WO2021057661A1 - Pharmaceutical composition for lowering blood sugar - Google Patents

Abstract

Disclosed is a pharmaceutical composition for lowering blood sugar, containing compound A (the structural formula thereof is as shown in formula I below) and/or a pharmaceutically acceptable salt thereof and metformin and/or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can realize the synergistic effect of lowering blood sugar.

Description

A kind of hypoglycemic medicine composition Technical field

The present invention belongs to the field of medical invention, and specifically relates to a pharmaceutical composition for the treatment of type II diabetes in mammals including humans, in particular a fixed dose containing compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof The combined pharmaceutical composition, the method for preparing the pharmaceutical composition, and the use of the pharmaceutical composition to treat type II diabetes in mammals, including humans.

Background technique

Diabetes affects millions of people around the world and is considered to be one of the main threats to human death in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys, and nerves. Worldwide, the socio-economic burden of diabetes is very heavy.

There are two main types of diabetes, named Type I and Type II. Type II diabetes (T2DM) accounts for more than 90% of all diabetes worldwide. Type I diabetes is characterized by lack of insulin, which is mainly caused by autoimmune-mediated destruction of pancreatic β-cells. 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.

Metformin has the effect of improving the blood glucose tolerance of type II diabetic patients and reducing the basal and postprandial blood glucose. Metformin hydrochloride does not stimulate insulin secretion. It mainly acts on the peripheral tissues of the pancreatic islets, increases the sensitivity of peripheral tissues to insulin, increases the uptake and utilization of glucose, inhibits the absorption of glucose by the intestinal wall, and helps reduce postprandial blood sugar. It can also inhibit the production and output of glycogen on New Year's Day and help control fasting blood sugar.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a class of new agents developed for the treatment or improvement of blood glucose production control in patients with type II diabetes. Oral bioavailable DPP-4 inhibitors can retain the biological function of GLP-1 by truncating the biological activity of DPP-4. Therefore, these oral effective inhibitors have gradually become the main intervention measures for patients with T2DM. The main representative drugs are the following: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin and Trelagliptin.

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 effectiveness and higher selectivity. Among them, including compound A, its chemical name is: (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-tri (Azin-4(5H)-yl)methyl)-4-fluorobenzonitrile, molecular formula: C ₁₇ H ₁₉ FN ₆ O, molecular weight: 342, chemical structural formula is the following formula (I):

Summary of the invention

The object of the present invention is to provide a combination of compound A and/or its chemically acceptable salt and metformin and/or its chemically acceptable salt for inhibiting the activity of dipeptidyl peptidase IV, the pharmaceutical composition can achieve reduction The synergistic effect of sugar is beneficial to improve the hypoglycemic effect and reduce adverse drug reactions.

Through experimental research, the present inventors surprisingly found that: Compound A and/or its chemically acceptable salt and metformin and/or its chemically acceptable salt are significantly more effective than the single drug, especially when compound A is used alone. The effect is better when the ratio of its salt to metformin or its salt is 1:20-1:350. Therefore, the combination of compound A or its salt and metformin or its salt has great clinical significance.

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

A hypoglycemic pharmaceutical composition, characterized in that the pharmaceutical composition is composed of compound A and/or its pharmaceutically acceptable salt and metformin and/or its pharmaceutically acceptable salt, wherein the compound A or its pharmaceutically acceptable salt The weight ratio of the above acceptable salt to metformin or its pharmaceutically acceptable salt is 1:20 to 1:350.

The aforementioned compound A and/or its pharmaceutically acceptable salt is a hypoglycemic pharmaceutical composition containing Compound A, or a pharmaceutically acceptable salt containing Compound A, or a pharmaceutically acceptable salt containing Compound A and Compound A Mix the resulting mixture in any ratio.

The mass ratio of the aforementioned compound A and/or its salt to metformin and/or its pharmaceutically acceptable salt is 1:20 to 1:350; specifically, in animal in vivo pharmacodynamics experimental studies, different dosage ratios There is a certain difference in the synergistic effect produced by the combination of compound A and metformin. When the mass ratio of compound A and/or its salt to metformin and/or its pharmaceutically acceptable salt is 1:20 to 1:350, The drug combination has a relatively high synergistic potential; more specifically, the mass ratio of the compound A and/or its salt to metformin and/or its salt can be any specific value between 1:20 and 1:350 , Such as: 1:20, 6:125, 6:212.5, 6:250, 6:375, 6:425, 6:500, 6:750, 6:850, 6:1000, 6:1500, 6:2000 , 1:350, etc.; preferably, the mass ratio of the compound A and/or its salt to metformin and/or its salt is 6:125, 6:212.5, 6:250, 6:375, 6:425, 6 : 500, 6: 750, 6: 850, 6: 1000, 6: 1500, 6: 2000.

The aforementioned compound A and/or its pharmaceutically acceptable salt has a daily human dosage of 6-24 mg, and the aforementioned metformin and/or its pharmaceutically acceptable salt has a human daily dosage of 250-2000 mg.

Further, the aforementioned pharmaceutical composition can be divided into specific dosage units according to the clinical administration dose. For example, the aforementioned pharmaceutical composition can be divided and prepared to contain Compound A and/or its pharmaceutically acceptable compounds. Accepted salt 6mg, or 12mg, or 18mg, or 24mg, containing metformin and/or its pharmaceutically acceptable salt 250mg, or 500mg, or 750mg, or 850mg, or 1000mg, or 1250mg, or 1350mg, or 1500mg, or 1700mg, or 1750mg, or 2000mg.

More specifically, when the compound A and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 6 mg, the metformin and/or its pharmaceutically acceptable salt contained in it may be 250 mg, or 500 mg, Or 750 mg, or 850 mg, or 1000 mg, or 1250 mg, or 1350 mg, or 1500 mg, or 1700 mg, or 1750 mg, or 2000 mg; when the compound A and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 12 mg When it contains metformin and/or its pharmaceutically acceptable salt may be 250mg, or 500mg, or 750mg, or 850mg, or 1000mg, or 1250mg, or 1350mg, or 1500mg, or 1700mg, or 1750mg, or 2000mg; When the compound A and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 24 mg, the metformin and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition may be 500 mg, or 750 mg, or 850 mg, or 1000mg, or 1250mg, or 1350mg, or 1500mg, or 1700mg, or 1750mg, or 2000mg.

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.

The above purpose of the invention is achieved by adopting the following technical solutions:

A method for preparing the aforementioned pharmaceutical composition comprises the step of mixing compound A and/or its salt with metformin and/or its pharmaceutically acceptable salt.

The mixing of the compound A and/or its salt with metformin and/or its pharmaceutically acceptable salt is a direct physical mixing of the two; the physical mixing method includes, but is not limited to, a direct mixing method and an equal incremental method; The equipment used for the physical mixing can be a conventional powder mixing equipment, preferably a V-type mixer.

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

One aspect of the present invention relates to a fixed-dose combination dosage form of Compound A or its pharmaceutically acceptable salt and metformin or its pharmaceutically acceptable salt 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, dripping pills, granules, granules, sustained release pellets or other oral dosage forms, and the like. A specific solid dosage form relates to a tablet containing a fixed-dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.

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

Another aspect of the present invention provides the use of the pharmaceutical composition of the present invention in the treatment of type 2 diabetes mellitus in mammals including humans, and the use includes administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a subject in need of the treatment.

Pharmaceutically acceptable salts of compound A or metformin include, but are not limited to, p-toluenesulfonate, benzoate, methanesulfonate, benzenesulfonate, phosphate, hydrochloride, sulfate, nitrate, di Phosphate, hydrobromide, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, palmitate, naphthalenesulfonate Acid salt, hydroxynaphthoate, laurate, lactate, malate, camphorsulfonate, ethanesulfonate, gluconate, glutamate, isethionate, mandelate , Pamoate (pamoate), mucate and pantothenate.

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

The pharmaceutical composition of the present invention is prepared by a wet granulation method, a dry granulation method, or a powder direct compression method.

In one embodiment, the pharmaceutical composition is prepared by a wet granulation method. In one such embodiment, the pharmaceutical composition is prepared by 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 providing tablets with higher radial strength.

The pharmaceutical composition obtained by the powder direct compression method, dry granulation method, or wet granulation method can be compressed into tablets, packaged or metered into sachets.

In a specific embodiment of the present invention, the pharmaceutical composition comprises (1) Compound A or its pharmaceutically acceptable salt, which is the first active pharmaceutical ingredient; (2) Metformin or its salt such as hydrochloride, is the second Kinds of active pharmaceutical ingredients; and (3) one or more pharmaceutically acceptable excipients.

The pharmaceutically acceptable excipients include binders, fillers, disintegrants, surfactants, lubricants, plasticizers, preservatives, flavoring agents, solubilizers, colorants, dispersants, sunscreens, and release agents. One or a mixture of two or more of the above-mentioned substances in speed modifiers, etc.

The binder includes, but is not limited to, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch slurry (such as corn starch slurry), sodium carboxymethyl cellulose, methyl cellulose, ethyl fiber Vegetarian, polyethylene glycol (such as PEG4000, PEG6000), gelatin solution, sucrose solution.

The fillers include, but are not limited to, microcrystalline cellulose, lactose, mannitol, starch (such as compressible starch), dextrin, sucrose, calcium bicarbonate, calcium sulfate, calcium sulfate dihydrate. The filler can be used alone or in a mixture of two types.

The disintegrant can be a conventional disintegrant, such as croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, dry starch, etc., or It is a new type of disintegrant. The disintegrant can be used alone, or two or more different disintegrants can be used in combination.

The surfactant can be an anionic, cationic or neutral surfactant. Anionic surfactants include sodium lauryl sulfate, sodium lauryl sulfonate, sodium oleyl sulfate, and sodium laurate mixed with stearate and talc. Cationic surfactants include benzalkonium chloride and alkyl trimethyl ammonium bromide. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and sorbitan ester. Embodiments of the wetting agent include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene stearates.

The lubricant includes, but is not limited to, stearic acid, sodium stearyl fumarate, magnesium stearate and other stearates, talc, micronized silica gel, sodium lauryl sulfate, hydrogenated vegetable oil (such as hydrogenated castor oil) , Glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate, pregelatinized starch (starch1500).

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

The preservatives include, but are not limited to, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, sodium potassium sorbate, calcium propionate, sodium propionate, paraben, isopropyl paraben.

The correctives include sweeteners, fragrances, glues and effervescent agents, wherein the sweeteners can be sucrose, stevioside, monosyrup, aromatic syrup, glycerin, sorbitol, sodium saccharin, and protein sugar; The mucilage agent 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, and sodium bicarbonate.

The solubilizing agent includes, but is not limited to, sorbitan fatty acids, polysorbates, polyoxyethylene fatty acid esters, phospholipids, cholesterol, stearates (such as sodium stearate), oleates (such as sodium oleate) , Sodium lauryl sulfate, sodium dodecyl sulfonate.

The coloring agent includes but not limited to beet red, carmine, carotene, lemon yellow, pine leaf blue, sodium copper chlorophyllin, caramel, aluminum lake, yellow iron oxide, brilliant blue.

The dispersing agents include, but are not limited to, sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, silicates, triethylhexyl phosphoric acid, methylpentanol, cellulose derivatives, polyacrylamide, Gol Gum, fatty acid polyethylene glycol ester.

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

The release rate regulator is selected from sucrose, sodium chloride, surfactant, polyethylene glycol (PEG).

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 a person of ordinary skill in the art, the above-mentioned auxiliary materials can be appropriately used according to the ordinary technical knowledge and common knowledge that they have mastered, and the present invention will not be further described.

The pharmaceutical composition can be prepared into a dosage form suitable for oral administration, such as: tablets (including ordinary tablets and coated tablets), buccal tablets, throat relievers, aqueous or oily suspensions, dispersible powders or Granules, emulsions, hard or soft capsules, syrups, pills, freeze-dried powders or tinctures. It can also be prepared into injections and creams, gels, ointments, emulsions, solutions, lotions, suspensions, tinctures, pastes, foams, aerosols, enemas, sprays suitable for topical administration. Suppositories, etc.

The metformin or its salt such as hydrochloride of the present invention may be released immediately or slowly, and compound A or its salt may be released immediately or slowly.

The present invention also provides a method for treating mammals including human type 2 diabetes by oral administration of a therapeutically effective amount of a fixed-dose combination pharmaceutical composition of the present invention to a subject in need of the treatment. In one embodiment, the subject in need of the treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet, but may also be in the form of a capsule.

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

Synthesis method of compound A of the present invention

The synthetic method of compound A was prepared according to the method described in Example 18 of PCT/CN2010/080370, so this disclosure is taken as a reference.

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

1. Provide a combination of compound A and/or its salt and metformin and/or its salt with pharmaceutical prospects, which can reduce blood sugar by limiting the mass ratio of compound A and/or its salt to metformin and/or its salt Synergistic effect is conducive to improving the hypoglycemic effect and reducing adverse drug reactions;

2. A method for preparing the aforementioned pharmaceutical composition is provided, which has simple steps and strong operability, and can realize industrial production to prepare the aforementioned pharmaceutical composition.

Therefore, the pharmaceutical composition of the present invention is more suitable for development as an excellent medicine for treating type II diabetes, which can be applied to the clinic, effectively guarantee the quality of the product, and provide a good guarantee for the safety and effectiveness of the medication.

detailed description

The present invention will be further described in detail below in conjunction with examples, but the implementation of the invention is not limited thereto. The doses of compound A benzoate used in the present invention are all based on compound A, and the doses of metformin hydrochloride are all based on metformin hydrochloride.

Example 1 Preparation of compound A benzoate-metformin hydrochloride composition

Add compound A benzoate (0.015 kg, calculated as compound A) into the V-type mixing cylinder, add metformin hydrochloride (1.25 kg), and mix for 30 minutes to obtain compound A benzoate-hydrochloric acid with a mass ratio of 6:500 Metformin pharmaceutical composition.

The same method can be used to prepare compound A benzoate-metformin hydrochloride pharmaceutical compositions with other mass ratios, such as compound A benzoate-metformin hydrochloride drugs with mass ratios of 6:125, 6:250, 6:850, etc. combination.

The same method is used to prepare a compound pharmaceutical composition of alogliptin benzoate\metformin with a mass ratio of 6:125.

Example 2 Pharmacodynamic experimental study

2.1. Laboratory animals and equipment

Male ICR mice, general grade, weighing 17-20g, animal source: purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

2.2. Animal grouping and handling

300 ICR mice were adaptively reared for one week and the experiment started, and 280 were selected for this experiment. After fasting for 5 hours, they were randomly divided into 28 groups according to body weight and blood glucose base value, with 10 animals in each group. The dosage design is shown in Table 2-1.

Table 2-1 Animal experiment grouping table

Remarks: The administration volume is 5mL/kg.

2.3. Experimental method

Each group of mice was orally orally administered with double distilled water, single drugs, and compound drugs in different proportions (see Table 2-1 for specific dosages). After 60 minutes, each group of mice received oral glucose 2.5g/kg. A small amount of blood was taken from the tail vein of the mice at 0, 15, 30, 60, and 120 minutes after the administration of glucose. The blood glucose changes of the mice were detected by the Roche blood glucose meter, and 120 minutes after the glucose load was calculated. The area under the blood glucose curve AUC _{0-120min Glu} (mmol/L.hr) decreasing rate and synergistic effect.

AUC _{0-120min Glu} decrease rate=(AUC _{0-120min Glu} blank control group-AUC _{0-120min Glu} administration group)/AUC _{0-120min Glu} blank control group×100%

Synergistic effect = _{reduction rate of compound drug AUC 0-120min Glu-} (compound A benzoate AUC _{0-120min Glu} reduction rate + metformin hydrochloride AUC _{0-120min Glu} reduction rate)

The statistical results of the blood glucose inhibition rate of ICR mice in each experimental group are shown in Table 2-2, and the results are expressed as "each group mean ± standard deviation". GraphPad Prism 6.0 statistical software was used to analyze the data of each group, and the one-way analysis of variance test method (Dunnett multiple comparison test) was used to compare whether there were statistical differences between the administration groups. When p<0.05, it is statistically significant.

Table 2-2 The blood glucose inhibition rate _{of AUC 0-120min Glu} after glucose load in ICR mice (n=10)

Note: Compared with the model group, *P<0.05, **P<0.01.

Draw the dose-effect relationship curve of the compound A benzoate and metformin hydrochloride single-drug data respectively, compare the theoretical inhibition rate with the experimental study on the area under the blood glucose time curve of ICR mice, and explore the best dose after the two drugs are combined. The results are shown in Tables 2-3 and 2-4.

Table 2-3 Comparison of the area under the blood glucose-time curve inhibition rate (%) and theoretical inhibition rate (%)

Table 2-4 Synergistic results of compound A benzoate and metformin hydrochloride in different dosage ratios (experimental value-theoretical value)

Remarks: Synergy ≥5%, indicating that the proportion has synergistic effect.

The results show that compound A benzoate and metformin hydrochloride can produce synergistic effects after combined use in the ratio of 1:20～:1:350. In the experimental dose range, compound A benzoate 0.3 mg/kg + metformin hydrochloride 21.25 mg/kg group, compound A benzoate 0.15 mg/kg + metformin hydrochloride 37.5 mg/kg group, compound A benzoate 0.15 mg/kg + metformin hydrochloride 50 mg/kg group, compound A benzal The salt acid salt 0.6mg/kg+ metformin hydrochloride 50mg/kg group has a higher synergistic potential.

Compound A benzoate 0.6 mg/kg + metformin hydrochloride 200 mg/kg group drug dose ratio combination (6:2000) has a synergistic effect of -8%, mainly because the hypoglycemic effect of this dose ratio combination has reached the drug effect platform. It failed to show a synergistic effect, but the same dose ratio combination (compound A benzoate 0.15 mg/kg + metformin hydrochloride 50 mg/kg group) had a synergistic effect of 9%, indicating that this ratio has a synergistic effect.

Example 3 Comparative Experimental Study

3.1. Laboratory animals and equipment

Male ICR mice, general grade, weighing 17-20g, animal source: purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

3.2. Animal grouping and handling

70 ICR mice were adaptively reared for one week and the experiment was started, and 60 mice were selected for this experiment. After fasting for 5 hours, they were randomly divided into 6 groups according to body weight and blood glucose base value, with 10 animals in each group. The dosage design is shown in Table 3-1.

Table 3-1 Animal experiment grouping and dosing table

Group	Dosage (mg/kg)*	Dosing frequency	Route of administration
Control group	—	single	Intragastric administration
Compound A Benzoate	0.6	single	Intragastric administration
Alogliptin Benzoate	0.6	single	Intragastric administration
Metformin Hydrochloride	21.25	single	Intragastric administration
Compound A benzoate + metformin hydrochloride	0.6+21.25	single	Intragastric administration
Alogliptin Benzoate + Metformin Hydrochloride	0.6+21.25	single	Intragastric administration

Note: *: The combination is administered in two doses, and the volume of each administration is 5 mL/kg.

The experimental method is the same as 2.3 experimental method.

The statistical results of the blood glucose inhibition rate and synergy of ICR mice in each experimental group are shown in Table 3-2.

Table 3-2 The blood glucose inhibition rate _{of AUC 0-120min} Glu after glucose load in ICR mice (n=10)

Note: Compared with the model group, *P<0.05, **P<0.01.

Dose-effect relationship curves were drawn on the data of compound A benzoate and metformin hydrochloride, and compared the theoretical inhibition rate with the experimental study on the area under the blood glucose time curve of ICR mice, and explored the optimal dose after the two drugs were used in combination. The results are shown in Tables 3-3 and 3-4.

Table 3-3 Comparison of the area under the blood glucose-time curve inhibition rate (%) and theoretical inhibition rate (%)

Table 3-4 Synergy results (experimental value-theoretical value)

Remarks: Synergy ≥5%, indicating that the proportion has synergistic effect.

The results showed that the combined administration of compound A benzoate\metformin hydrochloride (6:125) and the combined administration of alogliptin benzoate\metformin (6:125) had synergistic effects of 8.0% and 5.0%, respectively. Compound A benzene The formate\metformin hydrochloride shows a more significant synergistic effect, which is better than alogliptin benzoate\metformin hydrochloride.

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, etc. made without departing from the spirit and principle of the present invention Simplified, all should be equivalent replacement methods, and they are all included in the protection scope of the present invention.

Claims (12)

1. A hypoglycemic pharmaceutical composition, characterized in that the pharmaceutical composition is composed of compound A and/or its pharmaceutically acceptable salt, and metformin and/or its pharmaceutically acceptable salt, wherein the compound A or its pharmaceutically acceptable salt The weight ratio of the above acceptable salt to metformin or its pharmaceutically acceptable salt is 1:20 to 1:350.
2. The hypoglycemic pharmaceutical composition according to claim 1, wherein the compound A and/or its pharmaceutically acceptable salt contains compound A in the hypoglycemic pharmaceutical composition, or contains compound A which is pharmaceutically acceptable The accepted salt, or a mixture containing Compound A and Compound A, or a pharmaceutically acceptable salt thereof, is mixed in any ratio.
3. The hypoglycemic pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of the compound A and/or its pharmaceutically acceptable salt to metformin and/or its pharmaceutically acceptable salt is 6: 125, 6: 212.5, 6: 250, 6: 375, 6: 425, 6: 500, 6: 750, 6: 850, 6: 1000, 6: 1500, 6: 2000.
4. The hypoglycemic pharmaceutical composition according to any one of claims 1-3, wherein the daily human dosage of the compound A and/or its pharmaceutically acceptable salt is 6-24 mg, metformin and/or The daily human dosage of the pharmaceutically acceptable salt is 250-2000 mg.
5. The hypoglycemic pharmaceutical composition according to any one of claims 1 to 4, characterized in that the hypoglycemic pharmaceutical composition is divided according to clinical administration doses and prepared into specific specifications of administration units, and the administration The pharmaceutical unit may contain 6 mg, or 12 mg, or 18 mg, or 24 mg of Compound A and/or its pharmaceutically acceptable salt, and 250 mg, or 500 mg, or 750 mg, or 850 mg, or 500 mg, or 750 mg, or 850 mg of metformin and/or its pharmaceutically acceptable salt. Or 1000 mg, or 1250 mg, or 1350 mg, or 1500 mg, or 1700 mg, or 1750 mg, or 2000 mg.
6. The hypoglycemic pharmaceutical composition according to any one of claims 1 to 5, wherein when the specific content of compound A and/or its pharmaceutically acceptable salt in the administration unit is 12 mg, metformin and/ The specific content of its pharmaceutically acceptable salt is 500 mg, or 850 mg, or 1000 mg.
7. The hypoglycemic pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt is selected from the group consisting of p-toluenesulfonate, benzoate, methanesulfonate, benzenesulfonate, Phosphate, hydrochloride, sulfate, nitrate, diphosphate, hydrobromide, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, lemon Acid salt, citrate, palmitate, naphthalenesulfonate, hydroxynaphthoate, laurate, lactate, malate, camphorsulfonate, ethanesulfonate, gluconate, Glutamate, isethionate, mandelate, pamoate (pamoate), mucate or pantothenate.
8. The hypoglycemic pharmaceutical composition according to any one of claims 1-7, wherein the hypoglycemic pharmaceutical composition is a tablet, a hard capsule, a soft capsule, an oral solution, a sustained-release agent, a dripping pill, and an infusion , Granules, sustained-release pellets or other oral dosage forms.
9. The hypoglycemic pharmaceutical composition according to any one of claims 1-8, wherein the metformin or a pharmaceutically acceptable salt thereof is released immediately or slowly.
10. The hypoglycemic pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition is administered once a day, twice a day or three times a day.
11. A method for preparing the hypoglycemic pharmaceutical composition according to any one of claims 1-10, wherein the method is wet granulation, dry granulation or direct powder compression.
12. The use of the hypoglycemic pharmaceutical composition according to any one of claims 1-11 in the preparation of drugs for treating diabetes in mammals including humans.