KR101436644B1 - Remedy for diabetic - Google Patents

Abstract

The present invention relates to a therapeutic agent for diabetes which shows an excellent improving action against insulin resistance. A diabetic agent, a pitavastatin, and enalapril or a salt thereof.

Description

{REMEDY FOR DIABETIC}

The present invention relates to a therapeutic agent for diabetes which shows an excellent improving action against insulin resistance.

Type Ⅱ diabetes mellitus is a disorder with impaired glucose tolerance, that is, a disease with high insulin resistance. It has been increasing recently in the background of environmental factors such as obesity and overeating. Japan has 7.4 million people and 150 million people worldwide, It is expected to reach 300 million in 2005. Insulin resistance is a state in which a cell that is under the action of insulin has a reduced sensitivity to insulin. It is known that the elevation of insulin resistance is not only a cause of type II diabetes, but also is closely related to the induction of hypertension and the progress of atherosclerosis.

Representative agents for improving insulin resistance include thiazolidine-based drugs. It is known that a thiazolidine-based drug represented by rosiglitazone or pioglitazone is bound to and activated by PPARγ, which is a nuclear receptor (see Non-Patent Document 1), and has an action of differentiating adipocytes. However, thiazolidine drugs have side effects such as hepatotoxicity, edema and weight gain, and are administered as adjunctive agents for sulfonylureas in the treatment of diabetes.

Diabetic patients are often accompanied by other diseases, and improvement of insulin resistance is not a problem of diabetes alone. Hyperlipidemia patients are often accompanied by hyperglycemia due to insulin resistance. In such patients, treatment for the purpose of improving insulin resistance in addition to improvement of lipid metabolism is necessary. In view of the fact that α glucosidase, an oral hypoglycemic agent, significantly reduces the risk of developing myocardial infarction by improving insulin resistance (see non-patent document 2), indicating the complex therapeutic utility of lipid metabolism abnormality and insulin resistance have. As described above, the thiazolidine-based medicines are expected to have side effects such as hepatotoxicity and weight gain. Therefore, safe and potent insulin resistance improving drugs are demanded in the field of treating hyperlipidemia.

(Patent Documents 1 to 3), which is one of the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors for the treatment of hyperlipidemia, As shown, a strong blood cholesterol-lowering action has been reported in the basal and clinical stages, while the KKAy mouse, a type II diabetes model, has been reported to improve the glucose tolerance (action to improve insulin resistance) (see Non-Patent Document 4 ). In addition, similarly to the HMG-CoA reductase inhibitor pravastatin, the action of improving the glucose tolerance in KKAy mice has been reported (see Patent Document 4). However, these effects of improving the glucose tolerance are not sufficiently effective.

Patent Document 1: Japanese Patent No. 2569746

Patent Document 2: U.S. Patent No. 5856336

Patent Document 3: European Patent No. 304063

Patent Document 4: International Publication No. 2004/096276 pamphlet

Non-Patent Document 1: J Biol Chem 270, 12953-12956, 1995

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

Non-Patent Document 3: Cardiovasc. Drug Rev. (2003) 21 (3), 199-215

Non-Patent Document 4: Therapeutic Research (0289-8020) Vol. 24, No. 7 Page 1329-1337 (2003.07)

DISCLOSURE OF INVENTION

Problems to be solved by the invention

Thus, in patients with hyperlipidemia accompanied by hyperglycemia according to insulin resistance, improvement of insulin resistance in addition to improvement of lipid metabolism is also important, but a drug useful for the combined treatment of lipid metabolism abnormality and insulin resistance is not known.

It is an object of the present invention to provide a medicament having a small side effect and exhibiting an excellent improving action against insulin resistance.

Means for solving the problem

The inventors of the present invention have conducted intensive studies in view of the above circumstances. As a result, the present inventors have found that, among the HMG-CoA reductase inhibitors, for example, when pravastatin is used as an ACE inhibitor, maleic acid enalapril is used alone, Showed only an improvement in the glucose tolerance or better. On the other hand, when pravastatin is used in combination with maleic acid in maleic acid, the effect of improving the glucose tolerance abnormality is greatly enhanced, and it is useful not only for the improvement of lipid metabolism but also for the improvement of insulin resistance.

It has been reported that an angiotensin converting enzyme (ACE) inhibitor which is a treatment for hypertension has an action of improving insulin resistance. For example, a report on the relationship between coercion using maleaceprile and improving insulin resistance (JRAAS (2003), 4 (2), 119-123), and reports of improvement in insulin resistance in a glucose challenge test using the KKAy mouse of temocapril (Hypertension, 2002; 40: 329). However, there is no example in which an HMG-CoA reductase inhibitor and an ACE inhibitor are used in combination as a new therapeutic method for improving lipid metabolism abnormality and improving the glucose tolerance abnormality. And it is not known at all what combination effects of the combination of pitavastatin and maleic acid on nalapril are exhibited.

That is, the present invention provides a therapeutic agent for diabetes, which comprises pitavastatin and enalapril or a salt thereof.

The present invention also provides a method of treating diabetes, which comprises administering pitavastatin and enalapril or a salt thereof in combination.

The present invention also provides use of pitavastatin and enalapril or a salt thereof for the manufacture of a therapeutic agent for diabetes.

Effects of the Invention

The therapeutic agent of the present invention is excellent in the treatment of diabetes mellitus, especially type II diabetes mellitus, with excellent resistance to glucose tolerance improvement (insulin resistance improving action). According to the present invention, complex treatment of lipid metabolism abnormality and insulin resistance becomes possible for a patient suffering from hyperlipidemia accompanied by hyperglycemia due to insulin resistance.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the AUC (area under the glucose concentration curve) of blood glucose concentration by concomitant administration of pitavastatin calcium (denoted as pitavastatin) and enalapril.

Fig. 2 is a graph showing the AUC (area under the glucose concentration curve) of blood glucose concentration by the concomitant administration of pravastatin sodium (indicated with pravastatin) and enalapril with maleic acid.

Carrying out the invention  Best form for

The pitavastatin used in the present invention includes pitavastatin, a salt thereof or a lactone thereof, and a solvate thereof with a hydrate thereof or a pharmaceutically acceptable solvent. Pitavastatin has cholesterol synthesis inhibitory activity based on HMG-CoA reductase inhibition and is known as a therapeutic agent for hyperlipemia. Examples of salts of pitavastatin include alkali metal salts such as sodium salts and potassium salts; Alkaline earth metal salts such as calcium salts and magnesium salts; An organic amine salt such as a phenethylamine salt, or an ammonium salt. Among them, pitavastatin is preferably a salt of pitavastatin, particularly preferably a calcium salt or a sodium salt.

The pitavastatin can be produced by the method described in U.S. Patent No. 5856336 or Japanese Patent Laid-Open No. 1-279866.

The enalapril used in the present invention is an ACE inhibitor and can be easily obtained as a commercial product. The salt of enalapril is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide and phosphate; And organic acid salts such as acetate, trifluoroacetate, fumarate, maleate, lactate, tartrate, citrate, succinate, malonate, methanesulfonate and p-toluenesulfonate. Of these, maleic acid salts are preferable.

The present invention relates to a method for evaluating the efficacy of pitavastatin or enalapril in the evaluation system using a KKAy mouse, as shown in Examples described later, in which pitavastatin and enalapril or a salt thereof are administered in combination. Or the salt thereof alone, the combined administration of both agents showed an action of remarkably improving the glucose tolerance.

The KKAy mouse is a type II diabetes model, and the effect of improving the insulin resistance of the drug, that is, the effect of improving the glucose tolerance abnormality can be evaluated according to whether or not the glucose tolerance in the KKAy mouse is improved. Therefore, the medicament of the present invention is useful for the treatment of diseases in which an abnormal glucose tolerance occurs, in particular type II diabetes.

The dosage form of pitavastatin 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, and for example, it can be suitably selected from the group consisting of a powder, granule, dry syrup, tablet, And their dosage forms can be prepared by blending a pharmacologically acceptable carrier with pitavastatin and enalapril or a salt thereof and by a production method well known to those skilled in the art.

In the case of preparing a solid preparation for oral use, tablets, granules, powders, capsules and the like are prepared by a conventional method after adding an excipient, a binder, a disintegrant, a lubricant, a colorant, a mating agent, can do. Examples of the excipient include lactose, sodium chloride, glucose, starch, microcrystalline cellulose and silicic acid. Examples of the binder include water, ethanol, propanol, syrup, gelatin , Hydroxypropylcellulose, methylcellulose, ethylcellulose, shellac, calcium phosphate and polyvinylpyrrolidone; examples of disintegrators include agar powder, sodium hydrogencarbonate, sodium laurylsulfate and stearic acid monoglyceride; Talc, stearate, borax, polyethylene glycol and the like. Examples of the coloring agent include? -Carotene, ferric yellow ferric oxide and caramel, and examples of the binding agent include sucrose and isoflavones.

When an oral liquid preparation is prepared, a liquid preparation, a syrup, an elixir, etc. may be prepared by a conventional method by adding a mating agent, a buffer, a stabilizer, a preservative, and the like. Examples of such an additive include those commonly used in the art, such as sucrose as a mating agent, sodium citrate as a buffer, tragacute as a stabilizer, and paraoxybenzoic acid ester as a preservative. .

When an injectable preparation is prepared, subcutaneous, intramuscular, and intravenous injections can be prepared by conventional methods by adding a pH adjuster, a stabilizer, and an isotonic agent. Such an additive may be any of those generally used in the art, and examples thereof include sodium phosphate as a pH regulator, sodium pyrophosphate as a stabilizer, and sodium chloride as an isotonizing agent.

The mode of use of the medicament of the present invention is not particularly limited, and both medicines may be administered simultaneously or separately at intervals. That is, the pitavastatin and enalapril or a salt thereof may be used as a single kit for the two medicines or as a kit (kit) for the two medicaments separately formulated. When the two drugs are separately formulated, the two formulations need not be the same. The number of administration of each component may be different.

In the present invention, when both drugs are administered as a single preparation, the blending ratio of pitavastatin and enalapril or a salt thereof is in the range of 1: 0.05 to 1:50 in mass ratio, and 1: 0.1 to 1:10 .

In the present invention, the dosage of both drugs is appropriately selected depending on the symptoms. The pitavastatin may be administered in an amount of 0.1 to 50 mg, preferably 1 to 20 mg per day, and enalapril or its salt may be administered once per day 1 to 50 mg, preferably 2.5 mg to 20 mg. The administration may be once a day, or divided into two or more times.

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

Example  One

The effect of the combination of pitavastatin calcium (hereinafter referred to as " pitavastatin ") and maleic acid enalapril in combination was evaluated by the following test method.

1. Disclosed animal and breeding environment

KKAy male mice (Japan Kurea Co., Ltd.) for 10 weeks. During the experimental period, the animals were kept in a cage maintained at a temperature of 23 ± 3 ° C and a humidity of 55 ± 15% in a light and dark cycle (light period from 7:00 am to 7:00 pm) Nippon Kurea Co., Ltd.) and tap water were freely ingested.

2. Preparation of preparation

Pitavastatin and enalapril maleate were suspended in a 0.5 mass% aqueous solution of carboxymethylcellulose (Iwai Chemical Co., Ltd.), 1 mg / ml of pitavastatin and 0.1 mg / ml of enalapril maleate Respectively. Further, since pitavastatin contains 9.43% water, a dose of 1.1 times the dose was corrected by weighing. The suspension was refrigerated (4 DEG C) with a shading beam, and the preparation was made every 7 days.

3. Test method

KKAy mice were divided into 4 groups (6 groups in each group), namely control group, pitavastatin single (10 mg / kg) group, maleic acid enalapril alone (1 mg / kg) group, pitavastatin 10 mg / kg) and maleic acid enalapril (1 mg / kg). Both drugs were orally administered at a dose of 10 ml / kg once a day for 21 days, and a 0.5 mass% aqueous solution of carboxymethylcellulose sodium (10 ml / kg) was orally administered to the control group. All groups were fasted for 18 hours from the last dose followed by oral glucose tolerance test. That is, the tip of the tail was cut by about 3 mm to bleed, and blood glucose concentration was immediately measured with MediSafe Reader (GR-101: Dermo Co.). After the measurement, an aqueous glucose solution (2 g / 10 ml / kg) was orally administered, and after 15, 30, 60 and 120 minutes, blood glucose concentration was measured in the same manner. In each group, the area under the curve (AUC) of the blood glucose concentration was calculated.

4. Statistical Analysis and Data Processing

Multidisciplinary comparisons between the control and drug-treated groups were conducted using Bartlett's analysis of variance-Dunnett's multiple comparison test to determine that a risk score of less than 5% was significant.

5. Results

The AUC (area under the glucose concentration curve) of the blood glucose concentration up to 2 hours after the glucose load is shown in Fig. 1 (mean value ± standard error n = 6 ** p <0.05 Dunnett's multiple comparison test). In addition, the AUC of the glucose concentration in the blood represents the amount of blood glucose exposure, and the decrease of this value is an index of the glucose tolerance improving action.

Comparative Example  One

Using pravastatin sodium (hereinafter, referred to as pravastatin) having a blood cholesterol lowering effect of 50 mg / kg in the same manner as 10 mg / kg of pitavastatin in place of pitavastatin, evaluation was carried out in the same manner as in Example.

1. Preparation of preparation

Pravastatin was prepared to have a concentration of 5 mg / ml.

2. Test method

(50 mg / kg), maleic acid enalapril alone (1 mg / kg), and pravastatin (50 mg / kg) were administered to 24 KKAy mice in the following four groups Kg) and nalapril (1 mg / kg) in maleic acid. The test was carried out in the same manner as in Example.

3. Total Analysis and Data Processing

And treated in the same manner as in Example.

4. Results

The AUC (area under the glucose concentration curve) of the blood glucose concentration up to 2 hours after the glucose load was shown in Fig. 2 (multiple comparison test of average ± standard error n = 6 Dunnett).

The above test results are summarized in the following conclusions.

The AUC of blood glucose concentration showed a decreasing tendency in the pitavastatin single group, pravastatin single group and mannosylnalapril single group compared to the control group. In the combination group, the AUC tended to decrease in the combination of pravastatin and maleic acid enalapril, and the combined effect was not observed. On the other hand, in the combination of pitavastatin and maleic acid enalapril, reduction of AUC, i.e., improvement of glucose tolerance abnormality was significantly enhanced (p < 0.05), and the effect was increased as compared with each single group (pitavastatin (0.67) relative to that of nalapril alone group (0.82) of pitavastatin alone group and maleapril alone group (0.82).

Therefore, it was confirmed that the combination administration of pitavastatin and maleic acid enalapril of the present invention has a remarkable ability to improve glucose tolerance, as compared with other HMG-CoA reductase inhibitor and enalapril maleate.

Claims (12)

A diabetes therapeutic agent characterized by containing pitavastatin and enalapril or a salt thereof selected from pitavastatin, a salt thereof, and a solvate thereof with a hydrate thereof and a pharmaceutically acceptable solvent. The method according to claim 1, A diabetes drug, a type II diabetes drug that improves insulin resistance. 3. The method according to claim 1 or 2, A drug for the treatment of diabetes wherein the pitavastatin is pitavastatin calcium. 3. The method according to claim 1 or 2, Wherein the salt of enalapril is nalapril in maleic acid. 3. The method according to claim 1 or 2, A drug for the treatment of diabetes, which is an agent for improving the glucose tolerance. 3. The method according to claim 1 or 2, Wherein the compounding ratio of pitavastatin and enalapril or a salt thereof is 1: 0.05 to 1: 50 by mass ratio. 3. The method according to claim 1 or 2, Wherein the dosage of pitavastatin is 0.1 to 50 mg per day and the dose of enalapril or its salt is 1 to 50 mg per day. 3. The method according to claim 1 or 2, A therapeutic agent for diabetes comprising a single preparation containing pitavastatin and enalapril or a salt thereof, or a pitavastatin and enalapril or a salt thereof as separate preparations. delete delete delete delete

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