TW200816995A - Pharmaceutical composition containing insulin sensitizers - Google Patents

Abstract

The present invention provides a therapeutic method for diabetes which can exhibits an excellent hypoglycaemia activity with little side effect. A medicine combining an insulin secretagogue and an insulin sensitizer.

Description

200816995 IX. Description of the Invention: [Technical Field] The present invention relates to a medicine for promoting insulin secretion promoting agent (suitable sulfonylurea agent) and an insulin resistance improving agent (suitable for the treatment and/or prevention of diabetes) medicine). The present invention relates to the use of the above-mentioned pharmaceutical agent for producing the above-mentioned medicine, or to the prevention or treatment of the above-mentioned diseases in which the above-mentioned medicine is administered to a warm-blooded animal (preferably human). [Prior Art] The insulin resistance improving agent is intended to reduce the blood sugar sputum by improving the insufficiency of insulin, and is administered as a therapeutic drug for diabetes to a patient. It is more known that insulin resistance improving agents are not only for diabetes, but also for glucose tolerance, hypertension, hyperlipidemia, diabetes mellitus (such as omental disease, nephropathy, neurological disorders), gestational diabetes, polycystic ovary Symptoms and the like are also caused by diseases such as insulin resistance or cardiovascular diseases such as atherosclerosis. Currently, commercially available insulin resistance improving agents include thiazolidinedione-based insulin resistance improving agents such as Octo Lida Zong and Rosik Lida Zong. The insufficiency of the action of insulin of these agents is due to the activation of PPAR (peroxisome proliferator-activated receptor) r. On the one hand, the insulin secretion promoting agent is administered to a patient with diabetes as a therapeutic drug for diabetes by a sulfonylurea agent (hereinafter referred to as SU agent) or a fast-acting insulin secretion promoting agent. However, side effects such as hypoglycemia or weight gain occur, and secondary ineffectiveness is also found due to long-term administration. Therefore, sufficient attention must be paid when using it. The combination of the insulin resistance improving agent and the SU agent is described, for example, in Patent Document 200816995. However, the effects of the combination of specific agents of the present invention remain unclear. [Patent Document 1] International Publication No. 98/36755 [Abstract] [Problems to be Solved by the Invention] In view of the above, the present inventors have a small side effect on long-term administration of drugs, and have an effect on most diabetic patients. As a result of repeated efforts by diabetes prevention and/or therapeutic agents, it has been found that an insulin secretion promoter and an insulin resistance improving agent can be combined to achieve the object, and the present invention has finally been completed. [Means for Solving the Problem] The present invention is: (1) A pharmaceutical composition comprising an insulin resistance improving agent and an insulin secretion promoting agent. (2) A pharmaceutical composition characterized in that an insulin resistance improving agent is combined with an insulin secretion promoting agent to reduce side effects of the sulfonylurea agent. (3) The pharmaceutical composition according to the above (1) is used for the prevention and treatment of diabetes mellitus which enhances the effect of lowering blood sugar. (4) The pharmaceutical composition according to any one of the above (1) to (3) wherein the insulin resistance improving agent is a thiazolidinedione-based insulin resistance improving agent. (5) The pharmaceutical composition according to any one of the above (1) to (3) wherein the insulin resistance improving agent is Piocrix or Rosicid. (6) The pharmaceutical composition according to any one of the above (1) to (3) wherein the insulin resistance improving agent is 5-{4-[(6-methoxy-1-methyl-γη-benzo) Imidazolyl-2-yl)methoxy]benzyldi1,3-1,3-thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof. The pharmaceutical composition according to any one of the above (1) to (6) wherein the insulin secretion promoter is a sulfonylurea agent. (8) The pharmaceutical composition according to any one of the above (1) to (6) wherein the insulin secretion promoting agent is Glimepiride, Glibenclamide or Curry Gliclazide. (9) The pharmaceutical composition according to any one of the above (1) to (6) wherein the insulin secretion promoting agent is Curry. (10) The pharmaceutical composition according to any one of the above (1) to (3), wherein the insulin secretion promoting agent is Kuley, and the insulin resistance improving agent is 5-{4-[(6-A) Oxy-1-methyl-11^benzimidazol-2-yl)methoxy]benzyldi1,3-1,3-thiazolidin-2,4-dione 1-hydrochloride. (11) The pharmaceutical composition according to any one of the above (1) to (6) wherein the insulin secretion promoting agent is a fast-acting insulin secretion promoting agent. (12) The pharmaceutical composition according to any one of (1) to (6) above, wherein the insulin secretion promoting agent is Nateglinide, Mitig 1 inide or R epag 1 inide. (13) The pharmaceutical composition according to any one of the above (1) to (6) wherein the insulin secretion promoting agent is nalhen Cullinin. (14) The pharmaceutical composition according to any one of the above (1) to (13) for preventing or treating sugar tolerance, hypertension, hyperlipidemia, diabetes mellitus, gestational diabetes, and more Cystic ovarian syndrome, atherosclerosis, diabetes. (15) A pharmaceutical composition according to any one of the above (1) to (13) which is for preventing or treating type 2 diabetes. The pharmaceutical composition according to any one of the above (1) to (15), which is a preparation for a compounding agent. (17) A pharmaceutical composition according to any one of the above (1) to (16) which is a preparation for oral administration. (18) Use of an insulin resistance improving agent and an insulin secretion promoting agent for producing a medicine containing an insulin resistance improving agent and an insulin secretion promoting agent as active ingredients. (19) The use of (18) above, wherein the insulin secretion promoting agent is a sulfonylurea. (20) As used in the above (18), wherein the insulin secretion promoting agent is Curry, Bili, Curry, or Curry. (21) The use according to any one of (18) to (20) above, wherein the insulin resistance improving agent is 5-{4-[(6-methoxy-1_methyl-111-benzimidazole- 2-yl)methoxy]benzyldi1,3-1,3-thiazolidin-2,4-dione or a pharmacologically acceptable salt thereof. (22) A method for treating diabetes, which comprises administering an insulin resistance improving agent and an insulin secretion promoting agent in combination. (23) A method of treating diabetes according to the above (22), wherein the insulin secretion promoting agent is a sulfonylurea agent. (24) The method for treating diabetes according to the above (22), wherein the insulin secretion promoting agent is kulima, kuli, or kulim. (25) The method of treatment according to any one of the above (22) to (24) wherein the insulin resistance improving agent is 5-{4-[(6-methoxy-1-methyl-1H-benzimidazole) -2-yl) methoxy]benzyl 1,3-thiazolidin-2,4-dione or a pharmacologically acceptable salt thereof. 200816995 "Insulin resistance improving agent" in the present invention is a general term for an agent for improving insulin resistance and enhancing insulin sensitivity, for example, [4_[2-(4-ethyl-2-pyridyl)ethoxy] of the following structural formula] Benzylthiazolidinedione (common name: Pioglitazone, Yipi Occidental), 5-[[4-[2-(methyl-2-pyridineamino)ethoxy] Phenyl]methyl]·2,4-thiazolidinedione (common name: Rosiglitazone, Yiluoxik Lida Zongmanate), 5-[[(3,4- Dihydro-3-methyl-4-oxo-2-quinazolinyl)methoxy]benzyl]-2,4-thiazolidinedione (common name: Balaglitazone, (2S) )-2-methoxy-3- [4-[3-(4-phenoxyphenoxy)propoxy]phenyl]propionic acid (LY-519818, common name: Navelitazar, AMG-131 (preferably p-toluenesulfonate of AMG-131), MBX-10 2C common name: Metaglidasen,

-9- .200816995

Occidental

Rosick Lidzong

Barak Lidzong

That Bekley Dazza AMG-131 Medak Lida

ΜΒΧ2040 (Medical Lida first analogue), 5-{4·[(6-methoxy-1-methyl-1 Η-benzimidazol-2-yl) methoxy group described in Japanese Patent No. 4,687,777 Benzylidene 1,3-thiazolidine-2,4-dione and its pharmacologically acceptable salt (preferably 5-{4-[(6-methoxy-1-methyl-1Η-benzimidazole-2) -yl) methoxy]benzyl}thiazolidin-2,4-dione 1 hydrochloride). Yipike Ou Lida Zong, Rosik Lida Zong, Barak Lida Zong, 5-{4-[(6-methoxy-b-methylbenzimidazol-2-yl)methoxy]benzyl bromide, A thiazolidinedione-based insulin resistance improving agent such as thiazolidine-2,4-dione and its music physic acid. Occidental is a US patent -10- 200816995

The compound of the present invention is a pharmacologically acceptable salt (hydrochloride, etc.). Rosiek Lidzong is a compound described in U.S. Patent No. 5,002,953, and the Roxik Lidazong of the present invention contains a pharmacologically acceptable salt (maleate or the like). The Beklikita is a compound described in the International Publication No. 02/1008 1 3 booklet, and the Bekliktarza of the present invention contains its pharmacologically acceptable salt (hydrochloride, etc.). Barak Lida Zong is a compound described in International Publication No. 97/41097, and the Barak Lida Zong of the present invention contains its pharmacologically acceptable salt (hydrochloride, etc.). The dexamethasone is a compound described in U.S. Patent No. 6,262,118, and the dextroprofen of the present invention comprises a pharmacologically acceptable salt (hydrochloride, etc.). AMG-131 is a compound described in International Publication No. 2001/579, International Publication No. 2001/579, and International Publication No. 2005/33074, and AMG-131 of the present invention contains its pharmacologically acceptable salt (salt). Acid salt, etc.). 5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione a compound represented by the following structure or a pharmacologically acceptable salt thereof

The compound described in the 5,886,014 and International Publication No. 00/7 1 540 booklet "Insulin secretion promoter" is not limited as long as it has an insulin secretion effect from pancreatic cold cells, and is preferably sulfonylurea. Agent (SU agent) or a fast-acting insulin secretion promoter, suitable for su. The "sulfonylurea (su agent)" is not limited to the receptor for pancreatic islet cells -11-200816995 (SUR 1), and there is no restriction on the agent that promotes insulin secretion. For example, the following structural formula

1-{4_[2·(3-ethyl-4-methyl-2-oxy-3-pyrroline-1-carboxyguanidino)ethyl]-benzenesulfonyl}-3-(() Trans-4-methylcyclohexyl)urea (common name: kulimamide), 1·{4·[2-(5-chloro-2-methoxybenzylamino)ethyl]benzenesulfonate Keb 3-cyclohexylurea (common name: GlibuHde or Curry will be hardened), 1_(3_吖bicyclo[3.3.0]oct-3-yl)-3 (for Toluenesulfonyl)urea (common name: Curry Bulajid), N-(butylammonium)-4-toluenesulfonyl (common name: Tolbutamide, etc., Yikuli will suffer The "fast-acting insulin secretion-promoting agent" is not limited to the SU receptor (SUR1) which acts on the pancreatic islet cells of the pancreatic sputum, and has an agent for promoting insulin secretion, for example, the following structural formula-12 - 200816995

Natal Kulini

Phenylalanine, such as N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (common name: 纳铁库利尼得), expressed by Mikuculini a derivative, 2-benzyl-3-(cis-hexahydroisoindol-2-ylcarbonyl)propionate (common name: Mikukulinide, Yimijikulinide Calcium Hydrate) 2-Ethoxy-4-[indolyl-[1-(2-piperidinylphenyl)-3-methyl-1-butyl]aminecarbonylmethyl]benzoic acid (common name: Lebakulini Get), Yi Natie Culiny. Further, if the above compound has an asymmetric carbon, it also includes an optical isomer and a mixture of these isomers. Further, it includes a hydrate of the above compound. According to the present invention, the insulin resistance improving agent and the insulin secretion promoting agent are used in combination for each of them, suggesting an excellent effect. Clinically, two drugs should be administered at the same time, so the insulin secretion promoter and the insulin resistance improving agent can be administered in the form of a compounding agent. Alternatively, each single agent can be administered at the same time. Alternatively, each single agent may be administered at appropriate intervals. The interval of administration to be achieved by the superior effects of the administration of such two agents can be confirmed by clinical or animal experiments. -13- 200816995 The pharmaceutical composition of the present invention is administered in various forms. The form of administration is not limited, and is determined depending on the form of each preparation, the age, sex and other conditions of the patient, the degree of the disease, and the like. For example, it can be administered orally in the form of a lozenge, a lozenge, a powder, a granule, a syrup, a liquid, a suspension, an emulsion, a granule, and a capsule. Suitable lozenge. These various preparations can be formulated according to a conventional method in a conventional pharmaceutical excipient, a binding agent, a disintegrating agent, a moisturizing agent, a dissolving agent, a flavoring, a odor, a coating agent, and the like, which are conventionally used in the field of pharmaceutical preparations. Chemical. ® When formed into a tablet form, the carrier can be widely used in the art, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid and the like. Water, ethanol, propanol, monosaccharide, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc., dry starch, alginic acid Sodium, amaranth, kelp gum, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium dodecyl sulfate, mono-hard glyceride, starch, lactose and other disintegrating agents, white sugar, A clogging inhibitor such as glyceryl tristearate, cocoa butter or hydrogen added oil, an absorption enhancer such as a fourth-grade ammonium base or sodium dodecyl sulfate, a moisturizer such as glycerin or starch, starch, lactose, kaolin, and bentonite A sorbent such as colloidal citric acid, a talc such as refined talc, stearate, boric acid, or polyethylene glycol. The tablet may, if necessary, be used as a tablet for applying a usual lotion, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated ingot or a double ingot, or a multi-layer ingot. When formed into a form of nine doses, the carrier can be widely used in the art, such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin-14-200816995, talc and other excipients, gum arabic, gum tragacanth End, gelatin, ethanol and other bonding agents, laminating agents such as kelp gelatin. Further, if necessary, a coloring agent, a preservative, a flavor, a flavor, a sweetener, or the like may be contained. The administration amount and administration ratio of each of the diabetes therapeutic agents used in the present invention vary widely depending on various activities such as the activity of the substance, the symptoms of the patient, the age, and the body weight. For example, in the case of insulin resistance improving agents, the doses of these two agents can be different because of the in vivo activity of the clinical and diabetic models. different. Further, depending on the excellent effects of the insulin resistance improving agent and the insulin secretion promoting agent, the amount can be lowered. The insulin resistance improving agent contained in the above-mentioned pharmaceutical preparation is not particularly limited and can be appropriately selected from a wide range, and is usually suitably contained in an amount of from 1 to 70% by weight, preferably from 1 to 30% by weight based on the total amount of the composition. The dosage is as described above, depending on the symptoms, age, body weight, dosage form, etc., usually for adults on the 1st, the lower limit is 〇.〇〇〇lmg/kg (preferably 0.001mg/kg, more preferably 0.01mg/kg) The upper limit is 30 mg/kg (preferably 3 mg/kg, more preferably 0.3 mg/kg) and can be administered in 1 or 2 doses. The amount of the insulin secretion-promoting agent contained in the above-mentioned pharmaceutical preparation is not particularly limited and is appropriately selected in a wide range, and is usually 1 to 70% by weight, preferably 1 to 30% by weight, based on the total composition. The dosage varies depending on the symptoms, age, body weight, dosage form, etc. 'usually for adults 1 day, the lower limit is 〇.〇〇〇lmg/kg (suitable 0.001mg/kg, more preferably 0.01mg/kg), the upper limit is 30mg /kg (preferably 3mg/kg, more preferably 3.3mg/kg) can be -15-.200816995 for 1 or 2 rounds. The ratio of the insulin resistance improving agent to the insulin secretion promoting agent can also be greatly changed, and the insulin secretion promoting agent and the present invention can be in the range of 1:10 0 0 to 10 0 ·1. The insulin resistance improving agent is capable of dividing each of the above-mentioned administration amounts by one time, or several times (should be one or two times a day), and each of them is administered at the same time or time. [Effects of the Invention] According to the present invention, when an insulin secretion-promoting agent is used in combination with an insulin resistance-improving agent, blood sugar can be greatly reduced, so that diabetes can be effectively prevented and treated. The medicine is also caused by diabetes-resistant diseases such as diabetes (especially type 2 diabetes), hyperglycemia, glucose insufficiency, hypertension, hyperlipidemia, diabetes mellitus, gestational diabetes, polycystic ovary syndrome, etc. Cardiovascular diseases such as atherosclerosis are also effective. It is possible to quickly improve hyperglycemia by selecting the type of each agent, the method of administration, and the amount of administration according to the symptoms. Even if it is administered for a long period of time, it is expected to have a hypoglycemic effect of stability, and the use of the by-products is rare. It is a preventive and therapeutic drug for the above diseases. [Embodiment] [Best Mode for Carrying Out the Invention] The present invention will be described in more detail by way of examples, but the invention is not limited thereto. [Examples] <Test Example 1 > Since 5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]-16-200816995 benzyl The 1,3-1,3-thiazolidin-2,4-dione hydrochloride (Compound A) and the sulphate sulphate (Compound B) are administered with a hypoglycemic effect to enhance the effect of insulin resistance. The 16-week-old male obese Zucker fatty mouse (sold by Charles River, Japan) was divided into a control group, a compound A group, a compound B group, and 4 groups (5/group). The feed (feed: FR-2, Funabashi Farm Company) in each group was freely ingested, and the compound a group and the sputum group were administered with a compound of the insulin resistance improving agent, 0.05 mg/kg, in the control group and the compound B group. One dose of solvent (0.5% CMC) 1 ® was administered orally for 1 week. Each group was hunted for one night, and the solvent was administered to the control group and the compound A group, and the compound B group and the sputum group were administered in a single dose of 6 mg/kg of the compound B of the SU agent. Single-return oral administration of solvent or SU agent, immediately before administration, administration of sputum. After 5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, and 4 hours, blood was collected from the tail vein of all individuals. Blood glucose was measured by a fully automatic sugar analyzer (Glucoroder-GXT, manufactured by A&T). From the blood glucose 各 at each time point of the measurement minus the blood glucose 投 obtained prior to the administration, the area under the blood glucose 値 curve is calculated for each individual ^, and the average 値 and standard error of the area under the blood glucose 値 curve of each group are calculated. As shown in Figure 1. The greater the reduction in area under the blood glucose curve, the higher the hypoglycemic effect. It is shown in Fig. 1 that the compound A group which only administered the solvent after the hunger strike showed the area under the curve of the blood glucose without change of the control group. On the one hand, the area under the blood glucose sputum curve of the compound B group and the sputum group after the hunger strike decreased, and the compound A was repeatedly administered to the sputum group, compared with the compound B group which did not administer the compound A. Significantly reduced. This is shown to enhance hypoglycemic action by using Compound -17-200816995 A with Compound B. The medicine of the present invention is useful for the prevention and treatment of diabetes because it is more effective than the separate administration of the medicament to lower blood sugar. Further, since the medicine of the present invention can be sufficiently used even when it is used in a small amount, it is possible to reduce the side effects (e.g., weight gain, hypoglycemia, etc.) of the SU agent in the treatment of diabetes. <Formulation Example> (Formulation Example 1) Capsule Compound A 1 mg Compound B 2 mg Lactose 117 mg Corn starch 5 8 mg Magnesium stearate 2 me Total 18 0 mg The powder of each of the above ingredients is thoroughly mixed and put Capsules can be used to make capsules. The amount of the active ingredient and the content and type of each additive are not limited thereto. -18- 200816995 (Formulation Example 2) Lozenge Compound A 1 mg Compound B 2 mg Lactose 94 mg Corn starch 42 mg Microcrystalline cellulose 6 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 1 ms Total 1 50 0 mg The powder of each of the above ingredients was thoroughly mixed, and compression-molded into 150 mg by weight of each tablet. These tablets may also be coated with sugar or film if necessary. The amount of the active ingredient and the content and type of each additive are not limited thereto. [Simple description of the diagram] Figure 1 shows the order of 5-{4-[(6-methoxy-1·methyl-1H-benzimidazol-2-yl)methoxy]benzyldi A graph showing the enhancing effect of the hypoglycemic effect of thiazolidine-2,4-dione 1 hydrochloride (Compound A) and Curry and Bitter (Compound B). (Test Example 1) -19 -

Claims (1)

200816995 X. Patent application garden: 1. A pharmaceutical composition which is composed of an insulin resistance improving agent and an insulin secretion promoting agent. A pharmaceutical composition characterized by combining an insulin resistance improving agent with an insulin secretion promoting agent to reduce side effects of a sulfonylurea agent. 3. The pharmaceutical composition of claim 1 is used for the prevention and treatment of diabetes which is more effective in lowering blood sugar than alone. The pharmaceutical composition according to any one of claims 1 to 3, wherein the insulin resistance improving agent is a thiazolidinedione-based insulin resistance improving agent. 5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the insulin resistance improving agent is Pi〇glit a ζ ο ne or Rosiglitazone . The pharmaceutical composition according to any one of claims 1 to 3, wherein the insulin resistance improving agent is 5-{4-[(6-methoxy-i-methyl-1H-benzoru Imidon-2-yl)methoxy]dolfidine 1,3-thiadopyridinium 2,4-dione or its pharmacologically acceptable salt. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretion promoting agent is a sulfonylurea agent. 8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretion promoting agent is GHmepinde, GHbenclannde or Curry Bula GHclazide. 9. The pharmaceutical composition of any one of the items S1 to 6 of the patent application range, wherein the insulin secretion promoter is Kuli. -20-200816995 10. The pharmaceutical composition according to any one of claims 1 to 3, wherein the insulin secretion promoting agent is Kuley, and the insulin resistance improving agent is 5-{4·[( 6-Methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyli1,3-1,3-thiazolidin-2,4-dione 1 hydrochloride. 11. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretion promoting agent is a fast-acting insulin secretion promoting agent. 12. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretion promoter is Nateglinide, Mitiglinide or Lebakuli Repaglinide. 13. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretion promoting agent is nalum Cullinin. 14. The pharmaceutical composition according to any one of claims 1 to 13, which is for preventing or treating sugar tolerance, blood pressure, dyslipidemia, diabetes mellitus, gestational diabetes, polycystic Ovarian syndrome, atherosclerosis, diabetes. 15. The pharmaceutical composition of any one of claims 1 to 13 for use in the prevention or treatment of type 2 diabetes. 16. The pharmaceutical composition according to any one of claims 1 to 15, which is a preparation for a compounding agent. 17. The pharmaceutical composition according to any one of claims 1 to 16, which is a preparation for oral administration. An insulin resistance improving agent and an insulin secretion promoting agent for use in the manufacture of a medicament containing an insulin resistance improving agent and an insulin secretion promoting agent as active ingredients. -21 - 200816995 19. The use of the item μ of the patent application, wherein the insulin secretion promoting agent is a sulfonylurea agent. 20·If the application of the scope of patent application is 18th, the insulin secretion promoter is Culme, the Curry, the Curry, or the library “Lei Lajid. 21·If the patent application range is 18 to 20 The use of any one of the items, wherein the insulin resistance improving agent is 5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl 1,3-thiazolidin-2,4-dione or a pharmacologically acceptable salt thereof 22. A method for treating diabetes, which is characterized by administering an insulin resistance improving agent and an insulin secretion promoting agent in combination. The method for treating diabetes according to the scope of claim 22, wherein the insulin secretion promoting agent is a sulfonylurea agent. 24. The method for treating diabetes according to the scope of claim 22, wherein the insulin secretion promoting agent is Culme, The treatment of diabetes according to any one of claims 22 to 24, wherein the insulin resistance improving agent is 5-{4-[(6) -Methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzylthiazole pyridine-2,4-dione or its pharmacological capacity Salt. -22-