Drug combination containing glucokinase activator and SGLT-2 inhibitor, preparation method and use thereof

Abstract

The present invention relates to a drug combination, which comprises a glucokinase activator or a pharmaceutically acceptable salt thereof, an isotope-labeled substance thereof, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof and an SGLT-2 inhibitor. The present invention further relates to a pharmaceutical composition, a fixed-dose compound preparation, and a preparation method and use of the pharmaceutical composition and the fixed-dose compound preparation.

Description

[0001] This application is a divisional application of an invention patent application with an application date of May 28, 2019, application number 201910453725.9, and invention name “Drug combination containing a glucokinase activator and an SGLT-2 inhibitor, and preparation method and use thereof”.

[0002] Priority claim

[0003] This application claims priority to Chinese invention patent application No. 201810556685.6, filed on May 31, 2018, the entire disclosure of which is incorporated herein by reference. Technical Field

[0004] The present invention relates to a drug combination, a composition and a fixed dose combination (FDC) preparation comprising a glucokinase activator (GKA) drug and a partner drug, a preparation method thereof and use thereof for treating certain diseases.

[0005] In a more detailed aspect, the present invention relates to a pharmaceutical combination, a pharmaceutical composition or a fixed-dose compound oral solid preparation comprising a glucokinase activator drug and a combination drug, and a method for preparing the same. The present invention also relates to the use of a pharmaceutical combination, a pharmaceutical composition or a fixed-dose compound preparation comprising a glucokinase activator for treating and / or preventing one or more diseases and medical conditions, including but not limited to type I diabetes, type II diabetes, diabetic nephropathy, renal impairment, impaired glucose tolerance, impaired fasting blood sugar, obesity and hypertension. In addition, the present invention also relates to a method for treating and / or preventing one or more diseases and medical conditions, comprising administering a therapeutically effective amount of the pharmaceutical combination, pharmaceutical composition or fixed-dose compound preparation of the present invention to a subject in need thereof. Background Art

[0006] Diabetes has become a common disease worldwide, with 425 million patients worldwide and 120 million in China (International Diabetes Federation, Diabetes Atlas, 2015). Type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), accounts for more than 90% of diabetic patients. Type II diabetes is a chronic metabolic dysfunction disease caused by hyperglycemia due to imbalance of blood sugar homeostasis caused by impaired insulin secretion and insulin resistance. The balance of blood sugar in the human body is mainly coordinated by two glucose-controlling hormones, insulin and glucagon.

[0007] The glucose sensor glucokinase (GK) senses changes in blood sugar and regulates the secretion of messenger glucose-controlling hormones, insulin and glucagon, as well as GLP-1 (glucagon-like peptide-1), forming a sensing system for regulating blood sugar homeostasis in the human body. Glucose reserves during glucose uptake and glucose supply during fasting controlled by glucose-controlling hormones constitute the regulation of blood sugar homeostasis in the human body. The organs involved in glucose storage are mainly liver, muscle and fat, which take up glucose under the action of blood sugar and insulin and convert it into liver glycogen, muscle glycogen and triglycerides. The main organ involved in glucose supply is the liver, which supplies glucose to the human body through glycogen synthesis and glycogen output under the action of blood sugar and glucagon. Insulin can also effectively regulate the activity of sodium-glucose cotransporter SGLT-2, and reabsorb glucose excreted by the kidneys when blood sugar rises, so that it can be used for glucose reserves in the human body. Glucose uptake and glycogen output, as well as the use of glucose by various organs, constitute the operating system for the balance of blood sugar homeostasis in the human body. The coordinated operation of the glucose sensing system and the operating system constitutes the random regulation of blood sugar homeostasis in the human body.

[0008] In diabetic patients, due to impaired function and expression of glucokinase, sensor dysfunction leads to early phase secretion disorder of glucose control hormone, affecting glucose uptake and output, resulting in postprandial hyperglycemia and preprandial hypoglycemia. Abnormal glucose control hormone signal instructions lead to abnormal function and expression of key proteins in the glucose uptake and output operation execution system, forming abnormal state operation and type II diabetes.

[0009] Existing oral hypoglycemic drugs for diabetes usually act on a single glucose-controlling organ and cannot effectively treat the problem of blood glucose homeostasis balance system disorders. Glucokinase activators represent a class of new drugs developed to treat or improve the disease state of patients with type II diabetes. For example, ((S)-2-[4-((2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (hereinafter referred to as HMS5552) can effectively improve the glucose sensor function of diabetic patients and is currently the most promising diabetes treatment drug to address the above clinical needs. Summary of the invention

[0010] Diabetic patients often encounter such a situation during treatment: the use of SGLT-2 inhibitors alone has poor efficacy and cannot control blood sugar at an ideal level, especially after using it for a period of time. In this regard, the inventors have found that combining SGLT-2 inhibitors with glucokinase activators can significantly improve the hypoglycemic effect of SGLT-2 inhibitors and reduce safety risks, thereby obtaining the drug combination, composition and compound preparation containing glucokinase activators and SGLT-2 inhibitors of the present invention.

[0011] More specifically, the combination of SGLT-2 inhibitors and glucokinase activators can improve the multi-organ function of patients in the middle and late stages, and more effectively treat diabetes and its accompanying diseases and complications; it can reduce the number of pills patients take and improve patient compliance; it reduces the total dose of drugs to achieve the same therapeutic effect, and achieves the maximum efficacy with the minimum dose, and has good effects and practical significance for the treatment or prevention of one or more symptoms of type 1 diabetes, type 2 diabetes, hyperglycemia, impaired glucose tolerance, obesity, etc.

[0012] On the other hand, the fixed-dose compound preparation containing a glucose kinase activator and a combination drug (a second or more active pharmaceutical ingredients) of the present invention not only has a better therapeutic effect than the use of these two or more drugs alone, but also solves the technical challenges commonly present in compound preparations. The fixed-dose compound preparation of the present invention can solve the problem of synchronous release and uniform content of two or more active ingredients, and can optimize the dissolution rate of the active ingredients contained in the preparation, especially allowing the active ingredients contained in the preparation to be quickly released in the small intestinal pH environment, which is beneficial for the drug to reach the target organs of the intestine, pancreatic islets and liver in a timely or simultaneous manner, achieving the clinical advantages of one target, multiple points and synergistic hypoglycemia, and playing a better therapeutic effect and reducing toxic and side effects. Secondly, the fixed-dose compound preparation containing a glucose kinase activator and a combination drug (a second or more active pharmaceutical ingredients) of the present invention also has a shorter disintegration time, and has good dissolution characteristics and / or enables the glucose kinase activator to have high bioavailability in patients.

[0013] The present invention provides a drug combination, a pharmaceutical composition, a fixed-dose compound preparation, especially a solid preparation, such as an oral solid preparation, such as a tablet, comprising a glucokinase activator, for example, HMS5552 having the structure shown below, or an isotope-labeled substance thereof, or a pharmaceutically acceptable salt thereof, and other oral hypoglycemic drugs.

[0014]

[0015] Specifically, the present invention also provides a drug combination, a pharmaceutical composition or a fixed-dose compound preparation comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and an SGLT-2 inhibitor. Further, examples of the SGLT-2 inhibitor include, but are not limited to, canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin, and pharmaceutically acceptable salts thereof. Preferably, the SGLT-2 inhibitor is selected from empagliflozin, dapagliflozin and canagliflozin.

[0016] More specifically, the present invention also provides a solid formulation of a fixed-dose combination comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a combination drug such as empagliflozin. The solid formulation is preferably a tablet, and more preferably a coated tablet. In one embodiment, the glucokinase activator such as HMS5552 is in the form of a solid dispersion.

[0017] More specifically, the present invention also provides a solid formulation of a fixed-dose combination comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a combination drug such as dapagliflozin. The solid formulation is preferably a tablet, and more preferably a coated tablet. In one embodiment, the glucokinase activator such as HMS5552 is in the form of a solid dispersion.

[0018] More specifically, the present invention also provides a solid formulation of a fixed-dose compound comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a combination drug such as canagliflozin (canagliflozin). The solid formulation is preferably a tablet, and more preferably a coated tablet. In one embodiment, the glucokinase activator such as HMS5552 is in the form of a solid dispersion.

[0019] The present invention also provides a drug combination, a pharmaceutical composition or a fixed-dose compound preparation of a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients) prepared by a dry or wet processing method. The release mode of the drug combination, the pharmaceutical composition or the fixed-dose compound preparation of the present invention is the rapid release of the two or more active pharmaceutical ingredients.

[0020] The present invention also provides a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients), which has a short disintegration time, has good dissolution characteristics and / or enables the glucokinase activator to have high bioavailability in patients. The present invention also provides a method for preparing a pharmaceutical composition or pharmaceutical preparation of a fixed dose combination of a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients, such as empagliflozin, dapagliflozin, canagliflozin) by a dry or wet processing method. Dry processing methods include dry compression (tabletting) and dry granulation; wet processing methods include wet granulation.

[0021] The present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients), as well as a method for preventing metabolic disorders (especially type II diabetes), slowing down the progression thereof, delaying or treating the metabolic disorders.

[0022] The present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients), as well as a method for improving glycemic control in patients in need thereof (especially patients with type 2 diabetes).

[0023] The present invention also provides drug combinations, pharmaceutical compositions or pharmaceutical preparations comprising the glucokinase activator drugs and the combination drugs, as well as methods for improving glycemic control in patients with inadequate glycemic control.

[0024] The present invention also provides a drug combination, a drug composition or a drug preparation comprising a glucokinase activator drug and a combination drug, as well as a method for preventing, slowing down or delaying the progression of diabetic nephropathy, renal dysfunction, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hypertension, insulin resistance and / or metabolic syndrome to type II diabetes.

[0025] The present invention also provides drug combinations, drug compositions and drug preparations comprising the glucokinase activator drugs and the combination drugs, as well as methods for preventing diseases or conditions including diabetic complications, slowing down their progression, delaying or treating the diseases or conditions.

[0026] Other objects of the present invention will be apparent to those skilled in the art from the above and below descriptions as well as from the embodiments. SUMMARY OF THE INVENTION

[0028] The first aspect of the present invention provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising the following components, and a preparation method and use thereof for treating diabetes and related diseases:

[0029] (a) a glucokinase activator, which is a compound selected from the following, or a pharmaceutically acceptable salt, an isotope-labeled substance, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof; preferably, the glucokinase activator is HMS5552; ​​more preferably, HMS5552 is in the form of a solid dispersion,

[0030]

[0031] (b) SGLT-2 inhibitors; and

[0032] (c) one or more excipients.

[0033] Another aspect of the present invention provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising the following components, and a preparation method and use thereof for treating diabetes and related diseases:

[0034] (a) a glucokinase activator, which is selected from a compound of HMS5552, or a pharmaceutically acceptable salt thereof, an isotope-labeled substance thereof, a crystalline form thereof, a hydrate, a solvate, a diastereomer or an enantiomer thereof; preferably, the glucokinase activator is HMS5552; ​​more preferably, HMS5552 is in the form of a solid dispersion;

[0035] (b) empagliflozin, dapagliflozin, canagliflozin, or pharmaceutically acceptable salts, isotope-labeled products, crystalline forms, hydrates, solvates, diastereomers or enantiomeric forms thereof; and

[0036] (c) one or more excipients.

[0037] In particular, one aspect of the present invention also relates to a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation containing a fixed-dose combination of HMS5552 solid dispersion and a combination drug (e.g., empagliflozin, dapagliflozin, canagliflozin), and a preparation method and use thereof.

[0038] definition

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; however, in the event of any conflict, the definitions in this specification shall prevail.

[0040] As used in the specification and claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0041] Unless otherwise specified, all percentages (%) in this specification are weight percentages (wt %).

[0042] All numerical values ​​or expressions used in the specification and claims relating to component amounts, process conditions, etc. should be understood to be modified by "about" in all cases. The term "about" when referring to an amount or a numerical range means that the indicated amount or numerical range is an approximation within the experimental variability (or within the statistical experimental error), so the amount or numerical range can vary between, for example, ±5 of the amount or numerical range.

[0043] All ranges involving the same component or property include endpoints, which can be independently combined. Since these ranges are continuous, they include every value between the minimum and maximum values. It should also be understood that any numerical range cited in the application is intended to include all subranges within the range.

[0044] When the invention is defined with respect to physical properties such as molecular weight or with respect to chemical properties in ranges, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "comprising" (and related terms such as "containing" or "including" or "having" or "including") includes embodiments such as any combination of substances, compositions, methods or processes, etc., which "consists of" or "consists essentially of" the described features.

[0045] "And / or" as used in this specification and claims should be understood as "either or both" of the associated components, that is, the components exist jointly in some cases and separately in other cases. Multiple components listed with "and / or" should be understood in the same way, that is, "one or more" associated components. In addition to the components specifically identified by the "and / or" clause, other components may optionally be present, whether related or unrelated to those specifically identified components. Therefore, as a non-limiting example, reference to "A and / or B", when used in conjunction with open-ended text such as "comprising", in one embodiment, may refer to only A (optionally including components other than B); in another embodiment, may refer to only B (optionally including components other than A); in yet another embodiment, refers to A and B (optionally including other components), etc.

[0046] It should be understood that in any method claimed herein that includes more than one step or act, the order of the method steps and acts is not necessarily limited to the order of the method steps and acts recited unless explicitly indicated to the contrary.

[0047] The abbreviations used herein have their usual meanings in the fields of chemistry, biology and pharmaceutical preparation.

[0048] Unless otherwise indicated, the term "SGLT-2 inhibitor" or any species thereof (such as "empagliflozin", "canagliflozin", "dapagliflozin") in the context of the present invention is also intended to include any pharmaceutically acceptable salt, crystalline form, hydrate, solvate, diastereomer or enantiomer thereof.

[0049] HMS5552, formerly known as RO5305552, its English name is Dorzagliatin, and its chemical name is (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide.

[0050] Unless otherwise indicated, weight % (wt %) is expressed as a percentage of the total weight of a pharmaceutical combination, composition or formulation.

[0051] Solid dispersion (SD) refers to a solid dispersion system formed by highly dispersing one or more active pharmaceutical ingredients into inactive excipients or carriers.

[0052] EUDRAGIT is the trade name of synthetic pharmaceutical excipients, which include methacrylic acid copolymers and methacrylate copolymers, commonly known as polyacrylic acid resins. Polyacrylic acid resin excipients are divided into different types according to their composition, proportion and degree of polymerization. Among them, Eudragit E is a polymer of dimethylaminoethyl methacrylate and methacrylate; Eudragit L is a polymer of methacrylic acid and methyl methacrylate, with free carboxyl group: ester = 1:1, and Eudragit S is a polymer of methacrylic acid and methyl methacrylate, with free carboxyl group: ester = 1:2.

[0053] As used herein, the term "tablet" is intended to include compressed pharmaceutical preparations of all shapes and sizes, whether coated or not.

[0054] The term "effective amount" or "therapeutically effective amount" refers to the amount of an agent sufficient to provide a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use refers to the amount of a composition comprising a compound as an active ingredient of the invention required to clinically significantly reduce the disease. In any individual case, an appropriate "effective" amount can be determined by a person of ordinary skill in the art using routine experimentation. Thus, the expression "effective amount" generally refers to the amount of an active substance when it has a therapeutic effect.

[0055] The terms "treat" or "treatment" used herein are synonymous with the term "prevent" and are intended to mean delaying the development of a disease, preventing the development of a disease, and / or reducing the severity of the symptoms that will develop or are expected to develop. Thus, these terms include improving existing disease symptoms, preventing additional symptoms, improving or preventing potential metabolic causes of symptoms, inhibiting a disorder or disease, e.g., preventing the development of a disorder or disease, alleviating a disorder or disease, regressing a disorder or disease, alleviating a condition caused by a disease or disorder, or stopping symptoms of a disease or disorder.

[0056] "Pharmaceutically acceptable" or "pharmacologically acceptable" refers to a substance that is not biologically or otherwise substantially undesirable, i.e., the substance can be administered to a subject without causing any undesirable biological effect or interacting in a deleterious manner with any other components of a composition in which it is contained.

[0057] The term "subject" as used herein includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human.

[0058] The compound as an active ingredient in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (e.g., fixed-dose combination preparation) containing a glucokinase activator of the present invention can form a salt. Unless otherwise specified, when referring to the compound in the present application, it should be understood that it includes reference to its salt. The term "salt (one or more)" used in the present application refers to acid salts formed with inorganic and / or organic acids and basic salts formed with inorganic and / or organic bases. In addition, when the compound contains a basic part (e.g., but not limited to, pyridine or imidazole) and an acidic part (e.g., but not limited to, carboxylic acid), zwitterions ("inner salts") can be formed and the zwitterions ("inner salts") are included in the term "salt (one or more)" used in the present application. It is preferably a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt, but other salts are also useful. The salt of the compound can be formed, for example, by the following method: reacting the compound with a certain amount (e.g., an equal amount) of an acid or a base in a medium, the medium being, for example, a medium in which the salt is precipitated or an aqueous medium (lyophilized after the reaction).

[0059] Polymorphic forms of the various compounds and their salts, solvates, esters and prodrugs are intended to be included in the present invention.

[0060] It should be understood that the terminology used herein is for the purpose of describing specific embodiments and is not intended to be limiting. In addition, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods, devices and materials are described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 Effects of empagliflozin alone and HMS5552 combined with empagliflozin on blood glucose after glucose load in normal mice ( n=10);

[0062] Figure 2 The AUC of empagliflozin alone and HMS5552 combined with empagliflozin after glucose load in normal mice 0-120min Impact n=10;***, P<0.001). DETAILED DESCRIPTION OF THE INVENTION

[0063] One aspect of the present invention relates to a drug combination, a pharmaceutical composition or a pharmaceutical preparation such as a fixed-dose combination preparation of a glucokinase activator (preferably HMS5552 or an isotope label or a pharmaceutically acceptable salt thereof) and a combination drug (e.g., empagliflozin, dapagliflozin, canagliflozin). The preparation may be a powder, granule, tablet, capsule, pouch or other solid form, etc. Specifically, one aspect of the present invention relates to a tablet containing a fixed-dose combination of a glucokinase activator and a combination drug (e.g., empagliflozin, dapagliflozin, canagliflozin).

[0064] In a specific aspect of the invention, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprises:

[0065] (1) a glucokinase activator or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof, or a crystalline form, hydrate, solvate, diastereomer or enantiomeric form thereof; preferably, the glucokinase activator is preferably HMS5552; ​​more preferably, HMS5552 is in the form of a solid dispersion, such as a solid dispersion containing a polymer carrier (e.g., a spray-dried powder);

[0066] (2) SGLT-2 inhibitors; preferably, they are selected from: empagliflozin, dapagliflozin, canagliflozin, or pharmaceutically acceptable salts, isotope-labeled substances, crystalline forms, hydrates, solvates, diastereomers or enantiomeric forms thereof; and / or

[0067] (3) fillers; and / or

[0068] (4) adhesive; and / or

[0069] (5) disintegrant; and / or

[0070] (6) lubricants or glidants; and / or

[0071] (7) Coating agent.

[0072] In one embodiment of the present invention, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation may also contain one or more excipients selected from one or more binders; one or more diluents (fillers); one or more disintegrants; one or more lubricants; one or more glidants; one or more surfactants or wetting agents; and one or more antioxidants; and one or more coating agents.

[0073] Drug combination, pharmaceutical composition or pharmaceutical preparation

[0074] Glucokinase activator + SGLT-2 inhibitor

[0075] In one embodiment, the present invention relates to a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation (preferably a fixed-dose combination preparation) comprising:

[0076] (a) a glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof, or a crystalline form, hydrate, solvate, diastereomer or enantiomeric form thereof

[0077]

[0078] (b) SGLT-2 inhibitors;

[0079] Preferably, examples of the SGLT-2 inhibitor include, but are not limited to, Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin, Luseogliflozin and Tofogliflozin, or pharmaceutically acceptable salts thereof;

[0080] More preferably, the SGLT-2 inhibitor is selected from empagliflozin, dapagliflozin and canagliflozin;

[0081] (c) one or more excipients;

[0082] The above drugs (a) and (b) are used simultaneously, separately or sequentially.

[0083] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is about 30:1 to 1:30, preferably about 20:1 to 1:12, and more preferably about 0.75:1, about 1:2, about 1:1, about 1:4, about 1:6, about 1:12, about 2:1, about 2.5:1, about 3:1, about 5:1, about 6:1, about 7.5:1, about 10:1, about 15:1 or about 20:1.

[0084] In one embodiment, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucokinase activator is present in a dosage (preferably a unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg. Preferably, the dosage (preferably a unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0085] In one embodiment, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, the SGLT-2 inhibitor is present in a dosage (preferably unit dose) range of about 1 mg to 500 mg, preferably about 5 mg to about 300 mg, preferably, wherein the dosage (preferably unit dose) of the SGLT-2 inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 100 mg, about 200 mg or about 300 mg, most preferably about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 100 mg or about 300 mg; preferably, the SGLT-2 inhibitor is empagliflozin, Its dosage (preferably unit dosage) is about 0.5 mg to about 50 mg, especially about 1 mg to about 25 mg; its preferred dosage is about 5 mg, about 10 mg, about 12.5 mg and about 25 mg; preferably, the SGLT-2 inhibitor is dapagliflozin, and its dosage (preferably unit dosage) is about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg; preferably, it is about 2.5 mg, about 5 mg and about 10 mg; preferably, the SGLT-2 inhibitor is canagliflozin, and its dosage (preferably unit dosage) is about 50 mg to about 500 mg, and the preferred dosage of canagliflozin is about 100 mg and about 300 mg.

[0086] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the above-mentioned glucose kinase activator is compound HMS5552, or an isotope-labeled substance thereof, or a pharmaceutically acceptable salt thereof.

[0087]

[0088] In one embodiment, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucokinase activator is in the form of a solid dispersion.

[0089] In one embodiment, the solid dispersion is obtained by spray drying, hot melting or freeze drying the glucokinase activator, or its isotope label, or its pharmaceutically acceptable salt together with a polymer carrier.

[0090] In one embodiment, the content of the glucokinase activator in the solid dispersion can vary from about 1 wt % to about 99 wt %, preferably 10 wt % to 90 wt %, based on the total weight of the solid dispersion. In one embodiment, the content of the glucokinase activator ranges from about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt %, about 15 wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19 wt %, about 20 wt %, about 21 wt %, about 22 wt %, about 23 wt %, about 24 wt %, about 25 wt %, about 26 wt %, about 27 wt %, about 28 wt %, about 29 wt %, about 30 wt %, about 31 wt %, about 32 wt %, about 33 wt %, about 34 wt %, about 35 wt %, about 36 wt %, about 37 wt %, about 38 wt %, about 39 wt %, about 40 wt %, about 41 wt %, about 42 wt %, about 43 wt %, about 44 wt %, about 45 wt %, about 46 wt %, about 47 wt %, about 48 wt %, about 49 wt %, about 50 wt %, about 51 wt %, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, about 60 wt%, about 61 wt%, about 62 wt%, about 63 wt%, about 64 wt%, about 65 wt%, about 66 wt%, about 67 wt%, about 68 wt%, about 69 wt%, about 70 wt%, about 71 wt%, about 72 wt%, about 73 wt%, about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, about 83 wt%, about 84 wt%, about 85 wt%, about 86 wt%, about 87 wt%, about 88 wt%, about 89 wt%, about 90 wt%, about 91 wt%, about 92 wt%, about 93 wt%, about 94 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, about 99 wt%, about 100 wt%, about 101 wt%, about 102 wt%, about 103 wt%, about 104 wt%, about 105 wt%, about 106 wt%, about 107 wt%, about 108 wt%, about 109 wt%, about 110 %, about 76 weight %, about 77 weight %, about 78 weight %, about 79 weight %, about 80 weight %, about 81 weight %, about 82 weight %, about 83 weight %, about 84 weight %, about 85 weight %, about 86 weight %, about 87 weight %, about 88 weight %, about 89 weight %, about 90 weight %, about 91 weight %, about 92 weight %, about 93 weight %, about 94 weight %, about 95 weight %, about 96 weight %, about 97 weight %, about 98 weight %, or about 99 weight %, or any range therebetween.

[0091] In one embodiment, the content of the glucokinase activator in the solid dispersion is about 1 wt % to about 20 wt %, about 2 wt % to about 40 wt %, about 30 wt % to about 60 wt %, about 60 wt % to about 80 wt %, about 70 wt % to about 90 wt %, or about 80 wt % to about 100 wt %, based on the total weight of the solid dispersion.

[0092] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucokinase activator is in the form of a solid dispersion, and in the solid dispersion, the weight ratio of the solid dispersion of the glucokinase activator to the SGLT-2 inhibitor is about 60:1 to 1:15, preferably about 40:1 to 1:6, more preferably about 1.5:1, about 1:1, about 2:1, about 1:2, about 1:3, about 1:6, about 4:1, about 5:1, about 6:1, about 10:1, about 12:1, about 15:1, about 20:1, about 30:1 or about 40:1 or any range therebetween.

[0093] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucose kinase activator is compound HMS5552, its isotope label or a pharmaceutically acceptable salt thereof, which is prepared together with a polymer carrier by spray drying, hot melting or freeze drying to obtain a solid dispersion.

[0094] In one embodiment, the polymer carrier in the solid dispersion in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is selected from a polypropylene resin polymer, which is a polymer compound formed by polymerizing acrylic acid (or methacrylic acid and their esters such as methyl ester, ethyl ester, etc.) in bulk (one monomer), or copolymerizing with methacrylic acid (or its esters such as methyl ester, ethyl ester, dimethylaminoethyl ester, etc.) in two monomers (binary) or three monomers (ternary) in a certain proportion.

[0095] In one embodiment, the polymer carrier used in the solid dispersion in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is selected from butyl methacrylate, copolymers of dimethylaminoethyl methacrylate and methyl methacrylate, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methyl methacrylate, copolymers of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride, copolymers of ethyl acrylate and methyl methacrylate, copolymers of methacrylic acid, methyl acrylate and methyl methacrylate, and copolymers of methacrylic acid and butyl acrylate.

[0096] In one embodiment, the above-mentioned polymer carrier is selected from butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1) copolymer, methacrylic acid and ethyl acrylate (1:1) copolymer, methacrylic acid and methyl methacrylate (1:2) copolymer, ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.2) copolymer, ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.1) copolymer, ethyl acrylate and methyl methacrylate (2:1) copolymer, methacrylic acid and butyl acrylate (35:65) copolymer, methacrylic acid and methyl methacrylate (1:1) copolymer, methacrylic acid and methyl methacrylate (35:65) copolymer.

[0097] In one embodiment, the polymer carrier is Eudragit, including Eudragit E, Eudragit L, Eudragit S, Eudragit RL and Eudragit RS, wherein Eudragit E is copolymerized with dimethylamino methacrylate and other neutral methacrylates, including polymers of dimethylaminoethyl methacrylate and methacrylate; Eudragit L and Eudragit S are copolymerized with methacrylic acid and methacrylates in different proportions, including copolymers of methacrylic acid and methyl methacrylate, wherein the free carboxyl group: ester = 1:1, or copolymers of methacrylic acid and methyl methacrylate, wherein the free carboxyl group: ester = 1:2; Eudragit RL and Eudragit RS are copolymers of acrylic acid and methacrylate containing certain quaternary amine groups, including copolymers of acrylic acid and methacrylate containing 10% quaternary amine groups and copolymers of acrylic acid and methacrylate containing 5% quaternary amine groups.

[0098] In one embodiment, the polymer carrier is selected from:

[0099] Eudragit E100, which is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1), including Eudragit E PO;

[0100] Eudragit L100 is a methacrylic acid copolymer type A, which is an anionic copolymer of methacrylic acid and methyl methacrylate (1:1);

[0101] Eudragit S100, which is a copolymer of methacrylic acid and methyl methacrylate (1:2);

[0102] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the polymer carrier in the HMS5552 solid dispersion is methacrylic acid copolymer type A (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

[0103] In one embodiment, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the weight ratio of HMS5552 to Eudragit L100 in the HMS5552 solid dispersion is about 1:10 to 10:1, about 1:9 to 9:1, about 2:3 to 9:1, about 3:4 to 9:1, about 4:5 to 9:1, about 5:6 to 9:1 or about 1:1 to 9:1; about 2:3 to 4:1, about 3:4 to 4:1, about 4:5 to 4:1, about 5:6 to 4:1 or about 1:1 to 4:1; about 2:3 to 7:3, about 3:4 to 7:1, about 4:5 to 7:1, about 5:6 to 7:1 or about 1:1 to 7:1; 4 to 7:3, about 4:5 to 7:3, about 5:6 to 7:3, or about 1:1 to 7:3; about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4, or about 5:6 to 6:5; about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4, or about 5:6 to 6:5, or any range therebetween.

[0104] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the weight ratio of HMS5552 to Eudragit L100 in the HMS5552 solid dispersion is about 1:1, about 2:3, about 3:2, about 1:4, about 4:1, about 3:4, about 4:3, about 4:5, about 5:4, about 5:6, about 6:5, about 7:3, about 3:7, about 1:9, about 9:1, or any range therebetween.

[0105] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the second active ingredient is empagliflozin. The pharmaceutical composition or fixed-dose combination preparation of the above-mentioned glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and empagliflozin comprises, by weight, about 1 to 48% of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 1 to 35% of empagliflozin; about 0 to 90% of filler; about 1 to 10% of binder; about 1 to 10% of disintegrant; about 0.1 to 5% of lubricant; about 0 to 3% of glidant; and about 0 to 5% of coating agent. The pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is prepared by a wet granulation method or a dry granulation method, preferably by a wet granulation method.

[0106] In one embodiment, in the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and empagliflozin, the dosage (preferably unit dosage) of the glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dosage (preferably unit dosage) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dosage (preferably unit dosage) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween. The dosage (preferably unit dosage) of the more preferred glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) is about 25 mg, about 50 mg, about 75 mg, about 100 mg. Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation), HMS5552 is present in the form of a solid dispersion.

[0107] In one embodiment, in the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and empagliflozin, the dose (preferably unit dose) of empagliflozin is about 0.5 mg to about 50 mg, especially about 1 mg to about 25 mg. The preferred dose (preferably unit dose) of empagliflozin is about 5 mg, about 10 mg, about 12.5 mg and about 25 mg. Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 is present in the form of a solid dispersion.

[0108] In the pharmaceutical combination, pharmaceutical composition or fixed-dose compound preparation of the present invention, the specific embodiments of the dosage (preferably unit dosage) of HMS5552 (or its isotope label or pharmaceutically acceptable salt) and empagliflozin are as follows:

[0109] (1) approximately 75 mg of HMS5552 and approximately 5 mg of empagliflozin;

[0110] (2) approximately 75 mg of HMS5552 and approximately 10 mg of empagliflozin;

[0111] (3) approximately 75 mg of HMS5552 and approximately 12.5 mg of empagliflozin;

[0112] (4) approximately 75 mg of HMS5552 and approximately 25 mg of empagliflozin;

[0113] (5) approximately 50 mg of HMS5552 and approximately 10 mg of empagliflozin;

[0114] (6) approximately 50 mg of HMS5552 and approximately 25 mg of empagliflozin;

[0115] (7) approximately 25 mg of HMS5552 and approximately 10 mg of empagliflozin;

[0116] (8) approximately 25 mg of HMS5552 and approximately 25 mg of empagliflozin;

[0117] (9) approximately 100 mg of HMS5552 and approximately 5 mg of empagliflozin;

[0118] (10) approximately 100 mg of HMS5552 and approximately 10 mg of empagliflozin;

[0119] (11) approximately 100 mg of HMS5552 and approximately 12.5 mg of empagliflozin; and

[0120] (12) approximately 100 mg of HMS5552 and approximately 25 mg of empagliflozin;

[0121] Preferably, in the above-mentioned drug combination, drug composition or drug preparation (preferably a fixed-dose combination preparation), HMS5552 is in the form of a solid dispersion.

[0122] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention is preferably in the form of a tablet.

[0123] In one embodiment, the above-mentioned tablet is a fixed-dose combination tablet of a glucokinase activator (HMS5552 or an isotope labelled substance or a pharmaceutically acceptable salt thereof) and empagliflozin.

[0124] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg empagliflozin) comprises the following components by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0125] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of empagliflozin) comprises the following components by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 10 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0126] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 12.5 mg empagliflozin) comprises the following components by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 12.5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0127] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 25 mg of empagliflozin) comprises the following components by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 25 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0128] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg of empagliflozin) comprises the following components by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0129] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of empagliflozin) comprises the following components by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 10 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0130] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 12.5 mg of empagliflozin) comprises the following components by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 12.5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0131] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 25 mg empagliflozin) comprises the following components by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 25 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0132] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg empagliflozin) comprises the following components by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0133] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of empagliflozin) comprises the following components by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 10 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0134] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 12.5 mg empagliflozin) comprises the following components by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 12.5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0135] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 25 mg empagliflozin) comprises the following components by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 25 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0136] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg of empagliflozin) comprises the following components by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0137] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of empagliflozin) comprises the following components by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 10 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0138] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 12.5 mg of empagliflozin) comprises the following components by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 12.5 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0139] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 25 mg of empagliflozin) comprises the following components by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 25 mg of empagliflozin; about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably contains a glucokinase activator and Eudragit L100 in a ratio of about 1:1.

[0140] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the second active ingredient is dapagliflozin (or dapagliflozin propylene glycol monohydrate). The above-mentioned drug combination, pharmaceutical composition or fixed-dose combination preparation of glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and dapagliflozin (or dapagliflozin propylene glycol monohydrate) contains, by weight, about 1 to 98% of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 0.1 to 30% of dapagliflozin or dapagliflozin propylene glycol monohydrate; about 0 to 85% of filler; about 1 to 25% of binder; about 1 to 15% of disintegrant; about 0.1 to 10% of lubricant; about 0 to 3% of glidant; and about 0 to 5% of coating agent. The pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is prepared by a wet granulation method or a dry granulation method, preferably by a wet granulation method.

[0141] In one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and dapagliflozin or dapagliflozin propylene glycol monohydrate, the dosage (preferably unit dosage) of the glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dosage (preferably unit dosage) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dosage (preferably unit dosage) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween. More preferably, the dosage (preferably unit dosage) of the glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) is about 25 mg, about 50 mg, about 75 mg, about 100 mg. Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation), HMS5552 is present in the form of a solid dispersion.

[0142] In one embodiment, the above-mentioned glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and dapagliflozin or dapagliflozin propylene glycol monohydrate drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), calculated based on the content of dapagliflozin, its dosage (preferably unit dose) is about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg, preferably, its dosage (preferably unit dose) is about 2.5 mg, about 5 mg and about 10 mg. Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 is present in the form of a solid dispersion.

[0143] In the pharmaceutical combination, pharmaceutical composition or fixed-dose compound preparation of the present invention, the specific embodiments of the dosage (preferably unit dosage) of HMS5552 (or its isotope label or pharmaceutically acceptable salt) and dapagliflozin are as follows:

[0144] (1) approximately 25 mg of HMS5552 and approximately 5 mg of dapagliflozin (or approximately 6.15 mg of dapagliflozin propylene glycol monohydrate);

[0145] (2) approximately 50 mg of HMS5552 and approximately 5 mg of dapagliflozin (or approximately 6.15 mg of dapagliflozin propylene glycol monohydrate);

[0146] (3) approximately 75 mg of HMS5552 and approximately 5 mg of dapagliflozin (or approximately 6.15 mg of dapagliflozin propylene glycol monohydrate);

[0147] (4) approximately 100 mg of HMS5552 and approximately 5 mg of dapagliflozin (or approximately 6.15 mg of dapagliflozin propylene glycol monohydrate);

[0148] (5) approximately 25 mg of HMS5552 and approximately 10 mg of dapagliflozin (or approximately 12.3 mg of dapagliflozin propylene glycol monohydrate);

[0149] (6) approximately 50 mg of HMS5552 and approximately 10 mg of dapagliflozin (or approximately 12.3 mg of dapagliflozin propylene glycol monohydrate);

[0150] (7) approximately 75 mg of HMS5552 and approximately 10 mg of dapagliflozin (or approximately 12.3 mg of dapagliflozin propylene glycol monohydrate);

[0151] (8) about 100 mg HMS5552 and about 10 mg dapagliflozin (or about 12.3 mg dapagliflozin propylene glycol monohydrate);

[0152] Preferably, in the above-mentioned drug combination, drug composition or drug preparation (preferably a fixed-dose combination preparation), HMS5552 is in the form of a solid dispersion.

[0153] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention is preferably in the form of a tablet.

[0154] In one embodiment, the above-mentioned tablet is a fixed-dose combination tablet of a glucokinase activator (HMS5552 or an isotope labelled substance or a pharmaceutically acceptable salt thereof) and dapagliflozin (or dapagliflozin propylene glycol monohydrate).

[0155] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 5 mg of dapagliflozin (or an amount of dapagliflozin propylene glycol monohydrate that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0156] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 5 mg of dapagliflozin (or an amount of dapagliflozin propylene glycol monohydrate that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0157] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 5 mg of dapagliflozin (or an amount of dapagliflozin propylene glycol monohydrate that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0158] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 5 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)) contains the following contents of each component by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) ; about 5 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can achieve this dose); about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0159] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0160] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0161] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0162] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can obtain this dose)) contains the following contents of each component by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) ; about 10 mg of dapagliflozin (or dapagliflozin propylene glycol monohydrate in an amount that can achieve this dose); about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0163] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the second active ingredient is canagliflozin (or canagliflozin hemihydrate). The above-mentioned drug combination, pharmaceutical composition or fixed-dose combination preparation of glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and canagliflozin (or canagliflozin hemihydrate) contains, by weight, about 1 to 80% of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 10 to 80% of dapagliflozin or canagliflozin hemihydrate; about 0 to 85% of filler; about 1 to 25% of binder; about 1 to 15% of disintegrant; about 0.1 to 10% of lubricant; about 0 to 3% of glidant; and about 0 to 5% of coating agent. The pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is prepared by a wet granulation method or a dry granulation method, preferably by a wet granulation method.

[0164] In one embodiment, in the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and canagliflozin (or canagliflozin hemihydrate), the dosage (preferably unit dosage) of the glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dosage (preferably unit dosage) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dosage (preferably unit dosage) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween. The dosage (preferably unit dosage) of the more preferred glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) is about 25 mg, about 50 mg, about 75 mg, about 100 mg. Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation), HMS5552 is present in the form of a solid dispersion.

[0165] In one embodiment, the above-mentioned glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt) and canagliflozin (or canagliflozin hemihydrate) in a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), calculated based on the content of canagliflozin, has a dosage (preferably a unit dose) of about 50 mg to about 500 mg, preferably, a dosage (preferably a unit dose) of about 100 mg or about 300 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 is present in the form of a solid dispersion.

[0166] In the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of the present invention, the specific embodiments of the dosage (preferably unit dosage) of HMS5552 (or its isotope-labeled substance or pharmaceutically acceptable salt) and canagliflozin (or canagliflozin hemihydrate) are as follows:

[0167] (1) about 25 mg of HMS5552 and about 100 mg of canagliflozin (or about 101.93 mg of canagliflozin hemihydrate);

[0168] (2) approximately 50 mg of HMS5552 and approximately 100 mg of canagliflozin (or approximately 101.93 mg of canagliflozin hemihydrate);

[0169] (3) approximately 75 mg of HMS5552 and approximately 100 mg of canagliflozin (or approximately 101.93 mg of canagliflozin hemihydrate);

[0170] (4) approximately 100 mg of HMS5552 and approximately 100 mg of canagliflozin (or approximately 101.93 mg of canagliflozin hemihydrate);

[0171] (5) approximately 25 mg of HMS5552 and approximately 300 mg of canagliflozin (or approximately 305.78 mg of canagliflozin hemihydrate);

[0172] (6) about 50 mg HMS5552 and about 300 mg canagliflozin (or about 305.78 mg canagliflozin hemihydrate);

[0173] (7) approximately 75 mg of HMS5552 and approximately 300 mg of canagliflozin (or approximately 305.78 mg of canagliflozin hemihydrate);

[0174] (8) approximately 100 mg HMS5552 and approximately 300 mg canagliflozin (or approximately 305.78 mg canagliflozin hemihydrate);

[0175] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention is preferably in the form of a tablet.

[0176] In one embodiment, the above-mentioned tablet is a fixed-dose combination tablet of a glucokinase activator (HMS5552 or an isotope-labeled substance or a pharmaceutically acceptable salt thereof) and canagliflozin (or canagliflozin hemihydrate).

[0177] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0178] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0179] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0180] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) ; about 100 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0181] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 25 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0182] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 50 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0183] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 75 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); About 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0-70% of an optional filler; about 2-8% of a binder; about 1-5% of a disintegrant; about 0.5-3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0184] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) / 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can obtain this dose)), comprises the following contents of each component by weight: about 100 mg of glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt) ; about 300 mg of canagliflozin (or canagliflozin hemihydrate in an amount that can achieve this dose); about 0 to 70% of an optional filler; about 2 to 8% of a binder; about 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucose kinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucose kinase activator and a polymer carrier, preferably contains a glucose kinase activator and Eudragit L100 in a ratio of about 1:1.

[0185] In one embodiment, the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) further comprises other excipients, wherein the excipients include but are not limited to one of a diluent, a flavoring agent (flavor), a sweetener and a coloring agent or a mixture thereof.

[0186] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation) of the present invention contains one or more optional fillers (diluents). Examples of fillers include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose (including microcrystalline cellulose and silicified microcrystalline cellulose), lactose, anhydrous or monohydrate lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol (including mannitol Pearlitol SD 200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin / dextrose binder, maltodextrin, compressible sugar and other known bulking agents or fillers and / or mixtures of two or more thereof.

[0187] Examples of preferred fillers (diluents) include microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose, mannitol, sorbitol, calcium dihydrogen phosphate (dihydrate), corn starch, pregelatinized starch, and powdered cellulose. Preferred fillers (diluents) are microcrystalline cellulose and silicified microcrystalline cellulose. Microcrystalline cellulose can be obtained from several suppliers, including Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105, and Avicel PH 200 manufactured by FMC Corporation.

[0188] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably fixed dose compound preparation) of the present invention contains one or more optional binders. Examples include, but are not limited to, carboxymethyl cellulose (including sodium carboxymethyl cellulose), hydroxypropyl cellulose (including hydroxypropyl cellulose EXF), corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC) (including hydroxypropyl methyl cellulose 2208), lactose, sucrose, gum arabic, ethyl cellulose, cellulose acetate and wax binders such as carnauba wax, paraffin, spermaceti, polyethylene or microcrystalline wax and other conventional binders and / or mixtures of two or more thereof. Further, in addition to the above-mentioned binders, binders suitable for the present invention also include, but are not limited to, alginic acid, microcrystalline cellulose, dextrin, gelatin, pullulan, liquid glucose, guar gum, methyl cellulose, polyethylene oxide, povidone and syrup and combinations thereof.

[0189] Preferred embodiments of the binder include hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HMPC), polyvinyl pyrrolidone (povidone), hydroxyethyl cellulose, starch 1500 and copolyvinylpyrrolidone. More preferred binders are hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidone.

[0190] In one embodiment, the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) contains one or more optional disintegrants. Examples of disintegrants suitable for the present invention include, but are not limited to, cross-linked sodium carboxymethylcellulose, crospovidone, lactose, sucrose, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, sodium starch glycolate, microcrystalline cellulose, light silicic anhydride, low-substituted hydroxypropyl cellulose and other known disintegrants.

[0191] In one embodiment, the disintegrant is selected from one or more of modified starch, modified cellulose polymer or polycarboxylic acid, specifically selected from cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, polacrilin potassium and carboxymethylcellulose calcium (CMC Calcium). In one embodiment, the disintegrant is cross-linked polyvinylpyrrolidone. In another embodiment, the disintegrant is sodium starch glycolate. In another embodiment, the disintegrant is cross-linked sodium carboxymethylcellulose. Cross-linked sodium carboxymethylcellulose NF type A is available on the market under the trade name "Ac-di-sol".

[0192] In one embodiment, the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) contains one or more lubricants. Examples of lubricants suitable for the present invention include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, palmitic acid stearyl glyceride, palmitic acid, myristic acid, hydrogenated vegetable oil (including hydrogenated castor oil) and fat and other known lubricants and / or mixtures of two or more thereof.

[0193] In one embodiment, embodiments of the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil, and mixtures thereof. A more preferred lubricant is magnesium stearate, or sodium stearyl fumarate, or mixtures thereof.

[0194] In one embodiment, the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) contains one or more glidants and / or anti-adhesive agents. Examples of glidants and / or anti-adhesive agents suitable for use in the present invention include, but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, calcium phosphate, magnesium trisilicate, talc and other forms of silicon dioxide such as aggregated silicates and hydrated silica gel.

[0195] In one embodiment, embodiments of the glidant include colloidal silicon dioxide, calcium phosphate, magnesium silicate and talc, or mixtures thereof. A preferred glidant is colloidal silicon dioxide.

[0196] In one embodiment, the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably fixed dose combination preparation) may also optionally contain one or more surfactants or wetting agents. The surfactant may be an anionic, cationic or neutral surfactant. Anionic surfactants include sodium lauryl sulfate, sodium dodecyl sulfate, 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 esters, polyvinyl alcohol and sorbitan esters. Embodiments of wetting agents include poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives and polyoxyethylene stearate.

[0197] In one embodiment, the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation) may also contain an optional antioxidant to give it chemical stability. Examples of antioxidants suitable for use in the present invention include, but are not limited to, tocopherol, ascorbic acid, gallic acid ester, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, potassium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite and combinations thereof.

[0198] In one embodiment, the antioxidant is selected from alpha-tocopherol, gamma-tocopherol, delta-tocopherol, extracts of natural sources enriched with tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). In one embodiment, the antioxidant is BHT or BHA.

[0199] In one embodiment, the preferred formulation of the fixed-dose combination preparation is a tablet prepared by a compression method. The tablet can be coated, and preferred examples of the coating substrate include sugar coating substrates, water-soluble film coating substrates, enteric film coating substrates, and the like.

[0200] Sucrose is used as the sugar coating base material. In addition, one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. can also be used in combination.

[0201] Examples of water-soluble film coating substrates include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc.; synthetic polymers such as polyvinyl acetal diethylaminoacetate, methacrylate aminoalkyl ester copolymer E [Eudragit E (trade name)], polyvinyl pyrrolidone, etc.

[0202] Examples of enteric film coating substrates include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, etc.; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], etc.

[0203] Preferred examples of coating additives include: plasticizers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), propylene glycol, triethyl citrate, castor oil, polysorbate, etc. or a mixture of two or more thereof; sunscreens such as titanium dioxide, etc.; colorants, dyes and lakes such as red iron oxide (ferric oxide), yellow iron oxide, etc.; flow aids such as talc, etc.

[0204] In one embodiment, the tablets may be coated with, for example, a mixture of hydroxypropylcellulose and hydroxypropylmethylcellulose containing titanium dioxide and / or other colorants, such as iron oxides, dyes, and lakes; a mixture of polyvinyl alcohol (PVA) and polyethylene glycol (PEG); or any other suitable immediate release coating agent. The coating provides taste masking and additional stability to the final tablet. Commercially available coating materials are Opadry, which is a preformulated powder mixture provided by Colorcon. For example, Opadry 03K12429.

[0205] In one embodiment, the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) may also be added with a sweetener and / or a flavoring agent as required.

[0206] In one embodiment, the binder is polyvinyl pyrrolidone or hydroxypropyl cellulose or hydroxypropyl methylcellulose, the filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose or calcium dihydrogen phosphate or mannitol or corn starch and pregelatinized starch, the disintegrant is cross-linked sodium carboxymethyl cellulose or cross-linked polyvidone or sodium starch glycolate, and the lubricant is magnesium stearate or sodium stearyl fumarate, and the glidant is colloidal silicon dioxide.

[0207] In one embodiment, the binder is hydroxypropyl cellulose, the filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose, the disintegrant is cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone or sodium starch glycolate, the lubricant is magnesium stearate or sodium stearyl fumarate, and the glidant is colloidal silicon dioxide.

[0208] In one embodiment, the binder is polyvinyl pyrrolidone, the filler is microcrystalline cellulose or silicified microcrystalline cellulose, the disintegrant is cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone, the lubricant is magnesium stearate or sodium stearyl fumarate, and the glidant is colloidal silicon dioxide.

[0209] In one embodiment, the binder is hydroxypropyl methylcellulose, the filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose, the disintegrant is cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone or sodium starch glycolate, the lubricant is magnesium stearate or sodium stearyl fumarate, and the glidant is colloidal silicon dioxide.

[0210] In one embodiment, the binder is hydroxypropyl cellulose, the filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose, the disintegrant is cross-linked sodium carboxymethyl cellulose, and the lubricant is magnesium stearate or sodium stearyl fumarate.

[0211] In one embodiment, the binder is polyvinyl pyrrolidone, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

[0212] Preparation method

[0213] In one embodiment, the pharmaceutical composition or fixed dose combination of the present invention is prepared by wet granulation (high shear and / or fluidized bed). Granulation is a process in which a binder is added to a solvent to prepare a binder solution, which is then added or directly added to a granulator to form wet granules. The steps involved in the wet granulation process include the following:

[0214] (1) adding the active pharmaceutical ingredient glucokinase activator (preferably HMS5552) and the combination drug (preferably empagliflozin, dapagliflozin, canagliflozin) into a granulator;

[0215] (2) adding an optional filler (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to the mixture obtained in step (1);

[0216] (3) adding an optional disintegrant (e.g., cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);

[0217] (4) For high shear granulation, a binder (e.g., hydroxypropyl cellulose or polyvinyl pyrrolidone or hydroxypropyl methylcellulose) is added to pure water to form a binder solution, which is then added to a granulator for stirring and granulation. For fluidized bed granulation, two active pharmaceutical ingredients are added to a fluidized bed and a binder solution is sprayed in by compressed air, wherein the binder solution is an aqueous solution of a binder and pure water;

[0218] (5) the obtained wet granules are granulated in a suitable granulator to obtain wet granules of suitable size;

[0219] (6) Granules prepared by high shear granulation are rack dried in an oven or dried in a fluidized bed dryer. For granules obtained by fluidized bed granulation, the granules are then dried in a fluidized bed;

[0220] (7) granulating on a suitable grinding machine to obtain dry particles of suitable size;

[0221] (8) Add optional filler (diluent, such as microcrystalline cellulose) and optional disintegrant (such as croscarmellose sodium) and mix with the dried granules in a suitable mixer;

[0222] (9) adding a lubricant (e.g., magnesium stearate and sodium stearyl fumarate) to the mixture of step (8);

[0223] (10) adding an optional glidant (e.g., colloidal silicon dioxide) to the mixture of step (9);

[0224] (11) filling the lubricated granule mixture of step (9) or (10) into vials, sachets or capsules or compressing into a desired tablet shape; and

[0225] (12) Optionally, the obtained tablet is film-coated.

[0226] In another embodiment, the pharmaceutical composition of the present invention is prepared by wet granulation (high shear and / or fluidized bed). Granulation is a process in which a binder and a second active ingredient are added to a solvent to form a binder solution (or suspension), which is then added to a granulator to form wet granules. The steps involved in the wet granulation process include the following:

[0227] (1) adding the active pharmaceutical ingredient glucokinase activator (preferably HMS5552) into a granulator;

[0228] (2) adding an optional filler (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to the mixture of step (1);

[0229] (3) adding an optional disintegrant (e.g., cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);

[0230] (4) For high shear granulation, a binder (e.g., hydroxypropyl cellulose or polyvinyl pyrrolidone or hydroxypropyl methylcellulose) is added to a solvent to be uniformly dispersed or dissolved, and then a prescribed amount of a second active ingredient (preferably empagliflozin, dapagliflozin, canagliflozin) is added to be dispersed or dissolved to form a uniform binder system. The system is added to a granulator for stirring and granulation. For fluidized bed granulation, an active pharmaceutical ingredient such as HMS5552 is added to a fluidized bed, and the binder system is sprayed in by compressed air, wherein the binder solution is a solution or suspension of a binder and pure water or an organic solvent (e.g., ethanol);

[0231] (5) the obtained wet granules are sized by granulating in a suitable granulator to obtain wet granules of suitable size;

[0232] (6) Granules prepared by high shear granulation are rack dried in an oven or dried in a fluidized bed dryer. For granules obtained by fluidized bed granulation, the granules are then dried in a fluidized bed;

[0233] (7) granulating on a suitable grinding machine to obtain dry particles of suitable size;

[0234] (8) Add optional filler (diluent, such as microcrystalline cellulose) and optional disintegrant (such as croscarmellose sodium) and mix with the dried granules in a suitable mixer;

[0235] (9) adding a lubricant (e.g., magnesium stearate and sodium stearyl fumarate) to the mixture of step (8);

[0236] (10) Optionally, adding a glidant (e.g., colloidal silicon dioxide) to the mixture of step (9);

[0237] (11) filling the lubricated granule mixture of (9) or (10) into vials, sachets or capsules or compressing into a desired tablet shape; and

[0238] (12) Optionally, the obtained tablet is film-coated.

[0239] The steps involved in the dry processing (direct compression or dry granulation) method include:

[0240] (1) Adding the active pharmaceutical ingredient glucokinase activator (preferably HMS5552) and the combination drug (preferably empagliflozin, dapagliflozin, canagliflozin) into a mixing barrel;

[0241] (2) adding an optional filler (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to step (1);

[0242] (3) adding an optional binder (e.g., hydroxypropyl cellulose or polyvinyl pyrrolidone or hydroxypropyl methyl cellulose) to the mixture obtained in step (1) or (2);

[0243] (4) adding a lubricant or a glidant to step (3) and mixing;

[0244] (5) The mixture of step (4) can be filled into vials, sachets or capsules or compressed into a desired tablet shape, or processed by a roller compactor;

[0245] (6) If the treatment is carried out by roller compaction, the mixture in step (3) is mixed in advance and then roller compacted; if necessary, the particles can be granulated on a suitable grinder to obtain particles of the desired size;

[0246] (7) In a suitable mixer, an optional diluent may be added to the granules obtained in step (6) to improve the compression properties;

[0247] (8) adding an optional disintegrant (e.g., cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate) to step (7);

[0248] (9) adding an optional lubricant or glidant to the mixture of step (8);

[0249] (10) filling the lubricated granule mixture of (9) or (10) into vials, sachets or capsules or compressing into a desired tablet shape; and

[0250] (11) Optionally, the tablets obtained in step (5) or step (10) may be film-coated.

[0251] In one embodiment of the present invention, the glucose kinase activator in the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of the present invention is in the form of a solid dispersion, which can be prepared by a method selected from spray drying, fluidized bed drying, solvent method, melt extrusion method, etc.

[0252] One embodiment of the present invention is a method for preparing a solid dispersion of a glucokinase activator by spray drying, which comprises the steps of:

[0253] (1) preparing a spray drying solution, comprising dissolving a polymer carrier and a glucokinase activator (preferably HMS5552) in a solvent;

[0254] (2) Spray drying: control the inlet air temperature, air volume, flow rate and pressure of the atomizing air flow, and the spray speed of the solution, etc.

[0255] In the embodiment of the present invention, the solvent used in the preparation of the solid dispersion of the glucokinase activator includes, but is not limited to, alkanols, esters, nitriles, cycloalkanes, aromatic hydrocarbons, ketones, etc. Specifically, the solvent is selected from the following solvents: anhydrous ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene and toluene. It can be a single solvent, a mixed solvent, or a mixture of an organic solvent and water.

[0256] Methods and uses for treating and / or preventing diseases

[0257] Another embodiment of the present invention relates to a method or use of using the composition or preparation (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose combination preparation) containing a glucokinase activator of the present invention to treat and / or prevent the following diseases and medical conditions, especially one or more diseases selected from type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood sugar and hyperglycemia, comprising administering a therapeutically effective amount of the composition or preparation (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose combination preparation) of the present invention to a subject:

[0258] - preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or

[0259] - Improved glycemic control and / or reduced fasting plasma glucose, postprandial plasma glucose and / or glycosylated haemoglobin HbA1c; or

[0260] - prevent, slow, delay or reverse the progression of impaired glucose tolerance, insulin resistance and / or metabolic syndrome to type 2 diabetes; or

[0261] - preventing, slowing down the progression of, delaying or treating a condition or disorder selected from the group consisting of: diabetic complications, such as cataracts and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, impaired learning and memory, neurodegeneration or cognitive impairment, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmia and vascular restenosis; or

[0262] - reducing body weight and / or body fat, or preventing an increase in body weight and / or body fat, or promoting a reduction in body weight and / or body fat; or

[0263] - prevent, slow down, delay or treat pancreatic beta cell degeneration and / or decreased pancreatic beta cell function, and / or improve and / or restore or protect pancreatic beta cell function and / or restore pancreatic insulin secretion function; or

[0264] - To prevent, mitigate, delay or treat diseases or conditions caused by abnormal accumulation of fat in the liver or ectopic fat; or

[0265] - Maintain and / or improve insulin sensitivity and / or treat or prevent hyperinsulinemia and / or insulin resistance; or

[0266] - prevent, slow the progression, delay or treat new onset diabetes after transplantation (NODAT) and / or post-transplant metabolic syndrome (PTMS); or - prevent, delay or reduce complications associated with NODAT and / or PTMS, including microvascular and macrovascular disease and events, transplant rejection, infection and death; or

[0267] -Treatment of hyperuricemia and hyperuricemia-related diseases; or

[0268] -Diabetic nephropathy, decreased renal function.

[0269] The present invention also provides a method for treating type II diabetes by orally administering a therapeutically effective amount of a pharmaceutical composition or preparation (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose compound preparation) containing a glucokinase activator and a combination drug 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. The composition or preparation (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose compound preparation) containing a glucokinase activator of the present invention can be administered once a day (QD), twice a day (BID) or three times a day (TID).

[0270] Specifically, the present invention relates to the following specific embodiments.

[0271] Embodiment I - Glucokinase activator + SGLT-2 inhibitor (e.g., empagliflozin)

[0272] Solution 1. A drug combination, a pharmaceutical composition or a fixed-dose combination preparation comprising:

[0273] (a) a glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt, isotope-labeled substance, crystalline form, hydrate, solvate, diastereomer or enantiomeric form thereof,

[0274]

[0275] (b) SGLT-2 inhibitors;

[0276] (c) one or more excipients;

[0277] The above drugs (a) and (b) are used simultaneously, separately or sequentially.

[0278] Scheme 2. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is about 30:1 to 1:30, preferably about 20:1 to 1:12, and more preferably about 0.75:1, about 1:2, about 1:1, about 1:4, about 1:6, about 1:12, about 2:1, about 2.5:1, about 3:1, about 5:1, about 6:1, about 7.5:1, about 10:1, about 15:1 or about 20:1.

[0279] Scheme 3. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1 or 2, wherein the glucose kinase activator is approximately 1 to 96% by weight; and the SGLT-2 inhibitor is approximately 0.1 to 80% by weight.

[0280] Scheme 4. The drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 3, wherein the glucokinase activator is a compound HMS5552 represented by the following formula or a pharmaceutically acceptable salt thereof, an isotope-labeled substance, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof,

[0281]

[0282] Embodiment 5. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Embodiments 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.

[0283] Scheme 6. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 5, wherein the glucose kinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is methacrylic acid copolymer type A (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

[0284] Embodiment 7. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 6, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6 or any range therebetween.

[0285] Scheme 8. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1 to 7, wherein the SGLT-2 inhibitor is selected from canagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), empagliflozin, iplagliflozin, lupagliflozin and topagliflozin, and pharmaceutically acceptable salts thereof; preferably, the SGLT-2 inhibitor is selected from empagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), and canagliflozin (or canagliflozin hemihydrate).

[0286] Scheme 9. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 8, wherein the glucokinase activator is present in a dosage (preferably a unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg, preferably, wherein the dosage (preferably a unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0287] Scheme 10. The drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-9, wherein the SGLT-2 inhibitor is present in a dosage (preferably unit dose) range of about 1 mg to 500 mg, preferably about 5 mg to about 300 mg, preferably, wherein the dosage (preferably unit dose) of the SGLT-2 inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 100 mg, about 200 mg or about 300 mg, most preferably about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 100 mg or about 300 mg; preferably, the SGLT-2 inhibitor is Empagliflozin, with a dosage (preferably unit dosage) of about 0.5 mg to about 50 mg, especially about 1 mg to about 25 mg; preferably, its dosage is about 5 mg, about 10 mg, about 12.5 mg and about 25 mg; preferably, the SGLT-2 inhibitor is dapagliflozin, with a dosage (preferably unit dosage) of about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg; preferably, it is about 2.5 mg, about 5 mg and about 10 mg; preferably, the SGLT-2 inhibitor is canagliflozin, with a dosage (preferably unit dosage) of about 50 mg to about 500 mg, and the preferred dosage of canagliflozin is about 100 mg and about 300 mg.

[0288] Scheme 11. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 10, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

[0289] Embodiment 12. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1 to 11, which is a tablet.

[0290] Embodiment 13. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 12, which is a coated tablet.

[0291] Scheme 14. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 13, wherein the coated tablet is a film-coated tablet, and the film-coating agent comprises:

[0292] a film coating substrate, such as hydroxypropylcellulose, hydroxypropylmethylcellulose or a mixture thereof;

[0293] optional plasticizers, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or mixtures thereof;

[0294] optional colorants such as red iron oxide, yellow iron oxide, or mixtures thereof;

[0295] Optional sunscreens such as titanium dioxide, and

[0296] Optional glidant.

[0297] Scheme 15. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 14, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.

[0298] Scheme 16. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 15, comprising, by weight:

[0299] About 1-96% of a glucokinase activator (preferably HMS5552 or an isotope-labeled substance or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0300] About 0.1-50% empagliflozin;

[0301] About 0-80% filler;

[0302] About 1 to 25% of a binder;

[0303] About 0-15% disintegrant;

[0304] About 0.1-10% lubricant;

[0305] About 0-3% of a glidant; and

[0306] About 0-5% coating agent.

[0307] Scheme 17. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 16, comprising, by weight:

[0308] About 1-48% of a glucokinase activator (preferably HMS5552 or an isotope-labeled substance or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0309] About 1-35% empagliflozin;

[0310] About 0-90% filler;

[0311] About 1-10% of a binder;

[0312] About 1-10% disintegrant;

[0313] About 0.1-5% lubricant;

[0314] About 0-3% of a glidant; and

[0315] About 0-5% coating agent.

[0316] Scheme 18. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 16, wherein the dosage (preferably unit dosage) of the active ingredient is, by weight:

[0317] about 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[0318] about 5 mg, about 10 mg, about 12.5 mg, and about 25 mg of empagliflozin;

[0319] About 0-80% filler;

[0320] About 1 to 25% of a binder;

[0321] About 0-15% disintegrant;

[0322] About 0.1-10% lubricant;

[0323] About 0-3% of a glidant; and

[0324] About 0-5% coating agent.

[0325] Scheme 19. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 5 mg empagliflozin), comprising the following amounts of each component by weight:

[0326] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0327] - about 5 mg of empagliflozin;

[0328] - about 0 to 70% filler;

[0329] - about 2 to 8% of a binder;

[0330] - about 1 to 5% disintegrant;

[0331] - About 0.5-3% lubricant;

[0332] - about 0 to 0.5% of a glidant; and

[0333] - About 0-5% coating agent.

[0334] Scheme 20. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 12.5 mg empagliflozin), comprising the following amounts of each component by weight:

[0335] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0336] - about 12.5 mg of empagliflozin;

[0337] - about 0 to 70% filler;

[0338] - about 2 to 8% of a binder;

[0339] - about 1 to 5% disintegrant;

[0340] - About 0.5-3% lubricant;

[0341] - about 0 to 0.5% of a glidant; and

[0342] - About 0-5% coating agent.

[0343] Scheme 21. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 10 mg empagliflozin), comprising the following amounts of each component by weight:

[0344] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0345] - about 10 mg of empagliflozin;

[0346] - about 0 to 70% filler;

[0347] - about 2 to 8% of a binder;

[0348] - about 1 to 5% disintegrant;

[0349] - About 0.5-3% lubricant;

[0350] - about 0 to 0.5% of a glidant; and

[0351] - About 0-5% coating agent.

[0352] Scheme 22. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 25 mg empagliflozin), comprising the following amounts of each component by weight:

[0353] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0354] - about 25 mg of empagliflozin;

[0355] - about 0 to 70% filler;

[0356] - about 2 to 8% of a binder;

[0357] - about 1 to 5% disintegrant;

[0358] - About 0.5-3% lubricant;

[0359] - about 0 to 0.5% of a glidant; and

[0360] - About 0-5% coating agent.

[0361] Scheme 23. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 25 mg empagliflozin), comprising the following amounts of each component by weight:

[0362] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0363] - about 25 mg of empagliflozin;

[0364] - about 0 to 70% filler;

[0365] - about 2 to 8% of binder;

[0366] - about 1 to 5% disintegrant;

[0367] - About 0.5-3% lubricant;

[0368] - about 0 to 0.5% of a glidant; and

[0369] - About 0-5% coating agent.

[0370] Scheme 24. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 10 mg empagliflozin), comprising the following amounts of each component by weight:

[0371] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0372] - about 10 mg of empagliflozin;

[0373] - about 0 to 70% filler;

[0374] - about 2 to 8% of binder;

[0375] - about 1 to 5% disintegrant;

[0376] - About 0.5-3% lubricant;

[0377] - about 0 to 0.5% of a glidant; and

[0378] - About 0-5% coating agent.

[0379] Scheme 25. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 100 mg HMS5552 / 10 mg empagliflozin), comprising the following amounts of each component by weight:

[0380] - about 100 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0381] - about 10 mg of empagliflozin;

[0382] - about 0 to 70% filler;

[0383] - about 2 to 8% of a binder;

[0384] - about 1 to 5% disintegrant;

[0385] - About 0.5-3% lubricant;

[0386] - about 0 to 0.5% of a glidant; and

[0387] - About 0-5% coating agent.

[0388] Scheme 26. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 25 mg empagliflozin), comprising the following amounts of each component by weight:

[0389] - about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0390] - about 25 mg of empagliflozin;

[0391] - about 0 to 70% filler;

[0392] - about 2 to 8% of a binder;

[0393] - about 1 to 5% disintegrant;

[0394] - About 0.5-3% lubricant;

[0395] - about 0 to 0.5% of a glidant; and

[0396] - About 0-5% coating agent.

[0397] Embodiment 27. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 150 mg of solid dispersion, about 5.00 mg of empagliflozin, about 88.10 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 6.50 mg of croscarmellose sodium, about 2.60 mg of magnesium stearate and about 7.80 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0398] Scheme 28. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 150 mg of a solid dispersion, about 12.50 mg of empagliflozin, about 99.30 mg of microcrystalline cellulose, about 8.40 mg of hydroxypropyl cellulose, about 7.00 mg of croscarmellose sodium, about 2.80 mg of magnesium stearate and about 8.40 mg of opadry, wherein the solid dispersion comprises HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0399] Embodiment 29. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 150 mg of solid dispersion, about 10.00 mg of empagliflozin, about 84.40 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 5.20 mg of croscarmellose sodium, about 2.60 mg of magnesium stearate and about 7.80 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0400] Embodiment 30. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 150 mg of solid dispersion, about 25.00 mg of empagliflozin, about 88.20 mg of microcrystalline cellulose, about 8.40 mg of hydroxypropyl cellulose, about 5.60 mg of croscarmellose sodium, about 2.80 mg of magnesium stearate and about 8.40 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0401] Scheme 31. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 200 mg of a solid dispersion, about 10.00 mg of empagliflozin, about 72.00 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 6.00 mg of croscarmellose sodium, about 3.00 mg of magnesium stearate and about 9.00 mg of opadry, wherein the solid dispersion comprises HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 100 mg of HMS5552.

[0402] Scheme 32. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 100 mg of a solid dispersion, about 10.00 mg of empagliflozin, about 96.80 mg of microcrystalline cellulose, about 6.60 mg of povidone, about 4.40 mg of croscarmellose sodium, about 2.20 mg of magnesium stearate and about 6.60 mg of opadry, wherein the solid dispersion comprises HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[0403] Scheme 33. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 100 mg of a solid dispersion, about 25.00 mg of empagliflozin, about 100.30 mg of microcrystalline cellulose, about 7.20 mg of hydroxypropyl cellulose, about 5.10 mg of croscarmellose sodium, about 2.40 mg of magnesium stearate and about 7.20 mg of opadry, wherein the solid dispersion comprises HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[0404] Scheme 34. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 50 mg of solid dispersion, about 25.00 mg of empagliflozin, about 309.00 mg of microcrystalline cellulose, about 8.00 mg of croscarmellose sodium, about 4.00 mg of micropowdered silica, about 4.00 mg of magnesium stearate and about 12.00 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 25 mg of HMS5552.

[0405] Scheme 35. A method for the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 34, which comprises blending the active ingredient with one or more excipients for granulation, preferably further filling the obtained granular mixture into vials, sachets or capsules or compressing it into a desired tablet shape; more preferably further coating the obtained tablet.

[0406] Scheme 36. A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation of Scheme 35, wherein the preparation is carried out by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[0407] Embodiment 37. The method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation according to any one of Embodiments 35-36, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[0408] Scheme 38. A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation according to any one of Schemes 35-37, wherein the glucokinase activator and a second or more active ingredients can also be prepared together in the form of a compound solid dispersion (i.e., a solid dispersion containing two or more active ingredients).

[0409] Scheme 39. A drug combination, pharmaceutical composition or fixed-dose combination preparation as described in any one of Schemes 1-34, which is used to prevent, slow the progression of, delay or treat one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or to improve blood sugar control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or to prevent, slow, delay or reverse diabetic complications.

[0410] Scheme 40. A method for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications, comprising administering to a subject a therapeutically effective amount of the drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-34.

[0411] Scheme 41. Use of the drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-34 in the preparation of a medicament for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the following, or preventing, slowing, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or improving blood sugar control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

[0412] Embodiment II - Glucokinase activator + SGLT-2 inhibitor (e.g., dapagliflozin)

[0413] Solution 1. A drug combination, a pharmaceutical composition or a fixed-dose combination preparation comprising:

[0414] (a) a glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt, isotope-labeled substance, crystalline form, hydrate, solvate, diastereomer or enantiomeric form thereof,

[0415]

[0416]

[0417] (b) SGLT-2 inhibitors;

[0418] (c) one or more excipients;

[0419] The above drugs (a) and (b) are used simultaneously, separately or sequentially.

[0420] Scheme 2. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is about 30:1 to 1:30, preferably about 20:1 to 1:12, and more preferably about 0.75:1, about 1:2, about 1:1, about 1:4, about 1:6, about 1:12, about 2:1, about 2.5:1, about 3:1, about 5:1, about 6:1, about 7.5:1, about 10:1, about 15:1 or about 20:1.

[0421] Scheme 3. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1 or 2, wherein the glucose kinase activator is approximately 1 to 98% by weight; and the SGLT-2 inhibitor is approximately 0.1 to 30% by weight.

[0422] Scheme 4. The drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 3, wherein the glucokinase activator is a compound HMS5552 represented by the following formula or a pharmaceutically acceptable salt thereof, an isotope-labeled substance, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof,

[0423]

[0424] Embodiment 5. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Embodiments 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.

[0425] Scheme 6. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 5, wherein the glucose kinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is methacrylic acid copolymer type A (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

[0426] Embodiment 7. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 6, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6 or any range therebetween.

[0427] Scheme 8. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1 to 7, wherein the SGLT-2 inhibitor is selected from canagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), empagliflozin, iplagliflozin, lupagliflozin and topagliflozin, and pharmaceutically acceptable salts thereof; preferably, the SGLT-2 inhibitor is selected from empagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), and canagliflozin (or canagliflozin hemihydrate).

[0428] Scheme 9. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 8, wherein the glucokinase activator is present in a dosage (preferably a unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg, preferably, wherein the dosage (preferably a unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0429] Scheme 10. The drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-9, wherein the SGLT-2 inhibitor is present in a dosage (preferably unit dose) range of about 1 mg to 500 mg, preferably about 5 mg to about 300 mg, preferably, wherein the dosage (preferably unit dose) of the SGLT-2 inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 100 mg, about 200 mg or about 300 mg, most preferably about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 100 mg or about 300 mg; preferably, the SGLT-2 inhibitor is Empagliflozin, with a dosage (preferably unit dosage) of about 0.5 mg to about 50 mg, especially about 1 mg to about 25 mg; preferably, its dosage is about 5 mg, about 10 mg, about 12.5 mg and about 25 mg; preferably, the SGLT-2 inhibitor is dapagliflozin, with a dosage (preferably unit dosage) of about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg; preferably, it is about 2.5 mg, about 5 mg and about 10 mg; preferably, the SGLT-2 inhibitor is canagliflozin, with a dosage (preferably unit dosage) of about 50 mg to about 500 mg, and the preferred dosage of canagliflozin is about 100 mg and about 300 mg.

[0430] Scheme 11. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 10, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

[0431] Embodiment 12. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1 to 11, which is a tablet.

[0432] Embodiment 13. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 12, which is a coated tablet.

[0433] Scheme 14. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 13, wherein the coated tablet is a film-coated tablet, and the film-coating agent comprises:

[0434] a film coating substrate, such as hydroxypropylcellulose, hydroxypropylmethylcellulose or a mixture thereof;

[0435] optional plasticizers, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or mixtures thereof;

[0436] optional colorants such as red iron oxide, yellow iron oxide, or mixtures thereof;

[0437] Optional sunscreens such as titanium dioxide, and

[0438] Optional glidant.

[0439] Scheme 15. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 14, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.

[0440] Scheme 16. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 15, comprising, by weight:

[0441] About 1-98% of a glucokinase activator (preferably HMS5552 or an isotope-labeled substance or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0442] About 0.1-30% dapagliflozin or dapagliflozin propylene glycol monohydrate;

[0443] About 0-85% filler;

[0444] About 1 to 25% of a binder;

[0445] About 0-15% disintegrant;

[0446] About 0.1-10% lubricant;

[0447] About 0-3% of a glidant; and

[0448] About 0-5% coating agent.

[0449] Scheme 17. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 16, comprising, by weight:

[0450] About 1-49% of a glucokinase activator (preferably HMS5552 or an isotope-labeled substance or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0451] About 0.5-20% dapagliflozin or dapagliflozin propylene glycol monohydrate;

[0452] About 0-90% filler;

[0453] About 1-10% of a binder;

[0454] About 1-10% disintegrant;

[0455] About 0.1-5% lubricant; and

[0456] About 0-5% coating agent.

[0457] Scheme 18. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 16, wherein the dosage (preferably unit dosage) of the active ingredient is, by weight:

[0458] about 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[0459] About 2.5 mg, about 5 mg, and about 10 mg of dapagliflozin or an amount of dapagliflozin propylene glycol monohydrate to achieve such dosage;

[0460] About 0-85% filler;

[0461] About 1 to 25% of a binder;

[0462] About 0-15% disintegrant;

[0463] About 0.1-10% lubricant;

[0464] About 0-3% of a glidant; and

[0465] About 0-5% coating agent.

[0466] Scheme 19. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate), which comprises the following amounts of each component by weight:

[0467] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0468] - about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0469] - about 0 to 70% filler;

[0470] - about 2 to 8% of a binder;

[0471] - about 1 to 8% disintegrant;

[0472] - About 0.5-3% lubricant;

[0473] - about 0 to 0.5% of a glidant; and

[0474] - About 0-5% coating agent.

[0475] Scheme 20. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate), which comprises the following amounts of each component by weight:

[0476] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0477] - about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0478] - about 0 to 70% filler;

[0479] - about 2 to 8% of binder;

[0480] - about 1 to 8% disintegrant;

[0481] - About 0.5-3% lubricant;

[0482] - about 0 to 0.5% of a glidant; and

[0483] - About 0-5% coating agent.

[0484] Scheme 21. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate), which comprises the following amounts of each component by weight:

[0485] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0486] - about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0487] - about 0 to 70% filler;

[0488] - about 2 to 8% of binder;

[0489] - about 1 to 8% disintegrant;

[0490] - About 0.5-3% lubricant;

[0491] - about 0 to 0.5% of a glidant; and

[0492] - About 0-5% coating agent.

[0493] Scheme 22. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate), which comprises the following amounts of each component by weight:

[0494] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0495] - about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0496] - about 0 to 70% filler;

[0497] - about 2 to 8% of a binder;

[0498] - about 1 to 8% disintegrant;

[0499] - About 0.5-3% lubricant;

[0500] - about 0 to 0.5% of a glidant; and

[0501] - About 0-5% coating agent.

[0502] Scheme 23. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 100 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate), which comprises the following amounts of each component by weight:

[0503] - about 100 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0504] - about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0505] - about 0 to 70% filler;

[0506] - about 2 to 8% of a binder;

[0507] - about 1 to 8% disintegrant;

[0508] - About 0.5-3% lubricant;

[0509] - about 0 to 0.5% of a glidant; and

[0510] - About 0-5% coating agent.

[0511] Scheme 24. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate), which comprises the following amounts of each component by weight:

[0512] - about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0513] - about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0514] - about 0 to 70% filler;

[0515] - about 2 to 8% of binder;

[0516] - about 1 to 8% disintegrant;

[0517] - About 0.5-3% lubricant;

[0518] - about 0 to 0.5% of a glidant; and

[0519] - About 0-5% coating agent.

[0520] Embodiment 25. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 150 mg of a solid dispersion, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 88.25 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 5.20 mg of croscarmellose sodium, about 2.60 mg of magnesium stearate and 7.80 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0521] Embodiment 26. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 100 mg of a solid dispersion, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 100.65 mg of microcrystalline cellulose, about 6.60 mg of hydroxypropyl cellulose, about 4.40 mg of croscarmellose sodium, about 2.20 mg of magnesium stearate and 6.60 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[0522] Embodiment 27. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 150 mg of a solid dispersion, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 91.50 mg of microcrystalline cellulose, about 8.10 mg of hydroxypropyl cellulose, about 5.40 mg of croscarmellose sodium, about 2.70 mg of magnesium stearate and 8.10 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0523] Embodiment 28. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 200 mg of a solid dispersion, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 75.55 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 6.30 mg of croscarmellose sodium, about 3.00 mg of magnesium stearate and 9.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 100 mg of HMS5552.

[0524] Embodiment 29. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of embodiment 18, comprising about 100 mg of a solid dispersion, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 113.06 mg of microcrystalline cellulose, about 7.20 mg of hydroxypropyl cellulose, about 5.04 mg of croscarmellose sodium, about 2.40 mg of magnesium stearate and 7.20 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[0525] Embodiment 30. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18, comprising about 50 mg of a solid dispersion, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 313.70 mg of microcrystalline cellulose, about 8.00 mg of hydroxypropyl cellulose, about 8.00 mg of croscarmellose sodium, about 4.00 mg of micronized silica, about 4.00 mg of magnesium stearate and 12.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 25 mg of HMS5552.

[0526] Scheme 31. A method for the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 30, which comprises blending the active ingredient with one or more excipients for granulation, preferably further filling the obtained granular mixture into a vial, a pouch or a capsule or compressing it into a desired tablet shape; more preferably further coating the obtained tablet.

[0527] Scheme 32. A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation of Scheme 31, wherein the preparation is carried out by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[0528] Embodiment 33. The method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation according to any one of Embodiments 31 to 32, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[0529] Scheme 34. A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation according to any one of Schemes 31 to 33, wherein the glucokinase activator and a second or more active ingredients can also be prepared together in the form of a compound solid dispersion (i.e., a solid dispersion containing two or more active ingredients).

[0530] Scheme 35. A drug combination, pharmaceutical composition or fixed-dose combination preparation as described in any one of Schemes 1-30, which is used to treat or prevent, slow the progression of, delay or treat one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or improve blood sugar control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or prevent, slow, delay or reverse diabetic complications.

[0531] Scheme 36. A method for treating or preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications, comprising administering to a subject a therapeutically effective amount of the drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-30.

[0532] Scheme 37. Use of the drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-30 for the preparation of a medicament for treating or preventing one or more metabolic disorders selected from the following, slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder, or preventing, slowing, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or improving blood sugar control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

[0533] Embodiment III - Glucokinase activator + SGLT-2 inhibitor (eg, canagliflozin)

[0534] Solution 1. A drug combination, a pharmaceutical composition or a fixed-dose combination preparation comprising:

[0535] (a) a glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt, isotope-labeled substance, crystalline form, hydrate, solvate, diastereomer or enantiomeric form thereof,

[0536]

[0537]

[0538] (b) SGLT-2 inhibitors;

[0539] (c) one or more excipients;

[0540] The above drugs (a) and (b) are used simultaneously, separately or sequentially.

[0541] Scheme 2. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is about 30:1 to 1:30, preferably about 20:1 to 1:12, and more preferably about 0.75:1, about 1:2, about 1:1, about 1:4, about 1:6, about 1:12, about 2:1, about 2.5:1, about 3:1, about 5:1, about 6:1, about 7.5:1, about 10:1, about 15:1 or about 20:1.

[0542] Scheme 3. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1 or 2, wherein the glucose kinase activator is about 1 to 80% by weight; and the SGLT-2 inhibitor is about 10 to 80% by weight.

[0543] Scheme 4. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1, wherein the glucokinase activator is a compound HMS5552 represented by the following formula or a pharmaceutically acceptable salt, an isotope-labeled substance, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof,

[0544]

[0545] Embodiment 5. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Embodiments 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.

[0546] Scheme 6. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 5, wherein the glucose kinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is methacrylic acid copolymer type A (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

[0547] Embodiment 7. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 6, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6 or any range therebetween.

[0548] Scheme 8. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1 to 7, wherein the SGLT-2 inhibitor is selected from canagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), empagliflozin, iplagliflozin, lupagliflozin and topagliflozin, and pharmaceutically acceptable salts thereof; preferably, the SGLT-2 inhibitor is selected from empagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), and canagliflozin (or canagliflozin hemihydrate).

[0549] Scheme 9. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 8, wherein the glucokinase activator is present in a dosage (preferably a unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg, preferably, wherein the dosage (preferably a unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0550] Scheme 10. The drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-9, wherein the SGLT-2 inhibitor is present in a dosage (preferably unit dose) range of about 1 mg to 500 mg, preferably about 5 mg to about 300 mg, preferably, wherein the dosage (preferably unit dose) of the SGLT-2 inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 100 mg, about 200 mg or about 300 mg, most preferably about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 100 mg or about 300 mg; preferably, the SGLT-2 inhibitor is Empagliflozin, with a dosage (preferably unit dosage) of about 0.5 mg to about 50 mg, especially about 1 mg to about 25 mg; preferably, its dosage is about 5 mg, about 10 mg, about 12.5 mg and about 25 mg; preferably, the SGLT-2 inhibitor is dapagliflozin, with a dosage (preferably unit dosage) of about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg; preferably, it is about 2.5 mg, about 5 mg and about 10 mg; preferably, the SGLT-2 inhibitor is canagliflozin, with a dosage (preferably unit dosage) of about 50 mg to about 500 mg, and the preferred dosage of canagliflozin is about 100 mg and about 300 mg.

[0551] Scheme 11. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 10, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

[0552] Embodiment 12. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1 to 11, which is a tablet.

[0553] Embodiment 13. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 12, which is a coated tablet.

[0554] Scheme 14. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 13, wherein the coated tablet is a film-coated tablet, and the film-coating agent comprises:

[0555] a film coating substrate, such as hydroxypropylcellulose, hydroxypropylmethylcellulose or a mixture thereof;

[0556] optional plasticizers, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or mixtures thereof;

[0557] optional colorants such as red iron oxide, yellow iron oxide, or mixtures thereof;

[0558] Optional sunscreens such as titanium dioxide, and

[0559] Optional glidant.

[0560] Scheme 15. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 14, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.

[0561] Scheme 16. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 15, comprising, by weight:

[0562] About 1-80% of a glucokinase activator (preferably HMS5552 or an isotope-labeled substance or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0563] About 10-80% canagliflozin or canagliflozin hemihydrate;

[0564] About 0-85% filler;

[0565] About 1 to 25% of a binder;

[0566] About 0-15% disintegrant;

[0567] About 0.1-10% lubricant;

[0568] About 0-3% of a glidant; and

[0569] About 0-5% coating agent.

[0570] Scheme 17. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 16, comprising, by weight:

[0571] About 1-80% of a glucokinase activator (preferably HMS5552 or an isotope-labeled substance or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0572] About 10-80% canagliflozin or canagliflozin hemihydrate;

[0573] About 0-85% filler;

[0574] About 1-10% of a binder;

[0575] About 1-10% disintegrant;

[0576] About 0.1-10% lubricant;

[0577] About 0-5% coating agent.

[0578] Scheme 18. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 16, wherein the dosage (preferably unit dosage) of the active ingredient is, by weight:

[0579] about 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[0580] About 100 mg and about 300 mg of canagliflozin or an amount of canagliflozin hemihydrate to achieve such dosage;

[0581] About 0-85% filler;

[0582] About 1 to 25% of a binder;

[0583] About 0-15% disintegrant;

[0584] About 0.1-10% lubricant;

[0585] About 0-3% of a glidant; and

[0586] About 0-5% coating agent.

[0587] Scheme 19. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 100 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate), which comprises the following amounts of each component by weight:

[0588] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0589] - about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[0590] - about 0-70% filler, such as microcrystalline cellulose;

[0591] - about 2-8% of a binder, such as hydroxypropylcellulose;

[0592] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[0593] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[0594] - about 0 to 0.5% of a glidant; and

[0595] - About 0-5% coating agent.

[0596] Scheme 20. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 100 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate), which comprises the following amounts of each component by weight:

[0597] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0598] - about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[0599] - about 0-70% filler, such as microcrystalline cellulose;

[0600] - about 2-8% of a binder, such as hydroxypropylcellulose;

[0601] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[0602] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[0603] - about 0 to 0.5% of a glidant; and

[0604] - About 0-5% coating agent.

[0605] Scheme 21. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 100 mg HMS5552 / 100 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate), which comprises the following amounts of each component by weight:

[0606] - about 100 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0607] - about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[0608] - about 0-70% filler, such as microcrystalline cellulose;

[0609] - about 2-8% of a binder, such as hydroxypropylcellulose;

[0610] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[0611] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[0612] - about 0 to 0.5% of a glidant; and

[0613] - About 0-5% coating agent.

[0614] Scheme 22. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 300 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate), which comprises the following amounts of each component by weight:

[0615] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0616] - about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[0617] - about 0-70% filler, such as microcrystalline cellulose;

[0618] - about 2-8% of a binder, such as hydroxypropylcellulose;

[0619] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[0620] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[0621] - about 0 to 0.5% of a glidant; and

[0622] - About 0-5% coating agent.

[0623] Scheme 23. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 300 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate), which comprises the following amounts of each component by weight:

[0624] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0625] - about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[0626] - about 0-70% filler, such as microcrystalline cellulose;

[0627] - about 2-8% of a binder, such as hydroxypropylcellulose;

[0628] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[0629] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[0630] - about 0 to 0.5% of a glidant; and

[0631] - About 0-5% coating agent.

[0632] Scheme 24. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 300 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate), which comprises the following amounts of each component by weight:

[0633] - about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0634] - about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[0635] - about 0-70% filler, such as microcrystalline cellulose;

[0636] - about 2-8% of a binder, such as hydroxypropylcellulose;

[0637] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[0638] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[0639] - about 0 to 0.5% of a glidant; and

[0640] - About 0-5% coating agent.

[0641] Scheme 25. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 150 mg of a solid dispersion, about 101.93 mg of canagliflozin hemihydrate, about 294.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.00 mg of croscarmellose sodium, about 6.00 mg of magnesium stearate and about 18.00 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0642] Scheme 26. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 100 mg of a solid dispersion, about 101.93 mg of canagliflozin hemihydrate, about 344.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.00 mg of croscarmellose sodium, about 6.00 mg of magnesium stearate and about 18.00 mg of opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[0643] Scheme 27. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 200 mg of a solid dispersion, about 101.93 mg of canagliflozin hemihydrate, about 244.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.0 mg of croscarmellose sodium, about 6.00 mg of magnesium stearate and about 18.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 100 mg of HMS5552.

[0644] Scheme 28. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 150 mg of a solid dispersion, about 305.78 mg of canagliflozin hemihydrate, about 226.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate and about 22.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0645] Scheme 29. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 100 mg of a solid dispersion, about 305.78 mg of canagliflozin hemihydrate, about 276.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate and about 22.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[0646] Scheme 30. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 18, comprising about 50 mg of a solid dispersion, about 305.78 mg of canagliflozin hemihydrate, about 326.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate and about 22.50 mg of Opadry, wherein the solid dispersion comprises HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 25 mg of HMS5552.

[0647] Scheme 31. A method for the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 30, which comprises blending the active ingredient with one or more excipients for granulation, preferably further filling the obtained granular mixture into a vial, a pouch or a capsule or compressing it into a desired tablet shape; more preferably further coating the obtained tablet.

[0648] Scheme 32. A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation of Scheme 31, wherein the preparation is carried out by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[0649] Embodiment 33. The method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation according to any one of Embodiments 31 to 32, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[0650] Scheme 34. A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose combination preparation according to any one of Schemes 31 to 33, wherein the glucokinase activator and a second or more active ingredients can also be prepared together in the form of a compound solid dispersion (i.e., a solid dispersion containing two or more active ingredients).

[0651] Embodiment 35. The drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1 to 30 is used to prevent, slow the progression of, delay or treat one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or to improve blood sugar control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or to prevent, slow, delay or reverse diabetic complications.

[0652] Scheme 36. A method for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance and, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications, comprising administering to a subject a therapeutically effective amount of the drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-30.

[0653] Scheme 37. Use of the drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1-30 for the preparation of a medicament for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the following, or preventing, slowing, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and / or metabolic syndrome; or improving blood sugar control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

[0654] The following examples further describe and illustrate the embodiments within the scope of the present invention. However, the present invention is not limited to the examples, and several modifications and substitutions made on the technical basis of the present invention all belong to the protection scope of the present invention. Example

[0655] Preparation of compound tablets of glucokinase activator

[0656] Chemicals used in the present invention can be purchased from companies such as Shin-Etsu Japan, Evonik Germany, JTBaker US, SCR China, Ashland US, FMC US, JRS Germany, Colorcon US, Capsugel, BASF, Zhenxing Reagent, etc. Production equipment and analytical testing instruments can be purchased from such companies as Sartorius, Nikon, Sympatec, Bruker, Gea Niro, Korsch, Erweka, Agilent, Quadro Engineering, Canada; Warters, US; TA, US; SOTAX, Switzerland; Mettler Toledo Instrument Newark, DE.

[0657] I. Preparation of Solid Dispersion of Glucokinase Activator

[0658] 1.1 Preparation of solid dispersion solution before spray drying

[0659] Example 1A (weight ratio of active ingredient to polymer is 1:9)

[0660] Weigh 6.75 g of Eudragit L100 (Evonik Germany), add it to anhydrous ethanol (JTBaker) under stirring, add 0.75 g of compound HMS5552 after it is completely dissolved, add enough anhydrous ethanol and continue stirring to obtain 50 ml of solution.

[0661] Example 2A (weight ratio of active ingredient to polymer is 3:7)

[0662] 5.25 g of Eudragit L100 (Evonik Germany) was weighed and added to anhydrous ethanol (JTBaker) under stirring. After it was completely dissolved, 2.25 g of compound HMS5552 was added. After adding enough anhydrous ethanol, stirring was continued to obtain 50 ml of solution.

[0663] Example 3A (weight ratio of active ingredient to polymer is 5:5)

[0664] Weigh 3.75 g of Eudragit L100 (Evonik Germany), add it to anhydrous ethanol (JTBaker / ) under stirring, add 3.75 g of compound HMS5552 after it is completely dissolved, add enough anhydrous ethanol and continue stirring to obtain 50 ml of solution.

[0665] Example 4A (weight ratio of active ingredient to polymer is 7:3)

[0666] Weigh 2.25 g of Eudragit L100 (Evonik Germany), add it to anhydrous ethanol (JTBaker) under stirring, and add 5.25 g of compound HMS5552 after it is completely dissolved. After adding enough anhydrous ethanol, continue stirring to obtain 50 ml of solution.

[0667] Example 5A (weight ratio of active ingredient to polymer is 8:2)

[0668] 1.5 g of Eudragit L100 (Evonik Germany) was weighed and added to anhydrous ethanol (JTBaker) under stirring. After it was completely dissolved, 6 g of compound HMS5552 was added. After adding enough anhydrous ethanol, stirring was continued to obtain 50 ml of solution.

[0669] Example 6A (weight ratio of active ingredient to polymer is 9:1)

[0670] 0.75 g of Eudragit L100 (Evonik Germany) was weighed and added to anhydrous ethanol (JTBaker) under stirring. After it was completely dissolved, 6.75 g of compound HMS5552 was added. After adding enough anhydrous ethanol, stirring was continued to obtain 50 ml of solution.

[0671] Example 7A (weight ratio of active ingredient to polymer is 6:4)

[0672] 3.0 g of Eudragit L100 (Evonik Germany) was weighed and added to anhydrous ethanol (JTBaker) under stirring. After it was completely dissolved, 4.5 g of compound HMS5552 was added. After adding enough anhydrous ethanol, stirring was continued to obtain 50 ml of solution.

[0673] Example 8A (weight ratio of active ingredient to polymer is 4:6)

[0674] 4.5 g of Eudragit L100 (Evonik Germany) was weighed and added to anhydrous ethanol (JTBaker) under stirring. After it was completely dissolved, 3.0 g of compound HMS5552 was added. After adding enough anhydrous ethanol, stirring was continued to obtain 50 ml of solution.

[0675] Example 9A (weight ratio of active ingredient to polymer is 5:5)

[0676] 187.5 g of Eudragit L100 (Evonik Germany) was weighed and added to anhydrous ethanol (revitalization reagent) under stirring. After it was completely dissolved, 187.5 g of compound HMS5552 was added and stirring was continued to obtain 2500 ml of solution.

[0677] 1.2 Preparation of solid dispersion of glucokinase activator

[0678] The solution prepared above is spray dried to prepare a solid dispersion of a glucokinase activator. The numbering of the obtained solid dispersion corresponds to the numbering of the above embodiment. Applicable spray drying equipment of the present invention includes but is not limited to spray drying equipment made by Niro GEA Process Engineering Inc., Buchi Labortechnik AG, ProCept and SPXANHYDROUS. Spray drying can be performed by selecting a suitable drying gas inlet temperature, air inlet volume, liquid inlet speed and atomization pressure so that the droplets are fully dried when they reach the wall of the device. This helps to ensure that the dried droplets are substantially solid, can form a fine powder, and will not stick to the wall or be difficult to collect in a cyclone. The obtained powder is subjected to secondary drying to ensure that the product meets the quality requirements.

[0679] Description of the production process of solid dispersion of glucokinase activator prepared by spray drying

[0680] The solutions prepared in Examples 1A-8A were spray dried to prepare solid dispersions, wherein the spray dryer was set with an air inlet temperature of 90-150°C and an air inlet flow rate of 0.3-0.5 m / s. 3 / min, the flow rate of the air flow is 15-30L / min, the spraying speed of the above solution is 5-7mL / min, and the solid dispersion 1-8 is obtained by spray drying.

[0681] The solution prepared in the above Example 9A is spray dried to prepare a solid dispersion, wherein the inlet temperature of the spray dryer is set at 90-150°C, the inlet flow rate is set at 20-30kg / h, the air flow rate is 3-30kg / h, the spray rate of the above solution is 5-200mL / min, and the solid dispersion 9 is obtained by spray drying.

[0682] According to the above method, solid dispersions 1-9 were prepared respectively, wherein:

[0683] The mass fraction of compound HMS5552 in solid dispersion 1 is 10%; the mass fraction of compound HMS5552 in solid dispersion 2 is 30%; the mass fraction of compound HMS5552 in solid dispersion 3 is 50%; the mass fraction of compound HMS5552 in solid dispersion 4 is 70%; the mass fraction of compound HMS5552 in solid dispersion 5 is 80%; the mass fraction of compound HMS5552 in solid dispersion 6 is 90%; the mass fraction of compound HMS5552 in solid dispersion 7 is 60%; the mass fraction of compound HMS5552 in solid dispersion 8 is 40%; and the mass fraction of compound HMS5552 in solid dispersion 9 is 50%.

[0684] II. Preparation of compound tablets

[0685] 2.1 Preparation of compound tablets by high shear wet granulation

[0686] The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the glucokinase activator and the combination drug are added to a high shear wet granulator, and a filler (e.g., microcrystalline cellulose, or silicified microcrystalline cellulose, or lactose) and a disintegrant (e.g., cross-linked sodium carboxymethyl cellulose, or cross-linked polyvinylpyrrolidone, or sodium starch glycolate) are added, and a portion of the binder powder is added and mixed under high shear stirring for 5 minutes. Within 1-6 minutes, the prepared binder (e.g., hydroxypropyl cellulose, or polyvinyl pyrrolidone, or hydroxypropyl methylcellulose) solution is added to the above dry mixture under high shear stirring for granulation. The wet granules are granulated on a Comil granulator to obtain wet granules of suitable size. The wet granules are dried in a tray oven at about 60°C or in a fluidized bed dryer (inlet air temperature 40-60°C) for 20-40 minutes. Then, the dried material is ground using a grinder to obtain particles of suitable size. After grinding, microcrystalline cellulose or silicified microcrystalline cellulose (for fillers with an added portion) and a disintegrant (e.g., cross-linked sodium carboxymethyl cellulose, or cross-linked polyvinylpyrrolidone, or sodium starch glycolate) are added to the granules and mixed in a barrel mixer. Then, a lubricant (magnesium stearate or sodium stearyl fumarate) and / or an optional glidant (micropowdered silica gel) are added thereto and further mixed uniformly. The lubricated mixture is tableted using a rotary tablet press to obtain tablets (plain tablets, uncoated core tablets) of different tablet weights and tablet shapes corresponding to different specifications. The resulting tablets are optionally coated with Film coating was performed to give a weight gain of about 3%, thereby obtaining film-coated tablets.

[0687] Example 1B HMS5552 + Empagliflozin Compound Tablets (Dosage Specification 75 mg / 5 mg)

[0688] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 5.00 1.92 HMS5552 solid dispersion* 150.00 57.69 Microcrystalline Cellulose 88.10 33.88 Hydroxypropyl Cellulose 7.80 3.00 Croscarmellose Sodium 6.50 2.50 Magnesium Stearate 2.60 1.00 Total weight of core 260.0 100.0 Obaday 7.80 3.00 Total weight of coated tablets 267.80 --

[0689] *150.00 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552.

[0690] Example 2B HMS5552 + Empagliflozin compound tablets (dosage specification 75 mg / 12.5 mg)

[0691] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 12.50 4.46 HMS5552 solid dispersion* 150.00 53.57 Microcrystalline Cellulose 99.30 35.47 Hydroxypropyl Cellulose 8.40 3.00 Croscarmellose Sodium 7.00 2.50 Magnesium Stearate 2.80 1.00 Total weight of core 280.00 100.0 Obaday 8.40 3.00 Total weight of coated tablets 288.40 --

[0692] *150.0 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552.

[0693] Example 3B HMS5552 + Empagliflozin Compound Tablets (Dosage Specification 75 mg / 10 mg)

[0694] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 10.00 3.85 HMS5552 solid dispersion* 150.00 57.69 Microcrystalline Cellulose 84.40 32.46 Hydroxypropyl Cellulose 7.80 3.00 Croscarmellose Sodium 5.20 2.00 Magnesium Stearate 2.60 1.00 Total weight of core 260.00 100.00 Obaday 7.80 3.00 Total weight of coated tablets 267.80 --

[0695] *150.00 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552.

[0696] Example 4B HMS5552 + Empagliflozin Compound Tablets (Dosage Specification 75 mg / 25 mg)

[0697] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 25.00 8.92 HMS5552 solid dispersion* 150.00 53.58 Microcrystalline Cellulose 88.20 31.50 Hydroxypropyl Cellulose 8.40 3.00 Croscarmellose Sodium 5.60 2.00 Magnesium Stearate 2.80 1.00 Total weight of core 280.00 100.00 Obaday 8.40 3.00 Total weight of coated tablets 288.40 --

[0698] *150.00 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552.

[0699] Example 5B HMS5552 + Empagliflozin Compound Tablets (Dosage Specification 100 mg / 10 mg)

[0700] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 10.00 3.33 HMS5552 solid dispersion* 200.00 66.67 Microcrystalline Cellulose 72.00 24.00 Hydroxypropyl Cellulose 9.00 3.00 Croscarmellose Sodium 6.00 2.00 Magnesium Stearate 3.00 1.00 Total weight of core 300.00 100.00 Obaday 9.00 3.00 Total weight of coated tablets 309.00 --

[0701] *200.00 mg HMS5552 solid dispersion is equivalent to 100 mg HMS5552.

[0702] Example 6B HMS5552 + dapagliflozin compound tablets (dosage specification 75 mg / 5 mg)

[0703] Prescription composition Unit prescription amount / mg %(w / w) Dapagliflozin Propylene glycol monohydrate** 6.15 2.36 MS5552 solid dispersion* 150.00 57.70 Microcrystalline Cellulose 88.25 33.94 Hydroxypropyl Cellulose 7.80 3.00 Croscarmellose Sodium 5.20 2.00 Magnesium Stearate 2.60 1.00 Total weight of core 260.00 100.00 Obaday 7.80 3.00 Total weight of coated tablets 267.80 --

[0704] *150.00 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552;

[0705] **6.15 mg of dapagliflozin propylene glycol monohydrate is equivalent to 5.0 mg of dapagliflozin free anhydrate.

[0706] Example 7B HMS5552 + dapagliflozin compound tablets (dosage specification 50 mg / 5 mg)

[0707] Prescription composition Unit prescription amount / mg %(w / w) Dapagliflozin Propylene glycol monohydrate** 6.15 2.80 HMS5552 solid dispersion* 100.00 45.45 Microcrystalline Cellulose 100.65 45.75 Hydroxypropyl Cellulose 6.60 3.00 Croscarmellose Sodium 4.40 2.00 Magnesium Stearate 2.20 1.00 Total weight of core 220.00 100.00 Obaday 6.60 3.00 Total weight of coated tablets 266.60 --

[0708] *100.00 mg HMS5552 solid dispersion is equivalent to 50 mg HMS5552;

[0709] **6.15 mg of dapagliflozin propylene glycol monohydrate is equivalent to 5.0 mg of dapagliflozin free anhydrate.

[0710] Example 8B HMS5552 + dapagliflozin compound tablets (dosage specification 75 mg / 10 mg)

[0711] Prescription composition Unit prescription amount / mg %(w / w) Dapagliflozin Propylene glycol monohydrate** 12.30 4.56 HMS5552 solid dispersion* 150.00 55.56 Microcrystalline Cellulose 91.50 33.89 Hydroxypropyl Cellulose 8.10 3.00 Croscarmellose Sodium 5.40 2.00 Magnesium Stearate 2.70 1.00 Total weight of core 270.00 100.00 Obaday 8.10 3.00 Total weight of coated tablets 278.10 --

[0712] *150.00 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552;

[0713] **12.30 mg of dapagliflozin propylene glycol monohydrate is equivalent to 10 mg of dapagliflozin free anhydrate.

[0714] Example 9B HMS5552 + dapagliflozin compound tablets (dosage specification 100 mg / 5 mg)

[0715] Prescription composition Unit prescription amount / mg %(w / w) Dapagliflozin Propylene glycol monohydrate** 6.15 2.05 HMS5552 solid dispersion* 200.00 66.67 Microcrystalline Cellulose 75.55 25.18 Hydroxypropyl Cellulose 9.00 3.00 Croscarmellose Sodium 6.30 2.00 Magnesium Stearate 3.00 1.00 Total weight of core 300.00 100.00 Obaday 9.00 3.00 Total weight of coated tablets 309.00 --

[0716] *200.00 mg HMS5552 solid dispersion is equivalent to 100 mg HMS5552;

[0717] **6.15 mg of dapagliflozin propylene glycol monohydrate is equivalent to 5.0 mg of dapagliflozin free anhydrate.

[0718] Example 10B HMS5552 + canagliflozin compound tablets (dosage specification 75 mg / 100 mg)

[0719] Prescription composition Unit prescription amount / mg %(w / w) Canagliflozin hemihydrate** 101.93 16.99 HMS5552 solid dispersion* 150.00 25.00 Microcrystalline Cellulose 294.07 49.01 Hydroxypropyl Cellulose 18.00 3.00 Croscarmellose Sodium 30.00 5.00 Magnesium Stearate 6.00 1.00 Total weight of core 600.00 100.00 Obaday 18.00 3.00 Total weight of coated tablets 618.00 --

[0720] *150.00 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552;

[0721] **101.93 mg of canagliflozin hemihydrate is equivalent to 100 mg of canagliflozin free anhydrate.

[0722] Example 11B HMS5552 + canagliflozin compound tablets (dosage specification 50 mg / 100 mg)

[0723] Prescription composition Unit prescription amount / mg %(w / w) Canagliflozin hemihydrate** 101.93 16.99 HMS5552 solid dispersion* 100.00 16.67 Microcrystalline Cellulose 344.07 57.35 Hydroxypropyl Cellulose 18.00 3.00 Croscarmellose Sodium 30.00 5.00 Magnesium Stearate 6.00 1.00 Total weight of core 600.0 100.00 Obaday 18.00 3.00 Total weight of coated tablets 618.00 --

[0724] *100.00 mg HMS5552 solid dispersion is equivalent to 50 mg HMS5552;

[0725] **101.93 mg of canagliflozin hemihydrate is equivalent to 100 mg of canagliflozin free anhydrate.

[0726] Example 12B HMS5552 + canagliflozin compound tablets (dosage specification 100 mg / 100 mg)

[0727]

[0728]

[0729] *200.00 mg HMS5552 solid dispersion is equivalent to 100 mg HMS5552;

[0730] **101.93 mg of canagliflozin hemihydrate is equivalent to 100 mg of canagliflozin free anhydrate.

[0731] Example 13B HMS5552 + canagliflozin compound tablets (dosage specification 75 mg / 300 mg)

[0732] Prescription composition Unit prescription amount / mg %(w / w) Canagliflozin hemihydrate** 305.78 40.77 HMS5552 solid dispersion* 150.00 20.00 Microcrystalline Cellulose 226.72 30.23 Hydroxypropyl Cellulose 22.50 3.00 Croscarmellose Sodium 37.50 5.00 Magnesium Stearate 7.50 1.00 Total weight of core 750.00 100.00 Obaday 22.50 3.00 Total weight of coated tablets 772.50 --

[0733] *200.00 mg HMS5552 solid dispersion is equivalent to 100 mg HMS5552;

[0734] **305.78 mg of canagliflozin hemihydrate is equivalent to 300 mg of canagliflozin free anhydrate.

[0735] Example 14B HMS5552 + canagliflozin compound tablets (dosage specification 50 mg / 300 mg)

[0736] Prescription composition Unit prescription amount / mg %(w / w) Canagliflozin hemihydrate** 305.78 40.77 HMS5552 solid dispersion* 100.00 13.33 Microcrystalline Cellulose 276.72 36.90 Hydroxypropyl Cellulose 22.50 3.00 Croscarmellose Sodium 37.50 5.00 Magnesium Stearate 7.50 1.00 Total weight of core 750.00 100.00 Obaday 22.50 3.00 Total weight of coated tablets 772.50 --

[0737] *100.00 mg HMS5552 solid dispersion is equivalent to 50 mg HMS5552;

[0738] **305.78 mg of canagliflozin hemihydrate is equivalent to 300 mg of canagliflozin free anhydrate.

[0739] Example 15B HMS5552 + canagliflozin compound tablets (dosage specification 25 mg / 300 mg)

[0740]

[0741]

[0742] *50.00 mg HMS5552 solid dispersion is equivalent to 25 mg HMS5552;

[0743] **305.78 mg of canagliflozin hemihydrate is equivalent to 300 mg of canagliflozin free anhydrate.

[0744] 2.2 Preparation of compound tablets by fluidized bed wet granulation

[0745] The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the glucokinase activator and the combination drug are added to a fluidized bed granulator, and an optional filler (e.g., microcrystalline cellulose) is added. The prepared binder (e.g., polyvinyl pyrrolidone) solution is sprayed into the mixture in the fluidized bed for granulation within 20-60 minutes, and then continued to dry in a fluidized bed dryer (inlet air temperature 40-60° C.). Then, the dried material is ground using a grinder to obtain particles of suitable size. After grinding, microcrystalline cellulose or silicified microcrystalline cellulose (for the prescription of the filler with an additional portion) is added to the particles and mixed in a barrel mixer. Then, a lubricant (magnesium stearate) and / or an optional glidant (micropowder silica gel) are added thereto and mixed evenly. The lubricated mixture is tableted using a rotary tablet press to obtain tablets (plain tablets, uncoated cores) of different tablet weights and tablet shapes corresponding to different specifications. The obtained tablets are optionally film-coated with a solid dispersion prepared according to the above-mentioned method for preparing a solid dispersion of a glucokinase activator to increase the weight by about 3%, thereby obtaining film-coated tablets.

[0746] Example 16B HMS5552 + Empagliflozin Compound Tablets (Dosage Specification 50 mg / 10 mg)

[0747] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 10.00 4.50 HMS5552 solid dispersion* 100.00 45.50 Microcrystalline Cellulose 96.80 44.00 Povidone 6.60 3.00 Croscarmellose Sodium 4.40 2.00 Magnesium Stearate 2.20 1.00 Total weight of core 220.00 100.0 Obaday 6.60 3.00 Total weight of coated tablets 226.60 --

[0748] *100.00 mg HMS5552 solid dispersion is equivalent to 50 mg HMS5552;

[0749] 2.3 Preparation of compound tablets by dry granulation

[0750] The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the above-mentioned glucose kinase activator and the combination drug are added to a mixing barrel, and a filler (e.g., microcrystalline cellulose) and a binder (e.g., hydroxypropyl cellulose) are added and mixed evenly. Then, the mixture is rolled by a roller rolling granulator to obtain a strip, which is then crushed and granulated by a grinder to obtain particles of a suitable size. After grinding, optional microcrystalline cellulose or silicified microcrystalline cellulose (for fillers with an added portion) and a disintegrant (e.g., cross-linked sodium carboxymethyl cellulose) are added to the particles and mixed in a barrel mixer. Then, a lubricant (magnesium stearate or sodium stearyl fumarate) and / or an optional glidant (micropowdered silica gel) are added thereto and further mixed evenly. The lubricated mixture is tableted using a rotary tablet press to obtain tablets (plain tablets, uncoated core tablets) of different tablet weights and tablet shapes corresponding to different specifications. The resulting tablets are optionally used Film coating was performed to give a weight gain of about 3%, thereby obtaining film-coated tablets.

[0751] Example 17B HMS5552 + dapagliflozin compound tablets (dosage specification 50 mg / 10 mg)

[0752] Prescription composition Unit prescription amount / mg %(w / w) Dapagliflozin Propylene glycol monohydrate** 12.30 5.13 HMS5552 solid dispersion* 100.00 41.67 Microcrystalline Cellulose 113.06 47.11 Hydroxypropyl Cellulose 7.20 3.00 Croscarmellose Sodium 5.04 2.10 Magnesium Stearate 2.40 1.00 Total weight of core 240.00 100.00 Obaday 7.20 3.00 Total weight of coated tablets 247.20 --

[0753] *150.00 mg HMS5552 solid dispersion is equivalent to 75 mg HMS5552;

[0754] **12.30 mg of dapagliflozin propylene glycol monohydrate is equivalent to 10 mg of dapagliflozin free anhydrate.

[0755] Example 18B HMS5552 + Empagliflozin Compound Tablets (Dosage Specification 50 mg / 25 mg)

[0756] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 25.00 10.40 HMS5552 solid dispersion* 100.00 41.70 Microcrystalline Cellulose 100.30 41.80 Hydroxypropyl Cellulose 7.20 3.00 Croscarmellose Sodium 5.10 2.13 Magnesium Stearate 2.40 1.00 Total weight of core 240.00 100.00 Obaday 7.20 3.00 Total weight of coated tablets 247.20 --

[0757] *100.00 mg HMS5552 solid dispersion is equivalent to 50 mg HMS5552;

[0758] 2.4 Preparation of compound tablets by direct compression of powder mixing

[0759] The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the glucose kinase activator and the combination drug are premixed uniformly according to the principle of geometric increase and added to a mixing barrel, and a filler (e.g., microcrystalline cellulose), a disintegrant (e.g., cross-linked sodium carboxymethyl cellulose) and an optional glidant (microsilica gel) are added to the granules and mixed in a barrel mixer. Then, a lubricant (magnesium stearate or sodium stearyl fumarate) is added thereto and mixed uniformly. The lubricated mixture is tableted using a rotary tablet press to obtain tablets (plain tablets, uncoated core tablets) of different tablet weights and tablet shapes corresponding to different specifications. The resulting tablets are optionally used Film coating was performed to give a weight gain of about 3%, thereby obtaining film-coated tablets.

[0760] The formula composition of the compound tablets described in the above preparation process is:

[0761] Example 19B HMS5552 + Empagliflozin Compound Tablets (Dosage Specification 25 mg / 25 mg)

[0762] Prescription composition Unit prescription amount / mg %(w / w) Empagliflozin 25.00 6.25 HMS5552 solid dispersion* 50.00 12.50 Microcrystalline Cellulose 309.00 77.25 Croscarmellose Sodium 8.00 2.00 Micro powder silica gel 4.00 1.00 Magnesium Stearate 4.00 1.00 Total weight of core 400.00 100.00 Obaday 12.00 3.00 Total weight of coated tablets 412.00 --

[0763] *50.00 mg HMS5552 solid dispersion is equivalent to 25 mg HMS5552.

[0764] Example 20B HMS5552 + dapagliflozin compound tablets (dosage specification 25 mg / 10 mg)

[0765] Prescription composition Unit prescription amount / mg %(w / w) Dapagliflozin Propylene glycol monohydrate** 12.30 3.075 HMS5552 solid dispersion* 50.00 12.50 Microcrystalline Cellulose 313.70 69.04 Hydroxypropyl Cellulose 8.00 2.00 Croscarmellose Sodium 8.00 2.00 Micro powder silica gel 4.00 1.00 Magnesium Stearate 4.00 1.00 Total weight of core 400.00 100.00 Obaday 12.00 3.00 Total weight of coated tablets 412.00 --

[0766] *50.00 mg HMS5552 solid dispersion is equivalent to 25 mg HMS5552;

[0767] **12.30 mg of dapagliflozin propylene glycol monohydrate is equivalent to 10 mg of dapagliflozin free anhydrate.

[0768] III. In vitro dissolution test of compound preparations containing glucokinase activators

[0769] The dissolution of the tablets was tested using the paddle method of the Chinese Pharmacopoeia (2015 edition) to test the dissolution of HMS5552 and another combination drug in a medium at pH 6.8. 5 ml of the sample was taken at 5 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes for HPLC analysis.

[0770] According to the above test method, the above-mentioned several fixed-dose tablets and their corresponding single-ingredient tablets were measured, and the dissolution results are as follows.

[0771] Table 1 Dissolution results of fixed-dose compound tablets prepared in Example 1B

[0772]

[0773] Table 2 Dissolution results of fixed-dose compound tablets prepared in Example 4B

[0774]

[0775] Table 3 Dissolution results of fixed-dose compound tablets prepared in Example 5B

[0776]

[0777] Table 4 Dissolution results of fixed-dose compound tablets prepared in Example 7B

[0778]

[0779] Table 5 Dissolution results of fixed-dose compound tablets prepared in Example 8B

[0780]

[0781] Table 6 Dissolution results of fixed-dose compound tablets prepared in Example 9B

[0782]

[0783] Table 7 Dissolution results of fixed-dose compound tablets prepared in Example 19B

[0784]

[0785] Table 8 Dissolution results of fixed-dose compound tablets prepared in Example 20B

[0786]

[0787] It can be seen from the dissolution results of the above fixed-dose combination preparations that the dissolution of the fixed-dose combination preparations of the present invention meets the requirements of rapid-release preparations.

[0788] IV. Physical properties of compound preparations containing glucokinase activators

[0789] The physical properties of the above-mentioned fixed-dose tablets were tested according to the pharmacopoeia-related instruments and methods, and the results are described as follows.

[0790] Table 9 Physical properties of fixed-dose compound tablet cores prepared in different embodiments

[0791]

[0792] Table 10 Physical properties of fixed-dose composite tablet cores prepared in different embodiments

[0793]

[0794] Table 11 Physical properties of fixed-dose composite tablet cores prepared in different embodiments

[0795]

[0796] Table 12 Physical properties of fixed-dose composite tablet cores prepared in different embodiments

[0797]

[0798] V. Pharmacodynamic study of compound preparations containing glucokinase activators

[0799] Example 1C

[0800] Effects of glucokinase activator and combination drug on glucose / sucrose tolerance in normal mice

[0801] Normal male C57BL / 6J mice were fasted for 6 hours and then orally administered with solvent control, 10 mg / kg empagliflozin, or 10 mg / kg HMS5552 combined with 10 mg / kg empagliflozin. One hour later, 2 g / kg glucose was orally administered. Blood was collected from the tail vein before administration (-60 minutes), before glucose administration (0 minutes), and 15, 30, 60, and 120 minutes after glucose administration to determine the whole blood glucose content. The area under the blood glucose curve (AUC0-120 min, mmol / l*min) from 0 to 120 minutes was analyzed and compared with the changes in the solvent control. The results showed that the hypoglycemic effect of 10 mg / kg HMS5552 combined with 10 mg / kg empagliflozin was significantly better than that of 10 mg / kg empagliflozin monotherapy, with statistical significance (P<0.001).

[0802] Empagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, reduces blood sugar by reducing glucose reabsorption in the kidneys, lowering the renal glucose threshold, and promoting glucose excretion from the urine. It can also reduce cardiovascular risk and cardiovascular death, and is used for type 2 diabetes with cardiovascular disease. HMS5552, a new type of glucokinase activator, can improve islet function, promote incretin secretion, and reduce insulin resistance in patients with type 2 diabetes. It has a dual therapeutic effect of reducing fasting and postprandial blood sugar. SGLT-2 inhibitors combined with HMS5552 have better blood sugar control efficacy and reduce the risk of diabetic complications for patients who fail to control blood sugar with SGLT-2 inhibitors, obese patients, and diabetic patients with cardiovascular disease.

[0803] The above-mentioned effectiveness study on HMS5552 combined with existing oral diabetes drugs (SGLT-2 inhibitors) shows that combined use can improve the efficacy of HMS5552 or existing hypoglycemic drugs, reduce safety risks, and improve medical effects. Developing HMS5552 and existing oral diabetes drugs into an oral fixed-dose combination preparation is currently the most promising compound diabetes treatment drug to address the above clinical needs.

[0804] 1. A drug combination comprising:

[0805] (a) a glucokinase activator, wherein the glucokinase activator is a compound represented by the following formula, or a pharmaceutically acceptable salt, an isotope-labeled substance, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof:

[0806]

[0807]

[0808] (b) SGLT-2 inhibitors;

[0809] The above drugs (a) and (b) are used simultaneously, separately or sequentially.

[0810] 2. The drug combination of technical solution 1, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is about 30:1 to 1:30, preferably about 20:1 to 1:12, and more preferably about 0.75:1, about 1:2, about 1:1, about 1:4, about 1:6, about 1:12, about 2:1, about 2.5:1, about 3:1, about 5:1, about 6:1, about 7.5:1, about 10:1, about 15:1 or about 20:1.

[0811] 3. The drug combination of technical solution 1 or 2, wherein the glucokinase activator is a compound HMS5552 represented by the following formula, or an isotope-labeled substance thereof or a pharmaceutically acceptable salt thereof,

[0812]

[0813] 4. The drug combination of any one of technical solutions 1 to 3, wherein the glucose kinase activator is in the form of a solid dispersion; preferably, the glucose kinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is methacrylic acid copolymer type A (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

[0814] 5. The drug combination of technical solution 4, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6.

[0815] 6. The drug combination described in any one of technical solutions 1 to 5, wherein the SGLT-2 inhibitor is selected from canagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), empagliflozin, iplagliflozin, lupagliflozin and topagliflozin, and pharmaceutically acceptable salts thereof; preferably, the SGLT-2 inhibitor is selected from empagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), and canagliflozin (or canagliflozin hemihydrate).

[0816] 7. The drug combination described in any one of technical solutions 1-6, wherein the glucose kinase activator is present in a dosage (preferably unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg, preferably, wherein the dosage (preferably unit dose) of the glucose kinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0817] 8. The drug combination of any one of technical solutions 1-7, wherein the SGLT-2 inhibitor is present in a dosage (preferably unit dose) range of about 1 mg to 500 mg, preferably about 5 mg to about 300 mg, preferably, the dosage (preferably unit dose) of the SGLT-2 inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 100 mg, about 200 mg or about 300 mg, most preferably about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 100 mg or about 300 mg; preferably, the SGLT-2 inhibitor is empagliflozin, and its dosage is about 1.5 mg to about 300 mg. The amount (preferably unit dose) is about 0.5 mg to about 50 mg, especially about 1 mg to about 25 mg; the preferred dose is about 5 mg, about 10 mg, about 12.5 mg and about 25 mg; preferably, the SGLT-2 inhibitor is dapagliflozin, and the dosage (preferably unit dose) is about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg; preferably about 2.5 mg, about 5 mg and about 10 mg; preferably, the SGLT-2 inhibitor is canagliflozin, and the dosage (preferably unit dose) is about 50 mg to about 500 mg, and the preferred dosage of canagliflozin is about 100 mg and about 300 mg.

[0818] 9. The drug combination according to any one of technical solutions 1 to 8, which is in the form of a pharmaceutical composition.

[0819] 10. The pharmaceutical composition described in technical solution 9 comprises a solid dispersion of a glucokinase activator and an SGLT-2 inhibitor, preferably, the weight ratio of the solid dispersion of the glucokinase activator to the SGLT-2 inhibitor is about 60:1 to 1:15, preferably about 40:1 to 1:6, more preferably about 1.5:1, about 1:1, about 2:1, about 1:2, about 1:3, about 1:6, about 4:1, about 5:1, about 6:1, about 10:1, about 12:1, about 15:1, about 20:1, about 30:1 or about 40:1.

[0820] 11. The pharmaceutical composition of technical solution 9 or 10, wherein the solid dispersion of the glucokinase activator is approximately 1 to 96% by weight; and the SGLT-2 inhibitor is approximately 0.1 to 80% by weight.

[0821] 12. The pharmaceutical composition according to any one of technical solutions 9 to 11, further comprising one or more excipients, preferably, the excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

[0822] 13. The pharmaceutical composition according to any one of technical solutions 9 to 12, which is in a form selected from tablets, capsules, pills and lozenges, preferably tablets, more preferably coated tablets.

[0823] 14. A fixed-dose combination preparation comprising:

[0824] (a) a glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof,

[0825] Isotopically labeled substances, their crystalline forms, hydrates, solvates, diastereomers or enantiomeric forms:

[0826]

[0827]

[0828] (b) SGLT-2 inhibitors;

[0829] (c) one or more excipients.

[0830] 15. The fixed-dose combination preparation of technical solution 14, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is about 30:1 to 1:30, preferably about 20:1 to 1:12, and more preferably about 0.75:1, about 1:2, about 1:1, about 1:4, about 1:6, about 1:12, about 2:1, about 2.5:1, about 3:1, about 5:1, about 6:1, about 7.5:1, about 10:1, about 15:1 or about 20:1.

[0831] 16. The fixed-dose combination preparation of technical solution 14 or 15, wherein the glucokinase activator is about 1 to 96% by weight; and the SGLT-2 inhibitor is about 0.1 to 80% by weight.

[0832] 17. The fixed-dose combination preparation of any one of technical solutions 14-16, wherein the glucokinase activator is a compound HMS5552 represented by the following formula, or an isotope-labeled substance thereof or a pharmaceutically acceptable salt thereof:

[0833]

[0834] 18. The fixed-dose combination preparation of any one of technical solutions 14-17, wherein the glucose kinase activator is in the form of a solid dispersion, preferably, wherein the glucose kinase activator is in the form of a solid dispersion comprising a polymer carrier, and the polymer carrier is methacrylic acid copolymer type A (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

[0835] 19. A fixed-dose combination preparation according to any one of technical solutions 14-18, wherein the weight ratio of the glucose kinase activator to the polymer carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, and more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6.

[0836] 20. A fixed-dose combination preparation of any one of technical solutions 14-19, wherein the SGLT-2 inhibitor is selected from canagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), empagliflozin, iplagliflozin, lupagliflozin and topagliflozin, and pharmaceutically acceptable salts thereof; preferably, the SGLT-2 inhibitor is selected from empagliflozin, dapagliflozin (or dapagliflozin propylene glycol monohydrate), and canagliflozin (or canagliflozin hemihydrate).

[0837] 21. A fixed-dose combination preparation according to any one of technical solutions 14-20, wherein the glucose kinase activator is present in a dosage (preferably unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg, preferably, wherein the dosage (preferably unit dose) of the glucose kinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0838] 22. A fixed-dose combination preparation according to any one of technical solutions 14 to 21, wherein the SGLT-2 inhibitor is present in a dosage (preferably unit dose) range of about 1 mg to 500 mg, preferably about 5 mg to about 300 mg, preferably, the dosage (preferably unit dose) of the SGLT-2 inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 100 mg, about 200 mg or about 300 mg, most preferably about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 100 mg or about 300 mg; preferably, the SGLT-2 inhibitor is empagliflozin , its dosage (preferably unit dosage) is about 0.5 mg to about 50 mg, especially about 1 mg to about 25 mg; the preferred dosage is about 5 mg, about 10 mg, about 12.5 mg and about 25 mg; preferably, the SGLT-2 inhibitor is dapagliflozin, and its dosage (preferably unit dosage) is about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg; preferably about 2.5 mg, about 5 mg and about 10 mg; preferably, the SGLT-2 inhibitor is canagliflozin, and its dosage (preferably unit dosage) is about 50 mg to about 500 mg, and the preferred dosage of canagliflozin is about 100 mg and about 300 mg.

[0839] 23. A fixed-dose combination preparation according to any one of technical solutions 14-22, wherein the weight ratio of the solid dispersion of the glucokinase activator to the SGLT-2 inhibitor is about 60:1 to 1:15, preferably about 40:1 to 1:6, and more preferably about 1.5:1, about 1:1, about 2:1, about 1:2, about 1:3, about 1:6, about 4:1, about 5:1, about 6:1, about 10:1, about 12:1, about 15:1, about 20:1, about 30:1 or about 40:1.

[0840] 24. The fixed-dose combination preparation of technical solution 23, wherein the solid dispersion of the glucokinase activator is approximately 1 to 96% by weight; and the SGLT-2 inhibitor is approximately 0.1 to 50% by weight.

[0841] 25. The fixed-dose combination preparation of any one of technical solutions 14-24, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

[0842] 26. The fixed-dose compound preparation of technical solution 25, wherein the binder is selected from polyvinyl pyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose; the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch or pregelatinized starch; the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or sodium starch glycolate; the lubricant is selected from magnesium stearate or sodium stearyl fumarate; and the glidant is selected from colloidal silicon dioxide or talc.

[0843] 27. The fixed-dose combination preparation of any one of technical solutions 14-26, which is a tablet.

[0844] 28. The fixed-dose combination preparation of technical solution 27, which is a coated tablet.

[0845] 29. The fixed-dose combination preparation of technical solution 28, wherein the coated tablet is a film-coated tablet, wherein the film-coating agent comprises:

[0846] a film coating substrate, such as hydroxypropylcellulose, hydroxypropylmethylcellulose or a mixture thereof;

[0847] optional plasticizers, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or mixtures thereof;

[0848] optional colorants such as red iron oxide, yellow iron oxide, or mixtures thereof;

[0849] Optional sunscreens such as titanium dioxide, and

[0850] Optional glidant.

[0851] 30. The fixed-dose combination preparation of technical solution 29, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.

[0852] 31. The fixed-dose combination preparation of any one of technical solutions 14-30, comprising, by weight:

[0853] - about 1 to 96%, preferably about 1 to 48% of a glucokinase activator, preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0854] - about 0.1 to 80%, preferably about 1 to 50% SGLT-2 inhibitor;

[0855] - about 0 to 80% filler;

[0856] - about 1 to 25% of a binder;

[0857] - about 0 to 15% of a disintegrant;

[0858] - about 0.1 to 10% lubricant;

[0859] - about 0-3% of a glidant; and

[0860] - About 0-5% coating agent.

[0861] 32. The fixed-dose combination preparation of technical solution 31, wherein the dosage of the active ingredient by weight (preferably unit dosage) is:

[0862] about 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[0863] About 5 mg, about 10 mg, about 12.5 mg and about 25 mg of empagliflozin.

[0864] 33. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 5 mg empagliflozin, and comprises the following contents of each component by weight:

[0865] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0866] - about 5 mg of empagliflozin;

[0867] - about 0 to 70% filler;

[0868] - about 2 to 8% of binder;

[0869] - about 1 to 5% disintegrant;

[0870] - About 0.5-3% lubricant;

[0871] - about 0 to 0.5% of a glidant; and

[0872] - About 0-5% coating agent.

[0873] 34. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 12.5 mg empagliflozin, and comprises the following contents of each component by weight:

[0874] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0875] - about 12.5 mg of empagliflozin;

[0876] - about 0 to 70% filler;

[0877] - about 2 to 8% of a binder;

[0878] - about 1 to 5% disintegrant;

[0879] - About 0.5-3% lubricant;

[0880] - about 0 to 0.5% of a glidant; and

[0881] - About 0-5% coating agent.

[0882] 35. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 10 mg empagliflozin, and comprises the following contents of each component by weight:

[0883] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0884] - about 10 mg of empagliflozin;

[0885] - about 0 to 70% filler;

[0886] - about 2 to 8% of a binder;

[0887] - about 1 to 5% disintegrant;

[0888] - About 0.5-3% lubricant;

[0889] - about 0 to 0.5% of a glidant; and

[0890] - About 0-5% coating agent.

[0891] 36. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 25 mg empagliflozin, and comprises the following contents of each component by weight:

[0892] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0893] - about 25 mg of empagliflozin;

[0894] - about 0 to 70% filler;

[0895] - about 2 to 8% of binder;

[0896] - about 1 to 5% disintegrant;

[0897] - About 0.5-3% lubricant;

[0898] - about 0 to 0.5% of a glidant; and

[0899] - About 0-5% coating agent.

[0900] 37. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 25 mg empagliflozin, and comprises the following contents of each component by weight:

[0901] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0902] - about 25 mg of empagliflozin;

[0903] - about 0 to 70% filler;

[0904] - about 2 to 8% of binder;

[0905] - about 1 to 5% disintegrant;

[0906] - About 0.5-3% lubricant;

[0907] - about 0 to 0.5% of a glidant; and

[0908] - About 0-5% coating agent.

[0909] 38. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 10 mg empagliflozin, and comprises the following contents of each component by weight:

[0910] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0911] - about 10 mg of empagliflozin;

[0912] - about 0 to 70% filler;

[0913] - about 2 to 8% of a binder;

[0914] - about 1 to 5% disintegrant;

[0915] - About 0.5-3% lubricant;

[0916] - about 0 to 0.5% of a glidant; and

[0917] - About 0-5% coating agent.

[0918] 39. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 10 mg empagliflozin, and comprises the following contents of each component by weight:

[0919] - about 100 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0920] - about 10 mg of empagliflozin;

[0921] - about 0 to 70% filler;

[0922] - about 2 to 8% of a binder;

[0923] - about 1 to 5% disintegrant;

[0924] - About 0.5-3% lubricant;

[0925] - about 0 to 0.5% of a glidant; and

[0926] - About 0-5% coating agent.

[0927] 40. The fixed-dose combination preparation of technical solution 32, wherein the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 25 mg empagliflozin, and comprises the following contents of each component by weight:

[0928] - about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0929] - about 25 mg of empagliflozin;

[0930] - about 0 to 70% filler;

[0931] - about 2 to 8% of a binder;

[0932] - about 1 to 5% disintegrant;

[0933] - About 0.5-3% lubricant;

[0934] - about 0 to 0.5% of a glidant; and

[0935] - About 0-5% coating agent.

[0936] 41. The fixed-dose combination preparation of technical solution 32, comprising about 150 mg of solid dispersion, about 5.00 mg of empagliflozin, about 88.10 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 6.50 mg of cross-linked carboxymethyl cellulose sodium, about 2.60 mg of magnesium stearate and about 7.80 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 75 mg of HMS5552.

[0937] 42. The fixed-dose combination preparation of technical solution 32 comprises about 150 mg of solid dispersion, about 12.50 mg of empagliflozin, about 99.30 mg of microcrystalline cellulose, about 8.40 mg of hydroxypropyl cellulose, about 7.00 mg of cross-linked carboxymethyl cellulose sodium, about 2.80 mg of magnesium stearate and about 8.40 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0938] 43. The fixed-dose combination preparation of technical solution 32 comprises about 150 mg of solid dispersion, about 10.00 mg of empagliflozin, about 84.40 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 5.20 mg of cross-linked carboxymethyl cellulose sodium, about 2.60 mg of magnesium stearate and about 7.80 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 75 mg of HMS5552.

[0939] 44. The fixed-dose combination preparation of technical solution 32 comprises about 150 mg of solid dispersion, about 25.00 mg of empagliflozin, about 88.20 mg of microcrystalline cellulose, about 8.40 mg of hydroxypropyl cellulose, about 5.60 mg of cross-linked carboxymethyl cellulose sodium, about 2.80 mg of magnesium stearate and about 8.40 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[0940] 45. The fixed-dose combination preparation of technical solution 32 comprises about 200 mg of solid dispersion, about 10.00 mg of empagliflozin, about 72.00 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 6.00 mg of cross-linked carboxymethyl cellulose sodium, about 3.00 mg of magnesium stearate and about 9.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 100 mg of HMS5552.

[0941] 46. ​​The fixed-dose combination preparation of technical solution 32 comprises about 100 mg of solid dispersion, about 10.00 mg of empagliflozin, about 96.80 mg of microcrystalline cellulose, about 6.60 mg of povidone, about 4.40 mg of cross-linked carboxymethyl cellulose sodium, about 2.20 mg of magnesium stearate and about 6.60 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 50 mg of HMS5552.

[0942] 47. The fixed-dose combination preparation of technical solution 32 comprises about 100 mg of solid dispersion, about 25.00 mg of empagliflozin, about 100.30 mg of microcrystalline cellulose, about 7.20 mg of hydroxypropyl cellulose, about 5.10 mg of cross-linked sodium carboxymethyl cellulose, about 2.40 mg of magnesium stearate and about 7.20 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[0943] 48. The fixed-dose combination preparation of technical solution 32, comprising about 50 mg of solid dispersion, about 25.00 mg of empagliflozin, about 309.00 mg of microcrystalline cellulose, about 8.00 mg of cross-linked carboxymethyl cellulose sodium, about 4.00 mg of micropowdered silica gel, about 4.00 mg of magnesium stearate and about 12.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 25 mg of HMS5552.

[0944] 49. The fixed-dose combination preparation of technical solution 31, wherein the dosage of the active ingredient by weight (preferably unit dosage) is:

[0945] about 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[0946] About 2.5 mg, about 5 mg and about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate.

[0947] 50. The fixed-dose combination preparation of technical solution 49, which is a tablet of 75 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight:

[0948] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0949] - about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0950] - about 0 to 70% filler;

[0951] - about 2 to 8% of binder;

[0952] - about 1 to 8% disintegrant;

[0953] - About 0.5-3% lubricant;

[0954] - about 0 to 0.5% of a glidant; and

[0955] - About 0-5% coating agent.

[0956] 51. The fixed-dose combination preparation of technical solution 49, which is a tablet of 75 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight:

[0957] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0958] - about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0959] - about 0 to 70% filler;

[0960] - about 2 to 8% of binder;

[0961] - about 1 to 8% disintegrant;

[0962] - About 0.5-3% lubricant;

[0963] - about 0 to 0.5% of a glidant; and

[0964] - About 0-5% coating agent.

[0965] 52. The fixed-dose combination preparation of technical solution 49, which is a tablet of 50 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight:

[0966] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0967] - about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0968] - about 0 to 70% filler;

[0969] - about 2 to 8% of binder;

[0970] - about 1 to 8% disintegrant;

[0971] - About 0.5-3% lubricant;

[0972] - about 0 to 0.5% of a glidant; and

[0973] - About 0-5% coating agent.

[0974] 53. The fixed-dose combination preparation of technical solution 49, which is a tablet of 50 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight:

[0975] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0976] - about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0977] - about 0 to 70% filler;

[0978] - about 2 to 8% of a binder;

[0979] - about 1 to 8% disintegrant;

[0980] - About 0.5-3% lubricant;

[0981] - about 0 to 0.5% of a glidant; and

[0982] - About 0-5% coating agent.

[0983] 54. The fixed-dose combination preparation of technical solution 49, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following components by weight:

[0984] - about 100 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0985] - about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0986] - about 0 to 70% filler;

[0987] - about 2 to 8% of a binder;

[0988] - about 1 to 8% disintegrant;

[0989] - About 0.5-3% lubricant;

[0990] - about 0 to 0.5% of a glidant; and

[0991] - About 0-5% coating agent.

[0992] 55. The fixed-dose combination preparation of technical solution 49, which is a tablet of 25 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight:

[0993] - about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[0994] - about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;

[0995] - about 0 to 70% filler;

[0996] - about 2 to 8% of binder;

[0997] - about 1 to 8% disintegrant;

[0998] - About 0.5-3% lubricant;

[0999] - about 0 to 0.5% of a glidant; and

[1000] - About 0-5% coating agent.

[1001] 56. The fixed-dose combination preparation of technical solution 49 comprises about 150 mg of a solid dispersion, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 88.25 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 5.20 mg of cross-linked sodium carboxymethyl cellulose, about 2.60 mg of magnesium stearate and 7.80 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[1002] 57. The fixed-dose combination preparation of technical solution 49 comprises about 100 mg of a solid dispersion, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 100.65 mg of microcrystalline cellulose, about 6.60 mg of hydroxypropyl cellulose, about 4.40 mg of cross-linked sodium carboxymethyl cellulose, about 2.20 mg of magnesium stearate and 6.60 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 50 mg of HMS5552.

[1003] 58. The fixed-dose combination preparation of technical solution 49 comprises about 150 mg of a solid dispersion, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 91.50 mg of microcrystalline cellulose, about 8.10 mg of hydroxypropyl cellulose, about 5.40 mg of cross-linked sodium carboxymethyl cellulose, about 2.70 mg of magnesium stearate and 8.10 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1 and contains about 75 mg of HMS5552.

[1004] 59. The fixed-dose combination preparation of technical solution 49 comprises about 200 mg of a solid dispersion, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 75.55 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 6.30 mg of cross-linked sodium carboxymethyl cellulose, about 3.00 mg of magnesium stearate and 9.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 100 mg of HMS5552.

[1005] 60. The fixed-dose combination preparation of technical solution 49, comprising about 100 mg of a solid dispersion, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 113.06 mg of microcrystalline cellulose, about 7.20 mg of hydroxypropyl cellulose, about 5.04 mg of cross-linked sodium carboxymethyl cellulose, about 2.40 mg of magnesium stearate and 7.20 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 50 mg of HMS5552.

[1006] 61. The fixed-dose combination preparation of technical solution 49, comprising about 50 mg of a solid dispersion, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 313.70 mg of microcrystalline cellulose, about 8.00 mg of hydroxypropyl cellulose, about 8.00 mg of cross-linked sodium carboxymethyl cellulose, about 4.00 mg of micropowdered silica gel, about 4.00 mg of magnesium stearate and 12.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 25 mg of HMS5552.

[1007] 62. The fixed-dose combination preparation of technical solution 31, wherein the dosage of the active ingredient by weight (preferably unit dosage) is:

[1008] about 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[1009] About 100 mg and about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate.

[1010] 63. The fixed-dose combination preparation of technical solution 62, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 100 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate, and comprises the following contents of each component by weight:

[1011] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[1012] - about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[1013] - about 0-70% filler, such as microcrystalline cellulose;

[1014] - about 2-8% of a binder, such as hydroxypropylcellulose;

[1015] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[1016] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[1017] - about 0 to 0.5% of a glidant; and

[1018] - About 0-5% coating agent.

[1019] 64. The fixed-dose combination preparation of technical solution 62, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 100 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate, and comprises the following contents of each component by weight:

[1020] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[1021] - about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[1022] - about 0-70% filler, such as microcrystalline cellulose;

[1023] - about 2-8% of a binder, such as hydroxypropylcellulose;

[1024] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[1025] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[1026] - about 0 to 0.5% of a glidant; and

[1027] - About 0-5% coating agent.

[1028] 65. The fixed-dose combination preparation of technical solution 62, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 100 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate, and comprises the following contents of each component by weight:

[1029] - about 100 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[1030] - about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[1031] - about 0-70% filler, such as microcrystalline cellulose;

[1032] - about 2-8% of a binder, such as hydroxypropylcellulose;

[1033] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[1034] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[1035] - about 0 to 0.5% of a glidant; and

[1036] - About 0-5% coating agent.

[1037] 66. The fixed-dose combination preparation of technical solution 62, which is a tablet of 75 mg HMS5552 / 300 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate, and comprises the following contents of each component by weight:

[1038] - about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[1039] - about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[1040] - about 0-70% filler, such as microcrystalline cellulose;

[1041] - about 2-8% of a binder, such as hydroxypropylcellulose;

[1042] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[1043] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[1044] - about 0 to 0.5% of a glidant; and

[1045] - About 0-5% coating agent.

[1046] 67. The fixed-dose combination preparation of technical solution 62, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 300 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate, and comprises the following contents of each component by weight:

[1047] - about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[1048] - about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[1049] - about 0-70% filler, such as microcrystalline cellulose;

[1050] - about 2-8% of a binder, such as hydroxypropylcellulose;

[1051] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[1052] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[1053] - about 0 to 0.5% of a glidant; and

[1054] - About 0-5% coating agent.

[1055] 68. The fixed-dose combination preparation of technical solution 62, wherein the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 300 mg canagliflozin or a corresponding amount of canagliflozin hemihydrate, and comprises the following contents of each component by weight:

[1056] - about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of about 1:1;

[1057] - about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;

[1058] - about 0-70% filler, such as microcrystalline cellulose;

[1059] - about 2-8% of a binder, such as hydroxypropylcellulose;

[1060] - about 1-5% of a disintegrant, such as croscarmellose sodium;

[1061] - about 0.5-3% of a lubricant, such as sodium stearyl fumarate or magnesium stearate;

[1062] - about 0 to 0.5% of a glidant; and

[1063] - About 0-5% coating agent.

[1064] 69. The fixed-dose combination preparation of technical solution 62, comprising about 150 mg of a solid dispersion, about 101.93 mg of canagliflozin hemihydrate, about 294.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.00 mg of cross-linked sodium carboxymethyl cellulose, about 6.00 mg of magnesium stearate and about 18.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 75 mg of HMS5552.

[1065] 70. The fixed-dose combination preparation of technical solution 62, comprising about 100 mg of a solid dispersion, about 101.93 mg of canagliflozin hemihydrate, about 344.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.00 mg of cross-linked sodium carboxymethyl cellulose, about 6.00 mg of magnesium stearate and about 18.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 50 mg of HMS5552.

[1066] 71. The fixed-dose combination preparation of technical solution 62, comprising about 200 mg of a solid dispersion, about 101.93 mg of canagliflozin hemihydrate, about 244.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.0 mg of cross-linked sodium carboxymethyl cellulose, about 6.00 mg of magnesium stearate and about 18.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 100 mg of HMS5552.

[1067] 72. The fixed-dose combination preparation of technical solution 62, comprising about 150 mg of a solid dispersion, about 305.78 mg of canagliflozin hemihydrate, about 226.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of cross-linked sodium carboxymethyl cellulose, about 7.50 mg of magnesium stearate and about 22.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 75 mg of HMS5552.

[1068] 73. The fixed-dose combination preparation of technical solution 62, comprising about 100 mg of a solid dispersion, about 305.78 mg of canagliflozin hemihydrate, about 276.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of cross-linked sodium carboxymethyl cellulose, about 7.50 mg of magnesium stearate and about 22.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 50 mg of HMS5552.

[1069] 74. The fixed-dose combination preparation of technical solution 62 comprises about 50 mg of a solid dispersion, about 305.78 mg of canagliflozin hemihydrate, about 326.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of cross-linked sodium carboxymethyl cellulose, about 7.50 mg of magnesium stearate and about 22.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 25 mg of HMS5552.

[1070] 75. A method for preparing a fixed-dose combination preparation according to any of the preceding technical solutions, the method comprising blending an active ingredient with one or more excipients for granulation, preferably further filling the obtained granular mixture into a vial, a pouch or a capsule or compressing it into a desired tablet shape; more preferably further coating the obtained tablet.

[1071] 76. The method for preparing a fixed-dose combination preparation of technical solution 75, wherein the preparation is by wet granulation (high shear and / or fluidized bed) or by dry processing (direct compression or dry granulation).

[1072] 77. The method for preparing a fixed-dose combination preparation according to any one of technical solutions 75-76, wherein the glucose kinase activator is prepared in the form of a solid dispersion.

[1073] 78. The method for preparing a fixed-dose combination preparation according to any one of technical solutions 75-77, wherein the glucokinase activator and a second or more active ingredients are prepared together in the form of a compound solid dispersion.

[1074] 79. A drug combination or a drug composition as described in any one of technical solutions 1-13 or a fixed-dose combination preparation as described in any one of technical solutions 14-74, which is used to prevent, slow the progression of, delay or treat one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function, and / or metabolic syndrome; or to improve blood sugar control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or to prevent, slow, delay or reverse diabetic complications.

[1075] 80. A method for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the following: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, renal impairment and / or metabolic syndrome; or improving blood sugar control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications, comprising administering to a subject a therapeutically effective amount of the drug combination or pharmaceutical composition described in any one of technical solutions 1-13 or the fixed-dose combination preparation described in any one of technical solutions 14-74.

[1076] 81. Use of the drug combination or pharmaceutical composition described in any one of technical solutions 1-13 or the fixed-dose combination preparation described in any one of technical solutions 14-74 in the preparation of a medicament for preventing one or more metabolic disorders selected from the following, slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder, or preventing, slowing, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, renal impairment and / or metabolic syndrome; or improving blood sugar control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

Claims

1. A drug combination comprising: (a) a glucokinase activator, wherein the glucokinase activator is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof: (b) an SGLT-2 inhibitor, which is dapagliflozin or a pharmaceutically acceptable salt thereof; The weight ratio of the glucokinase activator to the SGLT-2 inhibitor is 20:1 to 1:

1.

2. The pharmaceutical combination of claim 1, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is 1:1, 2:1, 2.5:1, 3:1, 5:1, 6:1, 7.5:1, 10:1, 15:1 or 20:

1.

3. The pharmaceutical combination of claim 1, wherein The glucokinase activator is a compound HMS5552 represented by the following formula:

4. The pharmaceutical combination of claim 1, wherein the glucokinase activator is in the form of a solid dispersion.

5. The pharmaceutical combination of claim 1, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, wherein the polymer carrier is methacrylic acid copolymer type A.

6. The pharmaceutical combination of claim 1, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, wherein the polymer carrier is an anionic copolymer of methacrylic acid and methyl methacrylate (1:1).

7. The pharmaceutical combination of claim 1, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, wherein the polymer carrier is Eudragit.

8. The pharmaceutical combination of claim 1, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, wherein the polymer carrier is Eudragit L100.

9. The pharmaceutical combination according to any one of claims 5 to 8, wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:10 to 10:

1.

10. The pharmaceutical combination of any one of claims 5-8, wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, 4:5 to 5:4 or 5:6 to 6:

5.

11. The pharmaceutical combination of any one of claims 5 to 8, wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:1, 2:3, 3:4, 4:5 or 5:

6.

12. The pharmaceutical combination of claim 1, wherein the SGLT-2 inhibitor is selected from dapagliflozin or dapagliflozin propylene glycol monohydrate.

13. The pharmaceutical combination of claim 1, wherein the glucokinase activator is present in a dosage range of 1 mg to 200 mg.

14. The pharmaceutical combination of claim 1, wherein the glucokinase activator is present in a dosage range of 25 mg to 100 mg.

15. The pharmaceutical combination of claim 1, wherein the dosage of the glucokinase activator is 25 mg, 50 mg, 75 mg or 100 mg.

16. The pharmaceutical combination of claim 1, wherein the dosage of the SGLT-2 inhibitor is 1 mg to 50 mg.

17. The pharmaceutical combination of claim 1, wherein the dosage of the SGLT-2 inhibitor is 2.5 mg, 5 mg, 10 mg or 25 mg.

18. The pharmaceutical combination of claim 1, wherein the dosage of the SGLT-2 inhibitor is 2.5 mg, 5 mg or 10 mg.

19. The pharmaceutical combination according to any one of claims 13 to 18, wherein the dosage is a unit dose.

20. A pharmaceutical composition comprising the pharmaceutical combination according to any one of claims 1 to 19.

21. The pharmaceutical composition of claim 20, comprising a solid dispersion of a glucokinase activator and a SGLT-2 inhibitor.

22. The pharmaceutical composition of claim 21, wherein the weight ratio of the solid dispersion of glucokinase activator to the SGLT-2 inhibitor is 40:1 to 2:

1.

23. The pharmaceutical composition of claim 21, wherein the weight ratio of the solid dispersion of glucokinase activator to the SGLT-2 inhibitor is 2:1, 4:1, 5:1, 6:1, 10:1, 12:1, 15:1, 20:1, 30:1 or 40:

1.

24. The pharmaceutical composition of claim 21, wherein the solid dispersion of the glucokinase activator is 1 to 96% by weight; and the solid dispersion of the SGLT-2 inhibitor is 0.1 to 80% by weight.

25. The pharmaceutical composition of claim 20, further comprising one or more excipients.

26. The pharmaceutical composition of claim 25, wherein the excipient is selected from a binder, a filler, a disintegrant, a lubricant, a glidant, a surfactant, a wetting agent, an antioxidant, a flavoring agent, a sweetener, a coloring agent or a coating agent.

27. The pharmaceutical composition of claim 20, which is in a form selected from the group consisting of tablets, capsules, pills and lozenges.

28. The pharmaceutical composition of claim 27, which is a tablet.

29. The pharmaceutical composition of claim 27, which is a coated tablet.

30. A fixed-dose combination preparation comprising: (a) a glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof: (b) an SGLT-2 inhibitor, which is dapagliflozin or a pharmaceutically acceptable salt thereof; (c) one or more excipients; The weight ratio of the glucokinase activator to the SGLT-2 inhibitor is 20:1 to 1:

1.

31. The fixed-dose combination preparation of claim 30, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is 1:1, 2:1, 2.5:1, 3:1, 5:1, 6:1, 7.5:1, 10:1, 15:1 or 20:

1.

32. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is 1-96% by weight; the SGLT-2 inhibitor is 0.1-80% by weight.

33. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is a compound HMS5552 represented by the following formula:

34. The fixed-dose combination formulation of claim 30, wherein the glucokinase activator is in the form of a solid dispersion.

35. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is methacrylic acid copolymer type A.

36. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is an anionic copolymer of methacrylic acid and methyl methacrylate (1:1).

37. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is Eudragit.

38. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is Eudragit L100.

39. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the weight ratio of the glucokinase activator to the polymer carrier is 1:10 to 10:

1.

40. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the weight ratio of the glucokinase activator to the polymer carrier is 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, 4:5 to 5:4 or 5:6 to 6:

5.

41. The fixed-dose combination preparation of claim 30, wherein The glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the weight ratio of the glucokinase activator to the polymer carrier is 1:1, 2:3, 3:4, 4:5 or 5:

6.

42. The fixed-dose combination formulation of claim 30, wherein the SGLT-2 inhibitor is selected from dapagliflozin or dapagliflozin propylene glycol monohydrate.

43. The fixed dose combination formulation of claim 30, wherein the glucokinase activator is present in a dosage range of 1 mg to 200 mg.

44. The fixed dose combination formulation of claim 30, wherein the glucokinase activator is present in a dosage range of 25 mg to 100 mg.

45. The fixed-dose combination formulation of claim 30, wherein the dose of the glucokinase activator is 25 mg, 50 mg, 75 mg or 100 mg.

46. ​​The fixed-dose combination preparation of claim 30, wherein the dosage of the SGLT-2 inhibitor is 1 mg to 50 mg.

47. The fixed-dose combination formulation of claim 30, wherein the dose of the SGLT-2 inhibitor is 2.5 mg, 5 mg, 10 mg or 25 mg.

48. The fixed-dose combination preparation of claim 30, wherein the dose of the SGLT-2 inhibitor is 2.5 mg, 5 mg or 10 mg.

49. The fixed-dose combination preparation according to any one of claims 30 to 48, wherein The glucokinase activator is in the form of a solid dispersion, and the weight ratio of the solid dispersion of the glucokinase activator to the SGLT-2 inhibitor is 40:1 to 2:

1.

50. The fixed-dose combination preparation of any one of claims 30 to 48, wherein The glucokinase activator is in the form of a solid dispersion, and the weight ratio of the solid dispersion of the glucokinase activator to the SGLT-2 inhibitor is 2:1, 4:1, 5:1, 6:1, 10:1, 12:1, 15:1, 20:1, 30:1 or 40:

1.

51. The fixed-dose combination preparation of claim 34, wherein the solid dispersion of the glucokinase activator is 1 to 96% by weight; and the solid dispersion of the SGLT-2 inhibitor is 0.1 to 50% by weight.

52. The fixed-dose combination formulation of claim 30, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

53. The fixed-dose combination formulation of claim 52, wherein the binder is selected from polyvinyl pyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose; the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch or pregelatinized starch; the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or sodium starch glycolate; the lubricant is selected from magnesium stearate or sodium stearyl fumarate; and the glidant is selected from colloidal silicon dioxide or talc.

54. The fixed-dose combination preparation of claim 30, which is a tablet.

55. The fixed-dose combination preparation of claim 54, which is a coated tablet.

56. The fixed-dose combination preparation of claim 55, wherein the coated tablet is a film-coated tablet, wherein the film-coating agent comprises: A film coating substrate selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof; an optional plasticizer selected from polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or mixtures thereof; an optional colorant selected from red iron oxide, yellow iron oxide, or mixtures thereof; Optional sunscreen selected from titanium dioxide, and Optional glidant.

57. The fixed-dose combination preparation of claim 56, wherein the coated tablet is a film-coated tablet, wherein the film-coating agent is Opadry.

58. The fixed-dose combination formulation of claim 30, comprising, by weight: -1~96% glucokinase activator; -0.1~80% SGLT-2 inhibitor; -0 to 80% filler; -1 to 25% adhesive; -0-15% disintegrant; - 0.1 to 10% lubricant; and -0~3% flow aid.

59. The fixed-dose combination preparation of claim 58, comprising 1 to 48% by weight of the glucokinase activator.

60. The fixed-dose combination formulation of claim 58, wherein the glucokinase activator is HMS5552.

61. The fixed-dose combination formulation of claim 58, wherein the glucokinase activator is a solid dispersion of HMS5552.

62. The fixed-dose combination formulation of claim 58, wherein the glucokinase activator is a solid dispersion comprising HMS5552 and a polymer carrier.

63. The fixed-dose combination formulation of claim 58, wherein the glucokinase activator is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio.

64. The fixed-dose combination preparation of claim 58, comprising 1 to 50% by weight of the SGLT-2 inhibitor.

65. The fixed-dose combination formulation of claim 58, wherein the dosage of the active ingredient is, by weight: 25 mg, 50 mg, 75 mg or 100 mg of HMS5552; 2.5 mg, 5 mg or 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate.

66. The fixed-dose combination preparation of claim 65, which is a tablet of 75 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 75 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate.

67. The fixed-dose combination preparation of claim 65, which is a tablet of 75 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 75 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -10 mg of dapagliflozin or the corresponding amount of dapagliflozin propylene glycol monohydrate.

68. The fixed-dose combination preparation of claim 65, which is a tablet of 50 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 50 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate.

69. The fixed-dose combination preparation of claim 65, which is a tablet of 50 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 50 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -10 mg of dapagliflozin or the corresponding amount of dapagliflozin propylene glycol monohydrate.

70. The fixed-dose combination preparation of claim 65, which is a tablet of 100 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 100 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate.

71. The fixed-dose combination preparation of claim 65, which is a tablet of 25 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 25 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -10 mg of dapagliflozin or the corresponding amount of dapagliflozin propylene glycol monohydrate.

72. The fixed-dose combination preparation of claim 65, which is a tablet of 25 mg HMS5552 / 5 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 25 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate.

73. The fixed-dose combination preparation of claim 65, which is a tablet of 100 mg HMS5552 / 10 mg dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate, and comprises the following contents of each component by weight: - 100 mg of HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit L100; and -10 mg of dapagliflozin or the corresponding amount of dapagliflozin propylene glycol monohydrate.

74. The fixed-dose combination formulation of claim 65, comprising 150 mg of a solid dispersion, 6.15 mg of dapagliflozin propylene glycol monohydrate, 88.25 mg of microcrystalline cellulose, 7.80 mg of hydroxypropyl cellulose, 5.20 mg of cross-linked sodium carboxymethyl cellulose and 2.60 mg of magnesium stearate, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a 1:1 ratio and contains 75 mg of HMS5552.

75. The fixed-dose combination formulation of claim 65, comprising 100 mg of a solid dispersion, 6.15 mg of dapagliflozin propylene glycol monohydrate, 100.65 mg of microcrystalline cellulose, 6.60 mg of hydroxypropyl cellulose, 4.40 mg of cross-linked sodium carboxymethyl cellulose and 2.20 mg of magnesium stearate, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a 1:1 ratio and contains 50 mg of HMS5552.

76. The fixed-dose combination formulation of claim 65, comprising 150 mg of a solid dispersion, 12.30 mg of dapagliflozin propylene glycol monohydrate, 91.50 mg of microcrystalline cellulose, 8.10 mg of hydroxypropyl cellulose, 5.40 mg of cross-linked sodium carboxymethyl cellulose and 2.70 mg of magnesium stearate, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a 1:1 ratio and contains 75 mg of HMS5552.

77. The fixed-dose combination formulation of claim 65, comprising 200 mg of a solid dispersion, 6.15 mg of dapagliflozin propylene glycol monohydrate, 75.55 mg of microcrystalline cellulose, 9.00 mg of hydroxypropyl cellulose, 6.30 mg of cross-linked sodium carboxymethyl cellulose and 3.00 mg of magnesium stearate, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a 1:1 ratio and contains 100 mg of HMS5552.

78. The fixed-dose combination formulation of claim 65, comprising 100 mg of a solid dispersion, 12.30 mg of dapagliflozin propylene glycol monohydrate, 113.06 mg of microcrystalline cellulose, 7.20 mg of hydroxypropyl cellulose, 5.04 mg of cross-linked sodium carboxymethyl cellulose and 2.40 mg of magnesium stearate, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a 1:1 ratio and contains 50 mg of HMS5552.

79. The fixed-dose combination formulation of claim 65, comprising 50 mg of a solid dispersion, 12.30 mg of dapagliflozin propylene glycol monohydrate, 313.70 mg of microcrystalline cellulose, 8.00 mg of hydroxypropyl cellulose, 8.00 mg of cross-linked sodium carboxymethyl cellulose, 4.00 mg of micropowdered silica gel, and 4.00 mg of magnesium stearate, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a 1:1 ratio and contains 25 mg of HMS5552.

80. Use of the pharmaceutical combination of any one of claims 1-19 or the pharmaceutical composition of any one of claims 20-29 in the preparation of a medicament for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the following, or preventing, slowing, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, renal impairment and / or metabolic syndrome; or improving blood sugar control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

81. Use of a combination of a glucokinase activator and an SGLT-2 inhibitor in the preparation of a medicament for preventing, slowing down the progression of, delaying or treating one or more metabolic disorders selected from the following, or preventing, slowing down, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, renal impairment and / or metabolic syndrome; or improving blood sugar control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; wherein the glucokinase activator is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof: The SGLT-2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof; The weight ratio of the glucokinase activator to the SGLT-2 inhibitor is 20:1 to 1:1.

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