Compound hypoglycemic pharmaceutical composition

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medical inventions, and specifically relates to a compound 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 empagliflozin, a method for preparing the pharmaceutical composition, and the 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] Empagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, can block the reabsorption of glucose in the kidneys and excrete excess glucose out of the body, thereby achieving the effect of lowering blood sugar levels. Moreover, this blood sugar-lowering effect is independent of β-cell function and insulin resistance.

[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 empagliflozin include GLYXAMBI: empagliflozin; linagliptin, with a ratio of, for example, 25 MG; 5 MG (1:0.2).

[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 compound combination of a dipeptidyl peptidase IV activity inhibiting compound A and / or a chemically acceptable salt thereof and empagliflozin. 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 empagliflozin is significantly higher than that of the single drug, especially when the ratio of compound A and / or its salt and empagliflozin is 0.2:1 to 3.0:1, respectively. Therefore, the composition of compound A or its salt and empagliflozin has 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 empagliflozin, wherein the weight ratio of compound A to empagliflozin is 0.2:1 to 3.0:1, calculated on a weight basis of compound A and empagliflozin, 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 empagliflozin, calculated as compound A and empagliflozin, can be any specific value between 0.2:1 and 3.0:1, such as: the weight ratio of compound A to empagliflozin is 0.2:1, 0.24:1, 0.3:1, 0.36:1, 0.4:1, 0.48:1, 0.5:1, 0.6:1, 0.72:1, 0.8:1, 0.84:1, 0.96:1, 1.0:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.4:1, 3.0:1, etc., calculated as compound A and empagliflozin, respectively; preferably, the mass ratio is 0.24:1, 0.48:1, 0.6:1, 0.96:1, 1.2:1, 1.6:1, 2.4:1.

[0015] The aforementioned compound A and / or its pharmaceutically acceptable salt is calculated based on compound A, and the daily dosage of empagliflozin is 6-24 mg per person, and the daily dosage of empagliflozin is 5-30 mg per person.

[0016] Furthermore, the aforementioned pharmaceutical composition may contain 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 contain 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg of empagliflozin.

[0017] More specifically, when the amount of Compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 6 mg, calculated as Compound A, the amount of Empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg; when the amount of Compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 12 mg, calculated as Compound A, the amount of Empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg; 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 Empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg; when the amount of Compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 24 mg, the amount of Empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg.

[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 empagliflozin.

[0021] The compound A and / or its salt is mixed with empagliflozin by directly physically mixing the two. The method of physical mixing includes but is not limited to direct mixing and equal incremental mixing. 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 empagliflozin. 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.

[0023] One aspect of the present invention relates to a dosage form for medical administration of a fixed dose combination of Compound A and / or a pharmaceutically acceptable salt thereof and Empagliflozin. 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 Empagliflozin.

[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 empagliflozin by dry granulation and wet granulation.

[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.

[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) Empagliflozin, 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 empagliflozin 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 compound combination of compound A and / or its salt and empagliflozin 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 empagliflozin, thereby improving the hypoglycemic effect and reducing adverse drug reactions;

[0051] 2. Provide a combination of compound A and / or its salt and empagliflozin with pharmaceutical prospects, wherein the combination of compound A and / or its salt + empagliflozin is superior to the combination of linagliptin + empagliflozin and reduces 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] Example 1 Preparation of Compound A-Empaligliflozin Compound Composition

[0059] Compound A benzoate (1.2 kg, calculated as Compound A) was added into a V-shaped mixing drum, and empagliflozin (1 kg) was added, and after mixing for 30 minutes, a Compound A-empagliflozin compound pharmaceutical composition with a mass ratio of 1.2:1 was obtained.

[0060] The same method can be used to prepare compound A-empagliflozin compound pharmaceutical compositions with other mass ratios, such as compound A-empagliflozin compound pharmaceutical compositions with mass ratios of 0.12:1, 0.24:1, 0.48:1, 0.6:1, 2.4:1, etc.

[0061] Using the same method, linagliptin and empagliflozin were taken to prepare a linagliptin\empagliflozin compound pharmaceutical composition with a mass ratio of 0.2:1.

[0062] Example 2 Pharmacodynamics Experimental Study

[0063] 2.1 Experimental animals and instruments

[0064] Male C57BL / 6J mice, 9-10 weeks old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0065] 2.2 Animal grouping and treatment

[0066] 100 C57BL / 6J mice were fed adaptively for one week before the experiment. 88 mice were selected for this experiment based on their weight and health. They were randomly divided into 11 groups, 8 mice in each group. The grouping and dosing information are shown in Table 2-1.

[0067] Table 2-1 Animal experiment grouping and dosing table

[0068]

[0069] Note: The dosage volume is 10 mL / kg, and the above dosages are calculated based on the free base.

[0070] 2.3 Experimental Methods

[0071] The mice were fasted overnight the day before administration. On the day of administration, each group of mice was administered the test substances corresponding to Table 2-1. 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 placed 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 tested.

[0072] 2.4 Urine testing

[0073] The urine testing method is detailed in Table 2-2.

[0074] Table 2-2. Urine testing methods

[0075] Test items Sample Type Sample volume (ml) Analytical methods Urine sugar test Urine 0.2ml Glucose oxidase method

[0076] 2.5 Experimental Results

[0077] Urine glucose concentrations are shown in Table 2-3.

[0078] Table 2-3. Urine glucose concentration

[0079]

[0080]

[0081] The results showed that compared with empagliflozin alone, the combination of compound A + empagliflozin can reduce the sugar excretion of mice, indicating that the combination of compound A + empagliflozin can reduce the risk of urinary tract infection.

[0082] 3 Oral glucose tolerance test (OGTT) study

[0083] 3.1 Experimental animals and instruments

[0084] Male C57BL / 6J mice, 9-10 weeks old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0085] 3.2 Animal grouping and treatment

[0086] 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.

[0087] Table 3-1 Animal experiment grouping and dosing table

[0088]

[0089] Note: The dosage volume is 10 mL / kg, and the above dosages are calculated based on the free base.

[0090] 3.3 Experimental Methods

[0091] 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.

[0092] 3.4 Experimental Results

[0093] The blood glucose decrease rate and blood glucose concentration of mice are shown in Table 3-2.

[0094] Table 3-2. Results of oral glucose tolerance test in mice

[0095]

[0096]

[0097] Note: One-way ANOVA, **P<0.01 vs blank solvent group.

[0098] 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 + empagliflozin, linagliptin + empagliflozin, and saxagliptin + empagliflozin was significantly improved.

[0099] Among them, the compound A + empagliflozin combination showed better performance in reducing the AUC of glucose in OGTT of mice than the combination of linagliptin + empagliflozin, the marketed product saxagliptin 5mg and empagliflozin 10mg. 0-120min effect.

[0100] 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 empagliflozin, wherein, based on compound A, the weight ratio of compound A to empagliflozin is 0.2:1 to 3.0:

1.

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 empagliflozin are composed, wherein, based on compound A, the weight ratio of compound A to empagliflozin is 0.2:1, 0.24:1, 0.3:1, 0.36:1, 0.4:1, 0.48:1, 0.5:1, 0.6:1, 0.72:1, 0.8:1, 0.84:1, 0.96:1, 1.0:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.4:1, and 3.0:

1.

4. The hypoglycemic pharmaceutical composition containing compound A according to any one of claims 1 to 3, characterized in that: The daily dosage of compound A and / or its pharmaceutically acceptable salt is 6-24 mg per person based on compound A, and the daily dosage of empagliflozin is 5-30 mg per person.

5. The hypoglycemic pharmaceutical composition containing compound A according to any one of claims 1 to 4, characterized in that: The glucose-lowering pharmaceutical composition contains 6 mg, 12 mg, 18 mg, or 24 mg of compound A and / or its pharmaceutically acceptable salt, calculated as compound A; and contains 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of empagliflozin.

6. The hypoglycemic pharmaceutical composition containing compound A according to any one of claims 1 to 5, characterized in that: When the amount of compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 6 mg, calculated as compound A, the amount of empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg; when the amount of compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 12 mg, calculated as compound A, the amount of empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg; 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 empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg; when the amount of compound A and / or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 24 mg, the amount of empagliflozin contained therein may be 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg.

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, naphthalenesulfonate, hydroxynaphthoate, laurate, lactate, malate, camphorsulfonate, ethanesulfonate, gluconate, glutamate, isethionate, mandelate, pamoate (pamoate), mucate or pantothenate.

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 empagliflozin is immediately released or slowly released; and 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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