Hypoglycemic pharmaceutical composition containing compound A

Abstract

The invention provides the hypoglycemic pharmaceutical composition of the compound A and / or the pharmaceutically acceptable salt thereof and the dapagliflozin and / or the pharmaceutically acceptable salt thereof with pharmaceutical prospects, and the pharmaceutical composition can reduce the risk of urinary tract infection of diabetic patients, is beneficial to improving the hypoglycemic effect, and reduces adverse drug reactions.

Description

Technical Field

[0001] The present invention belongs to the field of medical inventions, and specifically relates to a pharmaceutical composition for treating type II diabetes in mammals, including humans, in particular a pharmaceutical composition containing a fixed-dose combination of compound A and / or a pharmaceutically acceptable salt thereof and dapagliflozin and / or a pharmaceutically acceptable salt thereof, a method for preparing the pharmaceutical composition, and use of the pharmaceutical composition for treating type II diabetes in mammals, including humans. Background Art

[0002] Diabetes affects millions of people worldwide and is considered one of the leading threats to human mortality in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys, and nerves. The socioeconomic burden of diabetes is high worldwide.

[0003] There are two main types of diabetes, named type I and type II, of which type II diabetes (T2DM) accounts for more than 90% of all diabetes worldwide. Type I diabetes is characterized by insulin deficiency, mainly caused by autoimmune-mediated destruction of pancreatic β cells, and type II diabetes is characterized by abnormal insulin secretion and subsequent insulin resistance. To prevent ketoacidosis, patients with type I diabetes must take exogenous insulin to survive. Although patients with type II diabetes are not as dependent on exogenous insulin as patients with type I diabetes, they may need exogenous insulin to control blood sugar levels.

[0004] Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to treat type 2 diabetes. It works by inhibiting sodium-glucose transporter 2 to prevent glucose from being reabsorbed into the blood, allowing excess glucose to be excreted from the body through the urine, thereby improving blood sugar control without increasing insulin secretion.

[0005] Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a class of new agents developed to treat or improve glycemic control in patients with type 2 diabetes. Orally bioavailable DPP-4 inhibitors can retain the biological function of GLP-1 by truncating the biological activity of DPP-4. Therefore, these orally effective inhibitors have gradually become the main intervention measures for patients with T2DM. The main representative drugs are as follows: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin and Trelagliptin.

[0006] Marketed products of the combination of dipeptidyl peptidase-IV (DPP-IV) inhibitor and dapagliflozin include QTERN: dapagliflozin; saxagliptin HYDROCHLORIDE, with a ratio of, for example, 10 MG; EQ5 MG BASE (1:0.5).

[0007] PCT / CN2010 / 080370 describes a series of DPP-IV inhibitors with a new core structure. Compared with other DPP-IV inhibitors, this series of compounds has the advantages of higher efficacy and higher selectivity. Among them, it includes compound A, whose chemical name is: (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazine-4(5H)-yl)methyl)-4-fluorobenzonitrile, molecular formula: C 17 H 19 FN6O, molecular weight: 342, chemical structure formula is as follows (I):

[0008] Summary of the invention

[0009] The object of the present invention is to provide a combination of a dipeptidyl peptidase IV activity inhibiting compound A and / or its chemically acceptable salt and dapagliflozin and / or its chemically acceptable salt. The pharmaceutical composition can reduce the risk of urinary tract infection in diabetic patients, help improve the hypoglycemic effect, and reduce adverse drug reactions.

[0010] Through experimental research, the inventors surprisingly found that the efficacy of the compound A and / or its chemically acceptable salt and dapagliflozin and / or its chemically acceptable salt is significantly higher than that of the single drug, especially when the ratio of compound A and / or its salt and dapagliflozin and / or its chemically acceptable salt is 0.2:1 to 5:1, respectively, calculated as compound A and dapagliflozin, the effect is better. Therefore, the composition composed of compound A or its salt and dapagliflozin is of great clinical significance.

[0011] The purpose of the present invention is achieved through the following technical solutions:

[0012] A hypoglycemic pharmaceutical composition containing compound A, the pharmaceutical composition consisting of compound A and / or a pharmaceutically acceptable salt thereof and dapagliflozin and / or a pharmaceutically acceptable salt thereof, wherein the weight ratio of compound A to dapagliflozin is 0.2:1 to 5:1, calculated on a weight basis on compound A and dapagliflozin, respectively.

[0013] The aforementioned compound A and / or its pharmaceutically acceptable salt is a mixture of compound A, or a pharmaceutically acceptable salt of compound A, or a mixture of compound A and a pharmaceutically acceptable salt of compound A in any proportion in the glucose-lowering pharmaceutical composition.

[0014] Specifically, the mass ratio of compound A and / or its salt to dapagliflozin and / or its salt, calculated as compound A and dapagliflozin, can be any specific value between 0.2:1 and 5:1, such as: the weight ratio of compound A to dapagliflozin is 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.8:1, 1.0:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3.0:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4.0:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1, 5:1, etc.; preferably, the mass ratio is 0.4:1, 0.6:1, 1.2:1, 1.6:1, 2.4:1, 3.6:1, 4.8:1.

[0015] The aforementioned compound A and / or its pharmaceutically acceptable salt is calculated as compound A, and the daily dosage of a human is 6-24 mg. The aforementioned dapagliflozin and / or its pharmaceutically acceptable salt is calculated as dapagliflozin, and the daily dosage of a human is 5-20 mg.

[0016] Furthermore, the aforementioned pharmaceutical composition contains 6 mg, or 12 mg, or 18 mg, or 24 mg of compound A and / or its pharmaceutically acceptable salt, calculated as compound A; and contains 5 mg, or 10 mg, or 15 mg, or 20 mg of dapagliflozin and / or its pharmaceutically acceptable salt, calculated as dapagliflozin.

[0017] More specifically, when the amount of Compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 6 mg, the amount of dapagliflozin and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition may be 5 mg, or 10 mg, or 15 mg, or 20 mg, calculated as dapagliflozin; when the amount of Compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 12 mg, the amount of dapagliflozin and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition may be 5 mg, or 10 mg, or 15 mg, or 20 mg, calculated as dapagliflozin. mg; when the compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 18 mg, calculated as compound A, the dapagliflozin and / or its pharmaceutically acceptable salt contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, calculated as dapagliflozin; when the compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 24 mg, calculated as compound A, the dapagliflozin and / or its pharmaceutically acceptable salt contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, calculated as dapagliflozin.

[0018] Another object of the present invention is to provide a method for preparing the aforementioned pharmaceutical composition, which has simple steps and strong operability, and can realize industrial production to prepare the aforementioned pharmaceutical composition.

[0019] The above invention objectives are achieved by adopting the following technical solutions:

[0020] A method for preparing the aforementioned pharmaceutical composition comprises the step of mixing compound A and / or its salt with dapagliflozin and / or its salt.

[0021] The compound A and / or its salt and dapagliflozin and / or its salt are mixed by directly physically mixing the two; the method of physical mixing includes but is not limited to direct mixing method and equal incremental method; the equipment used for physical mixing can be conventional powder mixing equipment, preferably a V-type mixer.

[0022] The present invention provides a pharmaceutical composition of a fixed dose combination of compound A and / or a pharmaceutically acceptable salt thereof and dapagliflozin and / or a pharmaceutically acceptable salt thereof. The two active pharmaceutical ingredients of the pharmaceutical composition of the present invention are immediately released or slowly released. The pharmaceutical composition of the present invention can be in the form of a tablet, and in particular a film-coated tablet, or can be other oral dosage forms such as capsules, etc.

[0023] One aspect of the present invention relates to a dosage form for a fixed dose combination of compound A and / or a pharmaceutically acceptable salt thereof and dapagliflozin and / or a pharmaceutically acceptable salt thereof for medical administration. The dosage form may be in powder or solid form, and includes tablets, hard capsules, soft capsules, oral solutions, sustained release agents, drop pills, granules, granules, sustained release pellets or other oral dosage forms, etc. A specific solid dosage form relates to a tablet containing a fixed dose combination of compound A or a pharmaceutically acceptable salt thereof and dapagliflozin.

[0024] The present invention also provides a method for preparing a pharmaceutical composition of a fixed-dose combination of Compound A and / or its salt and dapagliflozin and / or its salt by a dry granulation method and a wet granulation method.

[0025] Another aspect of the present invention provides use of the pharmaceutical composition of the present invention in treating type 2 diabetes in mammals, including humans, which comprises administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a subject in need of such treatment.

[0026] Pharmaceutically acceptable salts of Compound A include, but are not limited to, toluenesulfonate, benzoate, methanesulfonate, benzenesulfonate, phosphate, hydrochloride, sulfate, nitrate, diphosphate, hydrobromide, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, palmitate, naphthenate, hydroxynaphthoate, laurate, lactate, malate, camphorsulfonate, ethanesulfonate, gluconate, glutamate, isethionate, mandelate, pamoate (pamoate), mucate and pantothenate; the pharmaceutically acceptable salt of dapagliflozin is selected from dapagliflozin propylene glycol monohydrate.

[0027] In a specific embodiment of the present invention, the pharmaceutical composition comprises (1) Compound A and / or a pharmaceutically acceptable salt thereof, as the first active pharmaceutical ingredient; (2) dapagliflozin and / or a pharmaceutically acceptable salt thereof, as the second active pharmaceutical ingredient; and (3) one or more pharmaceutically acceptable excipients.

[0028] The pharmaceutically acceptable excipients include one or a mixture of two or more of adhesives, fillers, disintegrants, surfactants, lubricants, plasticizers, preservatives, flavoring agents, solubilizers, colorants, dispersants, opacifiers, release rate regulators, etc.

[0029] The binder includes, but is not limited to, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch slurry (such as corn starch slurry), sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyethylene glycol (such as PEG4000, PEG6000), gelatin solution, and sucrose solution.

[0030] The fillers include, but are not limited to, microcrystalline cellulose, lactose, mannitol, starch (such as compressible starch), dextrin, sucrose, calcium bicarbonate, calcium sulfate, and calcium sulfate dihydrate. The fillers can be used alone or in combination.

[0031] The disintegrant can be a conventional disintegrant, such as cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, dry starch, etc., or a novel disintegrant. The disintegrant can be used alone or in combination of two or more different disintegrants.

[0032] 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 alkyl trimethyl ammonium bromide. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol and sorbitan esters. Embodiments of wetting agents include poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives and polyoxyethylene stearic acid esters.

[0033] The lubricant includes, but is not limited to, stearic acid, sodium stearyl fumarate, magnesium stearate and other stearates, talc, micro-powdered silica gel, sodium lauryl sulfate, hydrogenated vegetable oil (such as hydrogenated castor oil), glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate, and pregelatinized starch (starch 1500).

[0034] The plasticizer includes but is not limited to polyethylene glycol, propylene glycol, and glycerin.

[0035] The preservatives include, but are not limited to, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, potassium sodium sorbate, calcium propionate, sodium propionate, parahydroxybenzoic acid, and isopropyl parahydroxybenzoate.

[0036] The flavoring agent includes sweetener, aromatic agent, syrup and effervescent agent, wherein the sweetener can be sucrose, stevioside, monosaccharide syrup, aromatic syrup, glycerol, sorbitol, saccharin sodium, protein sugar; the syrup can be sodium alginate, gum arabic, gelatin, methyl cellulose, sodium carboxymethyl cellulose; the effervescent agent can be an organic acid such as citric acid, tartaric acid, sodium bicarbonate.

[0037] The solubilizers include, but are not limited to, sorbitan fatty acids, polysorbates, polyoxyethylene fatty acid esters, phospholipids, cholesterol, stearates (such as sodium stearate), oleates (such as sodium oleate), sodium dodecyl sulfate, and sodium dodecyl sulfonate.

[0038] The coloring agent includes but is not limited to beetroot red, carmine, carotene, lemon yellow, pine leaf orchid, sodium copper chlorophyllin, caramel, aluminum lake, yellow iron oxide, and brilliant blue.

[0039] The dispersant includes, but is not limited to, sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, silicates, triethylhexyl phosphate, methyl amyl alcohol, cellulose derivatives, polyacrylamide, guar gum, and polyethylene glycol esters of fatty acids.

[0040] The sunscreen includes but is not limited to titanium dioxide, zinc oxide, and yellow iron oxide.

[0041] The release rate regulator is selected from sucrose, sodium chloride, surfactants, and polyethylene glycol (PEG).

[0042] In order to make the effect of the specific formulation more perfect, the present invention will appropriately add one or more of the above-mentioned excipients. For those of ordinary skill in the art, the above-mentioned excipients can be appropriately used according to their common technical knowledge and common knowledge, and the present invention will not be further described.

[0043] The pharmaceutical composition can be prepared into dosage forms suitable for oral administration, such as tablets (including ordinary tablets and coated tablets), lozenges, throat lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, syrups, pills, lyophilized powders or tinctures. It can also be prepared into injections and creams, gels, ointments, emulsions, solutions, lotions, suspensions, tinctures, pastes, foams, aerosols, enemas, sprays, suppositories, etc. suitable for topical administration.

[0044] The dapagliflozin and / or its salt of the present invention can be either immediately released or slowly released, and the compound A or its salt can be either immediately released or slowly released.

[0045] The present invention also provides a method for treating type 2 diabetes in mammals, including humans, by orally administering a therapeutically effective amount of a fixed-dose combination pharmaceutical composition of the present invention to 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, or it may be in the form of a capsule.

[0046] Pharmaceutical compositions containing fixed-dose combinations may be administered once daily (QD), twice daily (BID), or three times daily (TID).

[0047] Synthesis method of compound A of the present invention

[0048] The synthesis method of compound A was prepared according to the method described in Example 3 of PCT / CN2010 / 080370, and the disclosure is hereby incorporated by reference. The benzoate salt of compound A was prepared according to CN201510034007.X.

[0049] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0050] 1. Provide a combination of Compound A and / or its salt and dapagliflozin and / or its salt with pharmaceutical prospects, which can reduce the risk of urinary tract infection in diabetic patients by limiting the mass ratio of Compound A and / or its salt to dapagliflozin and / or its salt, thereby improving the hypoglycemic effect and reducing adverse drug reactions;

[0051] 2. Provide a combination of Compound A and / or its salt and dapagliflozin and / or its salt with pharmaceutical prospects, wherein the combination of Compound A and / or its salt + dapagliflozin and / or its salt is superior to the combination of alogliptin and / or its salt + dapagliflozin and / or its salt in reducing the AUC of glucose in OGTT of mice 0-120min It is beneficial to improve the hypoglycemic effect;

[0052] 3. Provide a method for preparing the aforementioned pharmaceutical composition, which has simple steps and strong operability, and can realize industrial production to prepare the aforementioned pharmaceutical composition.

[0053] Therefore, the pharmaceutical composition of the present invention is more suitable for being developed into an excellent pharmaceutical composition for treating type II diabetes, exhibiting a synergistic effect and providing a good guarantee for the safety and effectiveness of medication. DETAILED DESCRIPTION

[0054] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0055] The dosage of the compound A benzoate used in the present invention is calculated based on compound A.

[0056]

[0057]

[0058] The dapagliflozin used in the present invention is dapagliflozin propylene glycol monohydrate, and the dosages thereof are all calculated based on dapagliflozin.

[0059]

[0060] The alogliptin used in the present invention is alogliptin benzoate, and the dosage is all calculated based on alogliptin.

[0061]

[0062] The saxagliptin used in the present invention is saxagliptin hydrochloride, and the dosage is all calculated based on saxagliptin.

[0063]

[0064] Example 1 Preparation of Compound A-Dapagliflozin Composition

[0065] Compound A benzoate (0.6 kg, calculated as Compound A) was added into a V-shaped mixing drum, and dapagliflozin propylene glycol monohydrate (1 kg, calculated as dapagliflozin) was added, and after mixing for 30 minutes, a Compound A-dapagliflozin pharmaceutical composition with a mass ratio of 0.6:1 was obtained.

[0066] The same method can be used to prepare compound A-dapagliflozin pharmaceutical compositions with other mass ratios, such as compound A-dapagliflozin pharmaceutical compositions with mass ratios of 0.2:1, 0.3:1, 1.2:1, 1.6:1, 2.4:1, 4.8:1, etc.

[0067] Using the same method, alogliptin benzoate and dapagliflozin propylene glycol monohydrate were taken, and the mass ratio of alogliptin and dapagliflozin was 2.4:1 to prepare an alogliptin\dapagliflozin compound pharmaceutical composition.

[0068] Example 2 Pharmacodynamics Experimental Study

[0069] 2.1 Experimental animals and instruments

[0070] Male C57BL / 6J mice, 9-10 weeks old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0071] 2.2 Animal grouping and treatment

[0072] 152 C57BL / 6J mice were fed adaptively for one week before the experiment. According to the weight and health status of the mice, 128 mice were selected for this experiment. They were randomly divided into 16 groups, 8 mice in each group. The grouping and dosing information are shown in Table 2-1.

[0073] Table 2-1 Animal experiment grouping and dosing table

[0074]

[0075]

[0076] Note: The dosage volume is 10 mL / kg, and the above dosages are calculated based on the free base.

[0077] 2.3 Experimental Methods

[0078] The mice were fasted overnight the day before administration. On the day of administration, each group of mice was administered with the test substances corresponding to Table 2. After administration, the animals in each group were placed in metabolic cages, 8 in each cage, and were allowed to eat and drink freely. Urine was collected in sections. 24 hours after administration, the urine was transferred to a 15 ml centrifuge tube and the total amount of urine was recorded. After mixing, 1 ml was taken out and centrifuged in a centrifuge (3000 rpm, 10 min) to remove impurities. The amount of urine collected in each group was counted, and the glucose concentration in the urine was detected.

[0079] 2.4 Urine testing

[0080] The urine testing method is detailed in Table 2-2.

[0081] Table 2-2. Urine testing methods

[0082] Test items Sample Type Sample volume (ml) Analytical methods Urine sugar test Urine 0.2ml Glucose oxidase method

[0083] 2.5 Experimental Results

[0084] Urine glucose is shown in Table 2-3.

[0085] Table 2-3. Urine Glucose

[0086]

[0087]

[0088] Note: The sugar excretion results are expressed as the sugar excretion amount (the sum of the sugar excretion amounts of the same dose of a single drug).

[0089] The results showed that compared with single-agent Compound A and dapagliflozin, the combination of Compound A + dapagliflozin can reduce the sugar excretion of mice, indicating that the combination of Compound A + dapagliflozin can reduce the risk of urinary tract infection.

[0090] 3 Oral glucose tolerance test (OGTT) study

[0091] 3.1 Experimental animals and instruments

[0092] Male C57BL / 6J mice, 9-10 weeks old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0093] 3.2 Animal grouping and treatment

[0094] 40 C57BL / 6J mice were fed adaptively for one week before the experiment. According to the weight and health status of the mice, 24 mice were selected for this experiment. They were randomly divided into 3 groups, 8 mice in each group, and 3 supplementary groups, 6 mice in each group. The grouping and dosing information are shown in Table 3-1.

[0095] Table 3-1 Animal experiment grouping and dosing table

[0096]

[0097]

[0098] Note: The dosage volume is 10 mL / kg, and the above dosages are calculated based on the free base.

[0099] 3.3 Experimental Methods

[0100] The mice were fasted overnight the day before administration. After blood glucose was measured by tail vein blood sampling, each group of mice was administered with the test substance corresponding to Table 3-1. 0.5h after administration, the mice were given 2.5g / kg glucose solution, and then the blood glucose level at the tip of the tail of the mice was measured using a handheld Roche blood glucose meter (Roche, Accu-chek). About 1mm of the tip of the mouse tail was cut off, and blood glucose was measured by squeezing the vein from the base of the tail to the tip of the tail. The blood glucose measurement time points were: before sugar administration (0 o'clock), 15, 30, 60 and 120 minutes after sugar administration. The blood glucose changes of animals within 2 hours after sugar administration were measured. The glucose tolerance of each experimental group was evaluated by calculating the area under the curve (AUC) of glucose.

[0101] 3.4 Experimental Results

[0102] The blood glucose decrease rate and blood glucose concentration of mice are shown in Table 3-2.

[0103] Table 3-2. Results of oral glucose tolerance test in mice

[0104]

[0105]

[0106] Note: One-way ANOVA, **P<0.01 vs blank solvent group.

[0107] The results of oral glucose tolerance showed that compared with the blank solvent, the AUC of the animals in the drug-treated group was significantly reduced, indicating that the glucose tolerance of animals treated with compound A + dapagliflozin, alogliptin + dapagliflozin, and saxagliptin + dapagliflozin was significantly improved.

[0108] Among them, compound A + dapagliflozin combination was superior to alogliptin + dapagliflozin and saxagliptin + dapagliflozin combination in reducing the AUC of glucose in OGTT of mice 0-120min effect.

[0109] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A hypoglycemic pharmaceutical composition containing compound A, characterized in that: The pharmaceutical composition consists of compound A and / or a pharmaceutically acceptable salt thereof and dapagliflozin and / or a pharmaceutically acceptable salt thereof, wherein the weight ratio of compound A to dapagliflozin is 0.2:1 to 5:1, calculated on the basis of compound A and dapagliflozin respectively.

2. The hypoglycemic pharmaceutical composition containing compound A according to claim 1, characterized in that: The compound A and / or its pharmaceutically acceptable salt is a mixture of compound A, or a pharmaceutically acceptable salt of compound A, or a mixture of compound A and a pharmaceutically acceptable salt of compound A in any proportion in the hypoglycemic pharmaceutical composition.

3. The hypoglycemic pharmaceutical composition containing compound A according to claim 1 or 2, characterized in that: The compound A and / or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable salt composition, wherein, based on compound A and dapagliflozin, the weight ratio of compound A to dapagliflozin is 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.8:1, 1.0:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3.0:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4.0:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1, and 5:

1.

4. The hypoglycemic pharmaceutical composition containing compound A according to any one of claims 1 to 3, characterized in that: The compound A and / or its pharmaceutically acceptable salt is calculated based on compound A, and the daily dosage of human beings is 6-24 mg. The dapagliflozin and / or its pharmaceutically acceptable salt is calculated based on dapagliflozin, and the daily dosage of human beings is 5-20 mg.

5. The hypoglycemic pharmaceutical composition containing compound A according to any one of claims 1 to 4, characterized in that: The hypoglycemic pharmaceutical composition is packaged according to the clinical dosage and prepared into dosage units of specific specifications. The dosage unit may contain 6 mg, 12 mg, 18 mg, or 24 mg of compound A and / or its pharmaceutically acceptable salt, calculated as compound A; and 5 mg, 10 mg, 15 mg, or 20 mg of dapagliflozin and / or its pharmaceutically acceptable salt, calculated as dapagliflozin.

6. The hypoglycemic pharmaceutical composition containing compound A according to any one of claims 1 to 5, characterized in that: In the pharmaceutical composition, when the amount of compound A and / or its pharmaceutically acceptable salt is 6 mg, the amount of dapagliflozin and / or its pharmaceutically acceptable salt may be 5 mg, 10 mg, 15 mg, or 20 mg, calculated as dapagliflozin; when the amount of compound A and / or its pharmaceutically acceptable salt is 12 mg, the amount of dapagliflozin and / or its pharmaceutically acceptable salt may be 5 mg, 10 mg, 15 mg, or 20 mg, calculated as dapagliflozin. ; When the amount of Compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 18 mg, calculated as Compound A, the amount of dapagliflozin and / or its pharmaceutically acceptable salt contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, calculated as dapagliflozin; when the amount of Compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 24 mg, the amount of dapagliflozin and / or its pharmaceutically acceptable salt contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, calculated as dapagliflozin.

7. The glucose-lowering pharmaceutical composition containing Compound A according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt of Compound A is selected from toluenesulfonate, benzoate, methanesulfonate, benzenesulfonate, phosphate, hydrochloride, sulfate, nitrate, diphosphate, hydrobromide, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, palmitate, naphthenate, hydroxynaphthoate, laurate, lactate, malate, camphorsulfonate, ethanesulfonate, gluconate, glutamate, isethionate, mandelate, pamoate (pamoate), mucate or pantothenate; and the pharmaceutically acceptable salt of dapagliflozin is selected from dapagliflozin propylene glycol monohydrate.

8. The glucose-lowering pharmaceutical composition containing compound A according to any one of claims 1 to 7, wherein the glucose-lowering pharmaceutical composition is a tablet, a hard capsule, a soft capsule, an oral solution, a sustained-release agent, a drop pill, an granule, a granule, a sustained-release pellet or other oral dosage form.

9. The glucose-lowering pharmaceutical composition containing Compound A according to any one of claims 1 to 8, wherein the dapagliflozin and / or a pharmaceutically acceptable salt thereof is immediately released or slowly released; Compound A and / or a pharmaceutically acceptable salt thereof is immediately released or slowly released.

10. Use of the hypoglycemic pharmaceutical composition containing compound A according to any one of claims 1 to 9 in the preparation of a medicament for treating diabetes in mammals including humans.

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