WO2008026668A1

WO2008026668A1 - Medicinal composition containing insulin resistance improving agent

Info

Publication number: WO2008026668A1
Application number: PCT/JP2007/066836
Authority: WO
Inventors: Shoichi Kanda; Ryutaro Nakashima
Original assignee: Daiichi Sankyo Company, Limited
Priority date: 2006-08-31
Filing date: 2007-08-30
Publication date: 2008-03-06
Also published as: TW200816995A

Abstract

It is intended to provide a method of treating diabetes which exerts an excellent hypoglycemic effect with little side effects. Namely, a drug wherein an insulin secretion promoter is combined with an insulin resistance improving agent.

Description

Specification

Pharmaceutical composition containing an insulin sensitizer

Technical field

[0001] The present invention relates to a medicament (preferably a medicament for treating and / or preventing diabetes) comprising a combination of an insulin secretagogue (preferably sulfonylurea) and an insulin resistance ameliorating agent. About.

[0002] Further, the present invention relates to the use of the above-mentioned drug for producing the above-mentioned medicine, or a method for preventing or treating the above-mentioned disease wherein the above-mentioned medicine is administered to a warm-blooded animal (preferably a human).

[0003] Insulin resistance improving agents are administered to patients as antidiabetic agents in order to lower blood glucose levels by improving insulin dysfunction. In addition, insulin sensitizers can be used for diabetic strength, glucose tolerance, hypertension, hyperlipidemia, diabetic complications (eg, retinopathy, nephropathy, neuropathy), gestational diabetes, polycystic ovary. It is known that diseases caused by insulin resistance such as syndrome are also effective for cardiovascular diseases such as atherosclerosis. Examples of insulin resistance improvers currently on the market include thiazolidinedione insulin resistance improvers such as piodaritazone and rosiglitazone. It is said that the amelioration of insulin dysfunction by these drugs is due to activation of PPAR (peroxisome proliferator activated receptor) ₇ .

[0004] On the other hand, sulfonylurea agents (hereinafter referred to as SU agents), fast-acting insulin secretion promoters, and the like are administered to diabetic patients as therapeutic agents for diabetes. However, since side effects such as hypoglycemia and weight gain occur and secondary inefficiency occurs due to long-term administration, sufficient caution is required during use.

[0005] A combination of an insulin resistance improving agent and a SU agent is described in Patent Document 1, for example. However, the effect of the specific drug combination of the present invention has not been clarified.

Patent Document 1: International Publication No. 98/36755 Pamphlet Disclosure of the invention

Problems to be solved by the invention

[0006] In view of the above situation, the present inventors have conducted extensive research on anti-diabetic and / or therapeutic agents that have few side effects even in long-term administration of drugs and are effective for many diabetic patients. The inventors have found that the object can be achieved by combining an insulin secretagogue and an insulin resistance improving agent, and have completed the present invention.

Means for solving the problem

[0007] The present invention provides:

The present invention

(1) A pharmaceutical composition comprising a combination of an insulin resistance improver and an insulin secretion promoter,

(2) A pharmaceutical composition characterized in that side effects of the sulfonylurea agent are reduced by combining an insulin resistance improver and an insulin secretion promoter,

(3) The pharmaceutical composition according to the above (1), which is used for the prevention and treatment of diabetes whose blood glucose lowering action is enhanced as compared with single administration,

(4) The pharmaceutical composition according to any one of the above (1) to (3), wherein the insulin resistance improving agent is a thiazolidinedione insulin resistance improving agent,

(5) Insulin resistance-improving drug power A pharmaceutical composition according to any one of the above (1) to sol (3), which is pioglitazone or rosiglitazone,

(6) Insulin resistance ameliorating power 5- {4-[(6_methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzylto 1,3-thiazolidine-2,4-dione or its The pharmaceutical composition according to any one of (1) to (3) above, which is a pharmacologically acceptable salt,

(7) 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 secretagogue is glimepiride, darivenclamide, or darliclazide,

(9) The pharmaceutical composition according to any one of (1) to (6) above, wherein the insulin secretagogue is darivenclamide, (10) The insulin secretagogue is darivenclamide, and the insulin resistance improving agent is 5_ {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3 -The pharmaceutical composition according to any one of (1) to (3) above, which is -thiazolidine-2,4-dione monohydrochloride,

(11) The pharmaceutical composition according to any one of (1) to (6) above, wherein the insulin secretagogue is a rapid-acting insulin secretagogue.

(12) The pharmaceutical composition according to any one of (1) to (6) above, wherein the insulin secretagogue is nateglinide, mitiglinide or levaglinide,

(13) The pharmaceutical composition according to any one of (1) to (6) above, wherein the insulin secretagogue is nateglinide,

(14) Above (1) to (13) for prevention or treatment of glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycystic ovary syndrome, atherosclerosis, diabetes A pharmaceutical composition according to any one of

(15) The pharmaceutical composition according to any one of (1) to (13) above, for the prevention or treatment of type 2 diabetes,

(16) The pharmaceutical composition according to any one of (1) to (15) above, which is a preparation for a combination drug,

(17) The 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 improver and an insulin secretagogue to produce a medicine containing an insulin resistance improver and an insulin secretagogue as active ingredients,

(19) The use according to the above (18), wherein the insulin secretagogue is a sulfonylurea agent,

(20) Insulin secretion promoter power Use according to (18) above, which is glimepiride, darivenclamide or darliclazide,

(21) Insulin resistance improver S, 5- {4-[(6_methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzylto 1,3-thiazolidine-2,4-dione Or a pharmacologically acceptable salt thereof, the use according to any one of (18) to (20) above,

(22) Administering an insulin resistance improver and an insulin secretagogue in combination A method of treating diabetes, characterized by

(23) The method for treating diabetes according to the above (22), wherein the insulin secretion promoter is a sulfonylurea agent,

(24) The therapeutic method according to the above (22), wherein the insulin secretagogue is glimepiride, darivenclamide, or daliclazide,

(25) Insulin resistance-improving agent 5- {4-[(6_methoxy-1-methyl-1H-benzimidazole-2-yl) methoxy] pendinoleto 1,3-thiazolidine-2,4-dione or its The therapeutic method according to any one of! /, (22) to (24) above, which is a pharmacologically acceptable salt.

[0008]

In the present invention, the “insulin resistance improving agent” is a general term for drugs that improve insulin resistance and enhance insulin sensitivity. For example, [4- [2- (4 -Ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione (generic name: pioglitazone, preferably pioglitazone hydrochloride), 5 _ [[4- [2- (methyl-2-pyridylamino) ethoxy Ci] phenyl] methyl] -2,4-thiazolidinedione (generic name: rosiglitazone, preferably rosiglitazone maleate), 5-[[((3,4-dihydro-3-methyl-4-oxo) 2-quinazolinyl) methoxy] benzyl] -2,4-thiazolidinedione (generic name: baraglitazone), (2S) _2-methoxy-3- [4- [3_ (4-phenoxyphenoxy) propoxy] hue Ninore] propanoic acid (LY-519818, generic name: nabeglitazar), AMG-131 (preferably AMG-1 31 para-toluenesulfonate), MBX-102 (generic name: metaglidacene),

[0009] [Chemical 1]

Pioglitazone

Rosiglitazone

N

One

[0010] ΜΒΧ 5- {4-[(6-Methoxy-1-methyl-1Η-benzimidazo mononole-2 1,3-thiazolidine-2,4-dione and pharmacologically acceptable salts thereof (preferably 5- {4-[(6_methoxy-1-methyl-1Η-benzimidazol-2-yl) methoxy] benzyl} thiazolidine-2,4-dione monohydrochloride). And pioglitazone, rosiglitazone, valaglitazone, 5- {4-[(6_methoxy-1-methyl-1Η-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2 It is a thiazolidinedione-based insulin resistance improving agent such as 4-dione and pharmacologically acceptable salts thereof.

[0011] Pioglitazone is a compound described in US Pat. No. 4,687,777, and pioglitazone of the present invention includes a pharmacologically acceptable salt thereof (hydrochloride, etc.). Rosiglitazone is a compound described in US Pat. No. 5,002,953, and rosiglitazone of the present invention includes pharmacologically acceptable salts thereof (such as maleate). Nabedalitazal is a compound described in the pamphlet of International Publication No. 02/100813. Tazar includes pharmacologically acceptable salts (hydrochlorides, etc.). Balaglitazone is a compound described in WO 97/41097 pamphlet, and the balaglitazone of the present invention includes pharmacologically acceptable salts (hydrochlorides and the like) thereof. Metagridacene is a compound described in US Pat. No. 6,262,118, and metaglidacene of the present invention includes pharmacologically acceptable salts thereof (hydrochlorides and the like). AMG-131 is a compound described in International Publication No. 2001/579 pamphlet, International Publication No. 2001/579 pamphlet and International Publication No. 2005/33074 pamphlet. Includes acceptable salts (hydrochlorides, etc.). 5- {4-[(6_Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl 卜 1,3-thiazolidine-2,4-dione is a compound represented by the following structure Or a pharmacologically acceptable salt thereof,

[0012] [Chemical 2]

[0013] The compounds described in JP-A-9-295970, EP 0745600, US Pat. No. 5,886,014 and WO 00/71540 pamphlet.

In the present invention, the “insulin secretion promoter” is not particularly limited as long as it is a drug having an action of secreting insulin from β-cells, and preferably a sulfonylurea agent (SU agent) or a fast-acting agent. Type insulin secretion promoter, and SU agent is preferable. “Sulfoninoreurea (SU)” is not particularly limited as long as it is an agent that acts on the SU receptor (SUR1) of prestigious Langerno and Suns 0 cells and promotes insulin secretion! / , For example, is represented by the following structural formula

[0015] [Chemical 3] Glimepiride Glibenclamide Gliclazide

Tolbutamide

[0016] 1- {4- [2- (3_Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl] -phenylsulfonyl} -3_ (& 113-4-methylcyclohexyl ) Urea (generic name: glimepiride), 1- {4- [2- (5_black mouth-2-methoxybenzamido) ethyl] phenylsulfonyl} -3_cyclohexylurea (generic name: glyburide or darribenclamide), 1_ (3-azabicyclo [3.3.0] oct-3-yl) -3- (para-tolylsulfonyl) urea (generic name: gliclazide), N- (butylcarbamoyl) -4-methylbenzenesulfonamide (generic name) : Tolptamide) and the like, and darbenbenclamide is preferred. The `` rapid-acting insulin secretagogue '' is not particularly limited as long as it is an agent that acts on the SU receptor (SUR1) of the precocious islets of Langernos / 3 cells and promotes insulin secretion. For example, represented by the following structural formula:

[0017] [Chemical 4]

Nateglinide

Mitiglinide

Levaglinide

[0018] Phenylalanine derivatives such as N- (trans_4-Isoprovircyclohexanecarbonyl) -D-phenylalanine (generic name: nateglinide), 2-benzyl-3_ (cis-hexahydroisoindrin-2- Ylcarbonyl) propionate (generic name: mitiglinide, preferably mitiglinide calcium hydrate), 2-ethoxy-4- [Ν- [1- (2-piperidinophenyl) -3-methyl-1-butyl ] Aminocarbonylmethyl] benzoic acid (generic name: levaglinide), and nateglinide is preferred.

[0019] In addition, when the compound has an asymmetric carbon, an optical isomer and a mixture of these isomers are also included. Furthermore, the hydrate of the said compound is also included.

[0020]

According to the present invention, the insulin resistance improving agent and the insulin secretagogue are superior in comparison with each single agent because they are combined and used. Clinically, it is convenient to administer both drugs at the same time. Therefore, the insulin secretagogue and the insulin resistance ameliorating agent can be administered in the form of a combination drug. Each single agent can also be administered simultaneously. In addition, each single agent can be administered in succession at an appropriate interval. The interval between doses allowed to achieve the superior effects achieved by the administration of both drugs can be confirmed clinically or by animal experiments.

[0021] The pharmaceutical composition of the present invention is administered in various forms. The dosage form depends on various dosage forms, the patient's age, sex and other conditions, the degree of disease, etc. It is determined. For example, it is orally administered in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, condyles and capsules. Preferably, it is a tablet.

[0022] These various preparations are known in general that can be used in known pharmaceutical preparation fields such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, coating agents, etc. It can be formulated using adjuvants.

[0023] In molding into a tablet form, conventionally known carriers can be widely used as carriers. For example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, key Excipients such as acids, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polybulurpyrrolidone, dry starch , Sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc., white sugar, stearin, cacao Disintegration inhibitors such as butter and hydrogenated oil, Class 4 Absorption accelerators such as ammonium base and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal key acid, purified talc, stearate, boric acid powder, polyethylene glycol Examples of such lubricants are as follows. Furthermore, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

[0024] In molding into a pill form, a conventionally known carrier can be widely used as a carrier. For example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, Examples thereof include binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran strength.

[0025] Further, if necessary, a colorant, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained.

[0026] The dose and administration ratio of each antidiabetic agent used in the present invention can vary greatly depending on various conditions such as activity of individual substances, patient symptoms, age, body weight and the like. For example, taking an insulin resistance improving agent as an example, pioglitazone and rosiglitazone are Since in vivo activity in clinical and diabetic animal models is different, these

The dosage of the two drugs can vary. Moreover, each dose can be reduced by the excellent effect of the combined use of an insulin resistance improving agent and an insulin secretagogue.

[0027] The insulin resistance improving agent contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

[0028] As described above, the dose varies depending on symptoms, age, body weight, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.001 mg / kg, moreover, 1 day for an adult) Preferably 0

• A maximum of 30 mg / kg (preferably 3 mg / kg, more preferably 0.3 mg / kg) can be administered once or twice.

[0029] The amount of the insulin secretagogue contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight, based on the total composition. It is appropriate that the amount be

[0030] The dose varies depending on symptoms, age, body weight, dosage form, etc.

1 day, the lower limit is 0.0001 mg / kg (preferably 0.001 mg / kg, more preferably 0.01 mg / kg), and the upper limit is 30 mg / kg (preferably 3 mg / kg, more preferably 0.3 mg / kg). Or do it twice.

[0031] The dose ratio of the insulin resistance ameliorating agent and the insulin secretagogue may also be in the range of 1: 1000 to 1000: 1 in force-weight ratio that can vary significantly.

[0032] In the present invention, the insulin secretion promoter and the insulin resistance ameliorating agent each have the above dosage once or several times a day (preferably once a day or Divided into two doses, each administered at the same time or separately at different times.

The invention's effect

[0033] According to the present invention, by using a combination of an insulin secretagogue and an insulin resistance improving agent, blood sugar is greatly reduced, and therefore it is possible to effectively prevent and treat diabetes. In addition, the drug is caused by insulin resistance such as diabetes (especially type 2 diabetes), hyperglycemia, glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycystic ovary syndrome, etc. Diseases such as atherosclerosis cardiovascular system It is also effective for diseases. Furthermore, by appropriately selecting the type, administration method, and dose of each drug according to the symptoms, rapid improvement of hyperglycemia and stable hypoglycemic effect even after long-term administration are expected, and side effects are manifested. Very few! /, Which can be a prophylactic and therapeutic drug for the above diseases

[0034] [Fig. 1] 5- {4-[(6_Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} _ 1,3-thiazolidine-2,4-dione 1 hydrochloric acid FIG. 3 is a graph showing the effect of enhancing blood glucose lowering effect by administering a salt (compound A) and darivenclamide (compound B) in combination. (Test Example 1) The best mode for carrying out the invention

Next, the ability to explain the present invention in more detail with reference to examples and the like. The present invention is not limited to these.

Example

5- {4-[(6_Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione hydrochloride (compound A) and daribenclamide Effect of concomitant administration of (Compound B) on hypoglycemic effect

16-week-old male obesity Zucker fatty rat (sold by Nippon Chiyar Suriba Co., Ltd.) with severe insulin resistance and increased blood glucose level was administered to the control group, compound A group, compound B group and combination group. Divided into 4 groups (5 / group). In all groups, feed (feed: FR-2, Funabashi Farm Co., Ltd.) can be freely consumed. Compound A, a combination group, and compound A 0.05 mg / kg, a control group, and compound B The group was orally administered with vehicle (0.5% CMC) only once a day for 1 week.

[0037] After all the groups were fasted overnight, the control group, compound A group, and the compound B group and the combination group were administered a single dose of compound B, 6 mg / kg, as the SU agent. Blood was collected from the tail vein of all individuals immediately before single oral administration of solvent or SU, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, and 4 hours after administration. The blood glucose level was measured using a sugar analyzer (Glucor ₀ der-GXT, manufactured by A & T Co., Ltd.). Calculate the area under the blood glucose curve for each individual from the value obtained by subtracting the blood glucose level immediately before administration from the blood glucose level measured at each time point. The mean value and standard error of the area under the blood glucose curve were calculated and shown in FIG. The lower the area value under the blood glucose level curve, the higher the blood glucose lowering effect.

From FIG. 1, the compound A group to which only the solvent was administered after fasting showed an area value under the blood glucose level curve that was not different from the control group. On the other hand, the area under the blood glucose level curve of the compound B group and the combination group to which the SU agent was administered after fasting decreased, and the compound A was administered to the combination group to which the compound A was repeatedly administered. As a result, the value decreased significantly compared to the compound B group. This indicates that the combined use of Compound A and Compound B enhanced the hypoglycemic effect.

[0039] Accordingly, the medicament of the present invention lowers blood glucose more effectively than single administration of a drug, and thus is useful for the prevention and treatment of diabetes. In addition, since the medicament of the present invention can provide a sufficient effect even when a smaller amount is used compared to the case where each drug is administered alone, side effects that the SU agent is considered to have in the treatment of diabetes Can reduce power (eg, weight gain, hypoglycemia).

[0040]

(Formulation Example 1) Capsule

Compound A 1 mg

Compound B 2 mg

Ratatose 117 mg

Corn starch 58 mg

Magnesium stearate 2 mg

180 mg total

Capsules can be produced by thoroughly mixing the powders of the components shown above and filling the capsules. The dose of active ingredient and the content of each additive are not limited to these.

[Formulation Example 2] Tablet

Compound A 1 mg

Compound B 2 mg Ratatose 94 mg

Corn 'starch 42 mg

Microcrystalline cellulose 6 mg

4 mg

Acid ma 1 mg

150 mg total

Mix the powder of each component shown above well and compress it into tablets of 150mg weight. If necessary, these tablets may be coated with sugar or film. The dosage of active ingredients and the content of each additive are not limited to these.

Claims

The scope of the claims

[I] A pharmaceutical composition comprising a combination of an insulin resistance improving agent and an insulin secretagogue

Yes

[2] A pharmaceutical composition characterized in that side effects of a sulfonylurea agent are reduced by combining an insulin resistance improving agent and an insulin secretagogue.

[3] The pharmaceutical composition according to claim 1, which is used for the prophylaxis and treatment of diabetes whose blood glucose lowering action is enhanced as compared with single administration.

[4] The pharmaceutical composition according to any one of claims 1 to 3, wherein the insulin resistance improving agent is a thiazolidinedione insulin resistance improving agent.

[5] Insulin resistance ameliorating power Pioglitazone or rosiglitazone

4. The pharmaceutical composition according to any one of 3.

[6] Insulin resistance improver 5- {4-[(6_methoxy-1-methyl-1H-benzimidazole-2

The pharmaceutical composition according to any one of claims 1 to 3, which is -yl) methoxy] benzylto 1,3-thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretagogue is a sulfonylurea agent.

[8] Insulin secretagogue promoting power glimepiride, darivenclamide, or darikulazide

The pharmaceutical composition according to any one of 1 to 6.

[9] The pharmaceutical composition according to any one of [1] to [6], wherein the insulin secretagogue is darivenclamide.

[10] Daribenclamide is the insulin secretagogue and 5- {4-[(6_methoxy-1-methylenole-1 H-benzimidazol-2-yl) methoxy] benzyl 卜 1, 3 The pharmaceutical composition according to any one of claims 1 to 3, which is -thiazolidin-2,4-dione monohydrochloride.

[I I] The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretagogue is a rapid-acting insulin secretagogue.

12. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretagogue is nateglinide, mitiglinide or levaglinide.

13. The pharmaceutical composition according to any one of claims 1 to 6, wherein the insulin secretagogue is nateglinide.

[14] Claims 1 to 1 3 for the prevention or treatment of glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycystic ovary syndrome, atherosclerosis, diabetes Pharmaceutical composition as described in any one of these.

[15] The pharmaceutical composition according to any one of claims 1 to 13, for 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 combination drug.

[17] The pharmaceutical composition according to any one of claims 1 to 16, which is a preparation for oral administration

[18] Use of an insulin sensitizer and an insulin secretagogue for producing a medicament comprising an insulin sensitizer and an insulin secretagogue as active ingredients.

19. The use according to claim 18, wherein the insulin secretagogue is a sulfonylurea agent.

[20] Insulin secretion promoter power Use according to claim 18, which is glimepiride, darivenclamide, or darikulazide.

[21] Insulin resistance improver 5- {4-[(6_methoxy-1-methyl-1H-benzimidazole-2

21. The use according to any one of claims 18 to 20, which is -yl) methoxy] benzylto 1,3-thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof.

[22] A method for treating diabetes, comprising administering an insulin resistance improving agent and an insulin secretagogue in combination.

23. The method for treating diabetes according to claim 22, wherein the insulin secretagogue is a sulfonylurea agent.

24. The method of treatment according to claim 22, wherein the insulin secretagogue is S, glimepiride, darivenclamide, or daliclazide.

[25] Insulin resistance improving agent 5- {4-[(6_methoxy-1-methyl-1H-benzimidazole-2-yl) methoxy] benzylto 1,3-thiazolidine-2,4-dione or its The treatment method according to any one of claims 22 to 24, which is a pharmacologically acceptable salt.