WO2007088705A1

WO2007088705A1 - Remedy for diabetic

Info

Publication number: WO2007088705A1
Application number: PCT/JP2007/000041
Authority: WO
Inventors: Taro Aoki; Katsutoshi Miyosawa
Original assignee: Kowa Co., Ltd.; Nissan Chemical Industries, Ltd.
Priority date: 2006-01-31
Filing date: 2007-01-30
Publication date: 2007-08-09
Also published as: JP5101306B2; JPWO2007088705A1; KR101436644B1; KR20080091082A

Abstract

A remedy for diabetic which shows an excellent effect of ameliorating insulin resistance. A remedy for diabetic characterized by containing pitavastatin or its derivative and enalapril or its salt.

Description

Specification

Diabetes treatment

Technical field

TECHNICAL FIELD [0001] The present invention relates to a therapeutic agent for diabetes that exhibits an excellent improving action on insulin resistance.

Background art

[0002] 1 Type 1 diabetes is a disease with abnormal glucose tolerance, that is, a disease that exhibits high insulin resistance, and has recently increased due to environmental factors such as obesity and overeating. There are 150 million patients worldwide, and it is expected to reach 300 million in 2005. Insulin resistance is a state in which the sensitivity of cells undergoing insulin action to insulin is reduced. Increased insulin resistance is the cause of type I diabetes, as well as the induction of hypertension and the progression of arteriosclerosis is known to be deeply involved.

Thiazolidine-based drugs are listed as representative drugs that improve insulin resistance. Rosiglitazone is a thiazolidine drug represented by pioglitazone, which is known to bind to and activate the nuclear receptor PPAR r (see Non-Patent Document 1) and to differentiate fat cells. . However, thiazolidine drugs have side effects such as hepatotoxicity, edema, and weight gain, and are administered as an adjunct to sulfonylureas in the treatment of diabetes.

[0003] Patients with diabetes often have other diseases, and improvement of insulin resistance is not just a problem for diabetes. Hyperlipidemia patients often have hyperglycemia due to insulin resistance, and such patients need treatment aimed at improving insulin resistance in addition to improving lipid metabolism abnormalities. . Qf darcosidase, an oral hypoglycemic agent, significantly reduces the risk of developing myocardial infarction by improving insulin resistance (see Non-Patent Document 2). This is a combination of abnormal lipid metabolism and insulin resistance. Of useful treatment has been pointed out The As mentioned above, since thiazolidine drugs are concerned about side effects such as hepatotoxicity and weight gain, a safe and powerful insulin resistance-improving drug is desired in the field of hyperlipidemia treatment.

[0004] Pitapastatin, which is one of 3-hydroxy-1,3-methyldaltalyl-Co A (HMG-Co A) reductase inhibitors, which is the first-line drug for the treatment of hyperlipidemia (see Patent Documents 1 to 3) As shown in Non-Patent Document 3, a strong blood cholesterol lowering effect has been reported in basic and clinical aspects, while KK Ay mice, which are type II diabetes models, have an effect of improving glucose tolerance (insulin Has been reported (see Non-Patent Document 4). Similarly, pravastatin, an HM G_Co A reductase inhibitor, has also been reported to improve glucose tolerance abnormalities in KKA y mice (see Patent Document 4). However, their glucose tolerance improving action does not show a sufficiently effective effect.

Patent Document 1: Japanese Patent No. 2569746

Patent Document 2: US Pat. No. 5,856,336

Patent Document 3: European Patent No. 304063

Patent Document 4: International Publication No. 2004Z096276

Non-Patent Document 1: J B i o l C h em 270, 1 2953- 1 2956, 1 995

Non-Patent Document 2: L ancet, (2002), 359: 2072

Non-Patent Document 3: C rd i o v a s c. D r u Re v. (2003) 2 1

(3), 1 99-2 1 5

Non-Patent Document 4: T he r a p e u t i c Re r e a r c h (0289—80 20) Vol. 24, No. 7, P a g e 1 329 _ 1 337 (July 2003) Disclosure of the Invention

Problems to be solved by the invention

[0005] Thus, in addition to improving lipid metabolism abnormalities, improving insulin resistance is important for hyperlipidemia patients with hyperglycemia due to insulin resistance. There are no known drugs useful for the combined treatment of dyslipidemia and insulin resistance.

An object of the present invention is to provide a drug which has few side effects and exhibits an excellent improving action on insulin resistance.

Means for solving the problem

[0006] In view of such circumstances, the present inventors have conducted intensive studies. As a result, among the HMG_CoA reductase inhibitors, pravastatin, for example, is combined with enalabril maleate, which is an ACE inhibitor. It showed only an effect of improving glucose tolerance abnormalities in the same way as when succinate was used alone. On the other hand, when pitapastatin was used in combination with enalapril maleate, its glucose tolerance ameliorating effect was greatly enhanced, and it was found useful not only for improving lipid metabolism abnormalities but also for improving insulin resistance. The present invention has been completed.

Angiotensin-converting enzyme (ACE) inhibitors, which are antihypertensive agents, have been reported to have an insulin resistance-improving effect. For example, antihypertensive effects and amelioration of insulin resistance using enalapril maleate are reported. Report on relationship (J RA AS (2003), 4 (2), 1 1 9-1 23), Report of improvement of insulin resistance in glucose tolerance test using KK A y mice of temocapril (H ypertension, 2002; 40 : 329). However, there is no combination of HMG-Co A reductase inhibitor and ACE inhibitor as a new treatment method to improve lipid metabolism abnormality and glucose tolerance abnormality. It is not known what the combination effect of the combination of pitapastatin and enalapril maleate would have on the glucose tolerance abnormality of diabetes. It was not known at all whether it would be effective.

[0007] That is, the present invention provides a therapeutic agent for diabetes comprising pitapastatins and enalapril or a salt thereof.

The present invention also provides a method for treating diabetes, characterized in that pitapastatins and enalapril or a salt thereof are administered in combination. The present invention also provides use of pitapastatins and enalapril or a salt thereof for the manufacture of a therapeutic agent for diabetes.

The invention's effect

[0008] The therapeutic agent of the present invention has an excellent glucose tolerance ameliorating action (insulin resistance improving action), and is useful for the treatment of diabetes, especially type I diabetes. In addition, according to the present invention, combined treatment of abnormal lipid metabolism and insulin resistance is possible for hyperlipidemic patients with hyperglycemia due to insulin resistance.

Brief Description of Drawings

[0009] FIG. 1 is a graph showing AUC (area under the glucose concentration curve) of blood glucose concentration by the combined administration of pitapastatin calcium (indicated as pitapastatin) and enalapril maleate.

[Fig. 2] A diagram showing AUC (area under the glucose concentration curve) of blood glucose concentration by the combined administration of pravastatin sodium (indicated as pravastatin) and enalapril maleate.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] Pitapastatin used in the present invention includes pitapastatin, a salt thereof or a lactone form thereof, and also includes a hydrate thereof and a solvate with a pharmaceutically acceptable solvent. Pitapastatins have cholesterol synthesis inhibitory activity based on inhibition of HMG-CoA reductase, and are known as therapeutic drugs for hyperlipidemia. Examples of the salt of pitapastatin include sodium salt, potassium salt and other alkali metal salts; calcium salt, magnesium salt and other alkaline earth metal salts; phenethylamine salt and other organic amine salts, and ammonium salts. Of these, as pitapastatins, salts of pitapastatin are preferable, and calcium salts and sodium salts are particularly preferable.

Pitapastatins can be produced by the methods described in US Pat. No. 5,856,636 and Japanese Patent Application Laid-Open No. 1-277966.

[001 1] Enalapril used in the present invention is an ACE inhibitor and can be easily obtained as a commercial product. The salt of enalapril is pharmaceutically acceptable. Inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc .; acetate, trifluoroacetate, fumarate, maleate, Examples include lactate, tartrate, citrate, succinate, malonate, methanesulfonate, and organic acid salts such as p-toluenesulfonate. Of these, maleates are preferred.

[0012] The present invention administers pitapastatins and enalapril or a salt thereof in combination, and as shown in the Examples below, in an evaluation system using KKA y mice, pitapastatins or enalapril or Compared to when each salt was administered alone, the combined administration of both drugs showed a marked improvement in impaired glucose tolerance.

K K Ay mice are a type I diabetes model, and the effect of improving the insulin resistance of a drug, that is, the effect of improving glucose tolerance, can be evaluated by whether the glucose tolerance in K K Ay mice is improved. Therefore, the drug of the present invention is useful for the treatment of diseases in which abnormal glucose tolerance occurs, particularly type I diabetes.

[0013] The administration form of pitapastatins and enalapril or a salt thereof in the therapeutic agent of the present invention can be appropriately selected according to the patient's condition and the like. For example, powders, granules, dry syrups, tablets, capsules, injections Any of these agents may be used, and these dosage forms can be produced by blending a pharmaceutically acceptable carrier with pitapastatins and enalapril or a salt thereof, and using conventional production methods known to those skilled in the art.

[0014] When preparing an oral solid preparation, after adding an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a corrigent, etc., a tablet, Granules, powders, capsules, etc. can be manufactured. Such additives may be those commonly used in the field, such as lactose, sodium chloride, glucose, starch, microcrystalline cellulose, silicic acid, etc. as excipients, as binders Water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropylcellulose, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc., as disintegrant, agar powder, sodium bicarbonate, sodium lauryl sulfate, stearin Acid monodalides, etc., refined talc, stearate, borax, polyethylene glycol, etc. as lubricants, ^ -carotene, yellow trioxide, caramel, etc. as colorants, white sugar, orange as flavoring agents Examples include skins.

[001 5] When preparing liquid preparations for oral use, liquid preparations, syrups, elixirs, etc. can be produced by conventional methods with the addition of corrigents, buffers, stabilizers, preservatives and the like. Such additives may be those commonly used in the field, such as sucrose as a flavoring agent, sodium citrate as a buffering agent, tragacanth as a stabilizer, and the like. Examples of the preservative include paraoxy benzoate.

When preparing injections, PH preparations, stabilizers, tonicity agents are added, and subcutaneous, intramuscular and intravenous injections can be produced by conventional methods. Such additives may be those commonly used in the field, such as sodium phosphate as a pH regulator, and sodium pyrosulfite as a stabilizer. Examples of the isotonic agent include sodium chloride.

[001 6] The mode of use of the drug of the present invention is not particularly limited, and both drugs may be administered simultaneously, or may be administered separately at intervals. That is, pitapastatin and enalapril or a salt thereof may be used as a set (kit) in which both drugs are formulated into a single preparation or both drugs are formulated separately. When both drugs are formulated separately, both drugs do not have to be in the same dosage form. The number of application of each component may be different.

In the present invention, when both drugs are administered as a single preparation, the compounding ratio of pitapastatins and enalapril or a salt thereof is in the range of 1: 0.05 to 1:50, and more preferably 1: 0.0. It is preferably in the range of 1 to 1:10.

[0017] In the present invention, the doses of both drugs are appropriately selected according to the symptoms, but pitapastatins should be administered at 0.1 to 5 O mg, preferably 1-2 O mg per day, Enalapril or a salt thereof should be administered at 1 to 5 O mg, preferably 2.5 to 2 O mg per day. The administration may be once a day, but may be divided into two or more. Example

[0018] Hereinafter, the present invention will be further described with reference to examples. However, the present invention is not limited to these examples.

[0019] Example 1

The following test method was used to evaluate the effect of pitapastatin calcium (hereinafter referred to as pitapastatin) and enalapril maleate on glucose tolerance.

1. Test animals and rearing environment

KKAy male mice (CLEA Japan, Inc.) 10 weeks old were tested. Throughout the experiment, the light-dark cycle (bright period due to room light: 7 am to 7 pm), kept in a breeding room maintained at a temperature of 23 ± 3 ° C and humidity of 55 ± 150/0, solid food (CE — 2: Nippon Claire Co., Ltd.) and tap water were given freely.

[0020] 2. Formulation preparation

Pitapastatin and enalapril maleate are suspended in a 0.5% by weight aqueous solution of carboxymethyl cellulose (Iwai Chemical Co., Ltd.). Pitapastatin is 1 mgZmL, and enalapril maleate is 0.1 mg ZmL. It was prepared as follows. Since pitapastatin contained 9.43% water, it was corrected by weighing 1.1 times the dose. The suspension was stored refrigerated (4 ° C) in a light-shielding bottle, and preparation was performed every 7 cells.

[0021] 3. Test method

24 KK Ay mice, 4 groups (6 mice in each group), namely, control group, pitapastatin alone (10 mgZk g) group, enalapril maleate alone (1 mgZk g) group, pitapastatin (1 OmgZk g) And enalapril maleate (1 mgZkg) was randomly divided into groups. For both drugs, 1 OmLZk g was orally administered once a day for 21 days, and 0.5 mass ⁰ / o aqueous solution (1 OmLZkg) of sodium carboxymethylcellulose was orally administered to the control group. In both groups, the oral darcos load test was performed after fasting for 18 hours from the last dose. That is, cut the tail tip about 3 mm and bleed, immediately The blood darcos concentration was measured with a Medisafe Reader (GR-101: Terumo Corporation). After the measurement, a glucose aqueous solution (2 gZ1 OmLZkg) was orally administered, and blood glucose concentration was measured by the same method after 15, 30, 60, 120 minutes. Furthermore, in each group, the area under the time curve (AUC) of blood glucose concentration was calculated.

[0022] 4. Statistical analysis and data processing methods

A multi-group comparison between the control group and the drug-administered group was carried out using the analysis of variance of Bart l ett and the multiple comparison test of Du nn ett, and a risk rate of less than 5% was judged to be significant.

[0023] 5. Results

AUC (area under the glucose concentration curve) of blood glucose concentration up to 2 hours after glucose load is shown in Fig. 1 (multiple comparison test of mean soil standard error n = 6 ** p <0.05 Du n ne t t). The blood glucose concentration A UC represents the amount of blood glucose exposure, and a decrease in this value is an indicator of the glucose tolerance improvement action.

[0024] Comparative Example 1

Evaluation was carried out in the same manner as in Examples, using pravastatin sodium (hereinafter referred to as blapastatin), which has a blood cholesterol lowering effect similar to that of pitapastatin 1 OmgZk g, instead of pitapastatin 5

1. Formulation preparation

Pravastatin was prepared to have a concentration of 5 mg Zm L, and the other procedures were performed in the same manner as in the examples.

[0025] 2. Test method

24 KK Ay mice were divided into the following 4 groups (6 animals each): control group, pravastatin alone (50 mgZk g) group, enalapril maleate alone (1 mgZk g) group, and pravastatin (50 mgZk g) and malee Randomly divided into the enalapril (I mgZk g) combination group. Same as example The test was conducted.

[0026] 3. Statistical analysis and data processing

The same treatment as in the example was performed.

4. Results

AUC (area under the glucose concentration curve) of blood glucose concentration up to 2 hours after glucose loading is shown in Fig. 2 (multiple comparison test with mean soil standard error n = 6 Du nnett).

[0027] The above test results are summarized in the following conclusions.

AUC of blood glucose concentration showed a decreasing tendency in the pitavastatin alone group, pravastatin alone group, and enalapril maleate alone group compared to the control group. In the combination group, in the combination group of pravastatin and enalapril maleate, the AUC remained in a decreasing trend and no combination effect was observed. On the other hand, in the pitapastatin and enalapril maleate combination group, the AUC decrease, that is, the glucose tolerance improvement action was significantly enhanced (p 0.05) compared to each single group, and the effect was synergistic. (Relative index of the pitapastatin and enalapril maleate combination group (0.67) <product of the relative index of the pitapastatin alone group and the maleate enalapril alone group (0.82)).

Therefore, it was confirmed that the combined administration of pitapastatin and enalapril maleate of the present invention has a marked glucose tolerance ameliorating action as compared with other combined administration of HMG_CoA reductase inhibitor and enalapril maleate. .

Claims

The scope of the claims

[I] A therapeutic agent for diabetes, comprising pitapastatins and enalabril or a salt thereof.

[2] The therapeutic agent for diabetes according to claim 1, which is a therapeutic agent for type 1 diabetes that improves insulin resistance.

[3] The therapeutic agent for diabetes according to claim 1 or 2, wherein the pitapastatin is pitapastatin calcium.

[4] The therapeutic agent for diabetes according to any one of claims 1 to 3, wherein the salt of enalapril is enalapril maleate.

[5] A method for treating diabetes, comprising administering pitavastatin and enalabril or a salt thereof in combination.

6. The method according to claim 5, wherein the diabetes is type 11 diabetes caused by an increase in insulin resistance.

7. The method according to claim 5 or 6, wherein the pitapastatin is pitapastatin calcium.

8. The method according to any one of claims 5 to 7, wherein the salt of enalabril is enalapril maleate.

[9] Use of pitapastatins and enalapril or a salt thereof for the manufacture of a therapeutic agent for diabetes.

10. The use according to claim 9, wherein the diabetes therapeutic agent is a type 1 diabetes therapeutic agent that improves insulin resistance.

[I I] The use according to claim 9 or 10, wherein the pitapastatin is pitapastatin calcium.

12. The use according to any one of claims 9 to 11, wherein the salt of enalapril is enalapril maleate.