TWI462925B - Pharmaceutical composition for the treatment of type 2 diabetes - Google Patents

Description

Pharmaceutical composition for treating type 2 diabetes

The present invention relates to a pharmaceutical composition for the treatment of type 2 diabetes, in particular comprising (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoro Fixed dose combination of methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or a salt thereof and metformin or a salt thereof (such as hydrochloride) A pharmaceutical composition, a method of preparing the pharmaceutical composition, and a method of treating type 2 diabetes using the pharmaceutical composition.

Type 2 diabetes is a chronic and progressive disease caused by the complex pathophysiology of dual endocrine defects involving insulin resistance and attenuating insulin secretion. Treatment for type 2 diabetes generally begins with diet and exercise followed by oral monotherapy with antidiabetic drugs. 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 employed. Combining two or more anti-diabetic agents into a single tablet 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 profile. Examples of commercially available combination tablets containing two oral anti-diabetic agents include Glucovance ^(TM) (metformin and glyburide), Avandament ^(TM) (metformin and rosiglitazone), and Metaglip ^(TM) (metformin and glipizide).

Metformin has been shown to be the only oral anti-diabetic agent that reduces the overall burden of microvascular and macrovascular diabetic complications and prolongs 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-4 (DPP-4) inhibitors represent a new class of agents developed to treat or improve glycemic control in patients with type 2 diabetes. Among the drugs currently used in clinical trials for the treatment of type 2 diabetes are 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. A review of the use of DDP4 in the treatment of type 2 diabetes can be found in the following publications: (1) H.-U. Demuth et al., "Type 2diabetes-Theraphy 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).

Has the following structural formula (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8- Methyl tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate is Compound A.

The present invention provides a pharmaceutical composition of a fixed dose combination of Compound A or a salt thereof and metformin prepared by a dry or wet treatment method. The pharmaceutical composition of the present invention provides immediate release of two active pharmaceutical ingredients Compound A or a salt thereof and metformin, and immediate release of Compound A or a salt thereof and slow release of metformin. In one embodiment, the pharmaceutical compositions of the invention are in the form of tablets, and in particular film-coated tablets, and may also be other oral dosage forms such as capsules.

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 via a dry or wet treatment method. Dry processing methods include dry compression and dry granulation, and wet processing methods include wet granulation.

Another aspect of the invention provides a method of treating type 2 diabetes by administering a therapeutically effective amount of a pharmaceutical composition of the invention to a subject in need of such treatment.

These and other methods will be apparent from the detailed description below.

Summary of invention

The present invention relates to a novel pharmaceutical composition comprising a fixed dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, a method of preparing the pharmaceutical composition and the use of the pharmaceutical composition for the treatment of Type 2 The method of diabetes. In particular, the invention relates to a pharmaceutical composition comprising a fixed dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin hydrochloride.

Compound A or its salt inhibited DPP4 activity longer than MK-0431, and the inhibitory intensity was greater than MK-0431. Therefore, the composition of Compound A or a salt thereof and metformin or a salt thereof is clinically significant.

Detailed description of the invention

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 can be in powder or solid form and includes tablets, capsules, sachets 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 hydrochloride (1,1-metformin hydrochloride).

Compound A or its salt inhibited DPP4 activity longer than MK-0431, and the inhibitory intensity was greater than MK-0431. Therefore, the composition of Compound A or a salt thereof and metformin or a salt thereof (e.g., hydrochloride) is clinically significant.

In a particular aspect of the invention, the pharmaceutical composition comprises (1) Compound A or a pharmaceutically acceptable salt thereof, one of two active pharmaceutical ingredients; (2) metformin or a salt thereof, such as a hydrochloride salt, Two active pharmaceutical ingredients; and (3) a lubricant or a glidant. In an embodiment of this aspect of the invention, the pharmaceutical composition may further comprise 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.

Pharmaceutically acceptable salts of Compound A include, but are not limited to, phosphates, hydrochlorides, sulfates, nitrates, hydrobromides, methanesulfonates, maleates, tartrates, succinates, acetates, Trifluoroacetate, fumarate, citrate, citrate, besylate, benzoate, naphthalenesulfonate, lactate, malate.

The dose concentration of Compound A or a salt thereof incorporated into the pharmaceutical composition of the present invention is from about 1 mg to about 500 mg of the active moiety. Preferably, the dose concentration of Compound A or a salt thereof is from about 25 mg to about 250 mg of the active moiety. The discrete dose concentrations are 25, 50, 75, 100, 150, 200, 300, 400 and 500 mg of the active moiety equivalent of Compound A or a salt thereof.

The unit dose concentration of the active moiety of Compound A or a salt thereof incorporated into the fixed-dose combination drug combination of the present invention is 25, 50, 75, 100, 150, 200, 300, 400 and 500 mg. Preferably, the dose concentration of Compound A or a salt thereof is 50 or 100 mg.

The unit dose concentrations of metformin hydrochloride incorporated into the fixed dose combination of the invention are 250, 500, 625, 750, 850, 1000 and 1500 mg. These unit dose concentrations of metformin hydrochloride represent dose concentrations approved for commercial treatment of type 2 diabetes in China and/or the United States.

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

(1) 25 mg of Compound A or a salt thereof (for example, phosphate 30.25 mg) and 250 mg of metformin hydrochloride;

(2) 25 mg of Compound A or a salt thereof (for example, phosphate 30.25 mg) and 500 mg of metformin hydrochloride;

(3) 50 mg of Compound A or a salt thereof (for example, phosphate 60.5 mg) and 250 mg of metformin hydrochloride;

(4) 50 mg of Compound A or a salt thereof (for example, phosphate 60.5 mg) and 500 mg of metformin hydrochloride;

(5) 50 mg of Compound A or a salt thereof (e.g., phosphate 60.5 mg) and 850 mg of metformin hydrochloride;

(6) 50 mg of Compound A or a salt thereof (for example, phosphate 60.5 mg) and 1000 mg of metformin hydrochloride;

(7) 100 mg of Compound A or a salt thereof (for example, phosphate 121.0 mg) and 250 mg of metformin hydrochloride;

(8) 100 mg of Compound A or a salt thereof (e.g., phosphate 121.0 mg) and 500 mg of metformin hydrochloride;

(9) 100 mg of Compound A or a salt thereof (e.g., phosphate 121.0 mg) and 850 mg of metformin hydrochloride;

(10) 100 mg of Compound A or a salt thereof (for example, phosphate 121.0 mg) and 1000 mg of metformin hydrochloride;

(11) 100 mg of Compound A or a salt thereof (e.g., phosphate 121.0 mg) and 1500 mg of metformin hydrochloride; the pharmaceutical composition of the present invention is prepared by a wet or dry treatment method. In one embodiment, the pharmaceutical composition is prepared via a wet processing method. In one class of this 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.

In a second embodiment, the pharmaceutical composition is prepared by a dry process. In one class of this embodiment, the pharmaceutical composition is prepared by direct compression or dry granulation. An embodiment of dry granulation is rolling.

The pharmaceutical composition obtained via dry or wet processing 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, and mixtures 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 compositions of the present invention optionally contain 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 compositions of the present invention may also 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 compositions of the present invention may also contain one or more surfactants or wetting agents as needed. The surfactant can 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 one embodiment, the antioxidant is BHT or BHA.

A preferred dosage form of the pharmaceutical composition of the invention is a tablet prepared via a compression process. 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.

In one embodiment of the invention, the pharmaceutical composition contains from about 3 to 20% by weight of Compound A, or a salt thereof, of one of two pharmaceutically active ingredients; from about 25 to 94% by weight of the second pharmacy The active ingredient is metformin or a salt thereof such as a hydrochloride; about 0 to 35% by weight of a binder; and about 0.1 to 10% by weight of a lubricant. In one of the embodiments, the binder is polyvinylpyrrolidone or hydroxypropylcellulose, and the lubricant is magnesium stearate or sodium stearyl fumarate. In this subclass of classes, the binder is polyvinylpyrrolidone, and a lubricant and sodium stearyl fumarate. In another class, the pharmaceutical composition optionally contains from about 0% to about 3% by weight of surfactant and/or from about 0% to about 70% by weight of diluent. In a subclass of this class, the surfactant is sodium lauryl sulfate and the diluent is microcrystalline cellulose.

In a second embodiment, the pharmaceutical composition of the invention is prepared via a wet granulation process and comprises from about 5 to 18% by weight of compound A or a salt thereof as one of two pharmaceutically active ingredients; by weight About 65 to 77% of the second pharmaceutically active ingredient is metformin or a salt thereof such as a hydrochloride; about 4 to 9% by weight of a binder; and about 1 to 2% by weight of a lubricant. In one class of this embodiment, the binder is polyvinylpyrrolidone or hydroxypropylcellulose and the lubricant is magnesium stearate or sodium stearyl fumarate. In this subclass of classes, the binder is polyvinylpyrrolidone. In another class, the pharmaceutical composition optionally contains from about 0.5 to about 1% by weight of surfactant and/or from about 5 to 15% by weight of diluent. In a subclass of this class, the surfactant is sodium lauryl sulfate and the diluent is microcrystalline cellulose.

In another embodiment of the present invention, a pharmaceutical composition for commercial development is envisaged as follows: 50 mg of Compound A or a salt thereof / 500 mg of metformin or a salt thereof such as a hydrochloride salt-eating tablet: about 9% by weight Compound A or a salt thereof; about 73% by weight of metformin or a salt thereof such as a hydrochloride; about 7% by weight of a binder; about 1 to 2% by weight of a lubricant; and, if necessary, by weight About 10% of the diluent and/or about 0.5% by weight of the surfactant is used. In one class of this embodiment, the active ingredient is Compound A or a salt thereof; the binder is polyvinylpyrrolidone, the lubricant is magnesium stearate or sodium stearyl fumarate, the diluent is microcrystalline cellulose, and the surface active The agent is sodium lauryl sulfate.

50 mg of Compound A or a salt thereof / 850 mg of metformin or a salt thereof such as a hydrochloride salt: about 6% by weight of Compound A or a salt thereof; about 76% by weight of metformin or a salt thereof such as hydrochloric acid Salt; about 7% by weight of binder; about 1 to 2% by weight of lubricant; and about 10% by weight of diluent and/or about 0.5% by weight of surfactant, if desired. In one class of this embodiment, the lubricant is magnesium stearate or sodium stearyl fumarate, the diluent is microcrystalline cellulose, and the surfactant is sodium lauryl sulfate.

50 mg of Compound A or a salt thereof / 1000 mg of metformin or a salt thereof such as a hydrochloride salt: about 5% by weight of Compound A or a salt thereof; about 77% by weight of metformin hydrochloride; by weight About 7% of the binder; about 1 to 2% by weight of the lubricant; and about 10% by weight of the diluent and/or about 0.5% by weight of the surfactant, as needed. In one class of this embodiment, the active ingredient is Compound A or a salt thereof; the binder is polyvinylpyrrolidone, the lubricant is magnesium stearate or sodium stearyl fumarate, the diluent is microcrystalline cellulose, and the surface active The agent is sodium lauryl sulfate.

100 mg of Compound A or a salt thereof / 500 mg of metformin or a salt thereof such as a hydrochloride salt: about 17% by weight of Compound A or a salt thereof; about 65% by weight of metformin hydrochloride; by weight About 7% of the binder; about 1 to 2% by weight of the lubricant; and about 9% by weight of the diluent and/or about 0.5% by weight of the surfactant, as needed. In one class of this embodiment, the active ingredient is Compound A or a salt thereof; the binder is polyvinylpyrrolidone, the lubricant is magnesium stearate or sodium stearyl fumarate, the diluent is microcrystalline cellulose, and the surface active The agent is sodium lauryl sulfate.

100 mg of Compound A or a salt thereof / 850 mg of metformin or a salt thereof such as a hydrochloride salt-soluble tablet: about 11% by weight of Compound A or a salt thereof; about 75% by weight of metformin hydrochloride; by weight About 7% of the binder; about 1 to 2% by weight of the lubricant; and about 4% by weight of the diluent and/or about 0.5% by weight of the surfactant, as needed. In one class of this embodiment, the active ingredient is Compound A or a salt thereof; the binder is polyvinylpyrrolidone, the lubricant is magnesium stearate or sodium stearyl fumarate, the diluent is microcrystalline cellulose, and the surface active The agent is sodium lauryl sulfate.

100 mg of Compound A or a salt thereof / 1000 mg of metformin or a salt thereof such as a hydrochloride salt-potency tablet: about 10% by weight of Compound A or a salt thereof; about 77% by weight of metformin hydrochloride; by weight About 7% of the binder; about 1 to 2% by weight of the lubricant; and about 4% by weight of the diluent and/or about 0.5% by weight of the surfactant, as needed. In one class of this embodiment, the active ingredient is Compound A or a salt thereof; the binder is polyvinylpyrrolidone, the lubricant is magnesium stearate or sodium stearyl fumarate, the diluent is microcrystalline cellulose, and the surface active The agent is sodium lauryl sulfate.

The metformin of the present invention or a salt thereof such as a hydrochloride may be either immediate 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 the granulation solution is added via fluidization, the granulation solution consisting of an aqueous solution of the binder, with or without surfactants ;

(4) The granules prepared by high-shear granulation were subjected to tray drying in an oven or dried in a fluidized bed dryer. For granules 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 may be filled into a vial, sachet or capsule or compressed into a desired tablet shape;

(9) and if desired, the resulting tablets can be film coated.

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

(1) adding the active pharmaceutical ingredient metformin hydrochloride 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, pouch or capsule or compressed into a desired tablet shape, or processed by a roller compressor;

(6) If the treatment 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 may be filled into a vial, pouch or capsule or compressed into a desired tablet shape;

(10) and if desired, the tablets obtained in Step 5 or Step 9 can be film coated.

The invention also provides a method of treating type 2 diabetes by orally administering to a subject in need of such treatment a therapeutically effective amount of a fixed dose combination pharmaceutical composition of the invention. 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. A pharmaceutical composition containing a fixed dose combination can be administered once daily (QD), twice daily (BID) or three times daily (TID).

The following examples further describe and illustrate embodiments within the scope of the invention. The examples and the test examples are provided for the purpose of illustration only, and are not intended to be construed as limiting the 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

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 obtained tablets are optional 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, for example, 60.5 mg of the compound A phosphate, and so on. The following examples 2 to 7 are the same and are not repeated. Metformin hydrochloride may also be metformin or other pharmaceutically acceptable salts. The following Examples 2 to 7 are the same and will not be repeated.

Example 2: Fixed dose combination of 50 mg of Compound A and 850 mg of metformin hydrochloride per tablet - wet granulation

Production method:

Tablets were prepared via wet granulation using essentially the procedure of Example 1 to provide 1103 mg of uncoated tablets. Tablets are optionally coated with a 27.9 standard II film coating formulation to provide 1131 mg coated film tablets.

Example 3: 50 mg of Compound A and 1000 mg of metformin hydrochloride fixed dose combination per tablet - wet granulation

Production method:

Tablets were prepared via wet granulation using essentially the procedure of Example 1 to provide 1286 mg of uncoated tablets. The obtained tablets are optional The II suspension (polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc, with or without colorant) was applied to an increase in weight of about 2.5% to provide 1319 mg of coated film tablets.

Example 4: Fixed dose combination of 50 mg of Compound A and 500 mg of metformin hydrochloride per tablet - wet granulation

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, purified water is added to the APIs in 3 to 5 minutes in addition to the polyvinylpyrrolidone binder. 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 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 (magnesium stearate) 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. Then, the obtained tablets are optional The II suspension (polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc, with or without colorants) was coated to a weight gain of about 2.5% to provide 692 mg of coated film tablets.

Example 5: Fixed dose combination of 50 mg of Compound A and 1000 mg of metformin hydrochloride per tablet - wet granulation

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 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 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 (magnesium stearate) was added thereto and additionally mixed for 100 rpm. The lubricated mixture was compressed using a rotary tablet press to provide 1286 mg of uncoated tablets. Then, the obtained tablets are optional The II suspension (polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc, with or without colorants) was coated to a weight gain of about 2.5% to provide 1319 mg of coated film tablets.

Example 6: Fixed dose combination of 100 mg of Compound A and 1000 mg of metformin hydrochloride per tablet - wet granulation

Production method:

Tablets were prepared via fluidized bed granulation using essentially the procedure of Example 1 to provide 1271.50 mg of uncoated tablets.

Example 7: Fixed dose combination of 100 mg of Compound A and 500 mg of metformin hydrochloride per tablet - wet granulation

Production method:

Tablets were prepared via fluidized bed granulation using essentially the procedure of Example 1 to provide 739.50 mg of uncoated tablets.

Test Example 1: In vitro activity and selectivity of Compound A and MK-0431

method:

Thaw DPP4-Glo. Buffer before use and equilibrate to room temperature. Pre-buffer frozen luciferin detection reagent, suspend DPP4-Glo. Add ultrapure water to the reaction and mix gently to make 1 mM reaction. Add the luciferin detection reagent to the brown bottle and add DPP4-Glo. The luciferin detection reagent should be dissolved within 1 minute, the test compound was dissolved in DMSO to 50 times the final concentration, 2 μL of the test compound was added in 50-fold concentration in each tube, and 2 μL of DMSO was added to the reverse control and the blank control. 46 μL of Tris buffer was added to each tube, 48 μL of Tris buffer was added to the blank, 2 μ LDPP 4 enzyme was added to each tube of the reverse control and the test sample, and the tubes were shaken and centrifuged. The contents of the tubes were all transferred to 96-well plates, and the ratio of the mixed reactants to DPP4-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 DPP4-Glo. and a mixture of reactants to each 96-well plate well, seal the plate with a sealing film, and use a plate shaker at 300-500 rpm. Slowly mix the 96-well material at /30 s. Incubate for 30 minutes to 3 hours at room temperature and measure the chemiluminescence count on a NOVOstar multi-function microplate reader.

Test Example 2: Single administration of Compound A and MK-0431, respectively

Inhibition of serum DPP4 activity in cynomolgus monkeys

There are 8 healthy adult cynomolgus monkeys, half male and half female. Fasting for more than 8 hours before administration, free drinking water. For oral administration, 0.75 ml of venous blood was taken before administration and at 1, 3, 9, 12 and 24 hours after administration, and centrifuged at 3000 rpm for 10 minutes to separate serum. The activity of DPP4 was determined, and the inhibitory effect and duration of serum DPP4 activity in cynomolgus monkeys after single administration of 10 mg/kg of Compound A or MK-O431 were observed. The serum A/MK-O431 was determined by liquid chromatography-tandem mass spectrometry. concentration. Cross-administration was used in the experiment, and at least 7 to 10 days after each administration, the next administration test was performed.

Table 2 shows that Compound A significantly inhibited serum DPP4 activity in cynomolgus monkeys after a single oral administration, and its strength and duration of maintenance were superior to those of the same dose of MK-O431. 10 mg/kg of Compound A allowed serum DPP4 activity within 12 hours. The inhibitor is maintained above 75%.

Test Example 3: Compound A and MK-0431 were administered in combination with metformin

Effect 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 rats, taking Compound A, MK-0431 (10 mg/kg body weight/day, orally) and metformin (100 mg/kg body weight/day). ; mixed in a commercial feed for 5 days 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 to 6). And analyzed by Dunnett's test, provided in Table 3. Use a 1% significance level.

The combination of Compound A and metformin in Table 3 significantly reduced the concentration of blood glucose and hemoglobin, and the intensity was greater than that of MK-O431 in combination with metformin.

Test Example 4: Glucose load in compound Wistar rats with genetic obesity and diabetes mellitus in combination with metformin, respectively, with compound A phosphate and MK-0431 phosphate

Male fertilized mice aged 13 to 14 weeks were divided into 5 groups, 5 rats, respectively taking Compound A phosphate, MK-0431 (30 mg/kg/day, orally) and metformin (100 mg/kg/day, oral). 7 days. An oral glucose load test (2 g glucose/kg/5 ml, orally) was performed immediately after fasting overnight. Blood was collected from the tail vein and analyzed by enzymatic method (Encore Chemical System; Baker) at 120 and 240 minutes before and after the glucose load test. Results were analyzed as Dunnett's test with mean (n=5) mean ± SD and in Table 4.

Table 4 clearly shows that the combination of Compound A phosphate and metformin significantly inhibited the increase in blood glucose after the glucose load test, and the intensity was greater than that of MK-O431 in combination with metformin.

There is no picture in this case

Claims (22)

A pharmaceutical composition comprising: (a) 3 to 20% by weight of (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)- Butylmethyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof; (b 25 to 94% by weight of metformin or a salt thereof; (c) 0.1 to 10% by weight of a lubricant; and (d) 0 to 35% by weight of a binder. The pharmaceutical composition according to claim 1, wherein the metformin salt is metformin hydrochloride. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises one or more excipients selected from the group consisting of: (a) a diluent; (b) a disintegrant; (c) a surface active agent (d) a wetting agent; or (e) an antioxidant. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: (a) 5 to 18% by weight of (R)-7-[3-amino-4-(2,4, 5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or its a pharmaceutically acceptable salt; (b) from 65 to 77% by weight of metformin or a salt thereof; (c) from 1 to 2% by weight of a lubricant; and (d) from 4 to 9% by weight of a viscosity mixture. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition additionally comprises 0.5 to 1% by weight of a surfactant and/or 5 to 15% by weight of diluent. The pharmaceutical composition according to claim 4, wherein the lubricant is magnesium stearate or sodium stearyl fumarate, and the binder is polyvinylpyrrolidone. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises: (a) 9% by weight of (R)-7-[3-amino-4-(2,4,5) -Trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or its pharmacy An acceptable salt; (b) 73% by weight of metformin or a salt thereof; (c) 1 to 2% by weight of a lubricant; and (d) 7% by weight of a binder. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition further comprises 0.5% by weight of a surfactant and/or 10% by weight of a diluent. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises: (a) 5% by weight of (R)-7-[3-amino-4-(2,4,5) -Trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or its pharmacy An acceptable salt; (b) 77% by weight of metformin or a salt thereof; (c) 1 to 2% by weight of a lubricant; and (d) 7% by weight of a binder. The pharmaceutical composition according to claim 9, wherein the drug The composition additionally comprises 0.5% by weight of surfactant and/or 10% by weight of diluent. A pharmaceutical composition comprising: (a) (R)-7-[3-amino-4-(2,4,5-trifluoro-benzene) present in a unit dose concentration of 25 to 500 mg Methyl)-butylmethyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof Or (b) metformin or a salt thereof in a unit dose concentration of 250, 500, 625, 750, 850, 1000, 1250 or 1500 mg; (c) 1 to 2% by weight of a lubricant; (d) 7% by weight of binder; and (e) 10% by weight of diluent, as needed; and (f) 0.5% by weight of surfactant, as needed. The pharmaceutical composition according to claim 11, wherein the lubricant is sodium stearyl fumarate, the binder is polyvinylpyrrolidone, and the optional diluent is microcrystalline cellulose, and the The surfactant required is sodium lauryl sulfate. The pharmaceutical composition according to claim 11, wherein the (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanyl]-3-tri Methyl fluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate or a pharmaceutically acceptable salt thereof at 25, 50, 75, 100 A unit dose concentration of 150, 200, 300, 400 or 500 mg is present, and the metformin or a salt thereof is present at a unit dosage concentration of 250, 500, 850, 1000, 1250 or 1500 mg. The pharmaceutical composition according to claim 13, wherein the (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanyl]-3-tri Methyl fluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate or a pharmaceutically acceptable salt thereof at a unit dose concentration of 50, 100 mg It is present, and the metformin or its salt is present in a unit dosage concentration of 500, 850 or 1000 mg. The pharmaceutical composition according to claim 1 and/or claim 13, wherein the pharmaceutical composition is a tablet dosage form or other oral dosage form. Use of a pharmaceutical composition according to claim 1 and/or 13 for the preparation of a medicament for the treatment of type 2 diabetes in humans. The pharmaceutical composition according to claim 1 and/or claim 13, wherein the pharmaceutical composition further comprises one or more agents selected from the group consisting of a flavoring agent, a coloring agent or a sweetener. The pharmaceutical composition according to claim 1 or 4, which is produced by a wet granulation method. The pharmaceutical composition according to claim 1 or 13, wherein the pharmaceutically acceptable salt is selected from the group consisting of phosphates, hydrochlorides, sulfates, nitrates, hydrobromides, methanesulfonates, horses. Acid salt, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, besylate, benzoate, naphthalene sulfonate, lactate Or malate. The pharmaceutical composition according to claim 1 or 13, wherein the metformin or a salt thereof is released immediately or slowly. The pharmaceutical composition according to claim 1 or 13, wherein For humans, (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetra The hydrogen-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof is administered in a daily dose of 25 mg to 1000 mg, and the metformin or its salt is administered in a daily dose of 250 mg to 3000 mg. The pharmaceutical composition according to claim 1 or claim 13, wherein the pharmaceutical composition is administered once a day, twice a day or three times a day.