Composition for enhancing the blood glucose-lowering effect of sulfonylurea drugs

Abstract

To provide an adjuvant that can maintain the therapeutic effect while reducing the dose of the SU drugs since sulfonylurea drugs (hereinafter also referred to as "SU drugs"'), which are antidiabetic drugs, induce pancreatic β cell exhaustion when used long-term in addition to the side effects of hypoglycemia and weight gain and have side effects of reduced efficacy (hypoglycemic effect) and renal damage.SOLUTION: If D-allulose is administered before or simultaneously with SU drug administration, the hypoglycemic effect of SU drugs will be enhanced. As a result, the above-mentioned problem is solved because the dose of SU drugs can be significantly reduced. Furthermore, since D-allulose has been eaten by humans, it can provide a highly safe drug when combined with SU drugs.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to a composition for enhancing the hypoglycemic effect of sulfonylurea drugs, which are hypoglycemic agents.

Background Art

[0002] Sulfonylurea drugs (hereinafter also referred to as "SU drugs") are excellent therapeutic agents for diabetes that promote endogenous insulin secretion. Unlike insulin injections, SU drugs exert an effect similar to a physiological reaction by increasing the insulin concentration in the portal vein. However, in addition to side effects such as hypoglycemia and weight gain, long-term use of SU drugs also causes side effects such as attenuation of the drug efficacy (hypoglycemic effect) and kidney damage due to exhaustion of pancreatic β cells. Therefore, although it is necessary to reduce the dosage when using SU drugs for a long time, there is a problem that the therapeutic effect decreases when doing so.

[0003] On the other hand, D-allose (hereinafter also referred to as "D-psicose") is known to have an effect of suppressing blood glucose elevation when orally ingested simultaneously with sucrose or starch (Patent Document 1), and to promote GLP-1 secretion when administered without sucrose and on an empty stomach (Patent Document 2).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to reduce the dosage of SU drugs that cause the above side effects when used for a long time.

Means for Solving the Problems

[0006] In an attempt to solve these problems, the inventors of the present invention discovered that, under conditions where D-allulose itself does not significantly exert a blood glucose-lowering effect, administering D-allulose before or simultaneously with an SU drug enhances the blood glucose-lowering effect of the SU drug, and as a result, the dosage of the SU drug can be significantly reduced. This led to the completion of the present invention.

[0007] In other words, the present invention was completed based on the above findings and consists of the following [1] to [9]. [1] A composition comprising D-allulose, which is administered in combination with a sulfonylurea drug, for enhancing the blood glucose-lowering effect of a sulfonylurea drug. [2] A blood glucose-lowering composition comprising D-allulose and a sulfonylurea drug. [3] The composition according to [1] or [2] above, wherein the amount of D-allulose is 0.008 to 2 g / kg body weight and the amount of sulfonylurea drug is 0.025 to 0.2 mg / kg body weight. [4] A composition according to any one of [1] to [3] above for reducing the dosage of sulfonylurea drugs. [5] A composition according to any of [1] to [4] above for improving the side effects of sulfonylurea drugs. [6] A composition according to any one of [1] to [5] above, which is administered on an empty stomach. [7] A composition according to any one of [1] to [6] above, administered to a patient whose fasting blood glucose level is 100 to 150 mg / dL. [8] A method for enhancing the blood glucose-lowering effect of sulfonylurea drugs, administered before or simultaneously with the administration of sulfonylurea drugs. [9] A method to enhance the blood glucose-lowering effect of sulfonylurea drugs by administering 0.008 to 2 g / kg of D-allulose in addition to 0.025 to 0.2 mg / kg of sulfonylurea drug. [Effects of the Invention]

[0008] This approach avoids side effects such as renal impairment caused by sulfonylurea (SU) drug administration and prevents a decrease in efficacy due to long-term administration of SU drugs. Furthermore, since D-allulose has a history of being consumed by humans, it can provide a highly safe drug when combined with SU drugs. [Brief explanation of the drawing]

[0009] [Figure 1] This image shows (A) a line graph showing the change in blood glucose levels over time when mice were orally administered 1 g / kg of D-allulose or physiological saline via gastric injection, and (B) a bar graph showing the area under the curve. [Figure 2] Figure 2(A) shows a line graph illustrating the change in blood glucose levels over time, and Figure 2(B) shows a bar graph illustrating the area under the curve, when mice were orally administered glibenclamide 1.5 mg / kg 60 minutes after being administered either D-allulose 1 g / kg or physiological saline. In Figure 2(A), ** indicates a statistically significant difference with p<0.01 as the significance level, showing the significant difference between the two groups at each time point. In Figure 2(B), ** indicates a statistically significant difference with p<0.01 as the significance level. [Figure 3] Figure 3(A) shows a line graph illustrating the change in blood glucose levels over time, and Figure 3(B) shows a bar graph illustrating the area under the curve, when mice were orally administered 1 g / kg of D-allulose or physiological saline, followed by oral administration of 0.3 mg or 0.75 mg / kg of glibenclamide 60 minutes later. (However, the group administered 0.75 mg / kg of glibenclamide after 1 g / kg of D-allulose is not shown.) * and ** in Figure 3(A) indicate statistically significant differences with p<0.05 and p<0.01, respectively, and show the significant difference compared to "physiological saline + glibenclamide 0.3 mg / kg" at each time point. ** in Figure 3(B) indicates statistically significant differences with p<0.01. [Figure 4] This is a bar graph showing the area under the blood glucose curve for all experiments 1-3. Different letters indicate statistically significant differences with a significance level of p<0.05. [Modes for carrying out the invention]

[0010] The present invention will be described in detail below, but the present invention is not limited to these descriptions.

[0011] In this invention, "sulfonylurea drugs" (SU drugs) refer to drugs that have an effect of promoting insulin secretion from pancreatic β cells and have a sulfonylurea skeleton. For example, second-generation drugs such as glibenclamide and gliclazide, as well as third-generation drugs such as glimepiride, fall into this category. Examples of commercially available SU drugs include "Euglucon" (product of Taiyo Pharma Co., Ltd.) and "Daonil" (product of Sanofi K.K.) for glibenclamide, "Glimicron" (product of Dainippon Sumitomo Pharma Co., Ltd.) for gliclazide, and "Amaryl" (product of Sanofi K.K.) for glimepiride. As mentioned above, SU drugs are diabetes medications that promote endogenous insulin secretion, but they have side effects such as hypoglycemia and weight gain, as well as reduced efficacy and renal impairment with long-term use.

[0012] "D-allulose," also known as D-psicose, can be extracted from plants such as Itea virginica, isomerized from D-glucose or D-fructose using alkaline isomerization (for example, Matsutani Chemical Industry Co., Ltd.'s product "Rare Sugar Sweet"), or isomerized from D-glucose or D-fructose using enzymatic methods utilizing enzymes (such as isomerase or epimerase) obtained from microorganisms or their recombinants (for example, Matsutani Chemical Industry Co., Ltd.'s product "Astraea").

[0013] Under conditions where D-allulose is not administered simultaneously with sucrose or starch, i.e., under conditions where no exogenous sugars such as diet are loaded, it does not have a significant blood glucose-lowering effect. Nevertheless, when D-allulose is administered under these conditions before or simultaneously with SU drugs, it significantly enhances the blood glucose-lowering effect of SU drugs. Here, the general effective dose of SU drugs depends on the degree of blood glucose-lowering effect required by the patient, but is generally said to be 1.25 mg to 10 mg per dose, preferably 1.25 to 2.5 mg, which translates to 0.025 to 0.2 mg / kg, preferably 0.025 to 0.05 mg / kg, when converted to a human adult (50 kg) body weight. Furthermore, the effective dose of SU drugs in mice is 0.1 to 3 mg / kg, preferably 0.3 to 1.5 mg / kg, based on experimental results using mice, so the conversion factor from human dose to mouse dose is estimated to be 0.5 to 120 or 12 to 60. On the other hand, experimental results described later show that the D-allulose dosage applied to mice is 1 g / kg, which, when converted to a human dose, is approximately 2 to 0.008 g / kg or 0.08 to 0.02 g / kg.

[0014] If D-allulose is administered at the above dose simultaneously with or before the administration of the sulfonylurea (SU) drug, a sufficient blood glucose-lowering effect can be observed even when the SU drug is administered at a dose of less than 1.25 mg per dose. This means that the dose of the SU drug may be reduced to approximately one-tenth, one-fifth, one-third, or even one-half of the typical dose. Furthermore, according to the composition of the present invention, problems such as side effects associated with SU drugs can be avoided.

[0015] D-allulose exerts the effects of the present invention when administered simultaneously with the SU drug, but it is more preferable to administer it before the SU drug, with a specific time interval of 10 to 90 minutes or 30 to 60 minutes before the SU drug administration.

[0016] The composition of the present invention may be in any form such as powder, granule, tablet, liquid, gel, etc., as long as it contains an effective amount that exhibits a hypoglycemic effect. Also, the number of administrations per day may be in a form that allows the above effective amount to be administered once a day. Furthermore, regarding the administration timing, it may be any of before meal, during meal, after meal, or between meals, but before meal, after meal, or between meals is preferred, and before meal or between meals is more preferred.

[0017] The administration target of the composition of the present invention may be any mammal, regardless of the degree of the individual's pathological condition. However, in individuals with slightly elevated fasting blood glucose, specifically, individuals with a fasting serum glucose concentration exceeding 100 mg / dL or individuals with a concentration of 100 - 150 mg / dL, the effects aimed at by the present invention are significantly exerted.

Examples

[0018] The excellent effects of the composition of the present invention are specifically shown below based on experimental results.

[0019] <Preparation of Experimental Animals> As experimental animals, C57BL / 6J male mice (30 mice, 8 - 13 weeks old) were used. The mice were pre - bred in individual cages for more than one week, handled by the experimenter, and acclimated to the breeding and experimental environment (12 - hour light - dark cycle. The light period is from 7:30 to 19:30).

[0020] <Method of Data Analysis> The following experimental data are expressed as mean ± standard error. For the results of Experiments 1 and 2, after two-way ANOVA, the Bonferroni test was performed to examine the significant differences between groups at each time point. For Experiment 3, after two-way ANOVA, the Dunnett test was performed to examine the significant differences between groups at each time point. The significance level was set at 5%. In Figure 2(A) which shows the results of Experiment 2, ** indicates p < 0.01. Figure 3(A) which shows the results of Experiment 3 is the test result compared with "saline + glibencamide 0.3 mg / kg", and * and ** mean p < 0.05 and p < 0.01, respectively. Also, Figure 1(B) and Figure 2(B) are bar graphs showing the results of all-group comparisons by unpaired t-test, and Figure 3(B) and Figure 4 are bar graphs showing the results of all-group comparisons by unpaired one-way ANOVA and Tukey test. The significance level was set at 5%. * and ** in Figure 2(B) and Figure 3(B) mean p < 0.05 and p < 0.01, respectively, and different alphabets in Figure 4 mean p < 0.05. <0000​​​​​​​​​On the day of the experiment, the mice acclimated by the above procedure (5 mice at 8 weeks old × 2 groups + 5 mice at 9 weeks old × 2 groups (crossover) = 10 mice × 2 groups) were fasted from 9:00, and blood was collected from the tail vein at 13:00 to measure blood glucose levels. After the measurement, D-allose solution (1 g / kg) or physiological saline was administered orally once into the stomach immediately. The dosage was set at 10 ml / kg. One hour after oral administration, blood was collected, and then immediately, an SU drug (glyburide, Glibenclamide) at 1.5 mg / kg (normal dosage for lowering blood glucose levels) was administered intraperitoneally. The solvent composition of the SU drug was physiological saline containing 0.1% dimethyl sulfoxide and 2% Tween 80, and the dosage was set at 10 ml / kg. After the administration of the SU drug, blood glucose levels at 30, 60, 90, 120, and 180 minutes later were measured over time by collecting blood from the tail vein (Figure 2). As a result, when the SU drug was administered after the administration of D-allose solution (1 g / kg), the blood glucose level decreased significantly compared to when the SU drug was administered after the administration of physiological saline. Also, in both groups, the blood glucose level rapidly decreased to less than 100 mg / dL 30 to 60 minutes after administration, and then the blood glucose level tended to recover gradually, but the blood glucose level remained less than 100 mg / dL even after 120 minutes had passed.

[0023] <Examination of the Dosage of SU Drug (Experiment 3) While D-allulose alone did not lower blood glucose levels, it was confirmed that the blood glucose-lowering effect of sulfonylurea (SU) drugs was enhanced when D-allulose was used in combination with SU drugs. Therefore, the next step was to investigate the effect of reducing the SU drug dosage. On the day of the experiment, mice acclimatized according to the above procedure (5 mice x 2 groups, 11 weeks old, for SU drug 0.75 mg / kg administration; 5 mice x 2 groups, 12 weeks old, for SU drug 0.3 mg / kg administration) were fasted from 9:00 AM, and blood was collected from the tail vein at 1:00 PM to measure blood glucose levels. Immediately after measurement, a single oral intragastric administration of D-allulose solution (1 g / kg) or physiological saline was administered. The dosage was 10 ml / kg. One hour after oral administration, blood was collected, and immediately afterward, SU drug (glibenclamide) 0.3 mg / kg or 0.75 mg / kg was administered intraperitoneally. The solvent composition of the sulfonylurea (SU) drug was physiological saline containing 0.1% dimethyl sulfoxide and 2% Tween 80, and the dose was 10 ml / kg. Blood glucose levels were measured sequentially by tail vein blood sampling at 30, 60, 90, 120, and 180 minutes after administration of the SU drug (Figure 3). As a result, when 0.3 mg / kg or 0.75 mg / kg of the SU drug was administered after administration of D-allulose solution (1 g / kg), blood glucose levels decreased significantly compared to when 0.3 mg / kg or 0.75 mg / kg of the SU drug was administered after administration of physiological saline. In addition, in all groups, blood glucose levels decreased rapidly 30 to 60 minutes after administration, and then tended to gradually recover. However, in the group administered physiological saline + 0.3 mg / kg of the SU drug, blood glucose levels did not fall below 100 mg / dL even after 60 minutes, indicating that its blood glucose-lowering effect was insufficient. On the other hand, in the group administered D-allulose solution (1 g / kg) + 0.3 mg / kg of sulfonylurea (SU) drug, blood glucose levels fell below 100 mg / dL 60 minutes after administration and recovered to above 100 mg / dL after 120 minutes. This was almost identical to the blood glucose time course in the group administered physiological saline + 0.75 mg / kg of SU drug, suggesting that D-allulose enhances the blood glucose-lowering effect of SU drugs, allowing for a reduction in the SU drug dose.

[0024] The area under the curve (AUC) shown on the right side of each graph illustrating the time course of blood glucose levels is collectively shown in Figure 4.

[0025] D-allulose does not significantly lower fasting blood glucose in healthy individuals (fasting blood glucose less than 100 mg / dL) or those with slightly elevated blood glucose levels (100-150 mg / dL). However, it has been found that when D-allulose is used in combination with sulfonylurea (SU) drugs, it enhances the hypoglycemic effect of SU drugs, allowing for a reduction in the dosage of SU drugs. Therefore, if D-allulose is used as an agent to enhance the hypoglycemic effect of SU drugs when administered in combination with them, or as a component of a hypoglycemic composition containing SU drugs and D-allulose, the dosage of SU drugs can be reduced, thereby avoiding side effects such as excessive hypoglycemia, weight gain, decreased efficacy during long-term administration, and renal damage caused by SU drugs.

Claims

1. A composition comprising D-allulose, administered in combination with a sulfonylurea drug, for enhancing the blood glucose-lowering effect of the sulfonylurea drug.

2. A blood glucose-lowering composition comprising D-allulose and a sulfonylurea drug.

3. The composition according to claim 1 or 2, wherein the amount of D-allulose is 0.008 to 2 g / kg body weight and the amount of sulfonylurea drug is 0.025 to 0.2 mg / kg body weight.

4. A composition according to any one of claims 1 to 3 for reducing the dosage of a sulfonylurea drug.

5. A composition according to any one of claims 1 to 4 for improving the side effects of a sulfonylurea drug.

6. A composition according to any one of claims 1 to 5, which is administered on an empty stomach.

7. A composition according to any one of claims 1 to 6, administered to a patient whose fasting blood glucose level is 100 to 150 mg / dL.

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