JP2008162949A - Diabetes-treating agent containing thiazolidinedione compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition containing a thiazolidinedione compound and excellent in the absorptivity of the medicine. <P>SOLUTION: This medicinal composition comprises blending cellulose, a cellulose derivative, a polyvinyl alcohol derivative, a polyvinyl alcohol derivative mixture or their mixture with 5-ä4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}thiazolidine-2,4-dione or its pharmacologically acceptable salt. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition containing a thiazolidinedione compound and having excellent solubility.

  Insulin resistance improving agents are used as effective drugs for diabetes and the like because they have the effect of improving insulin resistance and lowering blood glucose levels. Examples of insulin resistance improving agents currently on the market include pioglitazone (Takeda Pharmaceutical) and rosiglitazone (Glaxo Smith Klein).

  In addition, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione which is an insulin resistance improving agent or a pharmacologically acceptable one thereof About the pharmaceutical composition containing the salt made, it is disclosed by patent document 1 and patent document 2, However, the effect by an additive is not described at all.

PCT / JP2006 / 31354 is mentioned as a prior application, and this application is an application concerning a preparation. On the other hand, this application is an application concerning the diabetic use of the preparation described in PCT / JP2006 / 31354, and the subject matter of this application is different from that of PCT / JP2006 / 31354.
International Publication No. 00/71540 Pamphlet International Application Number PCT / JP2006 / 301058

Insulin resistance improving agents are required to have high absorbability into the body due to their mechanism of action, and accordingly, stable and high solubility over time is required. However, high-purity 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (hereinafter referred to as Compound A) However, since the solubility of the hydrate is extremely low, the compound A hydrates in the body after administration, so that the active ingredient is absorbed into the body. There was concern that the absorbency would be low. Therefore, the inventors have identified high-purity 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable product thereof. As a result of intensive studies on the stability of pharmaceutical compositions containing the salts obtained, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine- A pharmaceutical composition comprising 2,4-dione or a pharmacologically acceptable salt thereof and cellulose, a cellulose derivative, a polyvinyl alcohol derivative, a polyvinyl alcohol derivative mixture or a mixture thereof as an additive has excellent solubility and solubility. Thus, the present invention has been completed by finding that it has stability over time and is useful as a pharmaceutical preparation for warm-blooded animals (particularly for humans).

The present invention
(1) The content of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is 98% by weight or more of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or pharmacologically acceptable thereof excluding water A therapeutic composition for diabetes containing one or more selected from a pharmaceutically acceptable cellulose, a cellulose derivative, a polyvinyl alcohol derivative, and a polyvinyl alcohol derivative mixture,
(2) The content of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is The antidiabetic agent according to (1), which is 99% by weight or more excluding water,
(3) Reduction of solubility of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof The antidiabetic agent according to (1) or (2) above, wherein
(4) Hydration of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof The antidiabetic agent according to (1) or (2) above, wherein
(5) Reduced solubility of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof Of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof. The therapeutic agent for diabetes according to the above (1) or (2), characterized by maintaining an excellent absorption rate in the body,
(6) Hydration of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof Which is prevented in an aqueous solution, the therapeutic agent for diabetes according to the above (1) or (2),
(7) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is an aqueous solution. Among them, the therapeutic agent for diabetes according to (1) or (2) above, wherein the solubility and solubility over time are excellent.
(8) Reduction of solubility of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof The therapeutic agent for diabetes according to (1) or (2) above, which is prevented in an aqueous solution,
(9) Decrease in solubility of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof The therapeutic agent for diabetes according to (1) or (2) above, which is prevented in the digestive tract of an animal,
(10) The therapeutic agent for diabetes according to any one of (1) or (9) above, which is a preparation for oral administration,
(11) The therapeutic agent for diabetes according to (10), wherein the preparation for oral administration is a tablet,
(12) The therapeutic agent for diabetes according to any one of (1) to (11) above, wherein the additive is pharmacologically acceptable cellulose or cellulose derivative.
(13) A pharmacologically acceptable cellulose or cellulose derivative is selected from methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910 and croscarmellose sodium. The therapeutic agent for diabetes according to the above (12), which is one or more selected from
(14) The therapeutic agent for diabetes according to any one of (1) to (13), wherein the additive is a pharmacologically acceptable polyvinyl alcohol derivative,
(15) The therapeutic agent for diabetes according to the above (14), wherein the pharmacologically acceptable polyvinyl alcohol derivative is a polyvinyl alcohol partial saponified product,
(16) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is 5- Any one of (1) to (15) above, which is {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride Antidiabetic drugs described in
(17) The antidiabetic agent according to any one of claims 1 to 16, which is produced by a dry granulation method,
(18) The antidiabetic agent according to any one of (1) to (16), which is produced by a wet granulation method,
(19) The therapeutic agent for diabetes according to any one of (1) to (18) above, which is used for treatment of diabetes,
(20) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazole-2-) for the manufacture of a therapeutic agent for diabetes according to any one of (1) to (19) above. Yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof, and one or more additives selected from cellulose, cellulose derivatives, polyvinyl alcohol derivatives and polyvinyl alcohol derivative mixtures use,
(21) 5- {4-[(6-methoxy-1-methyl-1H-benzimidazole-2-) for the manufacture of a therapeutic agent for diabetes according to any one of (1) to (20) above. Yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof and a pharmacologically acceptable cellulose or cellulose derivative,
(22) A method of administering 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof Wherein the 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is required (I) 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof And (ii) pharmacologically acceptable cellulose, cellulose derivative, polyvinyl alcohol derivative, and a mixture of polyvinyl alcohol derivatives and a mixture of two or more of the following: A method comprising co-administering an additive,
(23) High purity 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof The method according to the above (22) for maintaining solubility and improving the absorption rate in the body,
(24) A method of treating a human to treat or prevent diabetes, the human being comprising: (i) high purity 5- {4-[(6-methoxy-1-methyl-1H-benzimidazole- 2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof and (ii) a pharmacologically acceptable cellulose, cellulose derivative, polyvinyl alcohol derivative and a mixture of polyvinyl alcohol derivatives 1 Treating with a pharmaceutical composition comprising a species or two or more additives,
(25) (i) High-purity 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof And (ii) treatment with a pharmaceutical composition comprising pharmacologically acceptable cellulose or a derivative thereof.

  5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione which is an active ingredient of the pharmaceutical composition of the present invention or pharmacologically thereof The acceptable salt is a compound represented by the following structure or a pharmacologically acceptable salt thereof, and is described in Patent Documents 1 and 2.

Preferred is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride.

  Cellulose and its derivatives as additives of the pharmaceutical composition of the present invention include, for example, crystalline cellulose (Avicel: Asahi Kasei etc.), crystalline cellulose carmellose sodium (Avicel RC: Asahi Kasei etc.), methylcellulose (Metroses SM: Shin-Etsu Chemical etc.) ), Ethyl cellulose (Etocel: Dow Chemical, etc.), hydroxypropyl cellulose (Nisso HPC: Nippon Soda etc.), low-substituted hydroxypropyl cellulose (L-HPC: Shin-Etsu Chemical, etc.), hydroxypropyl methylcellulose 2208 (Metrouse 90SH: Shin-Etsu Chemical) Hydroxypropyl methylcellulose 2906 (Metroze 65SH: Shin-Etsu Chemical, etc.), Hydroxypropyl methylcellulose 2910 (Metrouse 60SH: Shin-Etsu Chemical, etc.), Hydroxypropyl cellulose phthalate 200731 (HPMCP: Shin-Etsu Chemical, etc.), Hi Droxypropyl cellulose phthalate 220824 (HPMCP: Shin-Etsu Chemical, etc.), hydroxypropyl methylcellulose acetate succinate (Shin-Etsu AQOAT: Shin-Etsu Chemical, etc.), carmellose (NS-300: Gotoku Pharmaceutical, etc.), carmellose calcium (ECG-505: Gotoku Pharmaceutical) ), Carmellose sodium (cellogen: Daiichi Kogyo Seiyaku etc.), croscarmellose sodium (Ac-Di-Sol: Asahi Kasei etc.), carboxymethyl ethyl cellulose (CMEC: Freund Sangyo etc.), cellulose acetate phthalate (CAP: sum) Photopure drugs, etc.), hydroxyethyl cellulose (NATROSOL: Aqualon etc.) or a mixture thereof, more preferably methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, Le cellulose 2906, hydroxypropylmethyl cellulose 2910, carmellose sodium, croscarmellose sodium or mixtures thereof.

Examples of the “polyvinyl alcohol derivative” and the “polyvinyl alcohol derivative mixture” include a polyvinyl alcohol complete saponified product, a polyvinyl alcohol partial saponified product, or a mixture containing these. More preferred are polyvinyl alcohol partial saponification products (GOHSENOL GL-05, Nippon Synthetic Chemical Industry Co., Ltd.).


In the present invention, a highly pure substance means a substance having a main component content of 97% by weight.

  In the present invention, the “content” is a quantitative value (% by weight) measured by quantitative analysis (preferably, the quantitative analysis method described in Reference Example 2). A quantitative value can be calculated | required from the face ratio, for example by measuring a target substance by HPLC.

  The cellulose, cellulose derivative, polyvinyl alcohol derivative, polyvinyl alcohol derivative mixture or mixture thereof used as an additive of the present invention is usually 0.1 to 30 parts by weight, preferably 0.5 to 25 parts by weight. The pharmaceutical composition of the present invention can be used in preparations that can be administered orally, such as tablets, capsules, pills, granules, or fine granules, but are preferably tablets.

  The pharmaceutical composition of the present invention may appropriately contain pharmaceutically acceptable additives. Such additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, pregelatinized starch, dextrin, carboxymethyl starch, carboxymethyl starch sodium Starch derivatives such as: pregelatinized starch; cellulose such as crystalline cellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium Derivatives; gum arabic; dextran; pullulan; light anhydrous silicic acid, calcium silicate, silicic acid hydrate, synthetic aluminum silicate, metasilicic acid aluminate Silicate derivatives such as gnesium; phosphate derivatives such as dicalcium phosphate; chloride derivatives such as sodium chloride; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; A mixture of, preferably a sugar derivative, a cellulose derivative or a mixture thereof, more preferably lactose, mannitol, crystalline cellulose or a mixture thereof), a binder (for example, the compounds exemplified in the above excipients; gelatin) Polyvinyl pyrrolidone; macrogol; or a mixture thereof, preferably a cellulose derivative or a mixture thereof, more preferably hydroxypropyl cellulose), a disintegrant (for example, the compounds exemplified in the above excipients); Pyrrolidone; or a mixture thereof, preferably a cellulose derivative or a mixture thereof Compounds, more preferably low substituted hydroxypropylcellulose, croscarmellose sodium or mixtures thereof), lubricants (eg stearic acid; stearic acid metal salts such as calcium stearate, magnesium stearate; benzoic acid) Benzoic acid metal salts such as sodium; waxes such as bee gum and geiro; boric acid; glycols; carboxylic acids such as fumaric acid and adipic acid; metal sulfates such as sodium sulfate; leucine; sodium lauryl sulfate, lauryl sulfate Lauryl sulfate metal salts such as magnesium; silicate derivatives exemplified in the above excipients; starch derivatives exemplified in the above excipients; hydrogenated vegetable oils; carnauba wax; sucrose fatty acid esters; or mixtures thereof, preferably Is a metal stearate, a silicate derivative or Mixtures thereof, more preferably calcium stearate, magnesium stearate, silicic anhydride or mixtures thereof), stabilizers (eg benzoic acid; benzoic acid metal salts such as sodium benzoate; methylparaben, propylparaben, etc. Paraoxybenzoic acid esters; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid; Benzoic acid metal salts, paraoxybenzoic acid esters or mixtures thereof, more preferably sodium benzoate, methylparaben, propylparaben or mixtures thereof), fluidizing agents (e.g. exemplified by the above excipients). Silicate invitation Body; talc; or mixtures thereof, preferably light silicic anhydride, talc or mixtures thereof, surfactants (eg, polysorbates such as polysorbate 80; polyoxyethylene hydrogenated castor oil 60, etc. Oxyethylene hydrogenated castor oils; sorbitan fatty acid esters; sucrose fatty acid esters; polyoxyethylene polyoxypropylene glycols; polyoxyethylene fatty acid ethers; stearic acid polyoxyls; or a mixture thereof, preferably polysorbate 80, Polyoxyethylene hydrogenated castor oil 60 or a mixture thereof), colorant (for example, yellow iron sesquioxide, iron sesquioxide, black iron oxide), antioxidant, flavoring agent (for example, commonly used sweetener, Kind of additives used, which may be acidulants, flavorings, etc.) or diluents And the amount will vary depending on the tablet, capsule or other dosage form drug, but is selected from well-known techniques in the field of formulation.

  For example, in the case of tablets, the content of the binder is usually 1 to 10 parts by weight (preferably 2 to 5 parts by weight) in the total drug composition, and the content of the disintegrant is usually 1 To 40 parts by weight (preferably 5 to 30 parts by weight), and the lubricant content is usually 0.1 to 10 parts by weight (preferably 0.5 to 3 parts by weight). The content is 0.1 to 10 parts by weight (preferably 0.5 to 5 parts by weight).

The pharmaceutical composition of the present invention can be easily produced by a known method (for example, a dry production method, a kneading method using water, a wet granulation method, etc.) using pharmaceutically acceptable additives.

The “wet granulation method” in the present invention is a method of granulating a powder using water or a mixture of water and alcohol as a granulating binder, and the Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman et al .: LEA & FEBIGER 1986) and Pharmaceutical Dosage Forms: Tablets volume 1 (Second Edition) (Herbert A. Lieberman et al .: MARCEL DEKKER INC. 1989). Here, granulation refers to the operation of making granules with almost uniform shape and size from raw materials such as powder, lump, solution or molten liquid, and final products such as granules, powders and fine granules are made. There are granulations and granulations that make intermediate products for manufacturing such as tablets and capsules. Examples of such production include, for example, the addition of active ingredients, stabilizers, excipients, binders, disintegrants and other types of auxiliaries as required, and mixing with a high speed agitation granulator. Then, an aqueous solution of a binder is added to the obtained mixture and kneaded to obtain a granulated product. The obtained granulated product is dried using a fluidized bed dryer, and the dried granulated product is forced to pass through a screen using a pulverizing granulator, a lubricant, a disintegrant. If necessary, other types of auxiliaries and the like may be added and mixed in a V-type mixer, and the resulting mixture may be tableted or filled into capsules to produce tablets or capsules, respectively. it can.

The dry production method in the present invention includes a direct tableting method and a dry granulation method. The “direct tableting method” is a method for preparing a raw material powder by direct compression molding. The “dry granulation method” is a method in which a raw material powder is compression-molded into a slug or a sheet and crushed by an appropriate method to prepare a granule. These methods include The Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman et al .: LEA & FEBIGER 1986) and Pharmaceutical Dosage Forms: Tablets volume 1 (Second Edition) (Herbert A. Lieberman et al .: MARCEL DEKKER INC. 1989) ). The obtained tablet can be sugar-coated or coated (preferably, coated) as necessary. For example, the resulting tablet is sprayed with a coating solution consisting of hydroxypropylmethylcellulose, polyvinyl alcohol, talc, titanium oxide, lactose, triacetin or polyethylene glycol, yellow iron or iron dioxide, and water in a pan coating machine. By doing so, a film coating can be applied.

  Moreover, after mixing with the high-speed agitation granulator and adding the aqueous solution of the binder and kneading, the kneaded product is granulated with an extrusion granulator, and then with a fence dryer. Granules can be produced by forcing the dried granules to pass through a screen using a crushing and granulating machine.

  The pharmaceutical composition of the present invention can be administered to warm-blooded animals (particularly humans) and is an active ingredient 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) The dose of methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof can vary depending on various conditions such as the patient's symptoms, age, body weight, etc. 0.001 mg / kg to 1 mg / kg (preferably 0.005 mg / kg to 0.05 mg / kg) per day can be administered to adults 1 to 3 times per day depending on symptoms.

According to the present invention, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof By preventing the formation of a hydrate, a pharmaceutical composition having excellent dissolution stability with time and excellent drug absorbability is provided.

EXAMPLES Next, although an Example, a formulation example, and a reference example are given and this invention is demonstrated further in detail, this invention is not limited to this. 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (hereinafter referred to as Compound A) used in the present invention Can be produced according to the method of Reference Example 1. The monohydrate of Compound A can be produced according to the method of Reference Example 3. The content of Compound A can be confirmed according to the method of Reference Example 2.

  The formulation additive used in the present invention is a commercial product. Opadry II 85F48993 (OPADRY II 85F48993: manufactured by Colorcon, Inc., hereinafter referred to as Opadry II) is a premixed product containing polyvinyl alcohol, a hiding agent, a plasticizer, etc., and Opagros 2 (OPAGLOS 2: Colorcon, Inc. Is a premix product containing carmellose sodium, concealing agent, anti-adhesive agent, etc., Opadry WHITE YS-1-18202A (OPADRY YS-1-18202A: Colorcon, Inc., hereinafter referred to as Opadry WHITE) Is a premix product containing hydroxypropyl methylcellulose, a masking agent and a plasticizer.

(Test Example 1)
Dissolution rate test 1 of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (compound A)
200 ml of JP 1st liquid (dissolved in 2.0 g of sodium chloride and dissolved in 7.0 ml of hydrochloric acid and water to make 100 ml. Normally used as a test solution that models the disintegration and elution of drugs in the stomach) About 40 mg of compound A or monohydrate of compound A and formulation additive [Select one of the following additives: lactose (lactose, BORCULO DOMO INGREDIENTS) 377.6 mg, croscarmellose sodium (Ac-Di- Sol, FMC International Co., Ltd.) 78.0 mg, Hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) 15.6 mg, Magnesium stearate (magnesium stearate, Nippon Oil & Fats Co., Ltd.) 5.2 mg, Yellow ferric oxide (Yellow trioxide) Iron, Tokikasei Co., Ltd.) 0.112 mg] was added, and the mixture was stirred with a stirrer at 37 ° C in a 300 ml conical beaker. 10 ml was sampled every 30 minutes, 1 hour, 3 hours, and 6 hours, and filtered using Acrodisc LC13 (PVDF, manufactured by Gelman Science). The initial 3 ml was discarded and the next 7 ml was taken into a test tube. 5 ml of this was taken with a whole pipette, transferred to a test tube containing 2 ml of methanol in advance, and mixed.

  For quantification, HPLC was used to determine solubility from a calibration curve prepared according to the method described below.

  A calibration curve is prepared by preparing methanol standard solutions of Compound A at concentrations of 400 μg / ml, 100 μg / ml, and 20 μg / ml, adding 5 ml of JP 1st liquid to 2 ml of each standard solution, mixing, and quantifying by HPLC. It was prepared by.

HPLC condition analysis column: L-column ODS (4.6 mmID × 15 cm, manufactured by Chemicals Evaluation and Research Institute)
Mobile phase: 0.01 mol / l acetate buffer (pH 5.0) / acetonitrile mixture (13: 7)
Flow rate: 1.0 ml per minute
Column temperature: 40 ° C
Detector: UV absorptiometer (measurement wavelength: 290 nm)
FIG. 1 shows the results of measuring the solubility of Compound A.

  As shown in FIG. 1, in the case of compound A alone ((I)), a decrease in solubility is observed with time. The cause of this decrease in solubility is that compound A changes to hydrate over time in JP 1st liquid, and the solubility of the monohydrate is extremely low ((VIII)). It is thought that this resulted in a decrease in the solubility of.

  Therefore, the effects of various additives were investigated for the purpose of preventing the decrease in solubility of Compound A, and the results are shown in Table 1. In Table 1, the test mixture groups containing additives containing cellulose and / or derivatives thereof are (II) and (IV) (hereinafter collectively referred to as “cellulose-containing group”), and cellulose and / or its The test mixture groups not containing the additive containing the derivatives are (V), (VI) and (VII) (hereinafter collectively referred to as “cellulose-free group”).

Until 1 hour after the start of the solubility test, there was little difference in the solubility between the cellulose-containing group and the cellulose-free group. However, thereafter, the solubility of the compound A and cellulose-free group rapidly decreased. On the other hand, the solubility of the cellulose-containing group continued to maintain a high solubility.

(Test Example 2)
Dissolution rate test of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Compound A) 2
200 ml of JP 1st liquid (dissolved in 2.0 g of sodium chloride and dissolved in 7.0 ml of hydrochloric acid and water to make 100 ml. Normally used as a test solution that models the disintegration and elution of drugs in the stomach) About 40 mg of Compound A or Compound A monohydrate and formulation additive [Select one of the following additives: Opadry II 23.9 mg, Polyvinyl alcohol (GOHSENOL GL-05, Nippon Synthetic Chemical Industry Co., Ltd., etc.) 17.2 mg, Opagros 2 23.9 mg] was added, and the mixture was stirred with a stirrer at 37 ° C. in a 300 ml conical beaker. 10 ml was sampled every 30 minutes, 1 hour, 3 hours, and 6 hours, and filtered using Acrodisc LC13 (PVDF, manufactured by Gelman Science). The initial 3 ml was discarded and the next 7 ml was taken into a test tube. 5 ml of this was taken with a whole pipette, transferred to a test tube containing 2 ml of methanol in advance, and mixed.

  For quantification, HPLC was used to determine solubility from a calibration curve prepared according to the method described below.

  A calibration curve is prepared by preparing methanol standard solutions of Compound A at concentrations of 400 μg / ml, 100 μg / ml, and 20 μg / ml, adding 5 ml of JP 1st liquid to 2 ml of each standard solution, mixing, and quantifying by HPLC. It was prepared by.

HPLC condition analysis column: L-column ODS (4.6 mmID × 15 cm, manufactured by Chemicals Evaluation and Research Institute)
Mobile phase: 0.01 mol / l acetate buffer (pH 5.0) / acetonitrile mixture (13: 7)
Flow rate: 1.0 ml per minute
Column temperature: 40 ° C
Detector: UV absorptiometer (measurement wavelength: 290 nm)

FIG. 2 shows the results of measuring the solubility of Compound A.

  Until 1 hour after the start of the solubility test, there was little difference in the solubility between Compound A alone and the additive-containing group. However, thereafter, the solubility of Compound A alone decreased rapidly. On the other hand, the solubility of the additive-containing group containing a cellulose derivative or polyvinyl alcohol continued to maintain a high solubility.

  From the above results, it can be seen that high solubility can be stably maintained by adding a cellulose derivative, a polyvinyl alcohol derivative, a polyvinyl alcohol derivative mixture, or an additive thereof to Compound A. The reason why such an effect is obtained is that the above-mentioned additive prevents the compound A from being hydrated, and further increases the solubility of the hydrated compound A.

Therefore, a pharmaceutical composition containing Compound A and cellulose, cellulose derivative, polyvinyl alcohol derivative, polyvinyl alcohol derivative mixture or mixture thereof as an additive enhances absorption of Compound A into the body by maintaining high solubility. Can be said to be an extremely excellent pharmaceutical composition.

(Formulation example 1)
Preparation of tablets of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (compound A) by wet granulation method Method Tablets containing Compound A and cellulose or a derivative thereof were obtained by the following method using the components of the types and amounts shown in Table 1. The dose of the active ingredient, the content and type of each additive are not limited to Table 1.

To Compound A, an excipient (lactose) and a disintegrant (croscarmellose sodium (Ac-Di-Sol) are added and mixed with a high-speed stirring granulator, and a binder (hydroxypropylcellulose) is added to the resulting mixture. An aqueous solution was added and kneaded to obtain a granulated product, which was dried using a fluidized bed dryer, and the dried granulated product was screened using a pulverizing granulator. Forced to pass through, added lubricant (magnesium stearate) and mixed with a V-type mixer.The resulting mixture was shaped using a 7 mm diameter punch to disperse the pigment (yellow ferric oxide) The desired coating (Opadry WHITE) aqueous solution was sprayed using a coating machine to obtain a desired tablet.
(Table 1)
________________________________
Ingredients Amount per tablet (mg)
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Compound A 10.9
Lactose 94.4
Ac-Di-Sol 19.5
Hydroxypropylcellulose 3.9
Magnesium stearate 1.3
Opadry WHITE 5.972
Yellow ferric oxide 0.028
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Total 136.0
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

(Formulation example 2)
Production of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (compound A) tablets by dry granulation method Method Using the types and amounts of components shown in Table 2, tablets containing compound A and cellulose or a derivative thereof were obtained by the following method. The dose of the active ingredient, the content and type of each additive are not limited to Table 2.

To compound A, an excipient (lactose (dilactose S)), a disintegrant (croscarmellose sodium (Ac-Di-Sol)) and a binder (hydroxypropylcellulose) are added and mixed by a V-type mixer. The obtained mixture was sieved with 30 mesh and further mixed with a V-type mixer to obtain a mixture, and a lubricant (magnesium stearate) was added to the obtained mixture and mixed with a V-type mixer. The obtained mixture was molded using a wrinkle having a diameter of 7 mm, and an aqueous coating (Opadry WHITE) solution in which a pigment (yellow ferric oxide) was dispersed was sprayed using a coating machine to obtain a desired tablet.
(Table 2)
________________________________
Ingredients Amount per tablet (mg)
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Compound A 10.9
Lactose 94.4
Ac-Di-Sol 19.5
Hydroxypropylcellulose 3.9
Magnesium stearate 1.3
Opadry WHITE 5.972
Yellow ferric oxide 0.028
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Total 136.0
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

(Reference Example 1)
5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride production method (1-1)
Acetonitrile (140.9 kg) was added to 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid (18.0 kg, 64.0 mol) produced according to the method described in JP-A-2001-72671, After cooling to an internal temperature of 8 ° C., thionyl chloride (8.3 kg, 69.8 mol) was added. Dimethylformamide (14.4 L) was further added, and the mixture was stirred at the same temperature to 15 ° C. for 3.5 hours. Here, tert-butyl N- (2-amino-5-methoxyphenyl) -N-methylcarbamate (15.7 kg, 62.2 mol) and triethylamine (8.4 kg, 83.0 mol) in acetonitrile (kept at 0 to 10 ° C.) 84.6 kg) The solution was added dropwise over 1 hour while cooling so that the reaction temperature was maintained at 0 to 5 ° C., and the mixture was further stirred at the same temperature for 2 hours. Next, water (144 L) was added over 22 minutes, and the mixture was stirred for 30 minutes while maintaining the internal temperature of 0 to 6 ° C., and then allowed to stand for 12 hours. The obtained crystals were filtered off, washed with water = 2: 1 solution (54 L), and N- {2- {4-[(2,4-dioxothiazolidine-5-yl) methyl] phenoxyacetylamino} Wet crystals of tert-butyl-5-methoxyphenyl} -N-methylcarbamate were obtained.

(1-2)
N- {2- {4-[(2,4-Dioxothiazolidine-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamic acid tert-obtained in (1-1) The suspension was refluxed in methanol (450 L) of wet butyl crystals for 25 minutes with stirring. The suspension was cooled to 0 to 5 ° C. and stirred at the same temperature for 1 hour, and then the precipitated crystals were separated by filtration. The obtained crystals were washed with methanol (54 L), and N- {2- {4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N- Wet purified crystals of tert-butyl methylcarbamate were obtained.

(1-3)
N- {2- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamic acid tert-obtained in (1-2) The purified butyl wet crystals were suspended in methanol (1080 L) and then refluxed to obtain a solution. The solution was cooled to 50 ° C. and filtered over 45 minutes. The residue was washed with 50 ° C. methanol (37 L). The filtrate and the washing solution were combined, 38% hydrochloric acid (20.9 kg) and then water (11.2 L) were poured at 48 ° C., and the mixture was stirred at the same temperature for 6 hours. The reaction solution was cooled to 0-5 ° C., stirred at the same temperature for 30 minutes, and allowed to stand for 12 hours. The obtained crystals were filtered off, washed with methanol (91 L), dried at 50 ° C. under reduced pressure, and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy. ] Benzyl} thiazolidine-2,4-dione hydrochloride (19.5 kg, 44.9 mol) was obtained (70% overall yield of Reference Example 1).

(Reference Example 2)
Method for quantitative analysis of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Compound A) The quantitative analysis method of is shown. The difference between (2-1) and (2-2) is the correction part regarding the water content contained in the purified composition of Compound A.
(2-1) Quantitative analysis of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Compound A) 1
Sample solution: acetonitrile-0.5% phosphoric acid aqueous solution (7:13)
Internal standard solution: Dissolve about 1 ml of methyl salicylate in the sample solution to make 200 ml.

  A standard solution was prepared as follows.

  About 0.04 g of the standard product of Compound A was accurately weighed into a 200 ml volumetric flask and dissolved by adding about 160 ml of sample solution, and then 10 ml of internal standard solution and sample solution were added to make 200 ml. After 10 ml of this solution was accurately placed in a 25 ml volumetric flask, a sample solution was added to make 25 ml.

  The measurement sample solution was prepared as follows.

  About 0.04 g of the sample was weighed into a 200 ml volumetric flask, and about 160 ml of the sample solution was dissolved. Then, 10 ml of the internal standard solution and the sample solution were added to make 200 ml. After 10 ml of this solution was accurately placed in a 25 ml volumetric flask, a sample solution was added to make 25 ml.

  The HPLC conditions are as follows.

Detection wavelength: 290nm
Column: L-column ODS 4.6 x 150 mm (Chemicals Evaluation and Research Institute)
Moving layer: 0.01M sodium acetate buffer (pH = 5) / acetonitrile mixture (13: 7)
Flow rate: 1ml / min (Adjust so that the internal standard retention time is about 17 minutes)
Column temperature: 40 ° C
Each peak area was determined from the chromatogram, and the content of Compound A was calculated according to the following formula.

Content of Compound A (%) = W1 × F1 × (QT / QS) × [1 / {W2 × (100-F2) / 100}] × 100
W1: Weighed amount of standard compound A (g)
W2: Weighed sample (g)
F1: Purity factor of standard compound A
F2: Moisture in sample measured with Karl Fischer moisture meter
QT: Peak area ratio between sample and internal standard
QS: Peak area ratio between Compound A standard product and internal standard substance As a result of analysis according to the above, the quantitative analysis value of Compound A used in Test Example 1 was 99.1% by weight. The quantitative analysis value of the crystals of Reference Example 1 was 99.4% by weight.
(2-2) Quantitative analysis of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Compound A) 2
Sample solution: acetonitrile-0.5% phosphoric acid aqueous solution (7:13)
Internal standard solution: Dissolve about 1 g of methyl salicylate in a sample solution (acetonitrile-water mixture 7:13) to make 200 ml.

  A standard solution was prepared as follows.

  About 0.02 g of a standard product of Compound A was accurately weighed into a 50 ml volumetric flask, dissolved by adding about 40 ml of sample solution, and then added with 5 ml of internal standard solution and sample solution to make 50 ml. After 10 ml of this solution was accurately placed in a 50 ml volumetric flask, a sample solution was added to make 50 ml.

  The measurement sample solution was prepared as follows.

  About 0.02 g of the sample was weighed into a 50 ml volumetric flask and dissolved by adding about 40 ml of the sample solution, and then 5 ml of the internal standard solution and the sample solution were added to make 50 ml. After 10 ml of this solution was accurately placed in a 50 ml volumetric flask, a sample solution was added to make 50 ml.

  The HPLC conditions are as follows.

Detection wavelength: 290nm
Column: L-column ODS 4.6 x 150 mm (Chemicals Evaluation and Research Institute)
Moving layer: 0.01M sodium acetate buffer (pH = 5) / acetonitrile mixture (13: 7)
Flow rate: 1 ml / min (Adjust so that the retention time of Compound A is about 10 minutes)
Column temperature: 40 ° C
Each peak area was determined from the chromatogram, and the content of Compound A was calculated according to the following formula.

Content of Compound A (%) = W1 × F1 × {(100-F2) / 100} × (QT / QS) × (1 / W2) × 100
W1: Weighed amount of standard compound A (g)
W2: Weighed sample (g)
F1: Purity factor of standard compound A
F2: Moisture (%) of the standard compound A
QT: Peak area ratio between sample and internal standard
QS: Peak area ratio between Compound A standard and internal standard As a result of analysis according to the above, the quantitative analysis value of Compound A used in Test Example 2 was 98.2% by weight.

(Reference Example 3)
Process for producing 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Compound A) monohydrate N- {2- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetylamino} -5-methoxyphenyl} -N-methylcarbamine produced according to the method described in JP-A-2001-72671 A suspension of tert-butyl acid (28.0 g, 54.31 mmol) in acetone (700 ml) was heated to 55 ° C., and water (234 ml) was added to the resulting solution. To this solution, 36% hydrochloric acid (46.2 ml) was added at the same temperature, and the reaction mixture was stirred at 55-58 ° C. for 5.5 hours. The reaction suspension was cooled to 25 ° C., and the precipitated crystals were filtered off and washed with a mixed solvent of acetone (58.8 ml) -water (25.2 ml). The obtained crystals were dried at 55 ° C. under reduced pressure to obtain the target compound (22.87 g, 50.61 mmol). Yield 93%.
Differential thermal analysis: about 77 ° C and about 99 ° C (endothermic equivalent to dehydration), about 203 ° C (endothermic), about 243 ° C (endothermic), about 281 ° C (endothermic).
¹ H-NMR (500 MHz, DMSO-d ₆ ) δ (ppm): 3.15 (1H, dd, J = 9.2 Hz, J = 14.1 Hz), 3.39 (1H, dd, J = 4.5 Hz, J = 14.1 Hz) , 3.94 (3H, s), 4.03 (3H, s), 4.95 (1H, dd, J = 4.5 Hz, J = 9.2 Hz), 5.67 (2H, s), 7.18 (2H, d, J = 8.7 Hz) , 7.19 (1H, brm), 7.30 (2H, d, J = 8.7 Hz), 7.54 (1H, d, J = 2.0 Hz), 7.74 (1H, d, J = 8.9 Hz), 12.09 (1H, s) .
Moisture analysis by volumetric Karl Fischer method: 4.27% (theoretical value of monohydrate: 3.99%).

5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Compound A) and formulation additives [the following additives Is a diagram showing the effect of maintaining the solubility of Compound A when adding one of them: hydroxypropylcellulose, croscarmellose sodium, yellow iron sesquioxide, lactose, magnesium stearate]. (Test Example 1) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride (Compound A) and formulation additives [the following additives FIG. 3 is a graph showing the effect of maintaining the solubility of Compound A when one is selected from: Opadry II, polyvinyl alcohol, and Opagros 2]. (Test Example 2)

Claims (21)

  5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof excludes water 98% by weight or more of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof A therapeutic agent for diabetes containing a purified composition and one or more selected from pharmacologically acceptable cellulose, cellulose derivatives, polyvinyl alcohol derivatives, and polyvinyl alcohol derivative mixtures as additives.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof excludes water The antidiabetic agent according to claim 1, which is 99% by weight or more.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is prevented from decreasing in solubility. The therapeutic agent for diabetes according to claim 1 or 2, wherein   Hydration of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is prevented. The therapeutic agent for diabetes according to claim 1 or 2, wherein   Prevents a decrease in solubility of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof The therapeutic agent for diabetes according to claim 1 or 2, wherein the absorption rate is maintained.   Hydration of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof comprises The antidiabetic agent according to claim 1 or 2, which is prevented in an aqueous solution.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof in an aqueous solution, The therapeutic agent for diabetes according to claim 1 or 2, which is excellent in solubility and stability over time of solubility.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof has reduced solubility. The antidiabetic agent according to claim 1 or 2, characterized in that it is prevented inside.   Reduced solubility of 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof The antidiabetic agent according to claim 1 or 2, which is prevented in the digestive tract.   The therapeutic agent for diabetes according to any one of claims 1 to 9, which is a preparation for oral administration.   The therapeutic agent for diabetes according to claim 10, wherein the preparation for oral administration is a tablet.   The antidiabetic agent according to any one of claims 1 to 11, wherein the additive is pharmacologically acceptable cellulose or a cellulose derivative.   The pharmacologically acceptable cellulose or cellulose derivative is selected from methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910 and croscarmellose sodium 1 The therapeutic agent for diabetes according to claim 12, which is a species or more.   The antidiabetic agent according to any one of claims 1 to 13, wherein the additive is a pharmacologically acceptable polyvinyl alcohol derivative.   The therapeutic agent for diabetes according to claim 14, wherein the pharmacologically acceptable polyvinyl alcohol derivative is a saponified product of polyvinyl alcohol.   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is 5- {4- The diabetes treatment according to any one of claims 1 to 15, which is [(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione hydrochloride. medicine.   The antidiabetic agent according to any one of claims 1 to 16, which is produced by a dry granulation method.   The antidiabetic agent according to any one of claims 1 to 16, which is produced by a wet granulation method.   The therapeutic agent for diabetes according to any one of claims 1 to 18, which is used for treating diabetes.   A 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} thiazolidine for the manufacture of a therapeutic agent for diabetes according to any one of claims 1 to 19. Use of 2,4-dione or a pharmacologically acceptable salt thereof and one or more additives selected from cellulose, cellulose derivatives, polyvinyl alcohol derivatives and polyvinyl alcohol derivative mixtures.   21. 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} for the manufacture of a therapeutic agent for diabetes according to any one of claims 1 to 20 Use of thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof and a pharmacologically acceptable cellulose or cellulose derivative.