size of compound (A) or a salt thereof to less than 35 ⁇ , preferably less than 30 ⁇ , a (solid) preparation showing superior dissolution property of compound (A) or a salt thereof can be obtained.
• the lower limit of the aforementioned average particle size is not particularly limited as long as it does not influence the productivity, it is preferably not less than about 1 urn, more preferably not less than about 5 ⁇ , particularly preferably not less than about 10 um.
• the present invention also provides a preparation
• the solid preparation can be produced in the same manner as the solid preparation of the present invention, and can be used for the treatment of diabetes and the like.
• polyvinylpyrrolidone produced many analogs. However, a mixture containing hydroxypropylcellulose instead of PVP suppressed production of analogue.
• a solid preparation comprising compound (A) or a salt thereof and hydroxypropylcellulose can suppress the production of an analogue as compared to the use of other binders (e.g., PVP, hypromellose etc.) .
• binders e.g., PVP, hypromellose etc.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 ⁇ as measured by a laser diffraction particle size analyzer and according to a dry method.
• the granulated powder (517.5 g) was measured, and mixed with microcrystalline cellulose (18 g) (manufactured by Asahi Kasei, CEOLUS KG-802) , crospovidone (47.7 g) (manufactured by BASF, Kollidon CL-F) , and magnesium stearate (1.8 g) in a plastic bag to give a mixed powder.
• microcrystalline cellulose 18 g
• crospovidone 47.7 g
• BASF Kollidon CL-F
• magnesium stearate 1.8 g
• preparation 1 tablette, long diameter 13.5 mmxshort diameter 8.5 mm, 650 mg per tablet
• composition of preparation 1 per tablet is shown in Table 1.
• microcrystalline cellulose (KG802) 20
• Compound (A' ) (2696 g) , metformin hydrochloride (53000 g) , and microcrystalline cellulose (2286 g) (manufactured by Asahi Kasei, CEOLUS PH-101) were measured and placed in a fluidized- bed dryer (WSG-60, POWREX CORPORATION) , and the mixture was granulated while spraying a 8 (w/w) % hydroxypropylcellulose (Nippon Soda Co., Ltd., grade SSL) solution (37100 g) . The granules were dried to give a granulated powder.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 m as measured by a laser
• cellulose 9540 g (manufactured by Asahi Kasei, CEOLUS KG-802) , and magnesium stearate (360 g) were added and they were mixed in a tumbler mixer (TM-400S, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-400S Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted at tableting pressure 14kN to give a tablet (long diameter 13.5 mm*short diameter 8.5 mm, 650 mg per tablet) .
• 0P7ADRY Red 03F45081 (1008 g) (manufactured by COLORCON JAPAN; containing hypromellose 2910, macrogol 6000, titanium oxide and red ferric oxide) and OPADRY Yellow 03F42240 (2016 g) (manufactured by COLORCON JAPAN; containing hypromellose 2910, macrogol 6000, titanium oxide and yellow ferric oxide) were suspended in purified water (27220 g) to prepare a coating solution.
• a coating machine DRC-1200DS, POWREX
• preparation 2 film-coated tablet
• Table 2 The composition of preparation 2 per tablet is shown in Table 2.
• preparation 3 tabletted, long diameter 13.5 mmxshort diameter 8.5 mm, 650 mg per tablet.
• Table 3 The composition of preparation 3 per tablet is shown in Table 3.
• microcrystalline cellulose (KG802) 20
• the sieved powder (11.5 g) obtained in Example 2 was mixed with crospovidone (0.4 g) (manufactured by BASF, Kollidon CL-F), microcrystalline cellulose (1.06 g) (manufactured by Asahi Kasei, CEOLUS KG-802), and magnesium stearate (0.04 g) in a glass bottle to give a mixed powder.
• crospovidone 0.4 g
• microcrystalline cellulose 1.06 g
• magnesium stearate 0.04 g
• the mixed, powder was tableted at tableting pressure 14kN to give preparation 4 (tablet, long diameter 13.5 mmxshort diameter 8.5 mm, 650 mg per tablet).
• the composition of preparation 4 per tablet is shown in Table 4. [0110]
• Compound (A' ) (1602 g) , metformin hydrochloride (53550 g) , and microcrystalline cellulose (2178 g) (manufactured by Asahi Kasei, CEOLUS PH-101) were measured and placed in a fluidized- bed dryer (WSG-60, POWREX CORPORATION) , and the mixture was granulated while spraying a 8 (w/w) % hydroxypropylcellulose (Nippon Soda Co., Ltd., grade SSL) solution (37800 g) . The granules were dried to give a granulated powder.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 um as measured by a laser
• cellulose (8938 g) (manufactured by Asahi Kasei, CEOLUS KG-802) , and magnesium stearate (327 g) were added and they were mixed in a tumbler mixer (TM-400S, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-400S Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted to give a tablet (long diameter 17.5 .
• OPADRY Red 03F45081 1000 g
• OPADRY Yellow 03F42240 2000 g
• preparation 5 film-coated tablet
• Table 5 The composition of preparation 5 per tablet is shown in Table 5.
• microcrystalline cellulose (KG802) 82
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 ⁇ as measured by a laser
• OPADRY Red 03F45081 (1056 g) (manufactured by COLORCON JAPAN; containing hypromellose 2910, macrogol 6000, titanium oxide and red ferric oxide) and OPADRY Yellow 03F42240 (2112 g) (manufactured by COLORCON JAPAN; containing hypromellose 2910,
• the coating solution was sprayed on the tablet (110900 g) obtained above until the tablet weight increased by
• preparation 6 film-coated tablet
• Table 6 The composition of preparation 6 per tablet is shown in Table 6.
• microcrystalline cellulose (KG802) 97
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 um as measured by a laser diffraction particle size analyzer and according to a dry method.
• the granulated powder (517.5 g) was measured, and mixed with microcrystalline cellulose (18 g) (manufactured by Asahi Kasei, CEOLUS KG-802) , crospovidone
• the mixed powder was tableted at tableting pressure 14kN to give preparation 7 (tablet, long diameter 13.5 mmxshort diameter 8.5 mm, 650 mg per tablet).
• composition of preparation 7 per tablet is shown in Table 7.
• microcrystalline cellulose (KG802) 20
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 ⁇ as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.2 mm ⁇
• the sieved powder (14380 g) was measured, and mixed with microcrystalline cellulose (1261 g) (manufactured by Asahi Kasei, CEOLUS KG-802), crospovidone (494.0 g) (manufactured by BASF, Kollidon CL-F), and magnesium stearate (52.00 g) in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-60 Showa Kagakukikai Co., Ltd.
• OPADRY Red 03F45081 (168 g) (manufactured by COLORCON JAPAN) and OPADRY Yellow 03F42240 (336 g) (manufactured by COLORCON JAPAN) were suspended in purified water (4536 g) to prepare a coating solution.
• a coating machine DRC-650DS, POWREX CORPORATION
• the coating solution was sprayed on the tablet (8715 g) obtained above until the tablet weight
• composition of preparation 8 per tablet is shown in Table 8.
• component weight (mg) compound (A' ) 25.43 metformin hydrochloride 1000 microcrystalline cellulose (PH101) 39.57 hydroxypropylcellulose 41
• microcrystalline cellulose (KG802) 97
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 ⁇ as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.2 ⁇ punching screen to give a sieved powder.
• the sieved powder (14180 g) was measured, and mixed with microcrystalline cellulose (1230 g) (manufactured by Asahi Kasei, CEOLUS KG-802), crospovidone (480.0 g) (manufactured by BASF, Kollidon CL-F) , and magnesium stearate (45.00 g) in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-60 Showa Kagakukikai Co., Ltd.
• OPADRY Red 03F45081 (160.0 g) (manufactured by COLORCON JAPAN) and OPADRY Yellow 03F42240 (320.0 g) (manufactured by COLORCON JAPAN) were suspended in purified water (4320 g) to prepare a coating solution.
• a coating machine DRC-650DS, POWREX CORPORATION
• the coating solution was sprayed on the tablets (8496 g) obtained above until the tablet weight
• preparation 9 film-coated tablet
• Table 9 The composition of preparation 9 per tablet is shown in Table 9.
• microcrystalline cellulose (KG802) 82
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 um as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.2 rnmcj) punching screen to give a sieved powder.
• the sieved powder (14200 g) was measured, and mixed with microcrystalline cellulose (1325 g) (manufactured by Asahi Kasei, CEOLUS KG-802), crospovidone (500.0 g) (manufactured by BASF, Kollidon CL-F) , and magnesium stearate (50.00 g) in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-60 Showa Kagakukikai Co., Ltd.
• OPADRY Red 03F45081 (156 g) (manufactured by COLORCON JAPAN) and OPADRY Yellow 03F42240 (321.0 g) (manufactured by COLORCON JAPAN) were suspended in purified water (4212 g) to prepare a coating solution.
• a coating machine DRC-650DS, POWREX CORPORATION
• the coating solution was sprayed on the tablets (8359 g) obtained above until the tablet weight
• preparation 10 film-coated tablet
• Table 10 The composition of preparation 10 per tablet is shown in Table 10.
• Example 2 The sieved powder (11.5 g) obtained in Example 2 was mixed with microcrystalline cellulose (0.4 g) (manufactured by Asahi Kasei, CEOLUS KG-802), croscarmellose sodium (1.06 g) (manufactured by FMC, Ac-Di-Sol) , and magnesium stearate (0.04 g) in a glass bottle to give a mixed powder.
• the mixed powder was tableted at tableting pressure 14kN to give comparison preparation 1 (tablet, long diameter 13.5 mmxshort diameter 8.5 mm, 650 mg per tablet).
• Table 11 The composition of comparison preparation 1 per tablet is shown in Table 11.
• microcrystalline cellulose (KG802) 20
• Example 2 The sieved powder (11.5 g) obtained in Example 2 was mixed with microcrystalline cellulose (0.4 g) (manufactured by Asahi Kasei, CEOLUS KG-802), sodium starch glycolate (1.06 g) (manufactured by DMV, Primojel) , and magnesium stearate (0.04 g) in a glass bottle to give a mixed powder.
• the mixed powder was tableted at tableting pressure 14kN to give comparison preparation 2 (tablet, long diameter 13.5 mmxshort diameter 8.5 mm, 650 mg per tablet) .
• Table 12 The composition of comparison preparation 2 per tablet is shown in Table 12.
• microcrystalline cellulose (KG802) 20
• crospovidone is superior in disintegration property and shows small variation in the disintegration property of respective preparations, as compared to a preparation containing
• croscarmellose sodium or sodium starch glycolate croscarmellose sodium or sodium starch glycolate.
• Example 1 and Example 7 were preserved in an open glass bottle under the conditions of 60°C, 75%RH for 2 weeks, and the total analog of compound (A' ) in the preparations was quantified by high performance liquid
• Example 1 showed preservation stability superior to that of the preparation of Example 7. That is, it has been clarified that a preparation containing hydroxypropylcellulose is superior in the
• microcrystalline cellulose (6700 g) (manufactured by Asahi
• Kasei, CEOLUS PH-101) were measured and placed in a fluidized- bed dryer (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a 6 (w/w) % hydroxypropylcellulose (Nippon Soda Co., Ltd., grade L) solution (33500 g) .
• the granules were dried to give a granulated powder.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 21.6 ⁇ as measured by a laser
• diffraction particle size analyzer and according to a dry method.
• a part of the obtained granulated powder was crushed by a Power Mill grinding machine (P-7S, Showa Kagakukikai Co., Ltd.) using a 1.5 ⁇ punching screen to give a sieved powder.
• the sieved powder (57340 g) was measured, croscarmellose sodium (3050 g) (manufactured by FMC, Ac-Di-Sol) , and magnesium stearate (610 g) were added and they were mixed in a tumbler mixer (TM-400S, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-400S Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted at tableting pressure 6kN to give a tablet (long diameter 8 mmxshort diameter 4.5 mm, 100 mg per tablet) .
• OPADRY White 03F480011 (4850 g) (manufactured by COLORCON JAPAN; containing hypromellose 2910, macrogol 6000 and titanium oxide) was suspended in purified water (43650 g) to prepare a coating solution.
• a coating machine DRC-1200DS, POWREX CORPORATION
• the coating solution was sprayed on the tablets (55000 g) obtained above until the tablet weight increased by 5 mg per tablet, and a 5 (w/w) % macrogol 6000 solution (550 g) was further sprayed to give preparation 1A (film-coated tablet) .
• the composition of preparation 1A per tablet is shown in Table 16.
• Compound (A' ) (19320 g) , D-mannitol (34540 g) and microcrystalline cellulose (6650 g) (manufactured by Asahi Kasei, CEOLUS PH-101) were measured and placed in a fluidized- bed dryer (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a 6 (w/w) % hydroxypropylcellulose (Nippon Soda Co., Ltd., grade L) solution (33260 g) . The granules were dried to give a granulated powder.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 23.1 m as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained granulated powder was crushed by a Power Mill grinding machine (P-7S, Showa Kagakukikai Co., Ltd.) using a 1.5 mmcj) punching screen to give a sieved powder.
• the sieved powder (57580 g) was measured, croscarmellose sodium (3063 g) (manufactured by FMC, Ac-Di-Sol) , and magnesium stearate (612.5 g) were added and they were mixed in a tumbler mixer (TM-400S, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• a tumbler mixer TM-400S, Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted at tableting pressure 7kN to give a tablet (long diameter 10.5 mmxshort diameter 5.5 mm, 175 mg per tablet).
• OPADRY White 03F480011 3983 g (manufactured by COLORCON JAPAN; containing hypromellose 2910, macrogol 6000 and titanium oxide) was suspended in purified water (35400 g) to prepare a coating solution.
• a coating machine DRC-1200DS, POWREX CORPORATION
• the coating solution was sprayed on the tablets (55000 g) obtained above until the tablet weight increased by 9 mg per tablet, and a 5(w/w)% macrogol 6000 solution (522 g) was further sprayed to give preparation 2A (film-coated tablet) .
• the composition of preparation 2A per tablet is shown in Table 17.
• a part of the obtained granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm ⁇
• the sieved powder 3892 g was measured, mixed with macrocrystalline cellulose (460.0 g) (manufactured by Asahi Kasei, CEOLUS PH-101) ,
• croscarmellose sodium (207.0 g) (manufactured by FMC, Ac-Di- Sol), and magnesium stearate (41.40 g) in a tumbler mixer (TM- 1S, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM- 1S Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted to give a tablet (diameter 8.0 mm, 200 mg per tablet).
• Hypromellose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in purified water (1854 g) , and a dispersion of titanium oxide (28.80 g) (manufactured by Freund Corporation) , yellow ferric oxide
• preparation 3A increased by 8 mg per tablet to give preparation 3A.
• the composition of preparation 3A per tablet is shown in Table 18.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 um as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 ⁇ punching screen to give a sieved powder.
• the sieved powder 3892 g was measured, mixed with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei, CEOLUS PH-101), croscarmellose sodium (207.0 g) (manufactured by FMC, Ac-Di-Sol) , and
• Hypromellose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in purified water (1854 g) , and a dispersion of titanium oxide (28.80 g) (manufactured by Freund Corporation) , yellow ferric oxide
• preparation 4A increased by 8 mg per tablet to give preparation 4A.
• the composition of preparation 4A per tablet is shown in Table 19.
• microcrystalline cellulose (PH101) 36 .78
• microcrystalline cellulose 453.1 g (manufactured by Asahi Kasei, CEOLUS PH-101) were measured and placed in a fluidized- bed granulation dryer (FD-5S, POWREX CORPORATION), and the mixture was granulated while spraying a 6(w/w)%
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 ⁇ as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• the mixed powder was tableted to give a tablet (diameter 8.0 mm, 200 mg per tablet) .
• Hypromellose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in purified water (1854 g) , and a dispersion of titanium oxide (28.80 g) (manufactured by Freund Corporation) , yellow ferric oxide
• preparation 5A increased by 8 mg per tablet to give preparation 5A.
• the composition of preparation 5A per tablet is shown in Table 20.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 um as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm ⁇ t> punching screen to give a sieved powder.
• the sieved powder 3892 g was measured, mixed with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei, CEOLUS PH-101) , croscarmellose sodium (207.0 g) (manufactured by FMC, Ac-Di-Sol) , and
• Hypromellose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in purified water (1854 g) , and a dispersion of titanium oxide (28.80 g) (manufactured by Freund Corporation) , yellow ferric oxide
• preparation 6A increased by 8 mg per tablet to give preparation 6A.
• the composition of preparation 6A per tablet is shown in Table 21.
• microcrystalline cellulose 36.78
• mannitol (2123 g) (manufactured by Rocket Japan, D—mannitol)
• microcrystalline cellulose 453.1 g (manufactured by Asahi Kasei, CEOLUS PH-101) were measured and placed in a fluidized- bed granulation dryer ( FD-5S, POWREX CORPORATION), and the mixture was granulated while spraying a 6(w/w)%
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 ⁇ as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• the mixed powder was tableted to give a tablet (diameter 8.0 mm, 200 mg per tablet).
• Hypromellose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in purified water (1854 g) , and a dispersion of titanium oxide (28.80 g) (manufactured by Freund Corporation) , yellow ferric oxide
• preparation 7A increased by 8 mg per tablet to give preparation 7A.
• the composition of preparation 7A per tablet is shown in Table 22.
• microcrystalline cellulose 36.78
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 25.6 urn as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm(j) punching screen to give a sieved powder.
• the sieved powder 3892 g was measured, mixed with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei, CEOLUS PH-101) , croscarmellose sodium (207.0 g) (manufactured by FMC, Ac-Di-Sol) , and
• Hypromellose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in purified water (1854 g) , and a dispersion of titanium oxide (28.80 g) (manufactured by Freund Corporation) , yellow ferric oxide
• preparation 8A increased by 8 mg per tablet to give preparation 8A.
• the composition of preparation 8A per tablet is shown in Table 23.
• microcrystalline cellulose 500.2 g were cast into a
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa agakukikai Co., Ltd.) using a 1.5 ⁇ punching screen to give a sieved powder.
• the sieved powder (3995 g) was measured, and mixed with croscarmellose sodium (212.5 g) , and magnesium stearate (42.50 g) in a tumbler mixer (TM-15, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-15 Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted to give a tablet (long diameter 10.5 mmxshort diameter 5.5 mm, 175 mg per tablet) .
• JAPAN JAPAN was suspended in purified water (4860 g) to prepare a coating solution.
• a coating machine DRC-500, POWREX
• preparation 9A film-coated tablet
• Table 24 The composition of preparation 9A per tablet is shown in Table 24.
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 23.1 ⁇ as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• the mixed powder was tableted to give a tablet (long diameter 10.5 mmxshort diameter 5.5 mm, 175 mg per tablet) .
• OPADRY White 03F48001 540.0 g (manufactured by COLORCON JAPAN) was suspended in purified water (4860 g) to prepare a coating solution.
• a coating machine DRC-500, POWREX
• preparation 10A film-coated tablet
• Table 25 The composition of preparation 10A per tablet is shown in Table 25.
• microcrystalline cellulose 500.2 g were cast into a
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 33.4 urn as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa agakukikai Co., Ltd.) using a 1.5 ⁇ punching screen to give a sieved powder.
• the sieved powder (3995 g) was measured, and mixed with croscarmellose sodium (212.5 g) , and magnesium stearate (42.50 g) in a tumbler mixer (TM-15, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-15 Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted to give a tablet (long diameter 10.5 mmxshort diameter 5.5 mm, 175 mg per tablet) .
• JAPAN JAPAN was suspended in purified water (4860 g) to prepare a coating solution.
• a coating machine DRC-500, POWREX
• preparation 11A film-coated tablet
• Table 26 The composition of preparation 11A per tablet is shown in Table 26.
• microcrystalline cellulose 500.2 g were cast into a
• Compound (A' ) used here was a pulverized product by PINMILL, which had an average particle size of 42.5 um as measured by a laser diffraction particle size analyzer and according to a dry method. A part of the obtained
• granulated powder was crushed by a Power Mill grinding machine (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mnuj) punching screen to give a sieved powder.
• the sieved powder (3995 g) was measured, and mixed with croscarmellose sodium (212.5 g) , and magnesium stearate (42.50 g) in a tumbler mixer (TM-15, Showa Kagakukikai Co., Ltd.) to give a mixed powder.
• TM-15 Showa Kagakukikai Co., Ltd.
• the mixed powder was tableted to give a tablet (long diameter 10.5 mmxshort diameter 5.5 mm, 175 mg per tablet) . ⁇ . '
• OPADRY White 03F48001 540.0 g (manufactured by COLORCON JAPAN) was suspended in purified water (4860 g) to prepare a coating solution.
• a coating machine DRC-500, POWREX
• comparison preparation 1A film-coated tablet
• Table 27 The composition of comparison preparation 1A per tablet is shown in Table 27.
• the results are shown in Table 28.
• the respective values in the Table show the average of the dissolution ratio (%) of 6 film-coated tablets.
• Example 9A, 10A and 11A were superior to the preparation of Comparative Example 1A in the dissolution property of compound (A' ) . That is, it has been clarified that compound (A) or a salt thereof having an average particle size of less than 35 um (e.g., 14.3 - 33.4 ⁇ ) is superior in the dissolution property from a preparation.
• a solid preparation containing compound (A) or a salt thereof, metformin or. a salt thereof and crospovidone which is superior in the
• compound (A) or a salt thereof having superior dissolution property can be provided.

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