TWI484955B - Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings - Google Patents

Description

Treatment of medical compositions including type 2 diabetes in human mammals

The present invention relates to a pharmaceutical composition for treating type 2 diabetes in a mammal including a human, particularly comprising (3aS, 5s, 6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro) -pyrrolidin-1-yl)-2-oxoethylamino)-N,N,5-trimethyl-hexahydrocyclopenta[C]pyrrole-2(1H)-carbenamide or pharmaceutically acceptable A pharmaceutical composition of a fixed dose combination of a salt and metformin or a pharmaceutically acceptable salt thereof (e.g., hydrochloride), a method of preparing the pharmaceutical composition, and a pharmaceutical composition comprising a type 2 in a mammal comprising a human The use of diabetes.

Type 2 diabetes is a chronic and progressive disease caused by the complex pathophysiology of dual endocrine defects involving insulin resistance and weakened insulin secretion. The treatment of type 2 diabetes generally begins with diet and exercise, followed by oral anti-diabetic monotherapy. For many patients, this regimen does not adequately control blood glucose during long-term treatment, which results in the need for combination therapy within a few years after diagnosis. However, co-prescription of two or more oral anti-diabetic drugs can lead to complex and difficult treatment options for many patients used.

Combining two or more anti-diabetic agents into a single formulation provides a possible means of delivering combination therapies that do not increase the complexity of the patient's daily treatment regime. The formulation is widely accepted in the symptoms of other diseases, such as hypertension (HYZAAR ^TM is a combination of losartan potassium and hydrochlorothiazide) and a cholesterol lowering (VYTORIN ^TM Ze by the combination of simvastatin and ezetimibe) of the. The choice of an effective and well tolerated treatment is a critical step in the design of a combined tablet. In addition, it is essential that the components have a mutual mechanism of action and a compatible pharmacokinetic step. Examples of oral antidiabetic agents containing two commercially available tablets include joint Glucovance ^TM (metformin and glyburide), Avandament ^TM (rosiglitazone and metformin) and Metaglip ^TM (glipizide and metformin).

Metformin represents the only oral anti-diabetic agent that has been shown to reduce the overall burden of microvascular and macrovascular diabetic complications and prolong the lifespan of patients with type 2 diabetes. In addition, metformin treatment is often associated with weight loss in overweight patients and improvement in fat profile in patients with dyslipidemia.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new class of agents developed to treat or improve glycemic control in patients with type 2 diabetes. The drugs used to treat human type 2 diabetes in current clinical trials include MK-0431, vildagliptin (LAF-237), saxagliptin (BMS-47718), P93/01 (Prosidon), SYR322 (Takeda), GSK823093. , Roche0730699, TS021 (Taisho), E3024 (Eisai) and PHX-1149 (Phenomix). For example, oral administration of vildagliptin to human type 2 diabetic patients has been found to reduce fasting glucose and postprandial glucose deviation associated with significantly reduced HbAIC levels. For a review of the use of DDP-IV for the treatment of type 2 diabetes, see the following publications: (1) H.-U. Demuth et al., "Type 2 diabetes - Therapy with dipeptidyl peptidase IV inhibitors", Biochim. Biophvs. Acta. 1751: 33-44 (2005) and (2) K. Augustyns et al., "Inhibitors of proline-specific dipeptidyl peptidases: DPP4 inhibitors as a novel approach for the treatment of Type 2 diabetes", Expert Opin. Ther. Patants, 15:1387 -1407 (2005).

At present, some DPP-IV inhibitors have been disclosed (US5462928, US5543396, WO9515309, WO2003004498, WO2003082817, WO2004032836, WO2004085661), wherein the DPP-IV inhibitor LAF-237 produced by Novartis shows good DPP-IV inhibitory activity and selection. Sex, and has been listed in 2007.

(3aS,5s,6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxoethylamino)- N,N,5-trimethyl-hexahydrocyclopenta[C]pyrrole-2(1H)-carbenamide is Compound A.

Compound A or its salt inhibited DPP-IV activity longer than LAF-237, and its inhibitory strength was greater than that of LAF-237. Through experimental research, the present inventors have surprisingly found that the compound effect of Compound A or its salt and metformin or its salt is significantly higher than that of the drug alone, especially when the compounding ratio of Compound A or its salt and metformin or its salt is 1: 5 to 1:20 is better. Therefore, the composition of Compound A or a salt thereof and metformin or a salt thereof (e.g., hydrochloride) is clinically significant.

The present invention provides a pharmaceutical composition of a fixed dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof. The two active pharmaceutical ingredients of the pharmaceutical composition of the invention are either immediate or slow release. The pharmaceutical composition of the present invention may be in the form of a tablet, and particularly a film-coated tablet, or other oral dosage forms such as capsules and the like.

One aspect of the invention relates to a dosage form for the pharmaceutical administration of a fixed dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof. The dosage form may be in the form of a powder or a solid, and includes tablets, hard capsules, soft capsules, oral solutions, sustained release agents, pills, granules, granules, sustained release pellets or other oral dosage forms and the like. Particular solid dosage forms relate to tablets containing a fixed dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of preparing a pharmaceutical composition of a fixed dose combination of Compound A or a salt thereof and metformin or a salt thereof by a dry granulation method and a wet granulation method.

Another aspect of the invention provides the use of a pharmaceutical composition of the invention in the treatment of a mammal, including human type 2 diabetes, comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the invention.

In a specific embodiment of the present invention, the pharmaceutical composition comprises (1) Compound A or a pharmaceutically acceptable salt thereof, which is the first active pharmaceutical ingredient; (2) metformin or a salt thereof such as hydrochloride, which is the second An active pharmaceutical ingredient; and (3) a lubricant or a glidant. In a particular embodiment of this aspect of the invention, the pharmaceutical composition may also contain one or more excipients selected from one or more binders (binding agents); one or more diluents; one or more surfaces An active agent or wetting agent; one or more disintegrants; and one or more antioxidants.

The pharmaceutically acceptable salts of Compound A or metformin include, but are not limited to, p-toluenesulfonate, phosphate, hydrochloride, sulfate, nitrate, hydrobromide, methanesulfonate, maleate, tartaric acid. Salt, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, besylate, benzoate, naphthalenesulfonate, lactate and malate.

The compound A or a salt thereof incorporated in the pharmaceutical composition of the present invention is administered in a daily dose of 25 mg to 300 mg. Preferably, Compound A or a salt thereof is administered in a daily dose of from 50 mg to 200 mg. Each individual dose is 25, 50, 75, 100, 150, 200, 250 and 300 mg of Compound A or a salt thereof per day.

The daily dose of metformin or its salt incorporated into the fixed dose combination of the present invention is from 250 mg to 3000 mg per day, and the individual dose per day is 250, 500, 750, 1000, 1500, 2000, 2500 and 3000 mg. These daily doses of metformin or its salts represent daily doses approved for commercial treatment of human Type 2 diabetes in China and/or the United States.

In the fixed dose combination of the present invention, a specific embodiment of the human daily dose of Compound A or a salt thereof and metformin or a salt thereof is as follows:

Compound A or its salt (mg) 25, 50, 75, 100, 150, 200, 250, 300

Metformin or its salt (mg) 250,500,750,1000,1500,2000,2500,3000

Any of a therapeutically effective amount of any of a therapeutically effective amount of Compound A or a salt thereof and metformin or a salt thereof, for example, 50+250, 50+500, 50+750, 100+250, 100+500, 100+750 and many more.

The two active pharmaceutical ingredients in the pharmaceutical composition of the present invention can be in four release forms:

The pharmaceutical composition of the present invention is prepared by a wet granulation method and a dry granulation method.

In one embodiment, the pharmaceutical composition is prepared via a wet granulation process. In one such embodiment, the pharmaceutical composition is prepared via a wet granulation process. In the wet granulation, high shear granulation or fluidized bed granulation can be applied. In one embodiment, the use of fluidized bed granulation has the advantage of making the tablet have a higher radial strength.

The pharmaceutical composition obtained by dry granulation and wet granulation can be compressed into tablets, packaged or metered into sachets.

The pharmaceutical composition contains one or more lubricants or glidants. Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil or a mixture thereof. A preferred lubricant is magnesium stearate or sodium stearyl fumarate or a mixture thereof. Examples of the glidant include colloidal cerium oxide, calcium phosphate, magnesium citrate, and talc.

The pharmaceutical composition of the present invention optionally contains one or more binders. Embodiments of the binder include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HMPC), hydroxyethylcellulose, starch 1500, polyvinylpyrrolidone (polypyridone), and coenopyrrolone. A preferred binder is polyvinylpyrrolidone.

The pharmaceutical composition of the present invention may further contain one or more diluents as needed. Examples of the diluent include mannitol, sorbitol, calcium dihydrogen phosphate dihydrate, microcrystalline cellulose, and powdered cellulose. A preferred diluent is microcrystalline cellulose. Microcrystalline cellulose can be obtained from several suppliers including Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200 manufactured by FMC Corporation.

The pharmaceutical composition of the present invention may further contain a disintegrating agent as needed. The disintegrant may be one of several modified starches, modified cellulose polymers or polycarboxylic acids, such as crosslinked sodium carboxymethylcellulose, sodium starch glycolate, potassium bolconlin and hydroxymethylcellulose. Calcium (CMC Calcium). In one embodiment, the disintegrant is crosslinked hydroxymethylcellulose sodium. Crosslinked hydroxymethylcellulose sodium NF type A is commercially available under the trade designation "Ac-di-sol".

The pharmaceutical composition of the present invention may optionally contain one or more surfactants or wetting agents. The surfactant may be an anionic, cationic or neutral surfactant. Anionic surfactants include sodium lauryl sulfate, sodium dodecyl sulfate, sodium oleyl sulfate, and sodium laurate mixed with stearic acid and talc. Cationic surfactants include benzalkonium chloride and alkyltrimethylammonium bromide. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, and sorbitan esters. Embodiments of the wetting agent include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene stearates.

An antioxidant may be added to the formulation as needed to give it chemical stability. The antioxidant is selected from the group consisting of α-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol enriched natural extract, L-ascorbic acid and its sodium or calcium salt, ascorbate palmitate, citric acid Propyl ester, octyl phthalate, dodecyl decanoate, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). In a specific embodiment, the antioxidant is BHT or BHA.

A preferred dosage form of the pharmaceutical composition of the present invention is a tablet prepared by a compression method. The tablet may be coated with a mixture of, for example, hydroxypropylcellulose and hydroxypropylmethylcellulose, which contains titanium dioxide and/or other colorants such as iron oxide, dyes and lakes; polyvinyl alcohol ( A mixture of PVA) and polyethylene glycol (PEG) containing titanium dioxide and/or other colorants such as iron oxide, dyes and lakes; or any other suitable immediate release coating. The coating provides taste masking and additional stability to the final tablet. A commercially available coating film is supplied by Colorcon for the preparation of a powder mixture. .

Finally, sweeteners and/or flavoring agents can be added if desired.

The metformin of the present invention or a salt thereof such as a hydrochloride may be either immediate release or slow release, and the compound A or a salt thereof may be either immediate release or slow release.

The pharmaceutical tablet compositions of the present invention may also contain one or more additional formulation ingredients selected from excipients known in the art of various pharmaceutical formulations. Depending on the desired properties of the pharmaceutical combination, any of the ingredients may be selected individually or in combination based on their known use in preparing the tablet composition. Such ingredients include, but are not limited to, diluents, compression aids, glidants, disintegrants, lubricants, perfumes, flavoring agents, sweeteners, and preservatives.

The term "tablet" as used herein is intended to include compressed drug dosage formulations of all shapes and sizes, whether coated or not. Substances that can be used for coating include hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide, talc, sweeteners, colorants, and flavoring agents.

In one embodiment, the pharmaceutical compositions of the invention are prepared via wet granulation (high shear and/or fluidized bed). Granulation is a method in which a binder is added to a granulation solution or added to a granulation cylinder to form granules. The steps involved in the wet granulation process include the following:

(1) adding the active pharmaceutical ingredient metformin or a salt thereof such as hydrochloride and Compound A or a salt thereof to the granulation cylinder;

(2) adding the disintegrant as needed to step 1;

(3) For high-shear granulation, a binder (such as polyvinylpyrrolidone or hydroxypropylcellulose) is dry-dried into a granulation cylinder and subjected to short-term dry mixing, followed by the addition of water, with or without a surfactant ( For example, sodium lauryl sulfate). For fluidized bed granulation, two active pharmaceutical ingredients are added to the granulator cartridge, and a granulation solution is added thereto by fluidization, the granulation solution consisting of an aqueous solution of the binder, with or without a surfactant;

(4) The granules prepared by high-shear granulation were subjected to tray drying in an oven or dried in a fluidized bed dryer. For particles prepared by fluidized bed granulation, the granules are dried in a fluid bed dryer;

(5) adjusting the size of the dried particles in a suitable mill;

(6) mixing an optional diluent such as microcrystalline cellulose and calcium dihydrogen phosphate dihydrate with dry granules in a suitable mixer;

(7) adding a lubricant or a glidant such as magnesium stearate and sodium stearyl fumarate to the mixture of step 6 in a suitable mixer;

(8) The lubricating particle mixture of step 7 can be filled into a vial, sachet or capsule or compressed into a desired tablet shape;

(9) The obtained tablets can be subjected to film coating if necessary.

The steps involved in the dry process (direct or dry granulation) process include:

(1) adding the active pharmaceutical ingredient metformin or a salt thereof and Compound A or a salt thereof to a suitable mixer;

(2) adding the disintegrant as needed to step 1;

(3) adding the optional binder and/or diluent to step 2;

(4) adding a lubricant or a flow aid to step 3;

(5) The mixture of step 4 can be filled into a vial, sachet or capsule or compressed into a desired tablet shape, or processed via a roller compressor;

(6) If processing is carried out via a roller compressor, the size of the particles may be adjusted in a suitable mill if necessary;

(7) In a suitable mixer, an optional diluent may be added to the obtained granules to improve compression properties;

(8) adding a lubricant or a glidant as needed to the mixture of step 7;

(9) The lubricating particle mixture of step 8 can be filled into a vial, sachet or capsule or compressed into a desired tablet shape;

(10) If necessary, the tablets obtained in the step 5 or the step 9 can be subjected to film coating.

The invention further provides a method of treating Type 2 diabetes in a mammal, including a human, in a therapeutically effective amount of a fixed dose combination pharmaceutical composition of the invention via oral administration of a subject in need of such treatment. In one embodiment, the subject in need of such treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet, which may also be in the form of a capsule.

The pharmaceutical composition containing the fixed dose combination can be administered once daily (QD), twice daily (BID) or three times daily (TID).

Method for synthesizing compound A of the present invention

(3aS,5s,6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxoethylamino)-N,N,5 - Synthesis of trimethyl-hexahydrocyclopenta[C]pyrrole-2(1H)-carboxamide (Compound A) was prepared according to the method described in Example 18 of PCT/CN2008/071014, so the disclosure is references.

The following examples further describe and illustrate embodiments within the scope of the invention. The examples and the test examples are given for the purpose of illustration only, and are not intended to be construed as limiting the invention, and various modifications may be made without departing from the spirit and scope of the invention.

Example 1: Fixed dose combination of 50 mg of Compound A and 500 mg of metformin hydrochloride per tablet - wet granulation

* Removed during processing.

Production method:

Compound A and metformin hydrochloride are fed to a high shear granulator or a fluidized bed granulator. In the case of high shear granulation, in addition to the polyvinylpyrrolidone binder, purified water containing sodium lauryl sulfate is added to the APIs (active pharmaceutical ingredient) over a period of 3 to 5 minutes. The wet material is either dried at 40 ° C or dried in a fluid bed dryer at an inlet temperature of 45 to 60 ° C for 3 to 6 minutes. In the case of fluidized bed granulation, purified water containing polyvinylpyrrolidone and sodium lauryl sulfate is added to the APIs over a period of 30 to 60 minutes. The wet material is dried in a fluid bed dryer at an inlet temperature of 45 to 60 °C. Then, the dried material is ground using a co-mill to obtain fine particles. After milling, microcrystalline cellulose was added to the granules and mixed in a double shell mixer for 200 revolutions. Then, a lubricant (sodium stearyl fumarate) was added thereto and additionally mixed for 100 rpm. The lubricated mixture was compressed using a rotary tablet press to provide 675 mg of uncoated tablets. The resulting tablets are used as needed The II suspension (polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc, with or without colorants) was applied to an increase in weight of about 2.5% to provide 692 mg of coated film tablets.

In particular, 50 mg of the compound A in the formulation may also be a pharmaceutically acceptable salt of the compound A. Metformin hydrochloride may also be metformin or other pharmaceutically acceptable salts.

Similarly, a formulation containing two active ingredients in different ratios, such as the ratio of Compound A or its salt to metformin or its salt, is prepared by adjusting the amount of Compound A or its salt, metformin or its salt in the formulation. 1, 1:5, 1:7.5, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, etc.

Test Example 1: In vitro activity and selectivity of Compound A and LAF-237

method:

Thaw DPP-IV-Glo. Buffer and balance to room temperature before use. Pre-buffer frozen luciferin detection reagent, suspend DPP-IV-Glo. Add ultrapure water to the matrix and mix gently to make 1 The mM substrate was placed in a brown bottle with DRP-IV-Glo. The luciferin detection reagent should be dissolved within 1 minute, the test compound was dissolved in DMSO to 50 times the final operating concentration, and 50 μl of the test compound was added to each tube to 2 μL, and added to the negative control group and the blank control group. 2 μL of DMSO, 46 μL of Tris buffer was added to each tube, 48 μL of Tris buffer was added to the blank control group, 2 μ of LDPP-IV enzyme was added to each tube of the negative control group and the test sample, and the tubes were shaken and centrifuged. All the contents of the test tube were transferred to a 96-well plate, and the ratio of the mixed substrate and DPP-IV-Glo was 1:49. Mix the vibrations to mix thoroughly. Allow to stand at room temperature for 30 to 60 minutes before use, add 50 μL of DPP-IV-Glo. and matrix mixture to the wells of each 96-well plate, seal the plate with a sealing film, and use a plate shaker at 300 The 96-well material was slowly mixed at 500 rpm/30 s. Incubate for 30 minutes to 3 hours at room temperature and measure the chemiluminescence count on a NOVOstar multi-function microplate reader.

Results: The inhibitory activity of Compound A on DPP-IV was superior to that of the control drug LAF-237, and the selectivity was also greater than that of LAF-237.

Test Example 2: Oral glucose tolerance of normal ICR mice in different proportions of pharmaceutical compositions

Male ICR mice were orally administered with double distilled water after 6 hours of fasting, different ratios (Compound A p-toluenesulfonate: metformin hydrochloride = 1:1, 1:5, 1:1.75, 1:10, 1:15) , 1:20, 1:30, 1:40, 1:50, 1:60) The same dose (100mg/kg) of the pharmaceutical composition, each group was orally administered with glucose 2.5g/kg for 30 minutes, for oral administration. Sugar tolerance test. Blood was taken at 0, 30, 60, and 120 minutes after the administration of the sugar, and serum glucose levels were measured.

Serum glucose determination method;

Glucose kit was used to determine the glucose content in the serum. 250 μl of the enzyme working solution was added, 5 μl of serum was added, and a blank tube (add 5 μl of double distilled water) and a standard tube (add 5 μl of glucose standard solution) were added, and the mixture was mixed, and the water bath was heated at 37 ° C for 20 minutes. Zero with a blank tube and colorimetric at OD505nm.

Serum glucose content BG (nmol / l) = OD _{sample tube} / OD _{standard tube} × 5.55

Data processing and statistical analysis;

1. Statistical analysis of data using mean ± SD and Student-t test

2. Calculate the percentage of blood glucose drop at 30 minutes after feeding sugar and the area under the curve AUC

*, P < 0.05; compared with the blank control group;

**, P < 0.01; compared with the blank control group;

***, P < 0.001; compared with the blank control group;

Test Example 3: Effect of Compound A p-toluenesulfonate and LAF-237 in combination with metformin hydrochloride in Wistar rats with hereditary obesity and diabetes

Male Wistar rats aged 14 to 19 weeks were divided into 5 groups of 5 to 6 animals each, taking Compound A p-toluenesulfonate, LAF-237 (10 mg/kg body weight/day, orally) and metformin salt. Acid salt (100 mg/kg body weight/day; mixed in a commercial feed at a rate of 5 ppm) for 14 days. Blood was taken from the tail vein, and plasma glucose and hemoglobin A1 were separately determined enzymatically using a commercial kit (NC-ROPET, Nippon Chemiphar CO.). The results were expressed as mean ± standard deviation of each group (n = 5-6). And analyzed by Dunnett's test, given in Table 3. Use a 1% significance level.

The combination of compound A p-toluenesulfonate and metformin hydrochloride in Table 3 significantly reduced the concentration of blood glucose and hemoglobin, which was stronger than Compound A p-toluenesulfonate, metformin hydrochloride, LAF-237 alone. Administration, in particular, is greater than the combination of LAF-237 and metformin hydrochloride.

Claims (9)

A pharmaceutical composition for treating type 2 diabetes in a mammal comprising humans, the pharmaceutical composition comprising a therapeutically effective amount of (3aS, 5s, 6aR)-5-(2-((2S,4S)-2-cyano) 4-fluoro-pyrrolidin-1-yl)-2-oxoethylamino)-N,N,5-trimethyl-hexahydrocyclopenta[C]pyrrole-2(1H)-carbenamide or its A pharmaceutically acceptable salt with metformin or a pharmaceutically acceptable salt thereof, wherein (3aS, 5s, 6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidine- 1-yl)-2-oxoethylamino)-N,N,5-trimethyl-hexahydrocyclopenta[C]pyrrole-2(1H)-carbenamide or a pharmaceutically acceptable salt thereof and metformin The weight ratio of the pharmaceutically acceptable salt thereof is from 1:5 to 1:20. The pharmaceutical composition according to claim 1, wherein the (3aS, 5s, 6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidine-1- Each of the peroxyn-6-oxyethylamino)-N,N,5-trimethyl-hexahydrocyclopenta[C]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof The daily dose is 25 to 300 mg, and metformin or a pharmaceutically acceptable salt thereof is used in an amount of 250 to 3000 mg per person per day. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a tablet, a hard capsule, a soft capsule, an oral solution, a sustained release agent, a pill, a granule, a granule, and a granule. Release pellets or other oral dosage forms. The pharmaceutical composition according to claim 1 or 2, wherein the (3aS, 5s, 6aR)-5-(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidine- 1-yl)-2-oxoethylamino)-N,N,5-trimethyl-hexahydrocyclopenta[C]pyridyl Oro-2(1H)-carbenamide or a pharmaceutically acceptable salt thereof is either immediate or slow release. The pharmaceutical composition according to claim 1 or 2, wherein the metformin or a pharmaceutically acceptable salt thereof is immediate release or slow release. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is administered once a day, twice a day or three times a day. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt is selected from the group consisting of p-toluenesulfonate, phosphate, hydrochloride, sulfate, nitrate, hydrobromide, Methanesulfonate, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, besylate, benzoate, naphthalene Sulfonate, lactate or malate. A method of preparing the pharmaceutical composition according to any one of claims 1 to 7, wherein the method is a wet granulation method and a dry granulation method. Use of the pharmaceutical composition according to any one of claims 1 to 8 for the preparation of a medicament for treating diabetes comprising a mammal of a human.