JP2007091641A - Combinational pharmaceutical for treating type-ii diabetes - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pharmaceutical as a combination of multiple pharmaceuticals for controlling the morbid state of type-II diabetes, and to provide a method for treating type-II diabetes using the new pharmaceutical. <P>SOLUTION: The new pharmaceutical is in the form of a combination of mitiglinide, a pharmacologically acceptable salt thereof or hydrate thereof and an α-glucosidase inhibitory medicament, especially voglibose. The method for treating type-II diabetes using the new pharmaceutical is provided. This new pharmaceutical or this method exhibits very significant effects of dropping early morning fasting blood sugar levels, blood sugar levels after meal and Hb (hemoglobin) A<SB>1c</SB>in type-II diabetics and can also ameliorate insulin resistance and lipid metabolism. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a medicament useful for the treatment of type 2 diabetes. More specifically, the present invention relates to a medicament comprising a combination of mitiglinide and an α-glucosidase inhibitor, and a method for treating type 2 diabetes using the same.

  For patients with type 2 diabetes, patient education for improving lifestyle such as diet and exercise therapy, pharmacotherapy that administers oral hypoglycemic drugs and insulin, and a combination of both are usually given. .

  As oral hypoglycemic drugs, insulin secretion promoters such as sulfonylurea drugs, sugar absorption regulators such as α-glucosidase inhibitors, insulin resistance improving drugs such as thiazolidine drugs and biguanides are used depending on the patient's condition. ing.

  Recently, a rapid-acting insulin secretion-promoting agent mitiglinide calcium hydrate [product name: Glufast (registered trademark)] has been developed as the oral hypoglycemic agent, and has been particularly evaluated.

By the way, in order to improve the pathological condition of diabetes, a combination therapy in which various drugs are administered in combination has been attempted. For example, a combined drug combining an α-glucosidase inhibitor and a non-sulfonylurea insulin secretagogue has been reported (see Patent Document 1). However, there is a specific combined effect of mitiglinide calcium hydrate and α-glucosidase inhibitor, in particular having a very strong synergistic lowering effect on early morning fasting blood glucose level, postprandial blood glucose level and HbA _1C , and insulin resistance and Until now, it has not been known about the effect of improving lipid metabolism and the safety of combination therapy.
JP 2001-316293 A

  An object of the present invention is to provide a novel medicine comprising a combination of a plurality of medicines in order to control the pathology of type 2 diabetes, and a method for treating type 2 diabetes using the same.

  As a result of intensive research in view of the above problems, the present inventors have found that a drug comprising a combination of mitiglinide calcium hydrate and an α-glucosidase inhibitor has extremely excellent therapeutic effects and safety, and the present invention. Was completed.

The medicament according to the present invention has an extremely strong lowering effect on early morning fasting blood glucose level, postprandial blood glucose level and HbA _{1C in} patients with type 2 diabetes, and can further improve insulin resistance and lipid metabolism.

  Mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof used in the present invention can be produced by a method described in JP-A-4-35659. Of mitiglinide, its pharmacologically acceptable salt or its hydrate, it is preferable to use mitiglinide calcium hydrate. When using mitiglinide calcium hydrate, the single dose is usually in the range of 5 to 45 mg, preferably in the range of 5 to 20 mg, particularly 5 to 10 mg.

  Examples of the α-glucosidase inhibitor include acarbose, voglibose, miglitol, emiglitate, and the like. Of these, acarbose or voglibose is preferable. The single dose when acarbose is used is preferably in the range of 50 to 100 mg, and the single dose when voglibose is used is preferably in the range of 0.2 to 0.5 mg.

  The medicament according to the present invention contains mitiglinide calcium hydrate and an α-glycosidase inhibitor three times a day before each meal (within 10 minutes before the start of the meal), particularly immediately before the meal (within 5 minutes before the start of the meal). It is preferred to administer a single formulation or two formulations obtained by formulating each separately.

  Since the medicament according to the present invention administers mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof and an α-glucosidase inhibitor at the same time or within an extremely short interval of 10 minutes, For example, the fact is preferably described in a package insert or a sales pamphlet of a medicine [product name: Glufast (registered trademark)] containing commercially available mitiglinide calcium hydrate as an active ingredient. A kit comprising a preparation containing mitiglinide calcium hydrate and a preparation containing voglibose is also preferred.

As a patient to be treated with the medicament according to the present invention, sufficient blood glucose control cannot be obtained by diet therapy, and it is necessary to introduce a drug therapy, and HbA _1C is 6.5% or more, particularly Even if an α-glucosidase inhibitor is taken, a patient whose HbA _1C is 6.5% or more is preferable.

(Example 1, Example 2, Comparative Example 1, Comparative Example 2)
The following clinical trials were conducted in patients with type 2 diabetes by a double-blind parallel group comparison study.

[Selection criteria]
Patients with type 2 diabetes who are unable to obtain sufficient glycemic control due to diet therapy and need to be introduced with pharmacotherapy, and whose HbA _1C is 6.5% or more and less than 8.5% and whose age is 20 years or older.

〔Investigational new drug〕
(1) 5 mg tablet of mitiglinide calcium hydrate (hereinafter sometimes referred to as “KAD-1229”)
(2) KAD-1229 5mg placebo tablet
(3) 10mg tablet of KAD-1229
(4) KAD-1229 10mg placebo tablet
(5) 0.2 mg tablet of voglibose
(6) Voglibose 0.2mg tablet Placebo tablet

[Method of administration]
0.2 mg tablet of voglibose once a day, 3 times a day just before every meal (within 5 minutes before the start of the meal), orally administered for 16 weeks (observation period: open-label period), then assigned as shown in Table 1 The study drug was orally administered 3 times a day immediately before every meal (within 5 minutes before the start of the meal) for 12 weeks (treatment period: double-blind period). The study drug was not allowed to be administered after meals, and was not administered if meals were not taken.

The following items were evaluated during and after the administration period.
(1) HbA _1C Value FIG. 1 shows the transition of the amount of change in HbA _1C value from the start of the treatment period.
When an insulin secretagogue such as sulfonylurea is used, the transition of the HbA _1C value becomes slower as the dosing period becomes longer, and sometimes increases. However, in the combination administration group, the HbA _1C value can be well controlled even in long-term administration.

FIG. 2 shows the amount of change in the HbA _1C value from the start of the treatment period at the end of the treatment period (HbA _1C change amount). It can be seen that in any case of the combination administration group, the HbA _1C value synergistically decreased as compared to the single administration group.

FIG. 3 shows the ratio of patients whose HbA _1C value decreased to less than 6.5% (HbA _1C target achievement rate) at the time of the final evaluation. It can be seen that the HbA _1C target achievement rate is clearly higher in the combination administration group than in the single administration group.

FIG. 4 shows the amount of change in HbA _1C in a patient group having a blood insulin level (IRI) at the start of the treatment period of less than 5 μU / mL and a patient group having a tendency of insulin resistance of 5 μU / mL or more. Indicates. In the single administration group, the amount of change in HbA _1C in the patient group having an insulin resistance tendency is greatly reduced as compared with the patient group having no insulin resistance tendency. On the other hand, in the combined administration group, it can be seen that a synergistic decrease in HbA _1C is also observed in the patient group who tends to have insulin resistance.

FIG. 5 shows the achievement rate of the HbA _1C target in a patient layer having a blood insulin level of 5 μU / mL or more at the start of the treatment period. Combined administration of KAD-1229 and voglibose to patients with insulin resistance-prone blood insulin levels of 5 μU / mL or higher controls HbA _1C levels much better than KAD-1229 or voglibose alone I understand. That is, it can be seen that the therapeutic target achievement rate in patients with insulin resistance is remarkably increased by the combined administration. This indicates that in patients with insulin resistance whose therapeutic goals are difficult to achieve with single administration, combined administration of KAD-1229 and voglibose improved the patient's insulin resistance and synergistically reduced HbA _1C. It is shown.

(2) Early morning fasting blood glucose level The change in the amount of change in the early morning fasting blood glucose level (FPG) from the start of the treatment period is shown in FIG. Compared to the single administration group, the combination administration group synergistically reduced early morning fasting blood glucose levels.

(3) Postprandial blood glucose 1-hour value and 2-hour value FIGS. 7 and 8 show changes in post-prandial blood glucose 1-hour value and 2-hour value from the start of the treatment period at the time of the final evaluation. The combination administration group synergistically decreased blood glucose levels compared to the single administration group. Moreover, it can be seen from the 1-hour postprandial blood glucose value that the glucose spike in the combination administration group is significantly suppressed as compared to the single administration group.

(4) Lipid Test Value FIG. 9 shows the amount of change in triglyceride (TG) and total cholesterol (TC) values in patients with hyperlipidemia. It can be seen that the TG value and the TC value are significantly reduced in the combination group compared to the single administration group.

(Example 3)
Voglibose once 0.2-0.3 mg or acarbose once 50-100 mg was orally administered three times a day immediately before each meal (within 5 minutes before the start of the meal) for 16 weeks (observation period). Subsequently, 10 mg of KAD-1229 was orally administered with voglibose or acarbose three times a day immediately before each meal (within 5 minutes before the start of the meal) for 28 weeks (treatment period).

Note that when _{HbA 1C} after 12 weeks the patient _{HbA 1C} of start time of the treatment period was 7.0% or more than 7.0%, and _{HbA 1C} of start time of the treatment period is over 6.5% 7 When HbA _1C after 12 weeks for patients who were less than 0.0% was 6.5% or more, KAD-1229 was increased to 20 mg at a time. In addition, KAD-1229 can be reduced at any time.

FIG. 10 shows the transition of the HbA _1C measurement value from the start of the observation period. The combined effect of KAD-1229 and voglibose or KAD-1229 and acarbose on HbA _1C measurement values was almost the same.

  Moreover, since no serious side effects were observed in the above clinical trials, safety in combination therapy was confirmed.

  As described above, by using mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof in combination with an α-glucosidase inhibitor such as voglibose, an extremely high therapeutic effect can be obtained and the same effect can be obtained. The dose of the α-glucosidase inhibitor necessary for the treatment can be reduced, and the therapeutic target achievement rate can be significantly increased. Therefore, the incidence of side effects such as gastrointestinal disorders such as abdominal distension, increased phlegm, diarrhea, loose stool and abdominal pain, which the α-glucosidase inhibitor has, can be reduced.

  A medicament comprising a combination of mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof and an α-glucosidase inhibitor is an extremely excellent medicament which has a high therapeutic effect and is safe.

FIG. 1 is a diagram showing the transition of the amount of change in the HbA _1C value from the start of the treatment period. FIG. 2 is a diagram showing the amount of change in HbA _1C from the start of the treatment period at the time of final evaluation. FIG. 3 is a diagram showing the HbA _1C target achievement rate from the start of the treatment period at the time of the final evaluation. FIG. 4 is a diagram showing the amount of change in HbA _1C value from the start of the treatment period in the final evaluation, stratified by the blood insulin value (IRI) of 5 μU / mL at the start of the treatment period. VK10 represents Example 1, VK5 represents Example 2, V represents Comparative Example 1, K10 represents Comparative Example 2, and IRI represents blood insulin level. FIG. 5 is a diagram showing the HbA _1C target achievement rate in a patient layer having a blood insulin value of 5 μU / mL or more at the start of the treatment period. VK10 represents Example 1, VK5 represents Example 2, V represents Comparative Example 1, and K10 represents Comparative Example 2. FIG. 6 is a diagram showing the transition of the amount of change in the early morning fasting blood glucose level (FPG) from the start of the treatment period. FIG. 7 is a diagram showing the amount of change in the postprandial blood glucose 1 hour value from the start of the treatment period at the time of the final evaluation. FIG. 8 is a diagram showing the amount of change in the 2-hour postprandial blood glucose value from the start of the treatment period at the time of the final evaluation. FIG. 9 is a diagram showing the transition of the lipid test from the start of the treatment period. FIG. 10 is a diagram showing the transition of the measured value of HbA _1C from the start of the observation period in the combined administration test with acarbose or voglibose.

Claims (26)

A pharmaceutical for the treatment of type 2 diabetes, comprising mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof and an α-glucosidase inhibitor. The medicament according to claim 1, wherein the treatment of type 2 diabetes is an improvement in blood glucose transition after meals. 2. The medicament according to claim 1, wherein the treatment of type 2 diabetes is a decrease in fasting blood glucose level in the early morning. The medicament according to claim 1, wherein the treatment of type 2 diabetes is a decrease in HbA _1C . The medicament according to claim 1, wherein the treatment of type 2 diabetes is suppression of glucose spikes. The medicament according to any one of claims 1 to 5, wherein the treatment of type 2 diabetes is improvement of insulin resistance. The medicament according to any one of claims 1 to 6, which is administered to an insulin resistant patient. The medicament according to any one of claims 1 to 6, which is administered to a patient having an HbA _1C value of 6.5% or more. The medicament according to claim 8, which is administered to a patient whose HbA _1C value is 6.5% or more after administering an α-glucosidase inhibitor for 16 weeks. A pharmaceutical for the treatment of hyperlipidemia, comprising mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof and an α-glucosidase inhibitor. The medicament according to claim 10, which is administered to a type 2 diabetic patient having an HbA _1C value of 6.5% or more. The medicament according to any one of claims 1 to 11, wherein the mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof is mitiglinide calcium hydrate. The medicament according to any one of claims 1 to 12, wherein the α-glucosidase inhibitor is voglibose. 14. The medicine according to claim 13, comprising voglibose and mitiglinide calcium hydrate in an amount necessary to reduce side effects caused by voglibose. 15. The medicine according to claim 14, wherein the side effect caused by voglibose is a digestive tract disorder. 6. The medicine according to any one of claims 13 to 5, which exhibits a synergistic HbA _1C lowering action as compared with the sum of the HbA _1C lowering action when mitiglinide calcium hydrate or voglibose is administered alone. The pharmaceutical according to any one of claims 12 to 16, wherein the single dose of mitiglinide calcium hydrate is 5 to 45 mg. The medicine according to any one of claims 13 to 17, wherein a single dose of voglibose is 0.2 to 0.5 mg. The medicine according to any one of claims 13 to 18, wherein mitiglinide calcium hydrate and voglibose are orally administered before a meal. 20. The medicament according to claim 19, wherein a single preparation comprising mitiglinide calcium hydrate and voglibose is administered. A drug containing mitiglinide calcium hydrate containing a document stating that it can be used in combination with an α-glucosidase inhibitor. The drug containing mitiglinide calcium hydrate according to claim 21, wherein the α-glucosidase inhibitor is voglibose. A kit comprising a preparation containing mitiglinide calcium hydrate and a preparation containing voglibose. A method for improving postprandial blood glucose transition in type 2 diabetes, comprising orally administering mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof and an α-glucosidase inhibitor before a meal. Mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof, and an α-glucosidase inhibitor are orally administered before a meal to thereby give mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof, or α -HbA _1C reduction method characterized by showing a synergistic HbA _1C reduction action compared with the sum of the HbA _1C reduction action when a glucosidase inhibitor is administered alone. Mitiglinide, a pharmacologically acceptable salt thereof or a hydrate thereof, and an α-glucosidase inhibitor are administered to a patient whose HbA _1C value is 6.5% or more after administration of an α-glucosidase inhibitor for 16 weeks. Is orally administered before meals, synergistically compared to the sum of the effects of lowering HbA _1C when mitiglinide, a pharmacologically acceptable salt or hydrate thereof, or an α-glucosidase inhibitor is administered alone. _{HbA 1C} reduction method characterized by indicating the specific _{HbA 1C} lowering effect.

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