TW201408290A - Solid preparation - Google Patents

Abstract

The present invention provides solid preparation superior in disintegration property and preservation stability. The present invention relates to a solid preparation containing (1) compound (A) or a salt thereof, (2) metformin or a salt thereof, and (3) crospovidone. It also relates to compound (A) or a salt thereof superior in dissolution property.

Description

Solid preparation

The present invention relates to containing [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy a solid preparation of (2,3-dihydro-1-benzofuran-3-yl)acetic acid (in the present specification, sometimes simply referred to as "compound (A)") or a salt thereof and metformin or a salt thereof Further, the present invention relates to a compound (A) excellent in solubility or a salt thereof and the like.

The compound (A) is a compound represented by the following formula:

The compound (A) and its salt have been reported as a GPR40 receptor agonist, which can be used as an insulin secretagin or a preventive or therapeutic drug for diabetes (Patent Document 1).

However, a solid preparation containing the compound (A) or a salt thereof and metformin or a salt thereof has not been reported.

[document list] [Patent Document]

Patent Document 1: US-A-2010/0004312

The present inventors have studied a solid preparation containing the compound (A) or a salt thereof and metformin or a salt thereof; as a result, they have not been able to obtain a better disintegration property, and the disintegration between individual preparations is different. .

Further, the compound (A) or a salt thereof in a solid preparation sometimes has poor solubility.

The present inventors have conducted intensive studies to solve the above problems, and found that the solid preparation containing the compound (A) or a salt thereof, metformin or a salt thereof, and the crosslinked polyvinylpyrrolidone is excellent in disintegration property and disintegration between the respective preparations. The variation is small, and the solubility in the specific range of the average particle diameter of the compound (A) is excellent; the present invention has been completed by further research.

Accordingly, the present invention provides the following: [1] A solid preparation comprising (1) [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonate) Propyl]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid or a salt thereof, (2) metformin or a salt thereof, and 3) a crosslinked polyvinylpyrrolidone (hereinafter sometimes referred to as a solid preparation of the present invention); [2] The solid preparation of the above [1], wherein the metformin or a salt thereof is metformin [3] The solid preparation of the above [1] or [2], further comprising hydroxypropylcellulose; [4] the solid preparation of the above [1], [2] or [3], further comprising micro Crystalline cellulose and magnesium stearate; [5][(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl 3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid or a salt thereof, having an average particle diameter of less than 35 μm; [6] a solid preparation comprising the above [ 5][(3S)-6-({2',6'-Dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy) -2,3-dihydro-1-benzofuran-3-yl]acetic acid or a salt thereof; [1-1] an enhancement comprising (1)[(3S)-6-({2',6'-di Methyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid Or a salt thereof, and (2) a method for disintegrating a solid preparation of metformin or a salt thereof, the method comprising adding a crosslinked polyvinylpyrrolidone to the solid preparation; [1-2] an improvement comprising (1) [( 3S)-6-({2',6'-Dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3- Dihydro-1-benzofuran-3-yl]acetic acid or a salt thereof, And (2) a method for changing the disintegration of a solid preparation of metformin or a salt thereof, the method comprising adding a crosslinked polyvinylpyrrolidone to the solid preparation; [1-3] an enhancement comprising (1) [(3S) -6-({2',6'-Dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro 1-benzofuran-3-yl]acetic acid or a salt thereof, (2) metformin or a salt thereof, and (3) A method for preserving stability of a solid preparation of crosslinked polyvinylpyrrolidone, which comprises adding hydroxypropylcellulose to the solid preparation; [1-4] a solid preparation comprising (1) [(3S) -6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-di Hydrogen-1-benzofuran-3-yl]acetic acid or a salt thereof, and (2) hydroxypropylcellulose.

The solid preparation of the present invention is used as a therapeutic drug for diabetes and the like, and is excellent in disintegration property; the disintegration change of each preparation is small. Further, the solid preparation of the present invention further containing hydroxypropylcellulose is excellent in storage stability. Specifically, the production of the active ingredient (particularly, the compound (A)) decomposition product or the like in the solid preparation is inhibited during the steps of the preparation process and the long-term (for example, 2 weeks) preservation process.

Further, according to the present invention, the solubility of the solid preparation containing the compound (A) or a salt thereof can be improved, and the amount of the active ingredient absorbed in the body can be increased, thereby improving the efficacy.

[Detailed Description of the Invention]

The invention is described in detail below.

The compound (A) or a salt thereof can be produced by a known method, for example, the method described in WO2008/001931 or the like.

Examples of the salt of the compound (A) include pharmacologically acceptable salts, for example, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

Preferable examples of the salt with an inorganic acid include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

Preferred examples of the salt with an organic acid include benzoic acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, and a salt formed of a sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.

Preferred examples of the salt with a basic amino acid include salts formed with arginine, lysine, ornithic acid; and preferred examples of the salt with an acidic amino acid include aspartame A salt formed by an acid, glutamic acid or the like.

The compound (A) or a salt thereof is preferably a free compound (A).

The compound (A) may be a solvate (for example, a hydrate) or an unsolvate (for example, a non-hydrate).

The compound (A) is preferably a hydrate, more preferably 0.5 hydrate.

The compound (A) can be labeled with an isotope (for example, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I) or the like.

Further, a ruthenium conversion compound in which ¹ H has been converted to ² H (D) is also encompassed in the compound (A).

The average particle diameter of the compound (A) or a salt thereof is preferably from about 5 to about 45 μm, more preferably from about 10 to about 40 μm, particularly preferably from about 15 to about 35. Mm. Such an average particle diameter provides a solid preparation excellent in solubility of the compound (A) or a salt thereof.

The average particle diameter of the compound (A) or a salt thereof is less than 35 μm, preferably less than 30 μm. However, the lower limit of the above average particle diameter is not particularly limited as long as it does not affect manufacturability; preferably not less than about 1 μm, more preferably not less than about 5 μm, and particularly preferably not less than about 10 μm. By using such an average particle diameter, the solid preparation containing the compound (A) or a salt thereof exhibits excellent solubility.

The above preferred average particle size is suitable for use in the manufacture of the solid state of the invention The preparation (containing the pulverized product obtained by grinding in the process of producing a solid preparation, and the mixed pulverized product obtained by grinding together with an excipient or the like) is used as the starting compound (A). In other words, the average particle diameter of the compound (A) may be different depending on the coagulation of the compound (A) or the like during the production of the solid preparation of the present invention or during the preservation of the solid preparation after the production.

In the present specification, the average particle size means that the particles are by weight. The distribution or quantity distribution (preferably the number distribution) is divided into 50% of the particle size of each of the coarse particles and the fine particles. The average particle diameter can be measured using a known measuring device such as a laser light diffraction particle distributing device (for example, HELOS & RODOS (trade name) (manufactured by SYMPATEC)) or the like.

When necessary, the compound (A) having a desired average particle diameter can also be produced by grinding a compound (A) having a large average particle diameter together with an excipient such as microcrystalline cellulose or the like. Here, the grinding is carried out according to a known method using, for example, a cutter mill, a hammer mill, a jet mill or the like.

In particular, the use of weak bonding force and large average particle size When the compound (A) is used to produce a solid preparation, it is necessary to strive to achieve a sufficient hardness of the preparation, for example, using a large amount of additives (for example, a binder, etc.). When the average particle diameter of the compound (A) becomes small, it is not necessary to use a large amount of additives (for example, a binder or the like), and the drug content in the solid preparation can be increased.

The compound (A) having the above average particle diameter is preferably preferred It is shown that "the particles of 0.1 μm or less are not more than 10% of the total amount, and the particles of 1000 μm or more of the particles are not more than 10% of the total amount", wherein the dispersibility is preferably the distribution of the particles by using laser light. The device takes measurements.

In the solid preparation of the present invention, the compound (A) or a salt thereof The content is usually from 0.5 to 90% by weight, preferably from 1 to 30% by weight, more preferably from 1 to 20% by weight, particularly preferably from 1 to 10% by weight.

The solid preparation of the present invention contains metformin or a salt thereof.

In the solid preparation of the present invention, metformin or a salt thereof is preferably metformin hydrochloride.

In the solid preparation of the present invention, the content of metformin or a salt thereof is usually from 50 to 95% by weight, preferably from 55 to 90% by weight, more preferably from 60 to 85% by weight, particularly preferably from 60 to 80% by weight.

The present invention contains a solid preparation of crosslinked polyvinylpyrrolidone.

In the solid preparation of the present invention, the content of the crosslinked polyvinylpyrrolidone is usually from 0.5 to 20% by weight, preferably from 1 to 15% by weight, more preferably from 1 to 10% by weight.

In addition to the above ingredients, the solid preparation of the present invention may contain A pharmaceutically acceptable carrier as long as it does not inhibit the efficacy of the present invention. As the pharmaceutically acceptable carrier in the present specification, various organic or inorganic carrier materials conventionally used as a preparation material can be used; they may be added in an appropriate amount, for example, an excipient, a binder, a glidant, and a lubricant. A agent, a colorant, a pH adjuster, a surfactant, a stabilizer, an acidulant, a flavoring agent, a coating agent or a coating additive are appropriately added.

Examples of excipients include microcrystalline cellulose and sugar alcohols. Such as D-mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, etc.; sugars such as lactose, sucrose, glucose, maltose, etc.; starches such as corn starch, potato starch, wheat starch, Rice starch, partially pre-gelatinized starch, pre-gelatinized starch, porous starch, etc.; light anhydrous citric acid, dextrin, carboxymethyl starch, gelatin, magnesium oxide, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate and sulfuric acid Calcium; better with microcrystalline cellulose.

In the solid preparation of the present invention, the content of the excipient is preferably It is from 1 to 90% by weight, more preferably from 2 to 80% by weight.

Adhesives only need to be dry or wet granulation and direct pressure An additive capable of binding particles during the ingot may be mentioned, for example, hydroxypropylcellulose [for example, grade: L, SL, SSL (trade name); Nippon Soda Co., Ltd.], hydroxypropyl group Hypromellose [for example, hydroxypropylmethylcellulose 2910, TC-5 (grade: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.] , polyvinylpyrrolidone (povidone), copolyvidone, etc.; preferably hydroxypropylcellulose.

In the solid preparation of the present invention, the content of the binder is preferably It is from 0.5 to 15% by weight, more preferably from 1 to 10% by weight.

Examples of glidants include talc, light anhydrous citric acid, hydrated cerium oxide and aluminum magnesium metasilicate.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid, talc, wax, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol 6000 and light Anhydrous citric acid; preferably magnesium stearate.

Preferred examples of the coloring agent include food coloring such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2, etc.; food aluminum lake coloring material, red iron oxide, yellow oxide Iron and so on.

Preferable examples of the pH adjuster include citric acid or a salt thereof, phosphoric acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, fumaric acid or a salt thereof, acetic acid or a salt thereof, amino acid or a salt thereof, and the like .

Preferred examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) diol, and the like.

Preferred examples of the stabilizer include succinic acid, tartaric acid, citric acid, lactic acid, fumaric acid, malic acid, ascorbic acid, acetic acid, acidic amino acid (for example, glutamic acid, aspartic acid), and the like. Inorganic salts (for example, alkali metal salts, alkaline earth metal salts), salts of such acids with inorganic bases (for example, ammonium), salts of such acids with organic bases (for example, meglumine), A salt formed by an acid and a basic amino acid (for example, arginine, lysine, or alginate), a hydrate thereof, a solvate thereof, or the like.

Preferred examples of the acidifying agent include ascorbic acid, citric acid, tartaric acid, malic acid and the like.

Preferred examples of the flavor include menthol, peppermint oil, lemon oil, vanilla extract and the like.

Preferable examples of the coating agent include a sugar coating agent, an aqueous film coating agent, an enteric film coating agent, a sustained release film coating agent, and the like.

As the sugar coating agent, for example, purified sucrose may be mentioned, and one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, and the like may be used in combination.

Examples of the aqueous film coating agent include cellulosic polymers such as hydroxypropylcellulose [for example, grade: L, SL, SSL (trade name); Nippon Soda Co., Ltd.], hydroxypropylmethylcellulose [e.g. , hydroxypropyl methylcellulose 2910, TC-5 (grade: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.], hydroxyethyl cellulose, methyl Hydroxyethyl cellulose or the like; synthetic polymer such as polyvinyl acetal diethylamine acetate, amine alkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, etc.; A saccharide such as amylopectin or the like.

Examples of the enteric film-coating agent include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and phthalic acid acetate fibers. Acrylic polymer such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trademark) Name)]; etc.; naturally occurring substances such as shellac.

Examples of the sustained-release film coating agent include cellulose polymers such as ethyl cellulose and the like; acrylic polymers such as aminoalkyl methacrylate Ester copolymer RS [Eudragit RS (trade name)], ethyl acrylate. Methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like.

Preferred examples of coating additives include, for example, opacifiers For example, titanium oxide or the like; a flow aid such as talc; a coloring agent such as red iron oxide, yellow iron oxide, etc.; a plasticizer such as polyethylene glycol 6000, triethyl citrate, castor oil, polysorbate, and the like; Organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid, and the like.

The above additives may be in an appropriate ratio of two or more mixture.

The solid preparation of the present invention preferably further comprises a hydroxypropyl group Cellulose to enhance the storage stability of the formulation.

Herein, improving the storage stability of the solid preparation means that For example, when the solid preparation is preserved for a long period of time (for example, 2 weeks), the production of the active ingredient (particularly, the compound (A)) decomposition product or the like in the preparation is inhibited; wherein the storage condition may be a severe condition (40 ° C) , 75% RH).

Regarding hydroxypropyl cellulose, for example, commercially available The following levels are available: L, SL, SSL, and SSL is preferred.

When the solid preparation of the present invention contains hydroxypropylcellulose, In the solid preparation, the content of the hydroxypropylcellulose is usually from 1 to 30% by weight, preferably from 2 to 25% by weight, more preferably from 3 to 20% by weight, particularly preferably from 3 to 10% by weight.

The solid preparation of the present invention preferably further contains microcrystalline fibers Vitamins are optimized for the physicochemical properties of the formulation (eg, manufacturability, tablet disintegration, tablet hardness).

When the solid preparation of the present invention contains microcrystalline cellulose, In the solid preparation, the content of the microcrystalline cellulose is usually from 1 to 30% by weight, preferably from 2 to 25% by weight, more preferably from 3 to 20% by weight.

The solid preparation of the present invention may further contain magnesium stearate, The physicochemical properties of the formulation (e.g., manufacturability, tablet disintegration, tablet hardness) are optimized.

When the solid preparation of the present invention contains magnesium stearate, it is solid The content of magnesium stearate in the preparation is usually from 0.01 to 10% by weight, preferably from 0.1 to 5% by weight, more preferably from 0.15 to 2% by weight.

The solid preparation of the present invention is preferably the following preparation.

[Solid preparation 1]

Solid preparation containing the following (1) to (6)

(1) Compound (A) or a salt thereof, (2) metformin or a salt thereof, (3) crosslinked polyvinylpyrrolidone, (4) an excipient (preferably, microcrystalline cellulose), (5) a binder A solid preparation of (preferably, hydroxypropylcellulose) and (6) a lubricant (preferably, magnesium stearate).

[Solid preparation 2]

Solid preparation containing the following (1) to (6)

(1) Compound (A) or a salt thereof, (2) metformin or a salt thereof, (3) crosslinked polyvinylpyrrolidone, (4) microcrystalline cellulose, (5) hydroxypropylcellulose, and (6) Magnesium stearate.

The content of the components of the solid preparation of the present invention is preferably the following amount; however, it is also possible to contain components other than the following components.

(1) Compound (A) or a salt thereof: 1 to 10% by weight

(2) metformin or its salt: 60 to 80% by weight

(3) Crosslinked polyvinylpyrrolidone: 1 to 10% by weight

(4) Microcrystalline cellulose: 3 to 20% by weight

(5) Hydroxypropyl cellulose: 3 to 10% by weight

(6) Magnesium stearate: 0.15 to 2 wt%

The content of the components of the solid preparation of the present invention is more preferably the following amount; however, it may also contain components other than the following ingredients.

(1) Compound (A) or a salt thereof: 1 to 5 wt%

(2) metformin or its salt: 70 to 80% by weight

(3) Crosslinked polyvinylpyrrolidone: 1 to 5 wt%

(4) Microcrystalline cellulose: 5 to 15% by weight

(5) Hydroxypropyl cellulose: 3 to 10% by weight

(6) Magnesium stearate: 0.15 to 2 wt%

Examples of the dosage form of the solid preparation of the present invention include granules, lozenges (for example, uncoated tablets, film-coated tablets) and the like; and among them, tablets are preferred.

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 an appropriate combination such as granulation, mixing, tableting (compression molding), coating, and the like.

As the granulation, for example, a granulation machine such as an agitating granulator, a fluidized bed granulator, a dry granulation machine or the like is used.

As for the mixing, for example, a mixer such as a V-type mixer, a drum type mixer or the like is used.

The ingot (compression molding) is usually carried out at a pressure of 0.3 to 35 kN/cm ² by using, for example, a single punch press, a rotary press, or the like.

The coating is used, for example, a film coating device, together with the aforementioned coating agent and coating additive.

The solid preparation of the present invention is preferably a coated film for the purpose of promoting ease of administration, strength of preparation, and the like.

Preferred examples of the coating agent and the coating additive for the coating film include those similar to those used for the aforementioned additives.

When the film is applied to the solid preparation of the present invention, the coating layer may be usually formed in an amount of from 1 to 10 parts by weight, preferably from 2 to 6 parts by weight, per 100 parts by weight of the solid preparation.

Specifically, the solid preparation of the present invention can be produced according to the following production steps. The amount of each starting material used in the following manufacturing steps is used to bring each of the finally obtained solid preparations to the aforementioned levels.

In a suitable mixer, the compound (A) or a salt thereof and metformin or a salt thereof are mixed with other additives (for example, an excipient, a binder, a disintegrating agent) as needed; and the mixture uses a binder (for example, hydroxypropyl group). An aqueous solution of cellulose or the like is granulated and sieved as necessary. Adding crosslinked polyvinylpyrrolidone, a lubricant (for example, magnesium stearate, etc.) and/or He is additive, molded into this mixture, and dried as needed to obtain a solid preparation of the present invention. Further, if necessary, the film coating solution is sprayed to obtain a film-coated tablet. Mixing and granulation can be carried out, for example, using a fluidized bed dryer granulator or the like. Molding can be carried out by using, for example, a rotary tablet press.

The film-coated tablet can be used, for example, by spraying a film coating agent using a film coater or the like (for example, a film substrate such as hydroxypropylmethylcellulose 2910 or the like; a plasticizer such as polyethylene glycol 6000; An aqueous solution of a mixture of a coloring agent such as titanium oxide, red iron oxide, yellow iron oxide or the like is applied to the uncoated tablet obtained by the above method.

The solid preparation of the present invention is preferably produced by a fluidized bed granulation method. Solid preparations, particularly tablets, produced by a fluid bed granulation process exhibit significant benefits of the present invention.

The solid preparation of the present invention is preferably a tablet containing a granule (for example, a granule obtained by the above granulation), wherein the granule is preferably contained in an amount of 70 to 100% by weight, more preferably 85 to 98% by weight, further preferably It is 80 to 95% by weight.

The term "granules" as used herein means particles having almost the same size and shape, which are subjected to wet granulation, dry granulation, heated granulation, etc. (preferably, dry granulation), and will be powdered. The starting materials of the form, block, solution, molten liquid and the like are prepared by plasmidization.

The granules usually have not more than 20% not less than 1000 μm, not more than 65% not more than 150 μm (using a 16M sieve, remaining on the sieve: not more than 20%; using a 100M sieve, passing through the sieve: not exceeding 65%) ), preferably not more than 5% not less than 1000 μm, not more than 55% not more than 150 μm (using 16M sieve, remaining on the sieve: not more than 5%; use 100M screen, through the screen: no more than 55%) of the particle size. Here, the particle size is, for example, a value obtained by measuring the weight of the granules remaining on the standard sieve after passing through the sieve.

For compounding (eg, tableting step) to obtain the solid state of the present invention The granules can be of different sizes and shapes during the preparation process.

The weight of the solid preparation of the present invention (for example, each lozenge The weight) is usually from 50 to 2000 mg, preferably from 70 to 1800 mg, more preferably from 80 to 1500 mg.

The solid preparation of the invention has excellent work as a medicament Effective, showing low toxicity and less side effects, in mammals (eg, humans, cows, horses, pigs, dogs, cats, monkeys, mice, rats, especially humans) can be used for prevention or treatment, for example, diabetes [For example, type 1 diabetes, type 2 diabetes, type 1.5 diabetes (LADA (latent adult autoimmune diabetes)), gestational diabetes, diabetes with impaired insulin secretion, obese diabetes, IGT (glycemic tolerance), IFG (fasting glucose abnormality), IFG (fasting blood glucose abnormality), diabetes complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disease, arteriosclerosis, bone deficiency, diabetes, high osmotic coma, infection (eg, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower amine infection), diabetic gangrene, dry mouth, hearing loss, cerebrovascular disease, peripheral blood circulation disorders, etc.], obesity, hyperlipemia Symptoms (eg, hypertriglyceridemia, hypercholesterolemia, intrahepatic HDL deficiency, postprandial hyperlipidemia), arteriosclerosis (eg, atherosclerosis), Hypertension, myocardial infarction, angina pectoris, cerebrovascular disease (eg, cerebral infarction, cerebral hemorrhage), insulin resistance syndrome, X syndrome, metabolic syndrome, etc.

In addition, the solid preparation of the present invention can also be used in the above various Secondary prevention of disease (eg, secondary prevention of cardiovascular conditions such as myocardial infarction, etc.) or inhibition of progression of various diseases described above [eg, progression from poor glucose tolerance to inhibition of diabetes; progression from diabetes to complications of diabetes ( Preferably, it is inhibition of diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, arteriosclerosis].

The solid preparation of the invention can be safely orally administered to the mammal Things.

The dosage of the solid preparation of the invention only needs to contain an effective amount The compound (A) or a salt thereof which is a pharmaceutically active ingredient. For example, when administered to an adult (weight: 60 kg), the effective amount is usually from 1 mg to 500 mg, preferably from 1 mg to 400 mg, more preferably from 10 mg to 250 mg, based on the free compound (A) (anhydrous). It is preferably 10 mg to 200 mg (further more preferably 12.5 mg, 25 mg, 50 mg, 100 mg) once a day.

The dose of the solid preparation of the present invention is only required to contain an effective amount of metformin or a salt thereof as a pharmaceutically active ingredient. For example, when administered to an adult (weight 60 kg), the effective amount is usually 300 mg to 2000 mg, preferably 400 mg to 1500 mg, more preferably 500 to 1000 mg (more preferably 500 mg, 850 mg, 1000 mg, based on the hydrochloride salt). ),Once a day.

The size of the solid preparation of the present invention depends on the shape of the solid preparation (round Shape, oval coated ingot, oval, etc.).

Particularly preferred examples of the solid preparation of the present invention include "Each tablet contains 12.5 mg of compound (A) or its salt in terms of free form (anhydrous) and 500 mg of a solid preparation of metformin or a salt thereof as a hydrochloride salt; "" each tablet contains 12.5 mg of the compound (A) or a salt thereof (anhydrous) and a hydrochloride salt in terms of a free form a solid preparation of 850 mg of metformin or a salt thereof; "each tablet contains 12.5 mg of the compound (A) or a salt thereof (anhydrous) and, based on the hydrochloride, 1000 mg of metformin or "solid preparation of salt"; "each tablet contains 25 mg of compound (A) or its salt (anhydrous) and a solid preparation of 500 mg of metformin or its salt in terms of free form"; a tablet containing 25 mg of the compound (A) or a salt thereof (anhydrous) and a solid preparation of 850 mg of metformin or a salt thereof based on the free form; "each tablet contains a free form a solid preparation of 25 mg of the compound (A) or a salt thereof (anhydrous) and 1000 mg of metformin or a salt thereof as a hydrochloride; "each tablet contains 50 mg of the compound (A) in terms of a free form or a salt (anhydrous) and a solid preparation of 500 mg of metformin or a salt thereof as a hydrochloride; "each tablet contains a free form, 50 mg of the compound (A) or a salt thereof (anhydrous) and a solid preparation of 850 mg of metformin or a salt thereof as a hydrochloride; "each tablet contains 50 mg of the compound in terms of a free form ( A) or its salt (none a solid preparation of 1000 mg of metformin or a salt thereof in terms of hydrochloride; "each tablet contains 100 mg of the compound (A) or a salt thereof (anhydrous) and hydrochloride as a free form. a solid preparation of 500 mg of metformin or a salt thereof; "each tablet contains 100 mg of the compound (A) or a salt thereof (anhydrous) and 850 mg of metformin or a salt thereof based on the free form, based on the free form. The solid preparation ";" each tablet contains 100 mg of the compound (A) or a salt thereof (anhydrous) and a solid preparation of 1000 mg of metformin or a salt thereof based on the free form.

The solid preparation of the present invention can be used in combination with one or more other kinds of agents (hereinafter sometimes abbreviated as "concomitant drugs").

Specific examples of the concomitant drug include one or more agents selected from the group consisting of a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipemia, a blood pressure lowering agent, a slimming agent, a diuretic, an antithrombotic agent, and the like.

Examples of therapeutic agents for diabetes include insulin preparations [for example, animal insulin preparations extracted from bovine and porcine pancreas, human insulin preparations synthesized using genetic engineering techniques using Escherichia coli (E, coli) or yeast, zinc insulin; protamine zinc Insulin, insulin fragment or derivative (eg, INS-1), oral insulin preparation]; insulin sensitizer [eg, pioglitazone or its salt (preferably hydrochloride), Lossilita Rosiglitazone or its salt (preferably maleate), metaglidasen, AMG-131, balaglitazone, MBX-2044, Livry Tazon ( Rivoglitazone), aleglitazar, chiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, see WO2007/013694 , compounds of WO2007/018314, WO2008/093639 or WO2008/099794]; alpha-glucosidase inhibitors [eg, voglibose, acarbose, miglitol, emili (emiglitate); insulin secretagogue [sulfonylurea (eg, tolbutamide) , glibenclamide, gliclazide, chlorpropamide, methanesulfonamide Tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole, etc., rapali Repaglinide, nateglinide, mitiglinide or its calcium salt hydrate], dipeptidyl peptidase IV inhibitor [eg, alogliptin or a salt thereof) (preferably benzoate), trelagliptin or a salt thereof (preferably succinate), vildagliptin, sitagliptin, sacha Sigmaxliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104]; β 3 agonist (for example, N-5984); GLP-1 receptor agonist [eg, GLP-1, GLP-1 MR preparation, liraglutide, exenatide, AVE-0010, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131, albiglutide]; amyloid agonist [eg, pramlintide]; phosphoric acid Tyrosine phosphatase inhibitor (eg, sodium vanadate); Inhibitors of glycogen production (eg, hepatic glycophospholytic enzyme inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, FBPase inhibitors); SGLT2 (sodium-glucose co-transporter 2) inhibitors [eg, depagliflozin, AVE2268, TS-033, YM543, TA-7284, remogliflozin, ASP1941]; SGLT1 inhibitor; 11 beta-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498, INCB-13739); adiponectin or its agonist; IKK inhibitor (eg, AS-2868); leptin resistance improving drug; somatostatin Receptor agonists; glucokinase activators [eg, piragliatin, AZD1656, AZD6370, TTP-355, described in WO2006/112549, WO2007/028135, WO2008/047821, WO2008/050821, WO2008 /136428 or a compound of WO2008/156757]; GIP (glucose-dependent insulin secretagogue); GPR119 agonist (eg, PSN821); FGF21, FGF analog, and the like.

Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors [eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT- 112, ranirestat (AS-3201), lidorestat (lidorestat); neurotrophic factors and their increasing drugs [eg, NGF, NT-3, BDNF, neurotrophins described in WO 01/14372 Manufacturing/secretion promoter (for example, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl] Oxazole), a compound described in WO2004/039365]; a PKC inhibitor [eg, ruboxistaurin mesylate]; an AGE inhibitor [eg, ALT946, N-benzoquinone methylthiazolium bromide ( ALT-766), EXO-226, pyridorin, pyridoxamine]; GABA receptor agonist [eg gabapentin, pregabalin]; serotonin norepinephrine Absorption inhibitors [eg, duloxetine]; sodium channel inhibitors [eg, lacosamide], reactive oxygen scavengers (eg, lipoic acid); cerebral vasodilators [eg, Taipu Tiapride, mexiletine]; somatostatin receptor agonist (eg, BIM23190); apoptosis signal-regulated kinase-1 (ASK-1) inhibitor, and the like.

Examples of therapeutic agents for hyperlipidemia include HMG-CoA reductase inhibitors [eg, pravastatin, simvastatin, lovastatin, atorvastatin, blessing) Fluvastatin, rosuvastatin, pitavastatin or a salt thereof (eg, sodium salt, calcium salt); squalene synthetase inhibitor (for example, as described in WO97/ a compound of 10224, for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxy) Phenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzo Indomethacin-3-yl]ethinyl]piperidine-4-acetic acid); a fibrate compound [eg, bezafibrate, clofibrate, octane fiber) Acidate (simfibrate), clinofibrate]; anion exchange resin [eg, colestyramine]; probucol; nicotinic acid drug [eg, nicom ( Nicomol), niceritrol, niaspan; decyl pentenoate; phytosterols (eg, soy sterol, γ-glutenol); cholesterol absorption inhibitors [ For example, Zetia]; CETP inhibitors [eg, dalcetrapib, anacetrapib]; omega-3 fatty acid preparations (eg, omega-3-acid ethyl esters 90) )Wait.

Examples of hypotensive agents include angiotensin converting enzyme inhibitors Formulations [eg, captopril, enalapril, deLapril, etc.]; angiotensin II antagonists [eg, candesartan cilexetil, Ken Destantan, losartan, losartan, eprosartan, valsartan, telmisartan, irbesartan , tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil, etc.; calcium antagonists [eg , manidipine, nifedipine, amlodipine, efenidipine, nicardipine, cilnidipine, etc. Beta blockers [eg, metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.] ; clonidine and the like.

Examples of slimming agents include monoamine absorption inhibitors [eg, Phentermine, sibutramine, mazindol, fluoxetine, tesofensine; serotonin 2C receptor agonist [eg, Luo Karslin (lorcaserin); serotonin 6 receptor antagonist; histamine H3 receptor antagonist; GABA modulator [eg, topiramate]; neuropeptide Y antagonist [eg, dimension Velneperit]; cannabinoid receptor antagonists [eg, rimonabant, taranabant]; brain gut peptide antagonist; brain gut peptide receptor antagonist; brain intestine Peptidase inhibitors; opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists; melanocortin 4 receptor agonists; 11 beta-hydroxysteroid dehydrogenase inhibition Agent (eg, AZD-4017); pancreatic lipase inhibitor [eg, orlistat, cetialat]; beta 3 agonist (eg, N-5984); dimercaptoglycerol Base transferase 1 (DGAT1) inhibitor; acetyl CoA carboxylase (ACC) inhibitor; stearyl-CoA desaturase inhibitor; microsomal triglyceride transporter inhibitor (eg, R-256918) Sodium-glucose co-transporter inhibitors (eg, JNJ-28431754, Rimogliflozin); NF κ B inhibitors (eg, HE-3286); PPAR agonists (eg, GFT-505, DRF-11605) Phosphotyrosine phosphatase inhibitor [eg, sodium vanadate, Trodusquemin]; GPR119 agonist (eg, PSN-821); glucokinase activator (eg, AZD-165) 6); leptin, leptin derivatives [eg, metrepeptin]; CNTF (ciliated neurotrophic factor); BDNF (brain-derived neurotrophic factor); cholecystokinin agonist; a peptide peptide-1 (GLP-1) preparation [eg, an animal GLP-1 preparation extracted from bovine or porcine pancreas, a human GLP-1 preparation synthesized using genetic engineering techniques using E. coli or yeast, a GLP-1 fragment or Derivatives (eg, exenatide, liraglutide); pancreatic amyloid preparations (eg, pramlamine, AC-2307); neuropeptide Y agonists [eg, PYY3-36, PYY3- 36 derivatives, obineptide, TM-30339, TM-30335]; acid-regulating agent preparation: FGF21 preparation (for example, an animal extracted from bovine or porcine pancreas) FGF21 preparation, human FGF21 preparation synthesized by genetic engineering techniques using Escherichia coli or yeast, FGF21 fragment or derivative); appetite reducing agent (for example, P-57) and the like.

Examples of diuretics include xanthine derivatives (for example, theobromine sodium, theobromine calcium citrate); (thiazide) preparation (eg, ethyl thiazide) Cyclopentathiophene Trichloromethylthiazide Dihydrochlorothiazide Hydrofluorothiazide Benzyldihydrochlorothiazide Pentafluorothiazide Polythiazide Methiophene An anti-aldosterone preparation (for example, spironolactone, triamine); a carbonic acid dehydratase inhibitor (for example, acetazolamide); a chlorobenzenesulfonamide preparation [eg, chlorthalidone, Mefruside, indapamide; azosemide, isosorbide, etacrynic acid, pitetanide, butyl phenoxy Bumetanide, furosemide, and the like.

Examples of antithrombotic agents include heparin [eg, heparin sodium, Heparin calcium, enoxaparin sodium, dalteparin sodium; warfarin (eg, warfarin potassium); antithrombin drugs [eg, argatroban, Dabigatran]; FXa inhibitors [eg, rivaroxaban, apixaban, edoxaban, YM150, see WO02/06234, WO2004/ 048363, WO2005/030740, WO2005/058823 or a compound of WO2005/113504]; thrombolytic agents [eg, urokinase, tisokinase, alteplase, nateplase, Mongolian Terpplase, pamiteplase]; platelet aggregation inhibitors [eg, ticlopidine) Hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentaenoate, beraprost sodium, sapo Acid ester (sarpogrelate) hydrochloride, etc.

Among the above concomitant drugs, an insulin sensitizer (preferably Piolitas hydrochloride, insulin preparation, α-glucosidase inhibitor (preferably Peixin, acarbose), sulfonylurea (preferably Ammann), dipeptidyl peptide An enzyme IV inhibitor (preferably, alogliptin benzoate) or the like is preferred.

When the solid preparation of the present invention is used in combination with a concomitant drug At the time of administration, there is no limitation on the administration time, and the administration can be carried out simultaneously or staggered.

In addition, the solid preparation of the present invention and accompanying drugs can be presented as a single The single preparation is administered to a subject to be administered, or may be administered to a subject to be administered in a single preparation containing the solid preparation of the present invention and the concomitant drug.

The dose of the concomitant drug can be used according to the clinical use of each drug. The dose is appropriately determined. Further, the mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately determined depending on the administration target, administration route, target disease, symptom, combination, and the like. For example, when the subject to be administered is a human, the amount of the concomitant drug used may be 0.01 to 100 parts by weight per 1 part by weight of the solid preparation of the present invention.

Using the companion drug system in this way provides the following excellent work Effect: for example, 1) enhancing the effect selected from the compound (A) or a salt thereof, metformin or a salt thereof, the action of one or more agents accompanying the drug (the synergistic effect of the action of the agent), 2) the decrease selected from the compound (A) or Its salt, metformin or its salt, The efficacy of one or more doses of the concomitant drug (the efficacy of the dose reduction compared to the single drug administration), 3) the reduction from the compound (A) or a salt thereof, metformin or a salt thereof, and one of the concomitant drugs Or the efficacy of multiple side effects of the drug.

The present invention also provides an improvement (reduction) of containing compound (A) or A method of changing the disintegration of a salt, a solid preparation with metformin or a salt thereof, the method comprising adding a crosslinked polyvinylpyrrolidone to a solid preparation. This 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 amount of the crosslinked polyvinylpyrrolidone added is the same as the amount of the crosslinked polyvinylpyrrolidone of the solid preparation of the present invention. The change in disintegration means, for example, a change in the disintegration of each tablet shown in the following experimental examples.

Specifically, the change in the disintegration property of the solid preparation of the present invention means the variation in the breakage time according to the Japanese Pharmacopoeia disintegration test method, that is, the standard deviation of the disintegration time when the multi-disintegration test is performed. For example, the standard deviation of the disintegration time according to the disintegration test method [test liquid is water, no disc) is preferably within 0.3 minutes.

The invention also provides a compound having an average particle diameter of less than 35 μm. (A) or a salt thereof, and a (solid) preparation containing a compound (A) having an average particle diameter of less than 35 μm or a salt thereof; the (solid) preparation can be produced in the same manner as the solid preparation of the present invention, and can be used for treating diabetes Wait.

Further, the (solid) preparation may further contain metformin or a salt thereof (preferably metformin hydrochloride). In another embodiment, the (solid) preparation may further comprise alogliptin or a salt thereof (preferably alogliptin benzoate).

Poor solubility will reduce the amount of active ingredient absorbed into the body and reduce its efficacy.

The compound (A) or a salt thereof can be obtained by setting the average particle diameter of the compound (A) or a salt thereof to be from about 5 to about 45 μm, preferably from about 10 to about 40 μm, more preferably from about 15 to about 35 μm. Excellent solubility (solid) formulation.

By setting the average particle diameter of the compound (A) or a salt thereof to be less than 35 μm, preferably less than 30 μm, a (solid) preparation which exhibits excellent solubility of the compound (A) or a salt thereof can be obtained. The lower limit of the average particle diameter is not particularly limited as long as it does not affect the manufacturability, and is preferably not less than about 1 μm, more preferably not less than about 5 μm, and particularly preferably not less than about 10 μm.

The invention also provides a compound (A) or a salt thereof and hydroxypropyl A formulation of a base cellulose; this 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.

As shown in the experimental examples below, a mixture of the compound (A) and a salt thereof and polyvinylpyrrolidone (PVP) produces many analogs. However, a mixture containing hydroxypropylcellulose in place of PVP inhibits the production of analogs.

Therefore, the solid preparation containing the compound (A) or a salt thereof and hydroxypropylcellulose can inhibit the production of the analog as compared with the use of other binders (for example, PVP, hydroxypropylmethylcellulose, etc.).

Example

The invention is described in detail below with reference to the examples, comparative examples, and experimental examples, which are not intended to be limiting.

For the following examples, comparative examples, and additives for the pharmaceutical preparations in the experimental examples, the Japanese Pharmacopoeia 16th was used. Edition), a suitable product of Japanese Pharmaceutical Codex or Japanese Pharmaceutical Excipients 2003.

Example 1

Measure [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)- 2,3-dihydro-1-benzofuran-3-yl]acetic acid 0.5 hydrate (in the present specification, sometimes referred to simply as compound (A')) (25.4 g), metformin hydrochloride (500 g), With microcrystalline cellulose (21.6 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101), placed in a fluid bed dryer at 7 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., The granulation of the mixture was carried out while the solution of the SSL grade) (400 g). The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. A granulated powder (517.5 g) was weighed in a plastic bag with microcrystalline cellulose (18 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-802), crosslinked polyvinylpyrrolidone (47.7 g) (manufactured by BASF, Kollidon CL-F) And magnesium stearate (1.8 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press at a pressure of 14 kN to obtain Formulation 1 (a tablet, a long diameter of 13.5 mm × a short diameter of 8.5 mm, and 650 mg per ingot). The composition of Formulation 1 per ingot is shown in Table 1.

Example 2

The compound (A') (2696 g), metformin hydrochloride (53000 g), and microcrystalline cellulose (2286 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluid bed dryer (WSG-60, POWREX CORPORATION). In the case of spraying 8 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., SSL grade) solution (37100 g), granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-7S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. A batch of the same sieved powder was remanufactured. The sieved powder (103500g) was weighed and cross-linked polyvinylpyrrolidone (3600g) was added. (Manufactured by BASF, Kollidon CL-F), microcrystalline cellulose (9540g) (manufactured by Asahi Kasei, CEOLUS KG-802), and magnesium stearate (360g), which equals the drum mixer (TM-400S, Showa Kagakukikai) Mixed in Co., Ltd.) to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press at a pressure of 14 kN to obtain a tablet (long diameter 13.5 mm × short diameter 8.5 mm, 650 mg per spindle).

OPADRY Red 03F45081 (1008g) (manufactured by COLORCON JAPAN; containing hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, titanium oxide and red iron oxide) and OPADRY Yellow 03F42240 (2016g) (manufactured by COLORCON JAPAN; containing hydroxypropyl The methylcellulose 2910, polyethylene glycol 6000, titanium oxide, and yellow iron oxide were suspended in purified water (27220 g) to prepare a coating solution. In a coating machine (DRC-1200DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (109200 g) until the weight of each tablet was increased by 18 mg, and further sprayed with 5 (w/w)% polyethylene glycol. 6000 solution (672 g) to give Formulation 2 (film-coated tablet). The composition of Formulation 2 per ingot is shown in Table 2.

Example 3

The sieved powder (11.5 g) obtained in Example 2 and microcrystalline cellulose (0.4 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-802) and crosslinked polyvinylpyrrolidone (1.06 g) were produced in a glass bottle (Manufactured by BASF, Kollidon). CL-F) and magnesium stearate (0.04 g) were mixed to obtain a mixed powder. The powder compact was subjected to a compaction at a pressure of 14 kN using a tablet press to obtain a preparation 3 (a tablet having a long diameter of 13.5 mm × a short diameter of 8.5 mm and a 650 mg per spindle). The composition of Formulation 3 per ingot is shown in Table 3.

Example 4

The sieved powder (11.5 g) obtained in Example 2 and crosslinked polyvinylpyrrolidone (0.4 g) (manufactured by BASF, Kollidon CL-F) and microcrystalline cellulose (1.06 g) were produced in a glass bottle (Manufactured by Asahi Kasei, CEOLUS) KG-802) and magnesium stearate (0.04 g) were mixed to obtain a mixed powder. The powder compact was subjected to a compaction at a pressure of 14 kN using a tablet press to obtain a preparation 4 (a tablet having a long diameter of 13.5 mm × a short diameter of 8.5 mm and a 650 mg per spindle). The composition of Formulation 4 per ingot is shown in Table 4.

Example 5

The compound (A') (1602 g), metformin hydrochloride (53550 g), and microcrystalline cellulose (2178 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluidized bed dryer (WSG-60, POWREX CORPORATION). The granulation of the mixture was carried out while spraying a solution of 8 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., SSL grade) (37800 g). The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-7S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. A batch of the same sieved powder was remanufactured. The sieved powder (104400g) was weighed and crosslinked polyvinylpyrrolidone (3488g) was added. (Manufactured by BASF, Kollidon CL-F), microcrystalline cellulose (8938g) (manufactured by Asahi Kasei, CEOLUS KG-802), and magnesium stearate (327g), which equals the drum mixer (TM-400S, Showa Kagakukikai) Mixed in Co., Ltd.) to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (long diameter: 17.5 mm × short diameter: 9.5 mm, 1075 mg per ingot).

OPADRY Red 03F45081 (1000g) (manufactured by COLORCON JAPAN; containing hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, titanium oxide and red iron oxide) and OPADRY Yellow 03F42240 (2000g) (manufactured by COLORCON JAPAN; containing hydroxypropyl The methylcellulose 2910, polyethylene glycol 6000, titanium oxide, and yellow iron oxide were suspended in pure water (27,000 g) to prepare a coating solution. In a coater (DRC-1200DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (107500 g) until the weight of each tablet was increased by 18 mg, and further sprayed with 5 (w/w)% polyethylene glycol. A 6000 solution (500 g) gave Formulation 5 (film-coated tablet). The composition of Formulation 5 per ingot is shown in Table 5.

Example 6

The compound (A') (1373 g), metformin hydrochloride (54000 g), and microcrystalline cellulose (2137 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluidized bed dryer (WSG-60, POWREX CORPORATION). The granulation of the mixture was carried out while spraying a solution of 8 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., SSL grade) (37800 g). The granules are dried to obtain a granulated powder. The compound (A') used herein is a pulverized product of PIMNILL, and the average particle diameter thereof is a laser diffraction particle size analyzer and according to a drying method. The measurement was 25.6 μm. Part of the obtained granulated powder was crushed by a Power Mill mill (P-7S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. A batch of the same sieved powder was remanufactured. The sieved powder (105900 g) was weighed, and crosslinked polyvinylpyrrolidone (3591 g) (manufactured by BASF, Kollidon CL-F), microcrystalline cellulose (9167 g) (manufactured by Asahi Kasei Co., CEOLUS KG-802), and magnesium stearate were added. (378 g), which was mixed in a drum mixer (TM-400S, Showa Kagakukikai Co., Ltd.) to obtain a mixed powder. The powder compact was mixed using a tablet press to obtain a tablet (long diameter 19.0 mm × short diameter 10.5 mm, 1260 mg per ingot).

OPADRY Red 03F45081 (1056g) (manufactured by COLORCON JAPAN; containing hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, titanium oxide and red iron oxide) and OPADRY Yellow 03F42240 (2112g) (manufactured by COLORCON JAPAN; containing hydroxypropyl Methylcellulose 2910, polyethylene glycol 6000, titanium oxide, and yellow iron oxide were suspended in pure water (28510 g) to prepare a coating solution. In a coater (DRC-1200DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (110900 g) until the weight of each tablet was increased by 36 mg, and further sprayed with 5 (w/w)% polyethylene glycol. A 6000 solution (528 g) gave Formulation 6 (film-coated tablet). The composition of Formulation 6 per ingot is shown in Table 6.

Example 7

The compound (A') (25.4 g), metformin hydrochloride (500 g), and microcrystalline cellulose (21.6 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluid bed drier. While (w/w)% polyvinylpyrrolidone (manufactured by BASF, Kollidon K30) solution (400 g), granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Measured granular powder (517.5g) in a plastic bag with microcrystalline cellulose (18g) (manufactured by Asahi Kasei, CEOLUS KG-802), cross-linked polyvinylpyrrolidone (47.7g) (manufactured by BASF, Kollidon CL-F), and stearic acid Magnesium (1.8 g) was mixed to obtain a mixed powder. The powder compact was subjected to a compaction at a pressure of 14 kN using a tablet press to obtain a preparation 7 (a tablet having a long diameter of 13.5 mm × a short diameter of 8.5 mm and a 650 mg per spindle). The composition of Formulation 7 per ingot is shown in Table 7.

Example 8

The compound (A') (489.6 g), metformin hydrochloride (19000 g) and microcrystalline cellulose (745.4 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluidized bed granulation dryer (FD-WSG). In -30, POWREX CORPORATION, granulation of the mixture was carried out while spraying a solution of 6 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., grade L) (12980 g). Dry granules, A granulated powder was obtained. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.2 mm Φ punched screen to obtain a sieved powder. The sieved powder (14380 g) was weighed in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.), and microcrystalline cellulose (1261 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-802), cross-linked polycondensation Vinylpyrrolidone (494.0 g) (manufactured by BASF, Kollidon CL-F) and magnesium stearate (52.00 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (long diameter: 19.0 mm × short diameter: 10.5 mm, 1245 mg per ingot).

OPADRY Red 03F45081 (168 g) (manufactured by COLORCON JAPAN) and OPADRY Yellow 03F42240 (336 g) (manufactured by COLORCON JAPAN) were suspended in pure water (4536 g) to prepare a coating solution. In a coating machine (DRC-650DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (8715 g) until the weight of each tablet was increased by 36 mg, and further sprayed with 5 (w/w)% polyethylene glycol. A 6000 solution (42.0 g) gave Formulation 8 (film-coated tablet). The composition of Formulation 8 per ingot is shown in Table 8.

Example 9

The compound (A') (515.3 g), metformin hydrochloride (17000 g) and microcrystalline cellulose (684.7 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluidized bed granulation dryer (FD-WSG). In -30, POWREX CORPORATION, granulation of the mixture was carried out while spraying a solution of 6 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., grade L) (11660 g). The granules are dried to obtain a granulated powder. The compound (A') used herein is a pulverized product of PINMILL, and its average particle diameter is measured by a laser diffraction particle size analyzer and according to drying. The method was determined to be 25.6 μm. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.2 mm Φ punched screen to obtain a sieved powder. The sieved powder (14,180 g) was weighed in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.), and microcrystalline cellulose (1230 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-802), cross-linked polycondensation Vinylpyrrolidone (480.0 g) (manufactured by BASF, Kollidon CL-F) and magnesium stearate (45.00 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (long diameter: 17.5 mm × short diameter: 9.5 mm, 1062 mg per ingot).

OPADRY Red 03F45081 (160.0 g) (manufactured by COLORCON JAPAN) and OPADRY Yellow 03F42240 (320.0 g) (manufactured by COLORCON JAPAN) were suspended in pure water (4320 g) to prepare a coating solution. In a coating machine (DRC-650DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (8496 g) until the weight of each tablet was increased by 30 mg, and further sprayed with 5 (w/w)% polyethylene glycol. A 6000 solution (40.0 g) gave Formulation 9 (film-coated tablet). The composition of Formulation 9 per ingot is shown in Table 9.

Example 10

The compound (A') (979.0 g), metformin hydrochloride (19000 g) and microcrystalline cellulose (807.0 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluidized bed granulation dryer (FD-WSG). In -30, POWREX CORPORATION, granulation of the mixture was carried out while spraying a solution of 6 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., grade L) (13300 g). The granules are dried to obtain a granulated powder. The compound (A') used herein is a pulverized product of PINMILL, and its average particle diameter is measured by a laser diffraction particle size analyzer and according to drying. The method was determined to be 25.6 μm. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.2 mm Φ punched screen to obtain a sieved powder. The sieved powder (14200 g) was weighed and mixed in a tumbler mixer (TM-60, Showa Kagakukikai Co., Ltd.) with microcrystalline cellulose (1325 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-802), cross-linked polycondensation Vinylpyrrolidone (500.0 g) (manufactured by BASF, Kollidon CL-F) and magnesium stearate (50.00 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (long diameter 13.5 mm × short diameter 8.5 mm, 643 mg per ingot).

OPADRY Red 03F45081 (156 g) (manufactured by COLORCON JAPAN) and OPADRY Yellow 03F42240 (321.0 g) (manufactured by COLORCON JAPAN) were suspended in pure water (4212 g) to prepare a coating solution. In a coater (DRC-650DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (8359 g) until the weight of each tablet was increased by 18 mg, and further sprayed with 5 (w/w)% polyethylene glycol. A 6000 solution (52.0 g) gave Formulation 10 (coating tablet). The composition of Formulation 10 per ingot is shown in Table 10.

Comparative example 1

The sieved powder (11.5 g) obtained in Example 2 and microcrystalline cellulose (0.4 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-802) and croscarmellose sodium (1.06 g) (FMC) were placed in a glass bottle. Manufactured, Ac-Di-Sol), and magnesium stearate (0.04 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press at a pressure of 14 kN to obtain a comparative preparation 1 (a tablet having a long diameter of 13.5 mm × a short diameter of 8.5 mm and a 650 mg per spindle). The composition of Comparative Ingot 1 per ingot is shown in Table 11.

Comparative example 2

The sieved powder (11.5 g) obtained in Example 2 and microcrystalline cellulose (0.4 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-802) and sodium starch glycolate (1.06 g) (manufactured by DMV, Primojel) were placed in a glass bottle. And magnesium stearate (0.04 g) was mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press at a pressure of 14 kN to obtain a comparative preparation 2 (a tablet having a long diameter of 13.5 mm × a short diameter of 8.5 mm and a 650 mg per spindle). The composition of Comparative Ingot 2 per ingot is shown in Table 12.

Experimental example 1

The disintegration time of the preparations obtained in Examples 3 and 4 and Comparative Examples 1 and 2 was measured according to the Disintegration Test Method of the Japanese Pharmacopoeia (16th Edition) [test liquid: water, no paper ingot, (N=6 values and The average value thereof)]; the results are shown in Table 13.

As shown in Table 13, the preparations of Examples 3 and 4 showed excellent results. Disintegration. Among the disintegration properties of the formulations, the formulations of Examples 3 and 4 showed a change in inhibition. That is, it has been clarified that the preparation containing crosslinked polyvinylpyrrolidone is excellent in disintegration property and the disintegration change of each preparation is small as compared with the preparation containing croscarmellose sodium or sodium starch glycolate.

Experimental example 2

The preparations obtained in Example 1 and Example 7 were stored in an open glass bottle at 60 ° C, 75% RH for 2 weeks, and all the analogs of the compound (A') were quantified by high performance liquid chromatography; In Table 14.

As shown in Table 14, the formulation of Example 1 showed better performance than the implementation. The storage stability of the formulation of Example 7. That is, it has been clarified that the preparation containing hydroxypropylcellulose is excellent in storage stability as compared with the preparation containing polyvinylpyrrolidone because the latter shows an analog which suppresses the production of the active ingredient as compared with the former. Furthermore, since the production of the analog is inhibited at the initial time point, it has been clarified that the preparation containing the hydroxypropylcellulose also inhibits the production of the analog during the preparation step of the preparation.

Experimental example 3

In the mortar, the compound (A') was mixed with the additives described in Table 15, and stored in an open glass bottle at 40 ° C, 75% RH for 2 weeks and at 60 ° C, in a closed state. Store in glass bottles for 2 weeks. All the analogs of the compound (A') after storage were quantified by high performance liquid chromatography; the results are shown in Table 15.

As shown in Table 15, the compound (A') and hydroxypropyl cellulose The mixture shows excellent storage stability. Namely, it has been clarified that the hydroxypropylcellulose inhibiting compound (A') analog is superior in efficacy to hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Example 1A

The compound (A') (17230 g), D-mannitol (37040 g) and microcrystalline cellulose (6700 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) were weighed and placed in a fluidized bed dryer (WSG-60, POWREX CORPORATION). In the case of spraying 6 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd., grade L) solution (33500 g), granulation of the mixture was carried out. Dry granules, get Granular powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 21.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-7S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (57340 g) was weighed, and croscarmellose sodium (3050 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (610 g) were added to make the drum mixer (TM) -400S, Showa Kagakukikai Co., Ltd.) was mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press at a pressure of 6 kN to obtain a tablet (long diameter 8 mm × short diameter 4.5 mm, 100 mg per spindle).

OPADRY White 03F480011 (4850 g) (manufactured by COLORCON JAPAN; containing hydroxypropylmethylcellulose 2910, polyethylene glycol 6000 and titanium oxide) was suspended in pure water (43650 g) to prepare a coating solution. In a coater (DRC-1200DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (55000 g) until the weight of each tablet was increased by 5 mg, and further sprayed with 5 (w/w)% polyethylene glycol. A 6000 solution (550 g) gave Formulation 1A (coating tablet). The composition of Formulation 1A per ingot is shown in Table 16.

Example 2A

The compound (A') (19320 g) and D-mannitol were weighed. (34540g) and microcrystalline cellulose (6650g) (manufactured by Asahi Kasei Co., CEOLUS PH-101), placed in a fluid bed dryer (WSG-60, POWREX CORPORATION), sprayed with 6 (w/w)% hydroxypropyl fiber While the solution (33260 g) of Nippon Soda Co., Ltd. (L) was carried out, granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 23.1 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was used in a Power Mill mill (P-7S, Showa) using a 1.5 mm Φ punched screen. Kagakukikai Co., Ltd.) was crushed to obtain a sieved powder. The sieved powder (57580 g) was weighed, and croscarmellose sodium (3063 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (612.5 g) were added to make it equal to the drum mixer ( Molded in TM-400S, Showa Kagakukikai Co., Ltd.) to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press at a pressure of 7 kN to obtain a tablet (long diameter 10.5 mm × short diameter 5.5 mm, 175 mg per spindle).

Make OPADRY White 03F480011 (3983g) (manufactured by COLORCON JAPAN; containing hydroxypropylmethylcellulose 2910, polyethylene glycol 6000 and titanium oxide) suspended in pure water (35400 g) to prepare a coating solution. In a coater (DRC-1200DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (55000 g) until the weight of each tablet was increased by 9 mg, and further sprayed with 5 (w/w)% polyethylene glycol. A 6000 solution (522 g) gave Formulation 2A (coating tablet). The composition of Formulation 2A per ingot is shown in Table 17.

Example 3A

The compound (A') (694.9 g), alogliptin benzoate (hereinafter referred to as compound III) (228.6 g), mannitol (3046 g) (manufactured by Rocket Japan, D-mannitol), and Microcrystalline cellulose (453.1 g) (manufactured by Asahi Kasei Co., CEOLUS PH-101), placed in a fluidized bed granulation dryer (FD-5S, POWREX CORPORATION), sprayed with 6 (w/w)% hydroxypropyl cellulose While (Nippon Soda Co., Ltd, L grade) solution (2430 g), granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Partially obtained granulated powder It was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3892 g) was weighed and crosslinked with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) in a tumbler mixer (TM-1S, Showa Kagakukikai Co., Ltd.) Sodium carboxymethylcellulose (207.0 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (41.40 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (8.0 mm in diameter, 200 mg per ingot).

Hydroxypropylmethylcellulose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in pure water (1854 g) to make titanium oxide (28.80 g) (manufactured by Freund Corporation) , a mixture of yellow iron oxide (1.440 g) (manufactured by UNIVAR) and red iron oxide (1.440 g) (manufactured by Kohnstam) in pure water (738.0 g) and hydroxypropylmethylcellulose 2910 solution to prepare Coating solution. The coating solution was sprayed on the above-obtained tablet (3600 g) in a coating machine (DRC-500DS, POWREX CORPORATION) until the weight of each tablet was increased by 8 mg to obtain Formulation 3A. The composition of Formulation 3A per ingot is shown in Table 18.

Example 4A

The compound (A') (694.9 g), the compound III (457.2 g), the mannitol (2818 g) (manufactured by Rocket Japan, D-mannitol), and the microcrystalline cellulose (453.1 g) were produced by Asahi Kasei. CEOLUS PH-101), placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION), sprayed with 6 (w/w) % hydroxypropyl cellulose (Nippon Soda Co., Ltd, grade L) solution At the same time as (2430 g), granulation of the mixture was carried out. Dry granules, get a granule Granular powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3892 g) was weighed and crosslinked with a microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) in a tumbler mixer (TM-1S, Showa Kagakukikai Co., Ltd.) Sodium carboxymethylcellulose (207.0 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (41.40 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (8.0 mm in diameter, 200 mg per ingot).

Hydroxypropylmethylcellulose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in pure water (1854 g) to make titanium oxide (28.80 g) (manufactured by Freund Corporation) , a mixture of yellow iron oxide (1.440 g) (manufactured by UNIVAR) and red iron oxide (1.440 g) (manufactured by Kohnstam) in pure water (738.0 g) and hydroxypropylmethylcellulose 2910 solution to prepare Coating solution. The coating solution was sprayed on the above-obtained tablet (3600 g) in a coating machine (DRC-500DS, POWREX CORPORATION) until the weight of each tablet was increased by 8 mg to obtain Formulation 4A. The composition of Formulation 4A per ingot is shown in Table 19.

Example 5A

The compound (A') (694.9 g), the compound III (914.3 g), mannitol (2360 g) (manufactured by Rocket Japan, D-mannitol), and microcrystalline cellulose (453.1 g) (manufactured by Asahi Kasei Co., Ltd.) were weighed. CEOLUS PH-101), placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION), sprayed with 6 (w/w) % hydroxypropyl cellulose (Nippon Soda Co., Ltd, grade L) solution At the same time as (2430 g), granulation of the mixture was carried out. Dry granules, get a granule Granular powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3892 g) was weighed and crosslinked with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) in a tumbler mixer (TM-1S, Showa Kagakukikai Co., Ltd.) Sodium carboxymethylcellulose (207.0 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (41.40 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (8.0 mm in diameter, 200 mg per ingot).

Hydroxypropylmethylcellulose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in pure water (1854 g) to make titanium oxide (28.80 g) (manufactured by Freund Corporation) , a mixture of yellow iron oxide (1.440 g) (manufactured by UNIVAR) and red iron oxide (1.440 g) (manufactured by Kohnstam) in pure water (738.0 g) and hydroxypropylmethylcellulose 2910 solution to prepare Coating solution. The coating solution was sprayed on the above-obtained tablet (3600 g) in a coating machine (DRC-500DS, POWREX CORPORATION) until the weight of each tablet was increased by 8 mg to obtain Formulation 5A. The composition of Formulation 5A per ingot is shown in Table 20.

Example 6A

The compound (A') (1390 g), the compound III (228.6 g), mannitol (2351 g) (manufactured by Rocket Japan, D-mannitol), and microcrystalline cellulose (453.1 g) (manufactured by Asahi Kasei, CEOLUS) were weighed. PH-101), placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION), sprayed with 6 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd, grade L) solution ( At the same time as 2430 g), granulation of the mixture was carried out. Dry granules, get a granule Granular powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3892 g) was weighed and crosslinked with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) in a tumbler mixer (TM-1S, Showa Kagakukikai Co., Ltd.) Sodium carboxymethylcellulose (207.0 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (41.40 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (8.0 mm in diameter, 200 mg per ingot).

Hydroxypropylmethylcellulose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in pure water (1854 g) to make titanium oxide (28.80 g) (manufactured by Freund Corporation) a mixture of yellow iron oxide (1.440 g) (manufactured by UNIVAR) and red iron oxide (1.440 g) (manufactured by Kohnstam) in pure water (738.0 g) and hydroxypropylmethylcellulose 2910 solution to prepare Coating solution. The coating solution was sprayed on the above-obtained tablet (3600 g) in a coating machine (DRC-500DS, POWREX CORPORATION) until the weight of each tablet was increased by 8 mg to obtain Formulation 6A. The composition of Formulation 6A per ingot is shown in Table 21.

Example 7A

The compound (A') (1390.0 g), the compound III (457.2 g), the mannitol (2123 g) (manufactured by Rocket Japan, D-mannitol), and the microcrystalline cellulose (453.1 g) were produced by Asahi Kasei. CEOLUS PH-101), placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION), sprayed with 6 (w/w) % hydroxypropyl cellulose (Nippon Soda Co., Ltd, grade L) solution At the same time as (2430 g), granulation of the mixture was carried out. Dry granules, get a granule Granular powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3892 g) was weighed and crosslinked with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) in a tumbler mixer (TM-1S, Showa Kagakukikai Co., Ltd.) Sodium carboxymethylcellulose (207.0 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (41.40 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (8.0 mm in diameter, 200 mg per ingot).

Hydroxypropylmethylcellulose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in pure water (1854 g) to make titanium oxide (28.80 g) (manufactured by Freund Corporation) a mixture of yellow iron oxide (1.440 g) (manufactured by UNIVAR) and red iron oxide (1.440 g) (manufactured by Kohnstam) in pure water (738.0 g) and hydroxypropylmethylcellulose 2910 solution to prepare Coating solution. In a coating machine (DRC-500DS, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (3600 g) until the weight of each tablet was increased by 8 mg to obtain Formulation 7A. The composition of Formulation 7A per ingot is shown in Table 22.

Example 8A

The compound (A') (1390 g), the compound III (914.3 g), mannitol (1666 g) (manufactured by Rocket Japan, D-mannitol), and microcrystalline cellulose (453.1 g) (manufactured by Asahi Kasei, CEOLUS) were weighed. PH-101), placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION), sprayed with 6 (w/w)% hydroxypropylcellulose (Nippon Soda Co., Ltd, grade L) solution ( At the same time as 2430 g), granulation of the mixture was carried out. Dry granules, get a granule Granular powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 25.6 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3892 g) was weighed and crosslinked with microcrystalline cellulose (460.0 g) (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101) in a tumbler mixer (TM-1S, Showa Kagakukikai Co., Ltd.) Sodium carboxymethylcellulose (207.0 g) (manufactured by FMC, Ac-Di-Sol) and magnesium stearate (41.40 g) were mixed to obtain a mixed powder. The mixed powder ingot was subjected to a tablet press to obtain a tablet (8.0 mm in diameter, 200 mg per ingot).

Hydroxypropylmethylcellulose 2910 (256.3 g) (manufactured by Shin-Etsu Chemical Co., Ltd., Metolose TC-5) was dissolved in pure water (1854 g) to make titanium oxide (28.80 g) (manufactured by Freund Corporation) , a mixture of yellow iron oxide (1.440 g) (manufactured by UNIVAR) and red iron oxide (1.440 g) (manufactured by Kohnstam) in pure water (738.0 g) and hydroxypropylmethylcellulose 2910 solution to prepare Coating solution. The coating solution was sprayed on the above-obtained tablet (3600 g) in a coating machine (DRC-500DS, POWREX CORPORATION) until the weight of each tablet was increased by 8 mg to obtain Formulation 8A. The composition of Formulation 8A per ingot is shown in Table 23.

Example 9A

Compound (A') (1477 g), D-mannitol (2574 g) and microcrystalline cellulose (500.2 g) were placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION) at spray 6 (w/ While the aqueous solution (2501 g) of % hydroxypropylcellulose (Nippon Soda Co., Ltd., L grade) was used, granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein is a pulverized product of PIMNILL, and the average particle diameter thereof is a laser light-emitting granule. The diameter analyzer was measured to be 14.3 μm according to the drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3995 g) was weighed in a tumbler mixer (TM-15, Showa Kagakukikai Co., Ltd.), with croscarmellose sodium (212.5 g), and magnesium stearate (42.50). g) Mixing to obtain a mixed powder. The powder compact was mixed using a tablet press to obtain a tablet (long diameter 10.5 mm × short diameter 5.5 mm, 175 mg per spindle).

OPADRY White 03F48001 (540.0 g) (manufactured by COLORCON JAPAN) was suspended in pure water (4860 g) to prepare a coating solution. In a coating machine (DRC-500, POWREX CORPORATION), a coating solution was sprayed on the above-obtained tablet (2975 g) until the weight of each tablet was increased by 9 mg to obtain Formulation 9A (coating tablet). The composition of Formulation 9A per ingot is shown in Table 24.

Example 10A

Compound (A') (1477 g), D-mannitol (2574 g) and microcrystalline cellulose (500.2 g) were placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION) at spray 6 (w/ While the aqueous solution (2501 g) of % hydroxypropylcellulose (Nippon Soda Co., Ltd., L grade) was used, granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 23.1 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3995 g) was weighed in a tumbler mixer (TM-15, Showa Kagakukikai Co., Ltd.), with croscarmellose sodium (212.5 g), and magnesium stearate. (42.50 g) was mixed to obtain a mixed powder. The powder compact was mixed using a tablet press to obtain a tablet (long diameter 10.5 mm × short diameter 5.5 mm, 175 mg per spindle).

OPADRY White 03F48001 (540.0 g) (manufactured by COLORCON JAPAN) was suspended in pure water (4860 g) to prepare a coating solution. In a coating machine (DRC-500, POWREX CORPORATION), a coating solution was sprayed on the above-obtained tablet (2975 g) until the weight of each tablet was increased by 9 mg to obtain Formulation 10A (coating tablet). The composition of Formulation 10A per ingot is shown in Table 25.

Example 11A

Compound (A') (1477 g), D-mannitol (2574 g) and microcrystalline cellulose (500.2 g) were placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION) at spray 6 (w/ w)% hydroxypropyl cellulose (Nippon While the aqueous solution (2501 g) of Soda Co., Ltd. L grade) was used, granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PINMILL, and its average particle diameter was 33.4 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3995 g) was weighed in a tumbler mixer (TM-15, Showa Kagakukikai Co., Ltd.), with croscarmellose sodium (212.5 g), and magnesium stearate (42.50). g) Mixing to obtain a mixed powder. The powder compact was mixed using a tablet press to obtain a tablet (long diameter 10.5 mm × short diameter 5.5 mm, 175 mg per spindle).

OPADRY White 03F48001 (540.0 g) (manufactured by COLORCON JAPAN) was suspended in pure water (4860 g) to prepare a coating solution. In a coating machine (DRC-500, POWREX CORPORATION), the coating solution was sprayed on the above-obtained tablet (2975 g) until the weight of each tablet was increased by 9 mg to obtain Formulation 11A (coating tablet). The composition of Formulation 11A per ingot is shown in Table 26.

Comparative Example 1A

Compound (A') (1477 g), D-mannitol (2574 g) and microcrystalline cellulose (500.2 g) were placed in a fluid bed granulation dryer (FD-5S, POWREX CORPORATION) at spray 6 (w/ While the aqueous solution (2501 g) of % hydroxypropylcellulose (Nippon Soda Co., Ltd., L grade) was used, granulation of the mixture was carried out. The granules are dried to obtain a granulated powder. The compound (A') used herein was a pulverized product of PITMILL, and its average particle diameter was 42.5 μm as measured by a laser diffraction particle size analyzer and according to a drying method. Part of the obtained granulated powder was crushed by a Power Mill mill (P-3S, Showa Kagakukikai Co., Ltd.) using a 1.5 mm Φ punched screen to obtain a sieved powder. The sieved powder (3995 g) was weighed in a tumbler mixer (TM-15, Showa Kagakukikai Co., Ltd.), with croscarmellose sodium (212.5 g), and magnesium stearate. (42.50 g) was mixed to obtain a mixed powder. The powder compact was mixed using a tablet press to obtain a tablet (long diameter 10.5 mm × short diameter 5.5 mm, 175 mg per spindle).

OPADRY White 03F48001 (540.0 g) (manufactured by COLORCON JAPAN) was suspended in pure water (4860 g) to prepare a coating solution. In a coating machine (DRC-500, POWREX CORPORATION), a coating solution was sprayed on the above-obtained tablet (2975 g) until the weight of each tablet was increased by 9 mg to obtain Comparative Formulation 1A (coating tablet). The composition of each of Comparative Ingots 1A is shown in Table 27.

Experimental Example 1A

Example 9A, Example 10A was determined according to the Japanese Pharmacopoeia Paddle method (rotation number 50 rpm, 37 ° C, phosphate buffer containing 0.1% sodium lauryl sulfate (pH 6.8), 900 mL, n=6). , The solubility of the compound (A') of the film-coated tablet of Example 11A and Comparative Example 1A; the results are shown in Table 28. The values in the table show the average of the dissolution rates (%) of the six film-coated tablets.

As shown in Table 28, the solubility of the compound (A') was carried out. The formulations of Examples 9A, 10A and 11A were all superior to the formulation of Comparative Example 1A. That is, it has been clarified from these preparations that the compound (A) having an average particle diameter of less than 35 μm (for example, 14.3 to 33.4 μm) or a salt thereof is excellent in solubility.

Industrial utilization

According to the present invention, a solid preparation containing the compound (A) or a salt thereof, metformin or a salt thereof and crosslinked polyvinylpyrrolidone excellent in disintegration property and storage stability can be provided. Furthermore, according to the present invention, solubility can be provided An excellent compound (A) or a salt thereof.

The present application is based on the patent application No. 2012-161025 filed in Japan, the entire content of which is incorporated herein.

Claims (6)

A solid preparation comprising (1) [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3- (Methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid or a salt thereof, (2) metformin or a salt thereof, and (3) a crosslinked polyvinylpyrrolidone. The solid preparation according to the above aspect of the invention, wherein the metformin or a salt thereof is metformin hydrochloride. The solid preparation according to claim 1 or 2, further comprising hydroxypropylcellulose. The solid preparation according to claim 3, further comprising microcrystalline cellulose and magnesium stearate. A compound which is [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy) And 2,3-dihydro-1-benzofuran-3-yl]acetic acid or a salt thereof, and having an average particle diameter of less than 35 μm. A solid preparation comprising [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy) according to item 5 of the patent application scope Bis[biphenyl-3-yl}methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid or a salt thereof.