TW201213331A - Pharmaceutical composition for the treatment of type 2 diabetes - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment of type 2 diabetes, wherein the pharmaceutical composition contains (R)-7-[3-amino-4-(2, 4, 5-trifluo-phenyl)-butyryl]-3-trifluomethyl-5, 6, 7, 8-tetrahydro-imidazo[1, 5-a]pyrazine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salts and metformin or its pharmaceutically acceptable salts (such as hydrochlorate), preparation method thereof and method of treating 2 type diabetes with the composition.

Description

201213331 VI. Description of the invention: [Technical field to which the invention belongs] Methyl-5,6,7,8^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^嗓 1 - 曱 vinegar or composition, a method of preparing the pharmaceutical composition and a method for treating type 2 diabetes. The composition of the music is used. [Prior art] is caused by insulin resistance and weakening of Tengdao Prime secretion = heavy internal #缺__ pathology results in (four) sexually transmitted diseases. 2. Type 2 diabetes treatment generally begins with diet and exercise, followed by oral anti-diabetic money monotherapy. For many patients, this - program and Full control of blood glucose during treatment results in the need for combination therapy within 2 years of diagnosis. However, a common prescription for two or more oral anti-diabetic agents is a treatment regimen for many patients employed. Providing two or more anti-diabetic agents, human sputum, may provide a possible way of not increasing the daily treatment of the patient. The preparation is widely accepted in other diseases, such as the high blood leg AAIiT. Los ^ l potassium and have a combination of dioxygen) and cholesterol (Lei ⑽, (iv) a combination of simvastatin and ezetimibe by myself Ze) of the. The choice of effective and well tolerated treatment is a key step in the design of the group a ^. In addition, it is essential that the components have mutual kinetics and residual pharmacokinetic steps. Examples of commercially available combination tablets containing plate-making anti-94996 3 201213331 diabetes agents include Gluc〇vanceTM (diterpenoid and glyburide), AvandamentTM (diguanide and rosiglitazone), and MetaglipTM (diterpenoid and glyph) Methylazine). A double sputum has been shown to be the only oral anti-diabetic agent that reduces the overall burden of microvascular and macrovascular diabetes complications and prolongs the lifespan of patients with type 2 diabetes. In addition, diterpene therapy is often associated with weight loss in overweight patients and improvement in fat profile in patients with abnormal jk lipids. 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, R〇che0730699, TS021 (Taisho), E3024 (Eisai) and PHX-1149 (Phenomix). For example, it has been found that oral administration of vildagliptin to human type 2 diabetic patients can reduce the 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: (l) H.-U. Demuth et al. 'Type 2diabetes-Theraphy with dipeptidyl peptidase IV inhibitors', Biochim. Biophvs. Acta. 1751: 33-44 (2005) and (2) K. Augustyss 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). 4 94996 . 201213331 [Description of the invention] has the formula (8)-7-[3-amino-4_(2,4, trifluoro-phenylbutenyl)_3'trifluoromethyl-5,6, UHM And „ 5_a] pyrazine-1-carboxylic acid oxime ester is compound A.

F

CH, F F

A Compound - A fixed dose, combined pharmaceutical composition for the preparation of (iv) ^ A or its salt and dif-biguanide via a dry or wet treatment. The second::the composition provides two active pharmaceutical ingredients of Compound A or its: and:: immediate release of biguanide and immediate release of Compound A or a salt thereof. In one embodiment, the drug of the present invention is especially coated (4) It may also be that the compound A provides a method for preparing a pharmaceutical composition by a money or wet treatment method: a combination of a dose of one and two f-biguanide: a method including a dry method (four) and a dry granulation method. The wet method, the other aspect provides the main method for the treatment via administration: the treatment of sputum with the sputum composition for the treatment of 2 urinary tracts 94996 5 201213331 According to the following detailed description, these and other methods It will be obvious. SUMMARY OF THE 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 a diterpene biguanide or a pharmaceutically acceptable salt thereof, a method of preparing the pharmaceutical composition and the use of the pharmaceutical composition A method of treating type 2 diabetes. In particular, the invention relates to a pharmaceutical composition comprising a combination of Compound A or a pharmaceutically acceptable salt thereof and metformin hydrochloride in a fixed dose. 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 the compound A or a salt thereof and the diterpene biguanide 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 a diterpene bismuth or a pharmaceutically acceptable salt thereof. The dosage form can be in powder or solid form and includes tablets, capsules, sachets and the like. A particular solid dosage form relates to a tablet containing a fixed dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin hydrochloride (1,1-diguanidine dihydrochloride). 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 the two active pharmaceutical ingredients, 6 94996 201213331; (2) metformin or a salt thereof, such as a salt; Agent or glidant. In the present invention, the pharmaceutical composition may further contain an ingredient of the formula: the excipient is selected from the group consisting of excipients, excipients or glutinous binders (binding agents). Or one or more release agents, one or more surfactants or disintegrants; and one or more antioxidants or pharmaceutically acceptable salts of Compound A include, but are not limited to, sulphates , acid salt, sulfate, salt, hydrogen salt, acid salt, maleate: tartrate, _ salt, acetate, trioxoacetate, bismuth fumarate, citrate, citrate , benzoate, benzoate, carbamate, lactate, malate. The concentration of the compound A or a salt thereof in the pharmaceutical composition of the present invention is from about 1 mg to about _mg of the active portion, and the dose concentration of the compound A or a salt thereof is from about 25 mg to about 25 Å. The amount of active part of the mg. Discrete dose concentrations are 25, 5Q, 75, (10), 15 Å, 200, 300, 400 and 500 gram of the active part 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, 5, 75, 1 , 150, 200, 300, 400 and 500 mg. Preferably, the compound or a salt thereof is administered at a dose concentration of 50 or 1 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 diterpene dihydrochloride hydrochloride represent dose concentrations approved for commercial treatment of type 2 diabetes in China and / 7 94996 201213331 or in the United States. In the combination of the invention and the dosage of the dose, the specific embodiment of the compound & or its dose concentration according to the dimethyl hydrazine or its salt such as the (iv) salt is as follows: (1) 25 mg of the compound a or a salt thereof (for example, phosphate) .2 and 250 mg of metformin hydrochloride; (2) 25 mg of compound A or its salt (eg phosphate 3〇. 2 and 500 mg of diterpene biguanide hydrochloride; (3.0 mg of a substance or its salt (eg scales) Acid salt 6. 5 mg) and 250 g of metformin hydrochloride; (4) 50 mg of mouth a or its salt (eg phosphate 6 〇 5 mg) and 500 mg of diterpene hydrazine hydrochloride; (5) 50 mg of 5 a or a salt thereof (for example, sulphate $ mg) and 850 mg of metformin hydrochloride; (6) 50 mg of Compound A or a salt thereof (e.g., phosphate 6 〇 5 mg) and 1000 mg of diterpene hydrazine hydrochloride; (7) 100 g of a compound A or a salt thereof (e.g., phosphate 121. 〇mg) and 250 mg of diterpene biguanide hydrochloride; (8) 100 mg of Compound A or a salt thereof (e.g., 121 Q mg of the acid salt) and 500 mg of diterpene guanidine hydrochloride (9) 100 grams of Compound A or its salt (eg, 121. 填 mg) and 850克二曱 biguanide hydrochloride; (10) 100 mg of Compound A or its salt (such as 121 mg of sulphate) and 1000 mg of diterpene dihydrochloride; (11) 100 mg of Compound A or its salt (eg dish) Acid salt 121 mg) g 94996 201213331 and 1500 g of diterpene dihydrochloride hydrochloride; / u The pharmaceutical composition of the present invention is prepared by a wet or dry treatment method. In one embodiment, the pharmaceutical composition The preparation is carried out by a wet treatment method. In one class of this embodiment, the pharmaceutical composition is prepared via a wet granulation method. 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 first embodiment, the pharmaceutical composition is carried out by a dry process, in this embodiment In the class, the pharmaceutical composition is prepared by a direct compression or granulation method. The embodiment of the dry granulation is a pressure barrier. The ruthenium net can be obtained by a dry or wet treatment method. Tablets, packaged or metered into sachets. ~ Compositions contain one or more lubricants or glidants. Examples of sodium carbonate include magnesium stearate, calcium stearate, stearic acid, stearyl fumarate, The preferred lubricant is stearic acid town two! Zha Teng Ma Ma Sodium or a mixture thereof. Examples of glidants include colloid-oxidized stone sputum, sputum, sulphuric acid and Talc. Agent: A pharmaceutical composition of the above-mentioned embodiment may contain one or more types of adhesives, including propylcellulose (HPC), propyl quinone (HMPC), and hydroxy groups. Ethyl cellulose, starch 1500, polyvinylpyrrole and co-call ratio _. The preferred adhesive is polyethylene 吼 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 513 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Cellulose and powdered cellulose. A preferred diluent is =rr cellulose available from several suppliers, including TM:

AvicelpH1 manufactured by Corporation (n, Avicei PHl〇3'AvicelPHl〇4AvicelpH2〇〇. 2'Avicel Ben, the pharmaceutical composition of Ming can also contain disintegrant as needed. The disintegration sword can be modified several kinds of modified temple powder. Cellulose polymer or ==, such as cross-linking via methylcellulose sodium, powdered sodium glycolate, potassium polacetin and calcium hydroxymethylcellulose (CMC Calcium). In one embodiment, cross-linking armor Cellulose nano. Cross-linking via a cellulose nanocapsule 1 is obtained on the market by the trade name "Ac_di_s〇1,. The pharmaceutical composition of the present invention may further contain one or more kinds of surfactants or turbid wetness as needed. The surfactant may be an anionic surfactant. The anionic surfactant includes lauryl I-steel, ten-silbin, sodium sulfate, and laurel mixed with stearic acid and cation. Surface activity · including benzalkonium chloride and dimethyl dimethylammonium chloride. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol and sorbitan ester. The embodiment of the aerosol includes mooring Sharm, polyoxygenated, polyoxyethylene castor oil derivatives and polyoxyethylene stearate. Soil can be added to the formulation as needed to give it chemical stability. The antioxidant is selected from the age of Bu Fertility Test, Bu Fertility Age, Fertility Enrichment Natural Extract, L_Ascorbic Acid and Its Sodium or Calcium Salt, Ascorbate Palmitate, Propyl Citrate, Octyl Citrate, Tannin Dialkyl ester, butylated hydroxymethyl bromide (BHT) and butylated hydroxybenzoquinone 94096 201213331 'Slot (10)). In one embodiment, the antioxidant is brittle or leg. A preferred dosage form is a tablet prepared by a compression process. The tablet may be coated with a mixture of, for example, propylcellulose and propylmethylcellulose, which contains digastric and/or other Colorants such as iron oxide, dyes and pigments; mixtures of polyethylene glycol (pvA) and polyethylene glycol (PEG) contain titanium dioxide and/or other colorants such as iron oxides, dyes and lakes; Any other suitable instant release coating The coating provides taste masking and additional stability to the final tablet. • Commercially available film is Opadry® supplied by Colorcon to formulate a powder mixture. Finally, if desired, sweeteners and/or additions can be added. In one embodiment of the present invention, the pharmaceutical composition contains about 3 to 20% by weight of the compound A or a salt thereof of the two pharmaceutically active ingredients; about 25 to 94% by weight a diterpene bismuth which is a second pharmaceutically active ingredient or a salt thereof such as a hydrochloride; about Q to 35% by weight of a binder; hydrazine and about 0.1 to 1% by weight of a lubricant by weight. In this embodiment In one class, the 'mixture agent is a polyethylene material or a propyl cellulose, and the lubricant is stearic acid or stearyl f. In this category, the mixture is polyvinylpyrrolidone, and the lubricant and hard fat (iv) 0 field horseshoe: steel. In another class, the pharmaceutical composition optionally contains from about 0% by weight. A surfactant and/or a G to 7 Torr diluent by weight. In the subclass of =, the surfactant is sodium lauryl sulfate and the diluent is microcrystalline cellulose. In a hydrazone-embodiment, the pharmaceutical composition of the present invention is activated to form gossip via wet granule 94096 11 201213331 and comprises about 5 8% by weight of two pharmaceutically acceptable compounds hydrazine or a salt thereof; From about 65 to: two are the second pharmaceutically active ingredient of metformin or a salt thereof such as hydrochloric acid, about 4 to _ binder; and about 1 by weight to find the factory: Μ. In one class of this embodiment, the binder is polyvinylpyrrolidone or (tetra)cellulose, and the lubricant is magnesium stearate or stearyl fumarate. In such subclasses, the binder is a polyethylene ester in each of the other classes, and the pharmaceutical composition optionally contains from about 0.5 to 1% by weight of surfactant and/or by weight. About 5 i 15% of the dilution J in this subclass of the class, the surfactant is sodium lauryl sulfate and the diluent is crystalline cellulose. In another embodiment of the present invention, a pharmaceutical composition for commercial development is envisaged as follows: 5 mg of the compound hydrazine or a salt thereof / 5 〇〇 mg of diterpene bismuth or a salt thereof such as a hydrochloride salt : about 9% by weight of compound A or a salt thereof; about 73% by weight of diterpene bismuth or a salt thereof such as hydrochloride; about 7% by weight of binder; about ten to one by weight of S % of lubricant; and about 1% by weight of dilution by weight and/or by weight: about 5% by weight of surfactant. 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 diterpene biguanide or a salt thereof such as a hydrochloride salt: 12 94996 201213331 About 6% by weight of Compound A or a salt thereof; about 76% 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, about 10% by weight, a diluent and/or by weight 0·5% surfactant. 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. A tablet of the potency of 50 mg of Compound A or a salt thereof/100 mg of diterpene biguanide or a salt thereof such as hydrochloride: • about 5% by weight of Compound A or a salt thereof; about 77% by weight of diterpene bismuth salt Acid salt; about 7% by weight of binder; about 1 to 2% by weight of lubricant; and, if necessary, about 10% by weight of diluent and/or about 0.5% by weight of surface Active agent. 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. φ l〇〇mg of Compound A or a salt thereof / 500 mg of diterpene biguanide or a salt thereof such as a hydrochloride salt of a tablet: about 17% by weight of Compound A or a salt thereof; about 65% by weight of two曱 biguanide hydrochloride; about 7% by weight of binder; about 1 to 2% by weight of lubricant; and about 9% by weight of diluent and/or about 0.5% by weight, as needed Surfactant. 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. 13 94996 201213331 lOOmg of Compound A or its salt / 850 mg of diterpene bismuth or a tablet such as hydrochloride salt: ί About 11% by weight of Compound A or its salt; about 7 (10) by weight of metformin hydrochloride a salt; about 7% by weight of a binder; about 11 to 2% by weight of a lubricant; and, if necessary, about 4% by weight of a diluent and/or about 0.5% by weight of a surfactant . In one class of this embodiment, the active ingredient is Compound A or a salt thereof; the binder is polyethylene. For pyrrolidone, the lubricant is stearic acid lock or sodium stearyl fumarate, the diluent is microcrystalline cellulose, and the surfactant is sodium lauryl sulfate. 100 mg of Compound A or a salt thereof / 100011 ^ metformin or a salt thereof such as a hydrochloride salt-soluble tablet: about 10% by weight of Compound A or a salt thereof; about 77% by weight of diterpene biguanide hydrochloride; About 7% by weight 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 . In one class of this embodiment, the active ingredient is Compound A or a salt thereof; the binder is polyethylene scale scaled steel, the lubricant is magnesium stearate or sodium stearyl fumarate, and the diluent is microcrystalline cellulose. And the surfactant is sodium lauryl sulfate. The monomethyl guanidine or its salt such as the hydrochloride salt can be either immediate or slow release. The pharmaceutical tablet composition of the present invention may further contain one or more additional preparation components selected from excipients known in the field of pharmaceutical preparations. 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 the preparation of the tablet composition. 14 94996 201213331 The ingredients include, but are not limited to, diluents, compression aids, flow aids Agents, solutions: lubricants, fragrances, flavoring agents, sweeteners and preservatives. The term "tablet" is used to include all shapes and sizes = formulations in a sturdy pharmaceutical agent, regardless of coating. Materials that can be used for coating include propylcellulose, propylmethylcellulose, dioxime, talc, sweeteners, colorants, and flavoring agents. In one embodiment, the pharmaceutical conjugates of the invention are prepared via wet granulation shear and/or fluidized bed). Granulation is a method in which a binder is added to granulation/reading 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 sigma A or a salt thereof to the granulation cylinder; (2) arbitrarily collapsing The decomposing agent is added to the step 1; (3) For the same shear granulation, the binder (such as polyvinylpyrrolidone = tetrakis) cellulose is dried and added to the granulated towel and mixed for short-term dry mixing. Luhe, followed by the addition of water, with or without the presence of a surfactant (such as 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 the mash granulation are subjected to tray drying in an oven or drying in a fluid bed dryer. For granules prepared by fluidized bed granulation, the granules are dried in a fluid bed dryer; (5) the size of the dried granules is adjusted in a suitable mill; (6) in a suitable mixer, The required diluent (such as microcrystalline 15 94996 201213331 cellulose and calcium dihydrogen phosphate dihydrate) is mixed with the dried granules; (7) a lubricant or a glidant (such as stearic acid and stearic fumaric acid) Sodium) is added 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 the desired monthly shape; (9) and The resulting tablets can be film coated if desired. The steps involved in the dry treatment (direct compression or dry granulation) method include: (1) adding the active pharmaceutical ingredient bisbiguanide 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 glidant to step 3; (5) The mixture of step 4 can be filled into vials, sachets or capsules or compressed into the desired tablet shape or processed by a roller compressor; (6) If processed via a roller compressor, if necessary The size of the granules can be adjusted in a suitable mill; (7) In a suitable mixer, optional diluent can be added to the resulting granules to improve compression; (8) Depending on the lubricant required Or a glidant is added 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 the desired tablet shape; 16 94996 201213331 (10) and if desired , step 5 Obtained by Step 9 tablets may be film coated. • The present invention also provides a method of treating type 2 diabetes by administering a therapeutically effective amount of a fixed dose combination drug combination of the present invention to a subject in need of such treatment by oral administration. 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 per day (QD), twice per week (BID) or three times per day (TID). • [Embodiment] 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 granulated compound A 50 mg Metformin hydrochloride 500 mg Polyethylpyrrolidone 48. 2 mg - Sodium sulfate (SLS) 3 45mg ^A^iLil(Avicel PH-102) 59. 3mg - 竺 富 fumarate 13. 8mg Purified waterwood for granulation step for high shear, 39. 8mg, or for fluidized bed 354mg ___ 〇t)adry® π 17. 2 mg of purified water* 68. 9 mg * removed during treatment. 17 94996 201213331 Manufacturing Method: :物Α#σ —Metformin hydrochloride is fed to a high shear granulator or a guillotine bed granule 2. In the case of shear granulation, pure water containing a sulfhydryl steel is added to the APIs (active pharmaceutical ingredient) at 3 to 5 minutes in addition to the polyethylation = transformation of the appearance. The wet material is either 40 C-dried or in a fluid bed dryer at the milk to (10). The inlet of c is dried for 3 to 6 minutes. In the case of fluidized bed granulation, purified water containing fine polyethylene and sodium lauryl sulfate is added to the APIs over a period of 3 to 60 minutes. The wet material is dried in a fluid bed dryer at a population temperature of 45 to 60 C. Money, the material mill grinds the dried material to obtain fine particles. After the grinding, the microcrystalline cellulose was added to the granules and mixed in a double-shell mixer for 2 rpm. Then, a lubricant (sodium stearyl fumarate) was added thereto and additionally mixed for 1 turn. The lubricated mixture was compressed using a rotary tablet press to provide 675 mg of uncoated tablets. The resulting tablets are optionally coated with a 〇padry@ π suspension (polyethylene glycol, polyethylene glycol, cerium oxide and talc, with or without a colorant) to a weight gain of about 2.5% to provide 692 mg of coated film. Agent. In particular, the compound A 50 mg in the prescription may also be a pharmaceutically acceptable salt of the compound a, for example, the compound A phosphate is 6〇5呃, and so on. The following examples 2 to 7 are the same, and are not repeated. . The diterpene hydrazine hydrochloride may also be metformin or other pharmaceutically acceptable salts. Embodiments 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 diterpene biguanide hydrochloride per tablet - wet granulation 94096 18 201213331 Compound A 50rag Diterpenoid hydrazine hydrochloride 850 mg Polyvinylpyrrolidone 78. 2 mg Laurel Sodium sulfate (SLS) 5.60mg Microcrystalline cellulose (Avicel PH-102) 96. lmg Sodium stearyl fumarate 22. 3rag Purified water for granulation step * For high shear, 64. 9mg, or for flow Bed 573 mg Opardry® Π 27. 9 mg Purified water for the coating step * 112 mg * Removed during treatment.

Method of manufacture: Tablets were prepared via wet granulation using essentially the procedure of Example 1 to provide 1103 mg of uncoated tablets. The tablets were optionally coated with 27.9 standard Opadry® enamel coating formulations to provide 1131 mg coated tablets. Example 3: 50 mg of Compound A and 1000 mg of metformin hydrochloride in a fixed dose combination per tablet - wet granulated compound A 50rag diterpene dihydrochloride hydrochloride 1000 mg polyvinylpyrrolidone 91. Omg sodium lauryl sulfate (SLS) 6. 50 mg of microcrystalline cellulose (Avicel PH-102) 112. 3 mg of sodium stearyl fumarate 26 mg of purified water for the granulation step * for high shear, 75. 5 mg, or for fluidized bed 667 mg Opardry® Π 32. 5 mg of purified water for the coating step * 130 mg * removed during the treatment. 19 94996 201213331 Method of manufacture: 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

Opadry®; [[suspension (polyvinyl alcohol, polyethylene glycol, titanium dioxide, and talc, with or without colorant) was applied to a weight gain of approximately 2.5% to provide 1319 mg of coated film. Example 4: ID of 50 mg of Compound A and 500 mg of diterpene biguanide hydrochloride: amount, combination / per tablet - wet granulation compound A _ dihydrazine hydrochloride - 50rag _ pyrrolidine _ ___ 500rag micro 曰 \ fiber ΪΤ (α7 Ϊ ^ Γ ρη-1 〇 2) ' -----48. 2mg .... magnesium sulfate for the granulation step of purified water -----______ 〇 y. Ding ——__6.89 For the cut, 39. 8mg, or Upadry® 玎 for coating the touch 7 △, /---i- - fluidized bed 354mg --17. 2rasf buckle, - Purified water in the soil * removed during the treatment - -___68. 9mg Manufacturing method: = to the high shear granulator or the muscle bed filament 0. In the case of high shear granulation, 'in 3 to 5 minutes __ purified water is added = two. ^ The substance is either dry on the machine carrier or in a fluidized bed: = two. The inlet temperature of C is dried for 3 to 6 minutes. In the case of fluidized bed granulation, the purified water of erpyrrolidone is added to the APIs at a minute (four) 94996 20 201213331. The wet material is dried in a fluid bed dryer at an inlet temperature of 45 to 6 (TC. Then, the dried material is ground using a co-grinder to obtain fine particles. After grinding, microcrystalline cellulose is added It was mixed into the granules and mixed in a double-shell mixer for 200 rpm. Then, a lubricant (magnesium stearate) was added thereto and additionally mixed for 100 rpm. The lubricated mixture was compressed by a rotary tableting machine to provide 675 mg of no The coating is applied to the Opadry 8 Π suspension (polyvinyl alcohol, polyethylene glycol, titanium dioxide, and talc) with or without a coloring agent to a weight increase of about 2.5%, thereby providing 692 mg. Film coated tablets.Example 5: Fixed dose combination of 50 mg of Compound A and 1 mg of metformin hydrochloride per tablet - Wet granulation compound A 50 mg Diterpenoid hydrazine hydrochloride _ lOOOOmg polyvinylpyrrolidone _ ____ 91. Omg microcrystalline cellulose (Avicel PH-102) 1 9 S 9 Smcr Magnesium stearate---- 1 UU · /j J 111 g —13.0 Sodium lauryl sulfate RC for purification of granulation step Water pair ^ Two shears, 75.5 mg, or Opadry® Π - fluidized bed 667 mg of purified water for the coating step * ----^__32. 5mg * Removed during the treatment -130mg Manufacturing method: Compound A and metformin hydrochloride The salt is introduced into the high shear granulator or the fluidized bed into (4). In the case of high shear granulation, in addition to the polyethylene 94996 21 201213331 t each ketone binder, the sodium sulphate is 3 to 5 minutes. Purified water is added to APis t. '3 has a ladle base drying or 45 to Z in fluidized bed drying or 3 to 6 minutes in peach drying. In the case of fluidized bed granulation ^ inlet temperature dry time The inside of the material containing the polyvinyl fluorenone to be wet to two minutes in a fluidized bed dry machine in 45 to Pis. Drying. Then, using a co-grinder to obtain fine particles on the dried material::: degree After the grinding, the crystallites were mixed with the double shells, which were mixed with the pottery, then added thereto and additionally mixed (10) by a mixing and converting machine for compression to provide 1286 mg of uncoated tablets. Servant tablets are optional 0padry® n. suspension (polyvinyl alcohol, poly Glycol, talc and titanium oxide, with or without colorant) coating film to 2.1 to provide a weight gain of coating tablet 1319mg., ', A wet granulation

-----, ___ * Removed during the treatment of Example 6: 1 ton of compound eight and 1 〇〇〇 milligram of bismuth double fox manufacturing method: 22 94996 201213331 tablets through fluidized bed granulation utilization basically Prepared for the method 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 granulated compound A 100 mg of diammonium hydrazide hydrochloride 500 mg polyvinylpyrrolidone 53.8 mg sodium lauryl sulfate (SLS) 3.84 mg of microcrystalline cellulose (Avicel PH-102) 66.5 mg of sodium stearyl fumarate 15.4 mg of purified water * 394 mg * removal of the manufacturing process during the treatment: tablet granulation by fluidized bed is basically the use of embodiment 1 The method was prepared to provide 739. 50 mg of uncoated tablets. Test Example 1: In vitro activity and selectivity of Compound A, MK-0431 Method of study: Thawing DPP4 - Glo. Buffered and equilibrated to room temperature before use, using gloverin detection reagent before buffering, suspension DPP4 - Glo. After adding ultrapure water to the reaction and mixing gently, a 1 mM reaction product was prepared, and the luciferin detection reagent was placed in a brown bottle, and DPP4 — G1 〇. was added. The luciferin detection reagent should be dissolved within 1 minute, the test compound dissolved in DMS0 to 50 times the final operating concentration, 50 times the concentration of the test compound 2 /zL was added to each tube, and added in the reverse control and the blank control. 2/zLDMSO, add 46/zL Tris buffer to each test 23 94996 201213331 tube, add B. Tris buffer to the blank control, and add 2 //LDPP4 enzyme to each tube of the reverse control and test sample. , vibrate to mix and centrifuge the tube. The contents of the tubes were all transferred to a 96-well plate, and the ratio of the reactants and Dpp4-Gl was mixed to 1:49. Mix the vibrations to mix thoroughly. Allow to stand at room temperature for 3 to 6 minutes before use, add 5 〇 / / L Dpp4_G1 〇 · and a mixture of reactants in each 96-well plate well, seal the plate with a sealing film, using a plate shaker The 96-well material was slowly mixed at 3 〇〇 5 rpm/30 s. Incubate for 3 to 3 hours at room temperature and detect chemiluminescence counts on a NOVOstar multifunction calibrator. [Table Π Test compound DPP4 DPP8 dppq ICso(M) ICso(M) Selection ratio (DPP8/DPP4) ICso(M) Selection ratio (DPP9/DPP4') Compound A 0.008 26.1 3263 " r 75.5 9438 MK-0431 0.019 25.8 1358 92.7 4879 Result: Compound A has better inhibitory activity against DPP4 than control drug MK_〇431, and selectivity is also stronger than MK-043. Test Example 2: Compound A, MK-0431, single administration to crab Inhibition of serum DPP4 activity Healthy adult cynomolgus monkeys, 8 males and females. Fasting for more than 8 hours before administration, free access to water. Oral administration, venous blood sputum was taken before administration and at 1, 3, 9, 12 and 24 hours after administration. 75 ml, centrifuged at 3000 rpm 〇 min, and the serum was separated. The activity of DPP4 was determined, and the inhibition of serum DPP4 activity and the duration of action of serum DPP4 after 1 〇mg/kg of Compound A or MK-0431 were observed. The liquid chromatography-tandem mass spectrometry was used to determine the compound A or 94096 in serum. 24 201213331 MK-0431 concentration. Cross-administration was used in the experiment, and at least 7 to 10 days after each administration, the next administration test was carried out. ^ [Table 2] Effect of oral administration of 10 mg/kg of compound Α or ΜΚ-0431 on DPP4 ^ activity of cynomolgus monkey (% DPP4 specific activity) Time of administration (h) 0 1 3 9 12 24 Compound A 100.0 23. 5+ 6. 5 3. 8+0. 6 9.1+1.6 22. 0+3.1 40. 9+4. 0 MK-0431 100.0 35. 7±9.8 12. 2+1.0 39. 0+3. 0 48. 9+ 3. 6 62. 5+2. 0 Table 2 shows that Compound A significantly inhibited the activity of DPP4 in cynomolgus monkeys after a single oral administration, and its strength and duration of maintenance were better than the equivalent dose of MK-0431, 10 mg/kg. Compound A maintained a serum DPP4 activity inhibitor of more than 75% within 12 hours. Test Example 3: Effect of Compound A and MK-0431 in Combination with Diterpenoid in Wistar Rats with Genetic Obesity and Diabetes Male Wistar rats aged 14 to 19 weeks were divided into 5 groups of 5 To 6 rats, respectively, take Compound A, MK-0431 (10 mg/kg body weight/day, orally), diterpene bismuth (1 〇〇mg/kg body weight/day; mix in a commercial feed at a ratio of 5 ppm) 14 day. 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 C0.). 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. 25 94996 201213331 [Table 3] ΜΚ-043]^κ-曱 two-color compound ^ 曱 曱 346+30 214+50* 327+46 185+13* 154+23* hemoglobin>.8±0. 4 ». 3+0. 6. 1±0. 6 4. 8±0. 5* 4. 2±0.4* *: P< 0.01 Compared with the control group, the combination of Compound A and metformin in Table 3 significantly reduced blood. The concentration of grape vines and hemoglobin is greater than the combination of MK-0431 and diterpene. Test Example 4: Compound A sulphate, MK-0431 phosphate in combination with diterpene bismuth in a glucose load study in genetically obese and diabetic Wistar rats divided 13 to 14 week old male fat rats 5 groups, 5 rats, respectively, taking Compound A phosphate, MK-043U each 30 mg/kg/day, orally) and metformin (l〇〇mg/kg/day, orally) for 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. The result is the average kd of each group (n=5) and

Dunnett's test analysis, provided in Table 4. 26 94996 201213331 [Table 4] Group blood polydextrose (mg/dl) Omin 120rain 240min Control 120+8 242±57 138+19 Compound A phosphate 103±11 137±17* 102+9* Diterpenoid 胍119±11 221±62 107±21* MK-0431 phosphate + metformin 109±5 116±7* 86±3* Compound A phosphate + diterpenoid 107+3 95+10* 64±5* *: with the control group T < 0. 01 Table 4 clearly shows that the combination of Compound A phosphate and diterpene bismuth significantly inhibited the increase in blood glucose after the glucose load test, and the intensity was greater than that of MK-0431 in combination with diterpene. [Simple description of the diagram] None [Key component symbol description] Benefit 27 94996

Claims (1)

201213331 VII. Patent Application Range: 1. A pharmaceutical composition comprising: (a) 3 to 20% by weight of (R)-7-[3-amino-4-(2, 4, 5-difluoro-phenyl)butanthyl]-3-trifluoromethyl-5,6,6-tetrahydro-imidazo[l,5-a]pyrazine-1-carboxylic acid methyl ester or its a pharmaceutically acceptable salt; (b) from 25 to 94% by weight of metformin or a salt thereof (such as a hydrochloride); ^ (C) from 0.1 to 10% by weight of a lubricant; and (d) 0 to 35% by weight of binder. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises one or more excipients selected from the group consisting of: (imaginal diluent, (b) disintegrant; (c) (a) a wetting agent; or (e) an antioxidant. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: (a) 5 to 5 by weight 18% (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-7,6,7,8-tetrahydro __Imidazo[1'5-a]pyrazine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof; (b) 65 to 77 Å/0 by weight of metformin or a salt thereof; (c) a pharmaceutical composition according to the third aspect of the invention, wherein the pharmaceutical composition further comprises a pharmaceutical composition according to the third aspect of the invention. 5% to 5% by weight of the surfactant and/or 5 to 15% by weight of the diluent. 94996 28 201213331 * 5. The pharmaceutical composition according to claim 3, wherein the The lubricant is magnesium stearate or sodium stearyl fumarate, and the combination The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises: (a) 9% by weight of (R)-7-[3-amino group- 4-(2,4,5-trioxo-phenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo[1,5-a]pyrazine-1- a carboxylic acid oxime ester or a pharmaceutically acceptable salt thereof; (b) 73% by weight of diterpene bismuth or a salt thereof; (c) 1 to 2% by weight of a lubricant; and (d) by weight The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition further comprises 5% by weight of surfactant and/or 10% by weight. 8. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises: (a) 5% by weight of (R)-7-[3-amino-4 -(2, 4, 5~three gas ~phenyl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo[1'5-a]pyrazine-1 - carboxylic acid oxime ester or a pharmaceutically acceptable salt thereof. (b) 77% by weight of diterpene bismuth or a salt thereof; (c) 1 to 2% by weight of a lubricant; and (d) by weight The pharmaceutical composition according to the invention of claim 8, wherein the '', T 53⁄4 music, and the delta material additionally comprise 5% by weight of the surfactant. And/or 10% by weight of diluent according to 94096 29 201213331. 10. A pharmaceutical composition comprising: (a) 0〇-7-[3-amino-4-(2,4,5-trifluoro) present in a unit dosage concentration of 25 to 500 mg -Phenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-p-indolo[1,5-a]B-pyrazine-1-hypoacid methyl ester or its pharmacy An acceptable salt or; (b) Diterpenoid 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 Lubricant; (d) 7% by weight of binder; and (e) 1% by weight of diluent, as needed; and (f) 0.5% by weight of surfactant . The pharmaceutical composition according to the first aspect of the invention, wherein the lubricant is sodium stearyl fumarate, the binder is polyvinylpyrrolidone, and the optional diluent is microcrystalline cellulose. And the desired surfactant is lauryl sulfate steel. 12. The pharmaceutical composition according to claim 1, wherein the 00~7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanyl]_3_3 Fluorinyl-5, 6, 7, 8-tetrahydro-n-miso-[1,5-a]° azine-1-hydroxy acid methyl hydrazide or a pharmaceutically acceptable salt thereof, 25, 50 a unit dose concentration of 75, 1 〇〇, 150, 300, 400 or 500 mg, and a unit dose of the metformin or its salt at 250, 500, 850, 1 〇〇〇, 1250 or 15 〇〇 mg The concentration is present. The pharmaceutical composition according to claim 12, wherein the 94096 30 201213331 7 [3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoro Methyl 5, 6, 7, 8-tetrahydro-flavored [^,5_a]n is a unit dose concentration of 5 (), (10) mg, or its pharmaceutically acceptable salt. It is present, and the metformin or a salt thereof is present in a unit dose concentration of 500, 85 or 1 mg. 14. The pharmaceutical composition according to claim 1 and/or (1), wherein the pharmaceutical composition is a tablet dosage form or other oral dosage form. 15. A method of treating type 2 diabetes in a human towel in need thereof, the method comprising: orally administering the pharmaceutical composition described in the patent application and/or item 12 of the human. 16. The pharmaceutical composition of claim 3, 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 4, wherein the pharmaceutical composition is prepared by a wet granulation method. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutically acceptable salt is selected from the group consisting of phosphate, hydrochloride, sulfate, stone, strontium salt, hydrogen &gt Lactate L (tetra), maleate, tartrate, chillate, acetate, trifluoroacetate, fumarate, citrate, benzoate, benzoate , carotene, lactic acid malate. The pharmaceutical composition according to claim 1 or 12, wherein the metformin or a salt thereof is released immediately or slowly. /, 2〇 · The pharmaceutical composition as described in the patent application No. 1 illusion 2, wherein 94996 31 201213331 for humans, (8)-7-[3-amino + (2, 4, 5_ three chaos _ phenyl , butyl aryl]-3-difluoromethyl-5, 6, 7, 8-tetrahydro-imidazolium &lt;, 5-pyridyl-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof The dose is from 25 mg to 1 mg, and the daily dose of metformin or its salt is from 25 mg to 3000 mg. The pharmaceutical composition according to claim 1 or 12, wherein the pharmaceutical composition is administered once a day, twice a day or three times a day. 32 94996 201213331 IV. Designated representative map: There is no schema in this case (1) The representative representative figure of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: This case does not represent the chemical formula 2 94996