JP2006193511A - Pharmaceutical composition for treatment of diabetes - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a highly safe treating method of diabetes which exhibits excellent effects and can suppress a side reaction. <P>SOLUTION: The pharmaceutical composition for preventing or treating diabetes comprises an FBPase inhibitor, and administration thereof at the initial stage of the time zone where the interval between meals is the longest allows exhibition of enhanced effects for prevention or treatments of diabetes. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention contains a FBPase inhibitor, has a high therapeutic effect, and can reduce side effects, such as diabetes, hyperglycemia, glucose intolerance, obesity, and diabetic complications (preferably diabetes). The present invention relates to a therapeutic agent and a method for administering the therapeutic agent.

  Further, the present invention includes diabetes, hyperglycemia, glucose intolerance, obesity, diabetic complications, which have a high therapeutic effect and can reduce side effects, including FBPase inhibitors and other antidiabetic agents. Preferably, it relates to a therapeutic agent for diabetes) and a method for administering the therapeutic agent.

  FBPase inhibitors are known to function to lower blood sugar by inhibiting gluconeogenesis in the liver. Diabetes, hyperglycemia, glucose intolerance, obesity, diabetic complications (eg, retinopathy) , Cataracts, nephropathy, peripheral nerve disorders, etc.) and the like (see, for example, Patent Documents 1 to 3).

  On the other hand, a biguanide agent has an action of lowering blood sugar without increasing body weight, and is therefore widely used in Europe and the United States as a therapeutic agent for diabetes. The biguanides currently on the market include metformin and are administered to patients with diabetes twice a day. However, biguanides such as metformin may cause adverse events such as gastrointestinal disorders (eg, nausea, dyspepsia) and rarely lactic acidosis due to lactic acid accumulation when used clinically. It is known that sufficient care is required when using it.

  In addition, it is known that there are many opportunities to use a combination of multiple antidiabetic drugs. However, as a conventional combination method, other drugs are used as they are in addition to the drugs used from the beginning, and only an additive effect can be expected. Therefore, at present, the optimal administration method for the combination of the drugs, that is, the effects of suppressing the disadvantages (side effects, etc.) while making the most of each advantage by using the drugs with different action mechanisms. Is needed.

There is a document disclosing the hypoglycemic effect of a combination of an FBPase inhibitor and another therapeutic agent for diabetes (see, for example, Patent Document 4). However, the specific administration method of the present invention is not described or suggested at all.
International Publication No. 00/14095 Pamphlet International Publication No. 01/47935 Pamphlet International Publication No. 01/66553 Pamphlet International Publication No. 02/03978 Pamphlet

  As a result of intensive studies aimed at developing a highly safe treatment method for diabetes that exhibits excellent effects and can suppress side effects (for example, gastrointestinal disorders), an FBPase inhibitor It was found that a high therapeutic effect can be obtained and side effects can be remarkably suppressed by using at a specific administration timing, and the present invention has been completed.

Furthermore, when a FBPase inhibitor is used in combination with another diabetes therapeutic agent (preferably, a biguanide agent), a high therapeutic effect can be obtained by administering at a specific timing, and side effects are remarkable. The present invention has been completed by finding that it can be suppressed.

The present invention
(1) A pharmaceutical composition comprising an FBPase inhibitor, characterized by the prevention of diabetes, which is enhanced in the prevention or treatment effect of diabetes by being administered at the beginning of the time period when the meal interval is the longest. Or a pharmaceutical composition for treatment,
(2) A pharmaceutical composition comprising an FBPase inhibitor, characterized in that the prophylactic or therapeutic effect of diabetes is enhanced by oral administration once a day at the beginning of the time period when the meal interval is the longest. A pharmaceutical composition for preventing or treating diabetes,
(3) The pharmaceutical composition according to the above (1) or (2), wherein the administration time zone is from after dinner to before going to bed,
(4) The pharmaceutical composition according to the above (1) to (3), wherein the administration time zone is after dinner,
(5) The pharmaceutical composition according to the above (1) to (4), comprising 1 to 400 mg of an FBPase inhibitor,
(6) The pharmaceutical composition according to the above (1) to (4), comprising 10 to 200 mg of an FBPase inhibitor,
(7) A kit for preventing or treating diabetes, including instructions that it should be used by oral administration once a day at the beginning of the time period after dinner and before going to bed, and containing an FBPase inhibitor as a unit dose A kit containing 1 to 400 mg and containing at least one such unit dose,
(8) A method for treating diabetes, characterized in that a pharmaceutical composition containing an FBPase inhibitor as an active ingredient is orally administered once a day in a time zone in which the subsequent meal interval is longest. Method of treatment,
(9) A kit for separately administering two different active ingredients over time in the treatment of diabetes, wherein (a) the first component contains a biguanide agent as an active ingredient, b) a kit wherein the second component is a pharmaceutical composition containing an FBPase inhibitor as an active ingredient,
(10) In the treatment of diabetes, a kit for preventing side effects by separately administering two different active ingredients over time, (a) the first ingredient contains a biguanide as an active ingredient (B) a kit wherein the second component is a pharmaceutical composition containing an FBPase inhibitor as an active ingredient,
(11) A kit for reducing the dose of biguanide and preventing side effects by separately administering two different active ingredients over time in the treatment of diabetes, comprising (a) first A pharmaceutical composition in which the component contains a biguanide agent as an active ingredient, (b) a kit in which the second component is a pharmaceutical composition containing an FBPase inhibitor as an active ingredient,
(12) (a) administering the first component when sugar uptake into the tissue to be treated is enhanced, and (b) administering the second component when gluconeogenesis of the treatment subject is enhanced. The kit according to any one of (8) to (11), which is specified.
(13) The kit according to any one of (8) to (11), wherein the second component is specified to be administered after dinner and before going to bed,
(14) It was specified that (a) the first component was administered between 4:00 and 12:00, and (b) the second component was administered to the treatment subject between 17:00 and 1:00 The kit according to (8) to (11) above,
(15) The kit according to any one of (10) to (14), wherein the side effect is a gastrointestinal disorder,
(16) The kit according to any one of (10) to (15), wherein the side effect is an increase in lactic acid level,
(17) The kit according to any one of (8) to 16, wherein the kit is packaged for oral administration.
(18) The kit according to any of (8) to (17) above, wherein the biguanide agent is metformin, phenformin or buformin,
(19) The kit according to any of (8) to (17) above, wherein the biguanide agent is metformin,
(20) The kit according to any one of (8) to (19), wherein the FBPase inhibitor is a drug that inhibits human FBPase,
(21) The FBPase inhibitor is 2-amino-5-isobutyl-4- {2- [5- (N, N′-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole or The kit according to any one of (8) to (19), which is a pharmacologically acceptable salt thereof,
(22) A kit for separately administering two active ingredients over time in the treatment of diabetes, wherein (a) the first component contains a biguanide agent as an active ingredient, (b) ) Use of a biguanide agent and an FBPase inhibitor for producing a kit whose second component is a pharmaceutical composition containing an FBPase inhibitor as an active ingredient,
(23) A therapeutic agent for diabetes, characterized in that a drug containing a biguanide agent as an active ingredient and a drug containing an FBPase inhibitor as an active ingredient are administered separately over time,
(24) A combination for use in association with each other in the treatment of diabetes, comprising (a) a pharmaceutical composition containing a biguanide agent as an active ingredient, and (b) a medicament containing an FBPase inhibitor as an active ingredient A combination for the treatment of diabetes, characterized in that the composition is administered separately over time;
(25) A method for treating diabetes, wherein (a) a pharmaceutical composition containing a biguanide agent as an active ingredient and (b) a pharmaceutical composition containing an FBPase inhibitor as an active ingredient are separated separately over time. A method of treatment, characterized by administration,
(26) A method for treating diabetes, wherein (a) a pharmaceutical composition containing a biguanide agent as an active ingredient and (b) a pharmaceutical composition containing an FBPase inhibitor as an active ingredient are separated separately over time. It is a therapeutic method characterized in that side effects caused by biguanide agents are reduced by administration.

In the present invention, the “FBPase inhibitor” is not particularly limited as long as it is a drug that inhibits the action of FBPase. For example, the phosphate ester amide skeleton described in WO 01/47935 is used as a prodrug moiety. Phosphoric ester amide compound, International Publication No. 00/14095, Journal of Medicinal Chemistry 45, 3865-3877 2002, Bioorganic & Medicinal Chemistry Letters 11 Examples of the compounds described in Vol. 17-21, 2001, are preferably phosphoric ester amide compounds, and particularly preferably 2-amino-5-isobutyl-4- {2- [5- (N , N′-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole and its salts.

  In the present invention, the “diabetes therapeutic agent” is not particularly limited as long as it is a drug generally prescribed for diabetic patients. For example, insulin preparations, biguanides, insulin secretagogues (SU agents, etc.), digestive enzyme inhibition Agents (α-glucosidase inhibitors and the like), insulin resistance improving agents and the like.

  In the present invention, the “biguanide agent” is not particularly limited as long as it is an agent having an anaerobic glycolysis promoting action, peripheral insulin action enhancement, intestinal glucose absorption inhibition, hepatic gluconeogenesis inhibition and the like. However, for example, 1,1-dimethylbiguanide monohydrochloride (generic name: metformin), phenformin, buformin, and the like can be mentioned, and metformin is particularly preferable.

  The administration route of the therapeutic agent for diabetes used in the present invention is generally an oral route. The unit dosage form is not particularly limited as long as it is prepared by a usual preparation technique, and examples thereof include powders, granules, tablets, and capsules.

  These various preparations are prepared according to conventional methods using known adjuvants that can usually be used in the pharmaceutical preparation field, such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents. Can be

  For example, when it is formed into a tablet form, conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, Disintegrating agents such as laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, 4th class Absorption accelerators such as monium base and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. Examples of these lubricants can be given. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  In molding into the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten. Furthermore, you may contain a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals as needed.

  The amount of the FBPase inhibitor contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

  The dose varies depending on symptoms, age, body weight, dosage form, etc., but is usually 0.001 mg (preferably 1 mg, more preferably 10 mg) as the lower limit for adults, and 2000 mg (preferably as the upper limit). 400 mg, more preferably 200 mg) can be administered.

  The amount of biguanide agent contained in the pharmaceutical preparation is not particularly limited and is appropriately selected over a wide range, but it is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

The dose varies depending on symptoms, age, body weight, dosage form, etc., but is usually 0.001 mg (preferably 0.01 mg, more preferably 0.1 mg) as the lower limit for adults, and 2550 mg as the upper limit. (Preferably 850 mg, more preferably 500 mg) can be administered once.

  According to the present invention, by administering an FBPase inhibitor at a specific timing, a high therapeutic effect can be obtained, and side effects can be remarkably reduced. Therefore, the therapeutic agent for diabetes of the present invention and its administration The method is extremely useful for the treatment of diabetes.

Furthermore, when combined with a therapeutic agent for diabetes having a mechanism of action different from that of an FBPase inhibitor, a high therapeutic effect can be obtained and side effects can be remarkably reduced by administration at specific timings. Therefore, the therapeutic agent for diabetes and the administration method thereof of the present invention are extremely useful for the treatment of diabetes.

  EXAMPLES Next, although an Example is given and this invention is demonstrated still in detail, this invention is not limited to these.

Compound A used in Examples is a compound described in International Publication No. 01/47935 pamphlet, and can be produced according to the method of the publication.
Example 1
2-amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole (compound A) and metformin Effect of timing administration on diabetes improvement Diabetes-onset 11-week-old Zucker diabetic obese (ZDF) rats are divided into 3 groups (7 animals / group), and feeding time is 17: 00-9 : 00, Compound A and metformin (purchased from Sigma) were repeatedly administered for 6 weeks. The doses of Compound A and metformin were both 100 to 150 mg / kg once a day and were administered at 9 am (9:00) or 4 pm (16:00). The group administered Compound A at 9:00 am was administered metformin at 4 pm (AM-Compound A / PM-Metformin administered group; Group A), and the group administered Metformin at 9 am was treated at 4 pm A was administered (AM-Metformin / PM-Compound A administration group; Group B), and the daily compound doses of both groups were made equal, and the remaining group (control group) received only the administration solvent per day. Administered once.

表１より、Ａ群の血中糖化ヘモグロビン率は、対照群と比較して低いものの有意差は得られなかった(P=0.0749, Tukey test)。これに対し、Ｂ群の血中糖化ヘモグロビン率は、対照群に比して有意に低く(P=0.0002, Tukey test)、Ａ群に比しても有意に低かった(P=0.0330, Tukey test)。以上のことから、ラットにおいては、「午前-メトホルミン・午後-化合物Ａ」の投与法が「午前-化合物Ａ・午後-メトホルミン」の投与法に比べて、顕著に糖尿病を改善することが示された。 Six weeks after repeated administration, blood was collected from the tail vein, and the rate of glycated hemoglobin in red blood cells was measured using DCA2000 manufactured by Bayer Medical. Glycated hemoglobin is widely used as an indicator for long-term treatment (glycemic control) of diabetic patients because it is produced by non-enzymatic combination of blood glucose and hemoglobin, and its ratio increases with the persistence of hyperglycemia. ing. The measured glycated hemoglobin rate was calculated for each group as the average value and standard error, and are shown in Table 1.
(Table 1)

From Table 1, the blood glycated hemoglobin rate in group A was lower than that in the control group, but no significant difference was obtained (P = 0.0749, Tukey test). In contrast, the blood glycated hemoglobin rate in group B was significantly lower than that in the control group (P = 0.0002, Tukey test) and significantly lower than that in group A (P = 0.0330, Tukey test). ). From the above, in rats, it is shown that the administration method of “AM-Metformin / PM-Compound A” significantly improves diabetes compared to the administration method of “AM-Compound A / PM-Metformin”. It was.

In other words, it was found that when the above two drugs are used in combination, even if the daily dose is the same, administration at a specific timing significantly enhances the action and effect.

The homeostasis of blood glucose is maintained by the balance between the production of sugar mainly derived from the liver and the uptake of sugar into each tissue. Glucogenesis in the liver is related to gluconeogenesis. In general, gluconeogenesis in the liver is enhanced during fasting, and uptake of sugar into tissues is considered to be relatively dominant during feeding.

  FBPase inhibitors inhibit gluconeogenesis by inhibiting FBPase, the rate-limiting enzyme in liver gluconeogenesis. Moreover, although the mechanism of action of metformin is not necessarily clear, as one of them, the promotion of sugar uptake in muscle is presumed.

  Considering the above, the results of this example show that gluconeogenesis is inhibited by administration of an FBPase inhibitor at the time of fasting when gluconeogenesis is enhanced, and at the time of ingestion where sugar uptake into the tissue is active, By promoting the uptake of sugar by administration of the biguanide, each drug is considered to work effectively and diabetes is remarkably improved.

  In the Examples, rats have shown excellent glycemic control by administration of an FBPase inhibitor in the morning because they are fasted during the day and administration of a biguanide in the afternoon because they are at night. On the other hand, in humans, the biguanide is administered in the morning (preferably before or after breakfast), and the afternoon (preferably after dinner to bedtime), since the day and night of feeding timing are usually reversed. It can be expected that a significant diabetes improvement effect can be obtained by administering an FBPase inhibitor in the previous step.

Based on the above, combining FBPase inhibitors and biguanides and using them at the optimal timing can reduce side effects while well controlling blood glucose levels, making it an extremely superior administration method for diabetic patients. It can be considered.

(Example 2)
2-amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole (Compound A) Effects of feeding Non-fasting control group, non-fasting compound A administration group, fasting control group, fasting compound A administration group of 36-week-old male Goto-Kakizaki (GK) rats (Nippon Charles River Co., Ltd.) exhibiting diabetes Were divided into 4 groups (6 animals / group).

Compound A (30 mg / kg) was orally administered to the group to which Compound A was administered, and only the administration solvent was orally administered to the two groups of controls. The two fasting groups were fasted from the day before oral administration of Compound A, and the two non-fasting groups were fasted immediately after oral administration of Compound A (until the start of fasting, solid food (FR2, Funabashi Farm) was ingested freely. ) Blood was collected from the tail vein immediately before oral administration of Compound A and 4 hours after administration, and the blood glucose level was measured by a potential measurement method (glucoloader GXT (manufactured by A & T)) using a glucose oxidase-immobilized electrode. For each individual, the change rate of the blood glucose level 4 hours after compound administration with respect to the value before compound administration is calculated as the blood glucose change rate by the following formula, and the average value and standard error of the blood glucose change rate for each group are shown in Table 2. Indicated.
[Change rate of blood glucose (%)] = 100 × ([blood glucose level 4 hours after compound administration] − [blood glucose level before compound administration]) / [blood glucose level before compound administration]
(Table 2)

  From Table 2, the blood glucose change rate in the control group showed no significant difference between non-fasting and fasting (P = 0.6439, t test), and the blood glucose level decreased to the same extent in both fasting and non-fasting . The rate of change in blood glucose 4 hours after administration of Compound A was significantly lower than the control group regardless of non-fasting or fasting (non-fasting: P = 0.0196, fasting: P = 0.0236, t test), compound A decreased the blood glucose level under any condition.

  On the other hand, when the change rate of blood glucose at 4 hours after administration of the non-fasting compound A administration group and the fasting compound A administration group was compared, the value was significantly low at the time of fasting (P = 0.0158, t test).

  From the above results, it was clarified that although compound A has a blood glucose lowering effect regardless of the feeding situation, administration in a time zone where the fasting time is long exhibits a more significant blood glucose lowering effect. .

  When this result is applied to humans, the fastest time (meal interval) in normal life is the longest from dinner to breakfast. Therefore, it is considered that the therapeutic effect of diabetes is enhanced by administering the FBPase inhibitor after dinner to bedtime.

  Furthermore, according to Examples 1 and 2, the administration timing is effective for enhancing the therapeutic effect of diabetes, not only in the case of treatment with a single agent of Compound A, but also in combination with other therapeutic agents for diabetes. It can be seen that a similar effect can be obtained.

Claims (26)

  A pharmaceutical composition comprising an FBPase inhibitor, wherein the prevention or treatment of diabetes is characterized in that the prevention or treatment effect of diabetes is enhanced by administration at the beginning of the time period when the meal interval is the longest. Pharmaceutical composition for   A pharmaceutical composition comprising an FBPase inhibitor, characterized in that the prophylactic or therapeutic effect of diabetes is enhanced by oral administration once a day at the beginning of the period when the meal interval is the longest. A pharmaceutical composition for preventing or treating.   The pharmaceutical composition according to claim 1 or 2, wherein the administration time zone is from after dinner to before going to bed.   The pharmaceutical composition according to claim 1 or 2, wherein the administration time zone is after dinner.   The pharmaceutical composition according to any one of claims 1 to 4, comprising 1 to 400 mg of an FBPase inhibitor.   The pharmaceutical composition according to any one of claims 1 to 4, comprising 10 to 200 mg of an FBPase inhibitor.   A method for treating diabetes, wherein a pharmaceutical composition containing an FBPase inhibitor as an active ingredient is orally administered once a day in a time zone in which the subsequent meal interval is the longest.   A kit for preventing or treating diabetes, including instructions that it should be used by oral administration once a day at the beginning of the time period after dinner and before going to bed, with 1 to 400 mg of FBPase inhibitor as a unit dose A kit containing and containing at least one such unit dose.   In the treatment of diabetes, a kit for separately administering two different active ingredients over time, (a) a pharmaceutical composition comprising a biguanide agent as an active ingredient, (b) A kit wherein the two components are pharmaceutical compositions containing an FBPase inhibitor as an active ingredient.   In the treatment of diabetes, a kit for preventing side effects by separately administering two different active ingredients over time, (a) a pharmaceutical composition in which the first ingredient contains a biguanide as an active ingredient And (b) a kit wherein the second component is a pharmaceutical composition containing an FBPase inhibitor as an active ingredient.   In the treatment of diabetes, a kit for reducing the dose of biguanide and preventing side effects by administering two different active ingredients separately over time, wherein (a) the first component is a biguanide A pharmaceutical composition containing an agent as an active ingredient, and (b) a kit wherein the second component is a pharmaceutical composition containing an FBPase inhibitor as an active ingredient.   Clarified that (a) the first component is administered when sugar uptake into the treated tissue is enhanced, and (b) the second component is administered when gluconeogenesis is enhanced in the treated subject. The kit according to any one of claims 8 to 11.   The kit according to any one of claims 8 to 11, wherein the second component is specified to be administered after dinner and before going to bed.   Claims that (a) the first component is administered between 4:00 and 12:00 and (b) the second component is administered to the treatment subject between 17:00 and 1:00. The kit according to 8 to 11.   The kit according to any one of claims 10 to 14, wherein the side effect is gastrointestinal disorder.   The kit according to any one of claims 10 to 15, wherein the side effect is an increase in lactic acid level.   17. Kit according to claims 8 to 16, packaged for oral administration.   The kit according to any one of claims 8 to 17, wherein the biguanide is metformin, phenformin or buformin.   The kit according to any one of claims 8 to 17, wherein the biguanide is metformin.   The kit according to any one of claims 8 to 19, wherein the FBPase inhibitor is a drug that inhibits human FBPase.   FBPase inhibitor is 2-amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole or pharmacologically The kit according to any one of claims 8 to 19, which is an acceptable salt.   In the treatment of diabetes, a kit for separately administering two kinds of active ingredients over time, wherein (a) a pharmaceutical composition comprising a biguanide agent as an active ingredient, (b) a second ingredient Use of a biguanide agent and an FBPase inhibitor for producing a kit whose component is a pharmaceutical composition containing an FBPase inhibitor as an active ingredient.   A therapeutic agent for diabetes, characterized in that a drug containing a biguanide agent as an active ingredient and a drug containing an FBPase inhibitor as an active ingredient are administered separately at intervals.   A combination for use in connection with each other in the treatment of diabetes, comprising (a) a pharmaceutical composition containing a biguanide agent as an active ingredient, and (b) a pharmaceutical composition containing an FBPase inhibitor as an active ingredient. A combination for the treatment of diabetes, characterized by being administered separately over time.   A method for treating diabetes, wherein (a) a pharmaceutical composition containing a biguanide agent as an active ingredient and (b) a pharmaceutical composition containing an FBPase inhibitor as an active ingredient are administered separately over time. A treatment method characterized by the above.   A method for treating diabetes, wherein (a) a pharmaceutical composition containing a biguanide agent as an active ingredient and (b) a pharmaceutical composition containing an FBPase inhibitor as an active ingredient are administered separately over time. The side effect resulting from a biguanide agent is reduced by this, The treatment method characterized by the above-mentioned.