JP5101306B2 - Diabetes treatment - Google Patents

Description

  The present invention relates to a therapeutic agent for diabetes showing an excellent improving action on insulin resistance.

Type II diabetes is a disease with abnormal glucose tolerance, that is, a disease exhibiting high insulin resistance, and has been increasing in recent years against the background of environmental factors such as obesity and overeating, with 7 million Japanese and 150 million worldwide. There are human patients and 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. It is known that an increase in insulin resistance causes type II diabetes, and is deeply related to the induction of hypertension and the progression of arteriosclerosis.
A representative drug that improves insulin resistance includes a thiazolidine drug. Thiazolidine drugs typified by rosiglitazone and pioglitazone are known to bind to and activate PPARγ, which is a nuclear receptor (see Non-Patent Document 1), and have an action to differentiate adipocytes. However, thiazolidine drugs have side effects such as hepatotoxicity, edema, and weight gain, and are administered as auxiliary drugs for sulfonylureas in the treatment of diabetes.

  Patients with diabetes often have other diseases, and improving insulin resistance is not just a problem for diabetes. Hyperlipidemia patients often have hyperglycemia due to insulin resistance, and such patients require treatment aimed at improving insulin resistance in addition to improving lipid metabolism abnormalities. Since α-glucosidase, which is an oral hypoglycemic agent, significantly reduces the risk of developing myocardial infarction due to the effect of improving insulin resistance (see Non-Patent Document 2), combined treatment of abnormal lipid metabolism and insulin resistance Usefulness has been pointed out. As described above, since thiazolidine drugs are concerned about side effects such as hepatotoxicity and weight gain, a safe and powerful insulin resistance improving agent is desired in the field of hyperlipidemia treatment.

Pitavastatin (see Patent Documents 1 to 3), which is one of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, which is a first-line drug for the treatment of hyperlipidemia, is not patented. As shown in Reference 3, a strong blood cholesterol lowering action has been reported in basic and clinical aspects, while an abnormal glucose tolerance improving action (insulin resistance improving action) has been reported in KKAy mice, which are type II diabetes models. (See Non-Patent Document 4). Similarly, pravastatin, an HMG-CoA reductase inhibitor, has also been reported to improve glucose tolerance abnormalities in KKAy mice (see Patent Document 4). However, their glucose tolerance abnormality improving action does not show a sufficiently effective effect.
Japanese Patent No. 2567746 US Pat. No. 5,856,336 European Patent No. 304063 International Publication No. 2004/096276 Pamphlet J Biol Chem 270,12953-12956, 1995 Lancet, (2002), 359: 2072. Cardiovasc. Drug Rev. (2003) 21 (3), 199-215 Therapeutic Research (0289-8020) Vol. 24, No. 7, Page 1329-1337 (2003.07)

Thus, for hyperlipidemia patients with hyperglycemia due to insulin resistance, improvement of insulin resistance is important in addition to improvement of lipid metabolism abnormality. There are no known drugs useful for treatment.
An object of this invention is to provide the chemical | medical agent which has few side effects and shows the outstanding improvement effect with respect to insulin resistance.

As a result of intensive investigations in view of such circumstances, the present inventors, as a result of HMG-CoA reductase inhibitors, for example, pravastatin, when combined with enalapril maleate, which is an ACE inhibitor, are used individually. It showed only an effect of improving glucose tolerance as much as that used in the above. On the other hand, when pitavastatin is used in combination with enalapril maleate, its glucose tolerance amelioration-improving action is greatly enhanced, and it is found useful not only for improvement of lipid metabolism abnormality but also for insulin resistance. Was completed.
Angiotensin converting enzyme (ACE) inhibitors, which are antihypertensive agents, have been reported to have an effect of improving insulin resistance. For example, a report on the relationship between antihypertensive effect and amelioration of insulin resistance using enalapril maleate (JRAAS ( 2003), 4 (2), 119-123), a report of improvement in insulin resistance in a glucose tolerance test using temocapril KKAy mice (Hypertension, 2002; 40: 329). However, there is no example of using a combination of an HMG-CoA reductase inhibitor and an ACE inhibitor as a new treatment method for improving lipid metabolism abnormality and improving glucose tolerance abnormality. It is not known what combination effect is shown for impaired glucose tolerance, and what combination effect is shown for impaired glucose tolerance when pitavastatin and enalapril maleate are used in combination It was not known.

That is, the present invention provides a therapeutic agent for diabetes containing pitavastatin and enalapril or a salt thereof.
The present invention also provides a method for treating diabetes, comprising 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 producing a therapeutic agent for diabetes.

  The therapeutic agent of the present invention has an excellent glucose tolerance improving action (insulin resistance improving action) and is useful for the treatment of diabetes, particularly type II diabetes. Further, according to the present invention, combined treatment of lipid metabolism abnormality and insulin resistance is possible for hyperlipidemia patients with hyperglycemia due to insulin resistance.

It is a figure which shows AUC (area under a glucose concentration curve) of the blood glucose level by combined administration of pitavastatin calcium (it describes with pitavastatin) and enalapril maleate. It is a figure which shows AUC (area under a glucose concentration curve) of blood glucose level by combined administration with pravastatin sodium (it expresses as pravastatin) and enalapril maleate.

The pitavastatin used in the present invention includes pitavastatin, a salt thereof or a lactone form thereof, and also includes a hydrate thereof and a solvate with a pharmaceutically acceptable solvent. Pitavastatins have cholesterol synthesis inhibitory activity based on inhibition of HMG-CoA reductase, and are known as therapeutic drugs for hyperlipidemia. 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; organic amine salts such as phenethylamine salts or ammonium salts. Among these, as pitavastatin, a salt of pitavastatin is preferable, and a calcium salt and a sodium salt are particularly preferable.
Pitavastatins can be produced by the methods described in US Pat. No. 5,856,336 and JP-A-1-279866.

  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. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc .; acetate, trifluoro Examples thereof include organic acid salts such as acetate, fumarate, maleate, lactate, tartrate, citrate, succinate, malonate, methanesulfonate, and p-toluenesulfonate. Of these, maleates are preferred.

The present invention administers a combination of pitavastatin and enalapril or a salt thereof, and as shown in the Examples below, in an evaluation system using KKAy mice, each of pitavastatin and enalapril or a salt thereof alone. Compared with the case of administration, the combined administration of both drugs showed an effect of remarkably improving the glucose tolerance abnormality.
The KKAy mouse is a type II diabetes model, and the insulin resistance improving effect of the drug, that is, the glucose tolerance abnormality improving effect can be evaluated by whether the glucose tolerance abnormality is improved in the KKAy mouse. Therefore, the drug of the present invention is useful for the treatment of diseases in which impaired glucose tolerance occurs, particularly type II diabetes.

  The administration 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 may be any of powders, granules, dry syrups, tablets, capsules, injections, etc. These dosage forms can be produced by blending a pharmaceutically acceptable carrier with pitavastatin and enalapril or a salt thereof and using a conventional production method known to those skilled in the art.

  When preparing an oral solid preparation, after adding an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a flavor, etc., tablets, granules, Powders, capsules and the like can be produced. Such additives may be those commonly used in the art, such as lactose, sodium chloride, glucose, starch, microcrystalline cellulose, silicic acid, etc. as excipients, Water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinyl pyrrolidone, etc. Examples of lubricants include purified talc, stearate, borax, and polyethylene glycol, examples of colorants include β-carotene, yellow ferric oxide, and carmela, and examples of flavoring agents include sucrose and orange peel.

When an oral liquid preparation is prepared, an oral solution, a syrup, an elixir or the like can be produced by adding a flavoring agent, a buffer, a stabilizer, a preservative and the like by a conventional method. Such additives may be those commonly used in the field, such as sucrose as a flavoring agent, sodium citrate as a buffer, tragacanth as a stabilizer, Examples of the preservative include paraoxybenzoic acid esters.
When an injection is prepared, a pH adjuster, a stabilizer, and an isotonic agent are added, and subcutaneous, intramuscular and intravenous injections can be produced by a conventional method. Such additives may be those commonly used in the art, such as sodium phosphate as a pH regulator, sodium pyrosulfite as a stabilizer, and isotonic agent. Examples include sodium chloride.

The usage form 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, pitavastatin and enalapril or a salt thereof may be used as a set (kit) by formulating both drugs as a single formulation or by formulating both drugs separately. When both drugs are formulated separately, both drugs do not have to be in the same dosage form. The frequency of administration of each component may be different.
In the present invention, when both drugs are administered as a single preparation, the compounding ratio of pitavastatin and enalapril or a salt thereof is in the range of 1: 0.05 to 1:50, more preferably 1: 0.1 to 1 in terms of mass ratio. : The range of 10 is preferable.

  In the present invention, the dosage of both drugs is appropriately selected depending on the symptoms, but pitavastatin is preferably administered in an amount of 0.1 to 50 mg per day, preferably 1 to 20 mg, and enalapril or a salt thereof is 1 to 5 mg per day. 50 mg, preferably 2.5 mg to 20 mg should be administered. In addition, administration may be performed once a day, but may be divided into two or more.

  EXAMPLES The present invention will be further described below with reference to examples, but the present invention is not limited to these examples.

Example 1
The following test method was used to evaluate the effect of pitavastatin calcium (hereinafter referred to as pitavastatin) and enalapril maleate on the glucose tolerance abnormality.
1. Test animals and rearing environment KKAy male mice (CLEA Japan, Inc.) 10 weeks old were tested. Throughout the experimental period, the light and dark cycle (period bright by room light: 7 am to 7 pm), raised in a breeding room maintained at a temperature of 23 ± 3 ° C. and a humidity of 55 ± 15%, solid feed (CE-2: Nippon Claire Co., Ltd.) and tap water were given freely.

2. Preparation of preparation Pitavastatin and enalapril maleate were suspended in a 0.5% by mass aqueous solution of carboxymethylcellulose (Iwai Chemical Co., Ltd.), and pitavastatin was prepared at 1 mg / mL and enalapril maleate at 0.1 mg / mL. . Since pitavastatin contained 9.43% water, 1.1 mass times the dose was weighed and corrected. The suspension was stored refrigerated (4 ° C.) in a light-shielding bottle, and preparation was performed every 7 days.

3. Test Method Twenty-four KKAy mice were divided into the following 4 groups (6 mice in each group): control group, pitavastatin alone (10 mg / kg) group, enalapril maleate alone (1 mg / kg) group, pitavastatin (10 mg / kg) and The enalapril maleate (1 mg / kg) combination group was randomly divided into groups. Both drugs were orally administered once a day at 10 mL / kg repeatedly for 21 days, and the control group was orally administered with a 0.5% by weight aqueous solution of carboxymethylcellulose sodium (10 mL / kg). Each group was fasted for 18 hours from the final administration, and then an oral glucose tolerance test was performed. That is, the tip of the tail was cut about 3 mm to cause bleeding, and the blood glucose concentration was immediately measured with a Medisafe leader (GR-101: Terumo Corporation). After the measurement, an aqueous glucose solution (2 g / 10 mL / kg) was orally administered, and the blood glucose concentration was measured by the same method after 15, 30, 60 and 120 minutes. Furthermore, in each group, the area under the time curve (AUC) of blood glucose concentration was calculated.

4). Statistical analysis and data processing method Multi-group comparison between the control group and the drug administration group was performed using Bartlett's analysis of variance-Dunnett's multiple comparison test, and a risk rate of less than 5% was determined to be significant.

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

Comparative Example 1
Evaluation was carried out in the same manner as in the Examples using pravastatin sodium (hereinafter referred to as pravastatin) 50 mg / kg, which has blood cholesterol lowering action to the same extent as pitavastatin 10 mg / kg instead of pitavastatin.
1. Formulation preparation Pravastatin was prepared to 5 mg / mL, and the other procedures were performed in the same manner as in the examples.

2. Test Method Twenty-four KKAy mice were divided into the following 4 groups (6 mice each): control group, pravastatin alone (50 mg / kg) group, enalapril maleate alone (1 mg / kg) group, and pravastatin (50 mg / kg) And enalapril maleate (1 mg / kg) combination group was randomly divided into groups. The test was conducted in the same manner as in the example.

3. Statistical analysis and data processing method It processed like the Example.
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 (mean ± standard error n = 6 Dunnett's multiple comparison test).

The above test results are summarized in the following conclusions.
AUC of blood glucose concentration showed a decreasing tendency in the pitavastatin alone group, the pravastatin alone group and the enalapril maleate alone group relative to the control group. Further, in the combination group, in the combination group of pravastatin and enalapril maleate, AUC remained in a decreasing trend and no combination effect was observed. On the other hand, in the pitavastatin and enalapril maleate combination group, the AUC decrease, that is, the glucose tolerance improvement action was greatly enhanced (p <0.05) compared to the respective single groups, and the effect was synergistic ( Relative index of pitavastatin and enalapril maleate combined administration group (0.67) <product of relative index of pitavastatin alone group and enalapril maleate alone group (0.82)).
Therefore, it was confirmed that the administration of pitavastatin and enalapril maleate according to the present invention has a marked glucose tolerance ameliorating action as compared with other HMG-CoA reductase inhibitors and enalapril maleate.

Claims (8)

A therapeutic agent for diabetes comprising pitavastatin selected from pitavastatin, a salt thereof or a lactone thereof, and a solvate thereof with a hydrate and a pharmaceutically acceptable solvent , and enalapril or a salt thereof.   The therapeutic agent for diabetes according to claim 1, which is a therapeutic agent for type II diabetes that improves insulin resistance.   The therapeutic agent for diabetes according to claim 1 or 2, wherein the pitavastatin is pitavastatin calcium.   The therapeutic agent for diabetes according to any one of claims 1 to 3, wherein the salt of enalapril is enalapril maleate.   The diabetes therapeutic agent according to any one of claims 1 to 4, which is a glucose tolerance abnormality improving agent.   The therapeutic agent for diabetes according to any one of claims 1 to 5, wherein the compounding ratio of pitavastatin and enalapril or a salt thereof is 1: 0.05 to 1:50 by mass ratio.   The therapeutic agent for diabetes according to any one of claims 1 to 5, wherein the dose of pitavastatin is 0.1 to 50 mg per day, and the dose of enalapril or a salt thereof is 1 to 50 mg per day.   The diabetes therapeutic agent of any one of Claims 1-7 which is a single formulation containing pitavastatin and enalapril or a salt thereof, or contains pitavastatin and enalapril or a salt thereof as separate formulations.

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