JP2013063947A - Drug promoting secretion of glp-1 and inhibiting secretion of gip - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an incretin hormone related drug which can promote secretion of GLP-1 while completely inhibiting secretion of GIP and is excellent in safety.SOLUTION: The drug which promotes secretion of GLP-1 (glucagon-like peptide-1) and inhibits secretion of GIP (glucose-dependent insulin secretion-stimulating polypeptide), includes a non-competitive inhibitor for sucrose-degrading enzyme such as L-arabinose, D-xylose, and D-tagatose and sucrose as active components, or includes the non-competitive inhibitor, but does not contain sucrose and separately use sucrose or sucrose-containing food in combination.

Description

  The present invention relates to an incretin hormone-related drug useful for treatment of impaired glucose tolerance and prevention of diabetes.

  The number of people suffering from diabetes in Japan is approximately 7.4 million in the national statistics (2004), and is said to be approximately 16.2 million including the reserve army (Ministry of Health, Labor and Welfare 2002 Diabetes Actual Survey). This is an increase of about 20% from (1997). As the cause of death, it is 10th in men and 9th in women (Ministry of Health, Labor and Welfare, 2005 demographic statistics), but including macrovascular disorders induced by complications with diabetes It is believed that the number will be even more serious.

  Glucose intolerance is attracting attention as an early symptom of the diabetes reserve army. Glucose tolerance abnormality is a symptom that blood glucose level after a meal is difficult to decrease, and is usually determined by a 75 g glucose tolerance test (75 gOGTT).

  In recent years, incretin hormone (glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1))-related drugs have attracted attention for the treatment of diabetes. GIP is mainly secreted by stimulation of K cells present in the upper intestine, while GLP-1 is secreted mainly by stimulation of L cells present in the lower intestine. Incretin hormones act on the pancreas to promote amplification of insulin secretion during hyperglycemia, but when the blood glucose level is not high, the amount of insulin secretion is not increased, so the risk of causing hypoglycemia is low. However, incretin hormone has a drawback that it is rapidly degraded by a degrading enzyme (DPP-4). Therefore, those having the action of inhibiting the decomposition (inhibitors of degrading enzymes or incretin hormone analogs that do not receive enzymatic action) have been developed as incretin hormone-related drugs. Such drugs are expected to have few side effects. However, since none of the incretin hormone-related drugs exist in nature, strict doctor control is required for the prescription, and the production cost is not low.

  Of the above-mentioned two types of incretin hormones, GLP-1 is effective in preventing obesity because it has an inhibitory effect on feeding as well as amplification of insulin secretion (non-patent document 1). Is desired. On the other hand, GIP has a fat accumulation action in addition to the amplification of insulin secretion (Non-patent Document 2), and is therefore not preferable for the treatment of impaired glucose tolerance and the prevention of diabetes that require weight control, and its secretion is suppressed. Is desirable.

  In addition to DPP-4 inhibitors and GLP-1 analogs, which are general incretin hormone interlinking drugs, as incretin hormone-related drugs that have the action of promoting GLP-1 secretion and suppressing GIP secretion Are known to be disaccharide-degrading enzyme inhibitors (α-GI agents) such as acarbose, voglibose and miglitol. However, the conventional α-GI agent can suppress the GIP secretion amount to some extent, but cannot completely suppress the secretion (Acarbose: Non-patent document 3, Voglibose: Non-patent document 4, Miglitol. : Non-patent document 5). Moreover, although the conventional alpha-GI agent can be taken orally with daily meals, it still requires a doctor's prescription.

Turton MD, et al. , Nature, 379, p69, 1996. Miyawaki, K .; , Et al. , Proc. Acad. Sci. USA, 96, p14843, 1999. Seifart, C.I. , Et al. , Diabetic Med. , 15, p485, 1998. G [o] ke, B.R. , Et al. , Digestion, 50, p493, 1995. Aoki, K .; , Et al. , Endocrine J .; , 57, p667, 2010.

  The present invention has been created in view of the current state of the prior art, and its purpose is to promote GLP-1 secretion while completely suppressing GIP secretion, and is excellent in safety. There is to provide incretin hormone related drugs.

  In order to solve such problems, the present inventors examined the action mechanism of a conventional α-GI agent. As the conventional α-GI agent is an antagonistic inhibitor, it inhibits its disaccharide-degrading enzyme. It has been found that the action is uneven, especially in the upper intestinal tract, the inhibition does not work very effectively, and K cells in the upper intestinal tract are stimulated to secrete GIP. If a non-antagonistic inhibitor is used in place of a competitive inhibitor in a specific amount relative to sucrose, there is no unevenness in the disaccharide-degrading enzyme inhibitory action, the inhibition works effectively in the upper intestine, and in the lower intestine Slow digestion and absorption of disaccharides. As a result, stimulation can be given to L cells in the lower intestine for a long time without stimulating K cells in the upper intestine, and GIP is secreted at all. And found that GLP-1 secretion can be amplified. In addition, many non-antagonistic α-GI agents have been conventionally used as food additives, and it was also confirmed that they are safe for the human body.

The present invention has been completed based on these findings and comprises the following (1) to (6).
(1) A drug for promoting secretion of GLP-1 (glucagon-like peptide-1) and suppressing secretion of GIP (glucose-dependent insulin secretion stimulating polypeptide), wherein the drug is non-sucrose-degrading enzyme A drug comprising a competitive inhibitor and sucrose as active ingredients, wherein the non-competitive inhibitor of sucrose degrading enzyme is L-arabinose, D-xylose and / or D-tagatose.
(2) The proportion of the sucrose-degrading enzyme non-antagonistic inhibitor to sucrose is 4.5 to 99% by weight in the case of L-arabinose or D-xylose, and 25 to 99 in the case of D-tagatose. The drug according to (1), wherein the drug is% by weight.
(3) A drug for promoting secretion of GLP-1 (glucagon-like peptide-1) and suppressing secretion of GIP (glucose-dependent insulin secretion stimulating polypeptide), wherein the drug is a non-sucrose-degrading enzyme. Contains a competitive inhibitor but no sucrose and the drug is taken at the same time as ingestion of sucrose or sucrose-containing food, taken within less than 10 minutes before ingestion, or 15 after ingestion A drug characterized by exerting an effect by interacting with a non-antagonistic inhibitor of sucrose degrading enzyme and sucrose when taken within minutes.
(4) When the proportion of the non-competitive inhibitor of sucrose-degrading enzyme to sucrose in the sucrose or sucrose-containing food to be taken is L-arabinose or D-xylose, 4.5 to 99% by weight In the case of D-tagatose, the drug according to (3), which is 25 to 99% by weight.
(5) The drug according to (4), wherein the sucrose-containing food is a Japanese-Western confectionery, a dairy product, a beverage, or drinking water.
(6) The drug according to any one of (1) to (5), which is used for treatment of impaired glucose tolerance or prevention of diabetes.

  Since the drug of the present invention comprises an non-antagonistic α-GI agent as an active ingredient, only the desired GLP-1 secretion is achieved while completely suppressing the secretion of GIP which is undesirable for treatment of impaired glucose tolerance and prevention of diabetes. Can be promoted. Further, many non-antagonistic α-GI agents have been conventionally used as food additives in general and are excellent in safety to the human body.

FIG. 1 is a graph showing temporal changes in blood glucose levels before and after administration in a sucrose + L-arabinose (vs. sucrose 5%) administration group, a sucrose administration group, and an arabinose administration group. FIG. 2 is a graph showing time-dependent changes in the amount of insulin in the serum before and after administration in the sucrose + L-arabinose (vs. sucrose 5%) administration group, sucrose administration group, and arabinose administration group. FIG. 3 is a graph showing changes over time in the amount of active GLP-1 in plasma before and after administration in a sucrose + L-arabinose (vs. sucrose 5%) administration group, a sucrose administration group, and an arabinose administration group. FIG. 4 is a graph showing temporal changes in the amount of total GLP-1 in plasma before and after administration in the sucrose + L-arabinose (vs. sucrose 5%) administration group, sucrose administration group, and arabinose administration group. FIG. 5 is a graph showing changes over time in the amount of GIP in plasma before and after administration of a sucrose + L-arabinose (vs. sucrose 5%) administration group, a sucrose administration group, and an arabinose administration group. FIG. 6 shows active GLP in plasma before and after administration of a sucrose + L-arabinose (vs. sucrose 1%, 2.5%, 4%, 5%, 10%, 20%) administration group and a sucrose administration group. It is a graph which shows the time-dependent change of the quantity of -1. FIG. 7 shows the amount of GIP in plasma before and after administration of sucrose + L-arabinose (vs. sucrose 1%, 2.5%, 4%, 5%, 10%, 20%) administration group and sucrose administration group. It is a graph which shows a time-dependent change. FIG. 8 shows active GLP in plasma before and after administration of sucrose + D-xylose (vs. sucrose 1%, 2.5%, 4%, 5%, 10%, 20%) administration group and sucrose administration group. It is a graph which shows the time-dependent change of the quantity of -1. FIG. 9 shows the amount of GIP in plasma before and after administration of sucrose + D-xylose (vs. sucrose 1%, 2.5%, 4%, 5%, 10%, 20%) administration group and sucrose administration group. It is a graph which shows a time-dependent change. FIG. 10 shows the amount of active GLP-1 in plasma before and after administration of sucrose + D-tagatose (vs. sucrose 10%, 20%, 30%, 40%, 50%) administration group and sucrose administration group. It is a graph which shows a time-dependent change. FIG. 11 is a graph showing changes over time in the amount of GIP in plasma before and after administration of a sucrose + D-tagatose (vs. sucrose 10%, 20%, 30%, 40%, 50%) administration group and a sucrose administration group. It is.

  The drug of the present invention is a sucrose-degrading enzyme antagonist-type inhibitor and non-antagonist-type inhibitor that uses an antagonistic inhibitor, so that L in the lower intestinal tract can be stimulated without stimulating K cells in the upper intestinal tract. It stimulates only cells to promote the secretion of desirable GLP-1 and suppress the secretion of undesirable GIP, and is extremely useful for the treatment of impaired glucose tolerance and the prevention of diabetes.

  As the non-antagonistic inhibitor which is an active ingredient of the drug of the present invention, any conventionally known inhibitor can be used, but it is desirable that it exists in nature from the viewpoint of safety, and moreover it is a general food from the viewpoint of eating experience. The thing derived from the plant used as is desirable. Moreover, when using the thing which does not exist almost in nature, it is desirable to use what is recognized that it can be added to food by a public institution. Preferable examples of non-antagonistic inhibitors include L-arabinose, D-xylose and D-tagatose, and these can be used alone or in combination.

  In order for the drug of the present invention to exert its effect, it is necessary to create a state in which an incompetent inhibitor of sucrose degrading enzyme and sucrose are present simultaneously in the intestine of the patient. For this purpose, it is preferable that sucrose is contained in the drug itself from the beginning, or a drug that does not contain sucrose is used in combination with sucrose or a sucrose-containing food.

  When sucrose is contained in the drug itself, it has the same effect as when a separate non-antagonistic inhibitor and sucrose are taken simultaneously. In this case, the proportion of the non-antagonistic inhibitor in the drug to sucrose is preferably 4.5% by weight or more from the viewpoint of the inhibitory effect on sucrose degrading enzyme. This is because the inhibitor can significantly inhibit sucrose degrading enzyme only when the proportion of the non-antagonistic inhibitor is not less than the above lower limit. The upper limit of the proportion of the non-antagonistic inhibitor is not particularly limited, but since there is no difference in effect even if it is increased to some extent, it is preferably at most 200% by weight from the viewpoint of the balance between economy and taste. . When the non-competitive inhibitor is L-arabinose or D-xylose, the blending ratio with respect to sucrose is preferably 4.5 to 99% by weight, and more preferably 4.5 to 75% by weight. . In the case of D-tagatose, it is preferably 25 to 99% by weight, more preferably 25 to 75% by weight.

  The dosage form of the drug of the present invention is not particularly limited, and can be, for example, tablet, granule, powder, capsule, gel, sol and the like. Formulation may be carried out in accordance with a known method. The non-antagonistic inhibitor of the active ingredient is mixed with saccharose and a pharmaceutically acceptable carrier such as starch, mannitol, carboxymethylcellulose, and further as necessary. It can be carried out by adding stabilizers, excipients, binders, disintegrants and the like.

  When a drug that does not contain sucrose is used in combination with a separate sucrose or sucrose-containing food, the drug should be taken at the same time as the sucrose or sucrose-containing food or within a certain time before and after the intake. is necessary. Taking drugs at the same time as ingestion of sucrose or sucrose-containing foods is certain in terms of effect, but taking into account the intestinal residence time of sucrose or non-competitive inhibitors, the intake time of both is not greatly separated It is preferable. Specifically, if the drug is taken too early, an incompetent inhibitor may not be present in the intestinal tract when sucrose or a sucrose-containing food is ingested. Within 5 minutes, more preferably within 5 minutes before ingestion. Also, after taking sucrose or a sucrose-containing food, sucrose that has reached the intestinal tract is decomposed by sucrose-degrading enzymes, and the K cells in the upper intestine are stimulated by the decomposition product, and GIP is Since it may be secreted, it is desirable to avoid it as much as possible, but within 15 minutes, preferably within 10 minutes after ingestion, it is acceptable in actual use situations.

  When a drug that does not contain sucrose is used in combination with a separate sucrose or sucrose-containing food, the proportion of the non-antagonistic inhibitor to sucrose in the sucrose or sucrose-containing food is basically in the drug itself. It is preferable to make it the same as in the case of containing sugar.

  The sucrose-containing food used together with the drug of the present invention is not particularly limited as long as it contains sufficient sucrose, such as candy, gum, cookies, cakes, pudding, jelly, bavarois and mousse. Japanese confectionery such as ice cream, yogurt; drinks such as coffee and tea; soft drinks Mention may be made of drinking water such as water, carbonated drinking water and drinking water containing fruit juice.

  When the drug of the present invention is taken simultaneously with the intake of sucrose-containing food, the drug of the present invention can be added to these foods in advance to take the form of the drug-containing food. In this case, alternative sweeteners such as sucralose, maltitol, xylitol, erythritol, aspartame, and acesulfame K can be added to prevent a decrease in the taste of food caused by the non-competitive inhibitor. Further, if necessary, thickeners such as carrageenan, agar, vegetable gums (guar gum, gum arabic, etc.), other insoluble dietary fibers, and water-soluble dietary fibers can be added to maintain the food form.

  The excellent effects (effects of promoting GLP-1 secretion and suppressing GIP secretion) are specifically described below. The description of the examples is given solely for the understanding of the invention, and the present invention is not limited to these examples.

Example 1: Verification test of effect when L-arabinose is used as non-antagonistic inhibitor
Test Method When sucrose and L-arabinose were administered to rats, when sucrose alone (control) was administered to rats, and when L-arabinose alone (control) was administered to rats, GLP-1 and GIP By examining the amount of secretion, the inhibitory effect on blood glucose level and insulin level was examined.

  First, 12 SD male rats (4 weeks old) acclimatized with a normal diet for 1 week were prepared, and these were divided into 3 groups of 4 animals, each group containing 2.5 g sucrose / kg body weight + 125 mg L-arabinose / Body weight kg (vs. sucrose 5%), sucrose 2.5 g / kg body weight, or L-arabinose 125 mg / kg body weight was orally administered.

  Portal vein blood and venous blood were collected from each rat before administration, 30 minutes after administration, and 60 minutes after administration. Prepare a blood collection tube pre-injected with a DPP-4 inhibitor and EDTA, add the collected portal vein blood, stir, immediately ice-cool, and centrifuge within 30 minutes after collection to obtain plasma It was. Next, from this plasma, the active GLP-1, total GLP-1 and GIP of each sample were quantified using an ELISA method. The collected venous blood was placed in a blood collection tube and centrifuged to obtain serum. Next, from this serum, the insulin level in the serum was quantified using an ELISA method, and the glucose level (blood glucose level) in the serum was measured using an enzymatic method. The value described in the graph of each characteristic value was an average value of measured values obtained from four rats.

The results of measurement are shown in FIGS. FIG. 1 is a graph showing changes over time in blood glucose levels before and after administration of a sucrose + L-arabinose administration group, a sucrose administration group (control), and an L-arabinose administration group (control), and FIGS. It is the same graph as FIG. 1 regarding the insulin level in serum, the amount of active GLP-1, the amount of total GLP-1, and the amount of GIP.

  1 and 2, it can be seen that when sucrose and L-arabinose were administered simultaneously, the increase in blood glucose level and serum insulin level was suppressed as compared with the case where sucrose alone was administered. 3 and 4, the administration of sucrose and L-arabinose promotes the secretion of active GLP-1 and total GLP-1, and the amount of active GLP-1 secretion is significant even after 60 minutes. I understand that there was. On the other hand, FIG. 5 shows that GIP was hardly secreted even when sucrose and L-arabinose were administered. 1-5, even if only L-arabinose was administered, the blood glucose level, the insulin level in serum, the amount of active GLP-1, the amount of total GLP-1, and the amount of GIP all changed. You can see that there wasn't.

Example 2: Examination of the effect of changing the dose of L-arabinose
Test Method The amount of L-arabinose administered to rats was changed from that in Example 1, and changes in the secretion amounts of GLP-1 and GIP were examined.

  First, 24 SD male rats (4 weeks old) acclimated for 1 week with a normal diet were prepared and divided into 6 groups of 4 rats, each group containing 2.5 g sucrose / kg body weight + 25 mg L-arabinose / Body weight kg (vs. sucrose 1%), sucrose 2.5 g / kg body weight + L-arabinose 62.5 mg / kg body weight (vs. sucrose 2.5%), sucrose 2.5 g / kg body weight + L-arabinose 100 mg / kg body weight (Vs. sucrose 4%), sucrose 2.5 g / kg body weight + L-arabinose 250 mg / kg body weight (vs. sucrose 10%), sucrose 2.5 g / kg body weight + L-arabinose 500 mg / kg body weight (vs. sucrose 20% ), Or 2.5 g sucrose / kg body weight. The treatment after administration was the same as in Example 1, and active GLP-1 and GIP were measured.

The results of measurement are shown in FIGS. FIG. 6 is a graph showing changes over time in the amount of active GLP-1 before and after administration in a sucrose + L-arabinose administration group and a sucrose administration group (control), and FIG. 7 is a sucrose + L-arabinose administration group. 5 is a graph showing the change over time in the amount of GIP before and after administration in the sucrose administration group (control). In addition, in FIG.6 and 7, the data of 5% with respect to sucrose measured in Example 1 were also written together.

  6 and 7, when 1%, 2.5% or 4% of L-arabinose was administered to sucrose, active GLP-1 was significantly detected after 60 minutes as compared with the case of administering sucrose alone. It can be seen that GIP also increased slightly. In addition, when 10% or 20% of L-arabinose was administered to sucrose, active GLP-1 increased, while GIP did not increase, but the extent was 5% L of sucrose. -It turns out that it was almost the same as the case of administering arabinose.

Example 3: Verification test of effect when D-xylose is used as non-competitive inhibitor
Test Method GLP-1 and GIP secretion levels were examined when sucrose and D-xylose were administered to rats at various blending ratios, and when sucrose alone (control) was administered to rats.

  First, 28 SD male rats (4 weeks old) acclimatized with a normal diet for 1 week were prepared, and these were divided into 7 groups of 4 animals, each group containing 2.5 g sucrose / kg body weight + 25 mg D-xylose / Body weight kg (vs. sucrose 1%), sucrose 2.5 g / kg body weight + D-xylose 62.5 mg / kg body weight (vs. sucrose 2.5%), sucrose 2.5 g / kg body weight + D-xylose 100 mg / kg body weight (4% sucrose), 2.5 g sucrose / kg body weight + 125 mg D-xylose / kg body weight (5% sucrose), 2.5 g sucrose / kg body weight + 250 mg D-xylose / kg body weight (10% sucrose) ), Sucrose 2.5 g / kg body weight + D-xylose 500 mg / kg body weight (vs. sucrose 20%), or sucrose 2.5 g / kg body weight. The treatment after administration was the same as in Example 1, and active GLP-1 and GIP were measured.

The results of measurement are shown in FIGS. FIG. 8 is a graph showing changes over time in the amount of active GLP-1 before and after administration in a sucrose + D-xylose administration group and a sucrose administration group (control), and FIG. 9 is a sucrose + D-xylose administration group. 5 is a graph showing the change over time in the amount of GIP before and after administration in the sucrose administration group (control).

  8 and 9, when 1%, 2.5%, or 4% of D-xylose is administered to sucrose, active GLP-1 is significant after 60 minutes as compared to the case of administering sucrose alone. It can be seen that the increase was accelerated and the GIP increased slightly. It can also be seen that when 5%, 10% or 20% D-xylose was administered to sucrose, active GLP-1 increased, while GIP did not increase.

Example 4: Verification test of effect when D-tagatose is used as noncompetitive inhibitor
Test Method GLP-1 and GIP secretion levels were examined when sucrose and D-tagatose were administered to rats at various blending ratios, and when sucrose alone (control) was administered to rats.

  First, 24 SD male rats (4 weeks old) acclimatized for 1 week with a normal diet were prepared, and each group was divided into 6 groups of 4 animals, each group containing 2.5 g sucrose / kg body weight + 250 mg D-tagatose / Body weight kg (vs. sucrose 10%), sucrose 2.5 g / kg body weight + D-tagatose 500 mg / kg body weight (vs. sucrose 20%), sucrose 2.5 g / kg body weight + D-tagatose 750 mg / kg body weight (vs. sucrose) 30%), sucrose 2.5 g / kg body weight + D-tagatose 1000 mg / kg body weight (40% sucrose), sucrose 2.5 g / kg body weight + D-tagatose 1250 mg / kg body weight (vs sucrose 50%), or sucrose Sugar 2.5 g / kg body weight was orally administered. The treatment after administration was the same as in Example 1, and active GLP-1 and GIP were measured.

The results of measurement are shown in FIGS. FIG. 10 is a graph showing temporal changes in the amount of active GLP-1 before and after administration in the sucrose + D-tagatose administration group and the sucrose administration group (control), and FIG. 11 is a sucrose + D-tagatose administration group. 5 is a graph showing the change over time in the amount of GIP before and after administration in the sucrose administration group (control).

  10 and 11, when 10% or 20% of D-tagatose is administered to sucrose, active GLP-1 significantly increases after 60 minutes as compared with the case of administering sucrose alone, It can also be seen that there was a slight increase. Moreover, when 30%, 40%, or 50% of D-tagatose was administered to sucrose, it was found that active GLP-1 increased while GIP did not increase.

  From the above results, L-arabinose, D-xylose, and D-tagatose are all non-competitive inhibitors of sucrose degrading enzymes, and effectively promote GLP-1 secretion while suppressing GIP secretion. And, in the case of L-arabinose or D-xylose, 4.5% by weight or more is sufficient for the proportion of the sucrose-degrading enzyme non-antagonistic inhibitor to sucrose. In the case, it is clear that 25% by weight or more is sufficient.

  The drug of the present invention can promote only the secretion of desirable GLP-1 while completely suppressing the secretion of GIP, which is undesirable for impaired glucose tolerance and diabetes among the incretin hormones. In addition, non-antagonistic α-GI agents, which are active ingredients of the drug of the present invention, are generally used conventionally as food additives and are excellent in safety to the human body. Therefore, the drug of the present invention is extremely suitable for daily intake for treatment of impaired glucose tolerance and prevention of diabetes.

Claims (6)

  A drug for promoting secretion of GLP-1 (glucagon-like peptide-1) and suppressing secretion of GIP (glucose-dependent insulin secretion stimulating polypeptide), wherein the drug is non-antagonistic inhibition of sucrose degrading enzyme A drug comprising an agent and sucrose as active ingredients, wherein the non-antagonistic inhibitor of sucrose degrading enzyme is L-arabinose, D-xylose and / or D-tagatose.   In the case of L-arabinose or D-xylose, the proportion of the sucrose-degrading enzyme non-antagonistic inhibitor to sucrose is 4.5 to 99% by weight, and in the case of D-tagatose, 25 to 99% by weight. The drug according to claim 1, wherein the drug is.   A drug for promoting secretion of GLP-1 (glucagon-like peptide-1) and suppressing secretion of GIP (glucose-dependent insulin secretion stimulating polypeptide), wherein the drug is non-antagonistic inhibition of sucrose degrading enzyme Contains the drug but does not contain sucrose and the drug is taken at the same time as ingestion of sucrose or sucrose-containing food, taken within less than 10 minutes before ingestion, or within 15 minutes after ingestion A drug characterized by exerting an effect by interacting with a non-competitive inhibitor of sucrose-degrading enzyme and sucrose when taken.   In the case of L-arabinose or D-xylose, the blending ratio of the sucrose-degrading enzyme non-antagonistic inhibitor to sucrose in the sucrose or sucrose-containing food to be taken is 4.5 to 99% by weight, In the case of D-tagatose, the drug according to claim 3, wherein the drug is 25 to 99% by weight.   The drug according to claim 4, wherein the sucrose-containing food is a Japanese-Western confectionery, a dairy product, a beverage, or drinking water.   The drug according to any one of claims 1 to 5, which is used for treatment of impaired glucose tolerance or prevention of diabetes.