Drug combination containing a glucokinase activator and a DPP-IV inhibitor, and 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 thereof, a hydrate, a solvate, a diastereoisomer or an enantiomer form, and a DPP-IV inhibitor. The present invention further relates to a pharmaceutical composition, a fixed-dose combination preparation, and a preparation method and use of the pharmaceutical composition and the fixed-dose combination preparation.

Description

[0001] This application is a divisional application of the patent application for invention with the application date of May 28, 2019, application number 201910453079.6, and invention title "Drug combination containing glucokinase activator and DPP-IV inhibitor, its preparation method and use".

[0002] Priority Claim

[0003] This application claims the priority of Chinese Patent Application No. 201810556685.6 with the application date of May 31, 2018, and the entire disclosure thereof is incorporated herein by reference. Technical Field

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

[0005] In more detail, the present invention relates to an oral solid preparation of a drug combination, pharmaceutical composition or fixed dose combination comprising a glucokinase activator drug and a partner drug, and its preparation method. The present invention also relates to the use of a drug combination, pharmaceutical composition or fixed dose combination 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 cognitive dysfunction, memory dysfunction, Alzheimer's disease, impaired glucose tolerance, impaired fasting glucose, 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, which includes administering a therapeutically effective amount of the drug combination, pharmaceutical composition or fixed dose combination preparation of the present invention to a subject in need thereof. Background Art

[0006] Diabetes has become a universal disease worldwide, with the current global patient population reaching 425 million, and the number of patients in China being as high as 120 million (International Diabetes Federation, Diabetes Atlas, 2015). Type II diabetes, namely non-insulin dependent diabetes mellitus (NIDDM), accounts for more than 90% of diabetes patients. Type II diabetes is a chronic metabolic disorder of hyperglycemia caused by the imbalance of blood glucose homeostasis in the human body due to insulin secretion disorders and insulin resistance. The balance of human blood glucose is mainly coordinated by two glucose-regulating hormones, insulin and glucagon.

[0007] The glucose sensor glucokinase (GK) senses blood glucose changes and regulates the secretion of the messenger glucose-regulating hormones, insulin, glucagon, and GLP-1 (glucagon-like peptide-1), constituting the sensing system for the regulation of human blood glucose homeostasis. The glucose uptake controlled by glucose-regulating hormones during glucose storage and glucose supply during fasting constitute the regulation of human blood glucose homeostasis. The organs involved in glucose storage mainly include the liver, muscle, and fat, which take up glucose under the action of blood glucose and insulin and convert it into 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 glucose and glucagon. Insulin can also effectively regulate the activity of the sodium-glucose cotransporter SGLT-2. When blood glucose rises, it reabsorbs the glucose excreted by the kidneys for use in human glucose storage. Glucose uptake, glycogen output, and the use of glucose by each organ constitute the operating system for the balance of human blood glucose homeostasis. The coordinated operation of the glucose sensing system and the operating system constitutes the stochastic regulation of human blood glucose homeostasis.

[0008] In diabetes patients, due to the impaired function and expression of glucokinase, the sensor function is disordered, resulting in the disorder of the early-phase secretion of glucose-regulating hormones, affecting glucose uptake and output, and causing postprandial hyperglycemia and preprandial hypoglycemia. The abnormal signal instructions of glucose-regulating hormones cause the abnormal function and expression of key proteins in the glucose uptake and output operation execution system, resulting in abnormal operation and the formation of type II diabetes.

[0009] Existing oral antidiabetic drugs for diabetes usually act on a single glucose-regulating organ and cannot effectively treat the problem of dysregulation of the blood glucose homeostasis system. Glucokinase activators represent a new class of drugs developed for treating or improving 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 antidiabetic drug to address the above clinical needs. SUMMARY OF THE INVENTION

[0010] In the treatment of diabetic patients, the following situation often occurs: the use of DPP-IV inhibitors alone has poor efficacy and cannot control blood glucose at an ideal level, especially after a period of use. In this regard, the present inventors have found that combining a DPP-IV inhibitor with a glucokinase activator can significantly improve the hypoglycemic effect of the DPP-IV inhibitor and reduce the safety risk, thus obtaining the pharmaceutical combination, composition and fixed-dose combination preparation containing a glucokinase activator and a DPP-IV inhibitor of the present invention.

[0011] More specifically, the combined use of different-acting oral antidiabetic drugs can improve the multi-organ function of mid- and late-stage patients and more effectively treat diabetes and its concomitant diseases and complications. It can reduce the number of pills taken by patients and improve patient compliance; reduce the total drug dose to achieve the same therapeutic effect, achieve the maximum drug efficacy with the minimum dose, and has good effects and practical significance for treating or preventing one or more of type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance, obesity, etc.

[0012] On the other hand, the fixed-dose combination preparation of the present invention containing a glucokinase activator and a combination drug (a second or more active pharmaceutical ingredients) not only has a better therapeutic effect than the separate use of these two or more drugs, but also solves the technical challenges usually existing in combination preparations. The fixed-dose combination preparation of the present invention can solve the problems 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 enabling the active ingredients contained in the preparation to be rapidly released in the small intestine pH environment, which is beneficial for the drugs to reach the intestinal, pancreatic islet and liver target organs in a timely or simultaneous manner, realizing the clinical advantage of multi-point synergistic hypoglycemia at one target, and achieving better therapeutic effects and reducing toxic and side effects. Secondly, the fixed-dose combination preparation of the present invention containing a glucokinase activator and a combination drug (a second or more active pharmaceutical ingredients) also has a shorter disintegration time limit, has good dissolution characteristics and / or enables the glucokinase activator to have high bioavailability in patients.

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

[0014]

[0015] Specifically, the present invention further provides a pharmaceutical combination, pharmaceutical composition, or fixed-dose combination preparation comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a DPP-IV inhibitor. Further, examples of the DPP-IV inhibitor include, but are not limited to, sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, denagliptin, megliptin, gosigliptin, teneligliptin, dulaglutide, and pharmaceutically acceptable salts thereof. Among them, sitagliptin, saxagliptin, vildagliptin, and linagliptin are preferred.

[0016] More specifically, the present invention further provides a solid preparation 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 sitagliptin. The solid preparation 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 further provides a solid preparation 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 vildagliptin. The solid preparation 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 further provides a solid preparation 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 saxagliptin. The solid preparation 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] More specifically, the present invention further provides a solid preparation of a fixed-dose combination comprising a glucokinase activator drug HMS5552 or a pharmaceutically acceptable salt thereof and a combination drug such as linagliptin. The solid preparation 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.

[0020] The present invention also provides a pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients) prepared by a dry or wet processing method. The release mode of the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of the present invention is the rapid release of the two or more active pharmaceutical ingredients.

[0021] The present invention also provides a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients), which has a short disintegration time limit, 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 (second or more active pharmaceutical ingredients, such as sitagliptin, saxagliptin, vildagliptin and linagliptin) by a dry or wet processing method. The dry processing method includes dry compression (tabletting) and dry granulation; the wet processing method includes wet granulation.

[0022] The present invention also provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients), and a method for preventing a metabolic disorder (especially type II diabetes), slowing down its progression, delaying or treating the metabolic disorder.

[0023] The present invention also provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients), and a method for improving blood glucose control in a patient in need (especially a patient suffering from type II diabetes).

[0024] The present invention also provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising a glucokinase activator drug and a combination drug, and a method for improving blood glucose control in a patient with insufficient blood glucose control.

[0025] The present invention also provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising a glucokinase activator drug and a combination drug, and a method for preventing, slowing down or delaying the progression of diabetic cognitive dysfunction, memory dysfunction, Alzheimer's disease, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hypertension, insulin resistance and / or metabolic syndrome into type II diabetes.

[0026] The present invention also provides a pharmaceutical combination, pharmaceutical composition and pharmaceutical preparation comprising a glucokinase activator drug and a combination drug, and a method for preventing a disease or disorder including diabetic complications, slowing down its progression, delaying or treating the disease or disorder.

[0027] Those skilled in the art can understand other purposes of the present invention through the context description and through the examples. Summary of the Invention

[0029] The first aspect of the present invention provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising the following components, and its preparation method and use for treating diabetes and its related diseases:

[0030] (a) A glucokinase activator, which is a compound selected from the following, or its pharmaceutically acceptable salt, its isotope-labeled substance, its crystalline form, hydrate, solvate, diastereoisomer or enantiomer form; preferably, the glucokinase activator is HMS5552; more preferably, HMS5552 exists in the form of a solid dispersion,

[0031]

[0032] (b) A DPP-IV inhibitor; and

[0033] (c) One or more excipients.

[0034] Another aspect of the present invention provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising the following components, and its preparation method and use for treating diabetes and its related diseases:

[0035] (a) A glucokinase activator, which is a compound selected from the HMS5552 compound, or its pharmaceutically acceptable salt, its isotope-labeled substance, its crystalline form, hydrate, solvate, diastereoisomer or enantiomer form;

[0036] Preferably, the glucokinase activator is HMS5552; more preferably, HMS5552 exists in the form of a solid dispersion;

[0037] (b) Sitagliptin, vildagliptin, saxagliptin, linagliptin, or its pharmaceutically acceptable salt, its isotope-labeled substance, its crystalline form, hydrate, solvate, diastereoisomer or enantiomer form; and

[0038] (c) One or more excipients.

[0039] In particular, one aspect of the present invention also relates to a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising a fixed-dose combination of a solid dispersion of HMS5552 and a combination drug (for example, sitagliptin, vildagliptin, saxagliptin, linagliptin), and its preparation method and use.

[0040] Definitions

[0041] Unless otherwise specified, 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 pertains. However, in case of conflict, the definitions in this specification shall prevail.

[0042] As used in the specification and claims, the singular forms "a", "an", and "the" include plural forms unless the context clearly dictates otherwise.

[0043] Unless otherwise specified, percentages (%) in this specification are by weight (wt%).

[0044] All numerical values or expressions referring to amounts of components, process conditions, etc. used in the specification and claims shall be understood to be modified in all instances by the term "about". When the term "about" refers to a quantity or numerical range, it means that the indicated quantity or numerical range is an approximation within experimental variability (or within the statistical error of an experiment), and thus the quantity or numerical range may vary, for example, between ±5 of the stated quantity or numerical range.

[0045] All ranges referring to the same component or property include the endpoints, which can be combined independently. 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 this application is intended to include all sub-ranges within that range.

[0046] When the present invention is defined in terms of a range for a physical property such as molecular weight or for a chemical property, all combinations and sub-combinations of the range and specific embodiments within it shall be included. The term "comprising" (and related terms such as "containing" or "including" or "having" or "includes") includes embodiments that, for example, are any combination of substances, compositions, methods, or processes, etc., that "consist of the described features" or "consist essentially of the described features".

[0047] The "and / or" used in this specification and claims shall be understood to mean "either or both" of the associated components, i.e., the components are present jointly in some cases and separately in other cases. Multiple components listed with "and / or" shall be understood in the same way, i.e., "one or more" of the associated components. Except for the components specifically identified in the "and / or" clause, other components may optionally be present, whether related or unrelated to those specifically identified components. Thus, as a non-limiting example, when referring to "A and / or B" and used to connect open-ended language such as "comprising", in one embodiment, it may refer only to A (optionally including components other than B); in another embodiment, it may refer only to B (optionally including components other than A); in yet another embodiment, it refers to A and B (optionally including other components), etc.

[0048] It should be understood that, unless expressly indicated to the contrary, in any method claimed herein that includes more than one step or act, the order of the steps and acts of the method need not be limited to the order of the steps and acts recited in the method.

[0049] The abbreviations used in the present invention have their ordinary meanings in the fields of chemistry, biology, and pharmaceutical formulations.

[0050] Unless otherwise specified, the term "DPP-IV inhibitor" or any of its species (such as "sitagliptin, vildagliptin, saxagliptin, linagliptin") in the context of the present invention is also intended to include any of its pharmaceutically acceptable salts, its crystalline forms, hydrates, solvates, diastereoisomers, or enantiomers.

[0051] HMS5552, formerly known as RO5305552, with the English name Dorzagliatin and the chemical name (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.

[0052] Unless otherwise specified, weight percent (wt%) is expressed as a percentage of the total weight of the drug combination, pharmaceutical composition, or pharmaceutical formulation.

[0053] A solid dispersion (SD) refers to a solid dispersion system formed by highly dispersing one or more drug active ingredients in an inactive excipient or carrier.

[0054] EUDRAGIT is a trade name for synthetic pharmaceutical excipients, which includes copolymers of methacrylic acid and methacrylate copolymers, generally referred to as polyacrylic resins. Polyacrylic resin excipients are divided into different types according to their composition, ratio, 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 a free carboxyl group:ester = 1:1, and Eudragit S is a polymer of methacrylic acid and methyl methacrylate, with a free carboxyl group:ester = 1:2.

[0055] The term "tablet" as used herein is intended to include compressed pharmaceutical formulations of all shapes and sizes, whether coated or uncoated.

[0056] The term "effective amount" or "therapeutically effective amount" means an amount of a reagent sufficient to provide a desired biological result. Such result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease and / or any other desired change in a biological system. For example, an "effective amount" for therapeutic use means an amount of a composition containing a compound that is the active ingredient of the present invention that is clinically significant to reduce a disease. In any 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 at which the active substance has a therapeutic effect.

[0057] As used in this application, the terms "treat" or "treatment" 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 ameliorating existing disease symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of the symptoms, inhibiting a disorder or disease, e.g., preventing the development of a disorder or disease, alleviating a disorder or disease, reversing a disorder or disease, alleviating the conditions caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

[0058] "Pharmaceutically acceptable" or "pharmacologically acceptable" means a substance that is not biologically or otherwise substantially undesirable, i.e., the substance can be administered to an individual without causing any undesirable biological effects or without interacting in a harmful manner with any other components of a composition containing such substance.

[0059] As used in this application, the term "subject" 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.

[0060] The compounds that are the active ingredients in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (e.g., fixed-dose combination preparation) containing a glucokinase activator according to the present invention may form salts. Unless otherwise specified, when referring to the said compounds in this application, it should be understood that it includes a reference to their salts. The term "salt(s)" used in this application refers to acid salts formed with inorganic and / or organic acids and basic salts formed with inorganic and / or organic bases. Additionally, when the said compound contains a basic moiety (e.g., but not limited to, pyridine or imidazole) and an acidic moiety (e.g., but not limited to, carboxylic acid), zwitterions ("inner salts") may be formed and the zwitterions ("inner salts") are included in the term "salt(s)" used in this application. Preferably, they are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts, but other salts are also useful. The salts of the said compounds can be formed, for example, by reacting the compound with a certain amount (e.g., an equal amount) of an acid or a base in a medium, which can be, for example, a medium in which the salt precipitates or an aqueous medium (lyophilized after the reaction).

[0061] Polymorphic forms of different compounds and their salts, solvates, esters and prodrugs are intended to be included in the present invention.

[0062] It should be understood that the terms used herein are for the purpose of describing specific embodiments and are not intended to be limiting. In addition, although any methods, devices and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, the preferred methods, devices and materials are described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 Are the dissolution results of Example 4B and the single-component tablets of the same dose;

[0064] Figure 2 Are the results of the pharmacodynamic animal study of HMS5552 combined with sitagliptin in type 2 diabetic model rats. DETAILED DESCRIPTION OF THE INVENTION

[0065] One aspect of the present invention relates to a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation such as a fixed-dose combination preparation of a glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) and a combination drug (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin). The preparation can be in the form of a powder, granule, tablet, capsule, sachet or other solid forms, 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., sitagliptin, vildagliptin, saxagliptin, linagliptin).

[0066] In a specific aspect of the present invention, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation contains:

[0067] (1) A glucokinase activator or a pharmaceutically acceptable salt thereof, or an isotopically labeled compound thereof, a crystalline form, a hydrate, a solvate, a diastereoisomer or an enantiomeric form thereof; preferably, the glucokinase activator is preferably HMS5552; more preferably, the form of HMS5552 is a solid dispersion form, such as a solid dispersion form containing a polymer carrier (e.g., spray-dried powder);

[0068] (2) A DPP-IV inhibitor; preferably, it is selected from: sitagliptin, vildagliptin, saxagliptin, linagliptin, or a pharmaceutically acceptable salt thereof, an isotopically labeled compound thereof, a crystalline form, a hydrate, a solvate, a diastereoisomer or an enantiomeric form thereof; and / or

[0069] (3) A filler; and / or

[0070] (4) A binder; and / or

[0071] (5) A disintegrant; and / or

[0072] (6) A lubricant or a glidant; and / or

[0073] (7) A coating agent.

[0074] In one embodiment of the present invention, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation may further contain one or more excipients, and the excipients are 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.

[0075] Pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation

[0076] Glucokinase activator + DPP-IV inhibitor drugs

[0077] In one embodiment, the present invention relates to a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), which comprises:

[0078] (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopically labeled compound thereof, a crystalline form, a hydrate, a solvate, a diastereoisomer or an enantiomeric form thereof

[0079]

[0080] (b) A DPP-IV inhibitor;

[0081] Preferably, it is selected from sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, denagliptin, meglitinide, gosogliptin, teragliptin, dulaglutide, and pharmaceutically acceptable salts thereof. Among them, sitagliptin, saxagliptin, vildagliptin, and linagliptin are preferred;

[0082] (c) one or more excipients;

[0083] Wherein the above-mentioned drugs (a) and (b) are used simultaneously, separately, or successively.

[0084] 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 DPP-IV inhibitor is about 1:10 to 100:1, preferably about 1:4 to 40:1, more preferably about 1:4, about 1:2, about 1:1, about 1.5:1, about 1.5:2, about 2:1, about 5:1, about 10:1, about 15:1, about 20:1 or about 40:1.

[0085] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucokinase activator is present in a dose range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg (preferably unit dose), preferably, wherein the dose of the glucokinase activator (preferably unit dose) is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0086] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation, the DPP-IV inhibitor is present in a dose (preferably unit dose) range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg. Preferably, the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg or about 100 mg, and most preferably about 2.5 mg, about 5 mg, about 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, and more preferably about 25 mg, 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is linagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 5 mg or about 10 mg, and more preferably about 5 mg; preferably, the DPP-IV inhibitor is saxagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 2.5 mg, about 5 mg or about 10 mg, and more preferably about 2.5 mg or about 5 mg; preferably, the DPP-IV inhibitor is vildagliptin, and its dose (preferably unit dose) is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, and most preferably about 50 mg.

[0087] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the above-mentioned glucokinase activator is compound HMS5552, or its isotope-labeled substance, or its pharmaceutically acceptable salt.

[0088]

[0089] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucokinase activator is present in the form of a solid dispersion.

[0090] In one embodiment, the solid dispersion is obtained by spray drying, hot melting or freeze drying of the glucokinase activator, or its isotope-labeled substance, or its pharmaceutically acceptable salt together with a polymer carrier.

[0091] In one embodiment, the content of the glucokinase activator in the solid dispersion, based on the total weight of the solid dispersion, can vary between about 1% by weight and about 99% by weight, preferably 10% to 90% by weight. In one embodiment, the content range of the glucokinase activator is about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, about 60% by weight, about 61% by weight, about 62% by weight, about 63% by weight, about 64% by weight, about 65% by weight, about 66% by weight, about 67% by weight, about 68% by weight, about 69% by weight, about 70% by weight, about 71% by weight, about 72% by weight, about 73% by weight, about 74% by weight, about 75% by weight, about 76% by weight, about 77% by weight, about 78% by weight, about 79% by weight, about 80% by weight, about 81% by weight, about 82% by weight, about 83% by weight, about 84% by weight, about 85% by weight, about 86% by weight, about 87% by weight, about 88% by weight, about 89% by weight, about 90% by weight, about 91% by weight, about 92% by weight, about 93% by weight, about 94% by weight, about 95% by weight, about 96% by weight, about 97% by weight, about 98% by weight, or about 99% by weight, or any range therebetween.

[0092] In one embodiment, the content of the glucokinase activator in the solid dispersion, based on the total weight of the solid dispersion, is about 1% to about 20%, about 2% to about 40%, about 30% to about 60%, about 60% to about 80%, about 70% to about 90%, or about 80% to about 100%.

[0093] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucokinase activator exists in the form of a solid dispersion, and in the solid dispersion, 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.

[0094] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the glucokinase activator is compound HMS5552, its isotope-labeled substance or its pharmaceutically acceptable salt, and a solid dispersion is obtained by spray drying, hot melting or freeze drying together with a polymer carrier.

[0095] 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 solid dispersion is selected from polypropylene resin polymers, which are formed by bulk polymerization of acrylic acid (or methacrylic acid and their esters such as methyl ester, ethyl ester, etc.) (one monomer), or copolymerization of methacrylic acid (or its esters such as methyl ester, ethyl ester, dimethylaminoethyl ester, etc.) with two monomers (binary) or three monomers (ternary) in a certain proportion to form a high molecular compound.

[0096] In one embodiment, the polymer carrier used in the solid dispersion in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is selected from copolymers of butyl methacrylate, 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 trimethylammonium chloride methacrylate, copolymers of ethyl acrylate and methyl methacrylate, copolymers of methacrylic acid, methyl acrylate and methyl methacrylate, and copolymers of methacrylic acid and butyl acrylate.

[0097] In one embodiment, the above polymer carrier is selected from the copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1), the copolymer of methacrylic acid and ethyl acrylate (1:1), the copolymer of methacrylic acid and methyl methacrylate (1:2), the copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium chloride methacrylate (1:2:0.2), the copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium chloride methacrylate (1:2:0.1), the copolymer of ethyl acrylate and methyl methacrylate (2:1), the copolymer of methacrylic acid and butyl acrylate (35:65), the copolymer of methacrylic acid and methyl methacrylate (1:1), the copolymer of methacrylic acid and methyl methacrylate (35:65).

[0098] In one embodiment, the above polymer carrier is Eudragit, including Eudragit E, Eudragit L, Eudragit S, Eudragit RL and Eudragit RS. Among them, Eudragit E is copolymerized from dimethylamino methacrylate and other neutral methacrylates, including the polymer of dimethylaminoethyl methacrylate and methacrylate; Eudragit L and Eudragit S are copolymerized from methacrylic acid and methacrylates in different ratios, including methacrylic acid and methyl methacrylate, free carboxyl group: ester = 1:1 or methacrylic acid and methyl methacrylate, free carboxyl group: ester = 1:2; Eudragit RL and Eudragit RS types are copolymers of acrylic acid and methacrylate containing certain quaternary amine groups, including the copolymer of acrylic acid and methacrylate containing 10% quaternary amine groups and the copolymer of acrylic acid and methacrylate containing 5% quaternary amine groups.

[0099] In one embodiment, the above polymer carrier is selected from:

[0100] Eudragit E100, which is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1), including Eudragit E PO;

[0101] Eudragit L100, which is type A of methacrylic acid copolymer and is an anionic copolymer of methacrylic acid and methyl methacrylate (1:1);

[0102] Eudragit S100, which is a copolymer of methacrylic acid and methyl methacrylate (1:2);

[0103] 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 type A methacrylic acid copolymer (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, more preferably Eudragit L100.

[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 1:10 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 7:3, 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.

[0105] 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.

[0106] 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 sitagliptin or sitagliptin phosphate monohydrate, and by weight, it contains: about 1-80% glucose kinase activator (preferably HMS5552 or its isotope-labeled substance or its pharmaceutically acceptable salt); about 1-80% sitagliptin (or sitagliptin phosphate monohydrate); about 0-55% filler; about 1-25% binder; about 0-15% disintegrant; about 0.1-10% lubricant, about 0-3% glidant and 0-5% coating agent.

[0107] In one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation of the above-mentioned glucokinase activator (preferably HMS5552 or its isotope-labeled substance or its pharmaceutically acceptable salt) and sitagliptin (or sitagliptin phosphate monohydrate) (preferably a fixed-dose combination preparation), by weight, it comprises: about 5-45% of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or its pharmaceutically acceptable salt); about 5-75% of sitagliptin or sitagliptin phosphate monohydrate; about 0-50% of a filler; about 1-10% of a binder; about 1-10% of a disintegrant; about 0.1-5% of a lubricant; about 0-0.5% of a glidant and 0-5% of a 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.

[0108] In one embodiment, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the dose (preferably the unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or a pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dose (preferably the unit dose) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dose (preferably the unit dose) 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 dose (preferably the unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or a pharmaceutically acceptable salt) is about 25 mg, about 50 mg, about 75 mg, about 100 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion.

[0109] In one embodiment, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the second active ingredient is sitagliptin (or sitagliptin phosphate monohydrate), and calculated by the content of sitagliptin, its dose (preferably the unit dose) is about 25 mg to about 200 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, more preferably about 25 mg, 50 mg or about 100 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion.

[0110] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), specific embodiments of the doses (preferably unit doses) of HMS5552 (or its isotopically labeled compound or pharmaceutically acceptable salt) and sitagliptin (or sitagliptin phosphate monohydrate) are as follows:

[0111] (1) about 25 mg of HMS5552 and about 50 mg of sitagliptin (or about 64.25 mg of sitagliptin phosphate monohydrate);

[0112] (2) about 50 mg of HMS5552 and about 50 mg of sitagliptin (or about 64.25 mg of sitagliptin phosphate monohydrate);

[0113] (3) about 75 mg of HMS5552 and about 50 mg of sitagliptin (or about 64.25 mg of sitagliptin phosphate monohydrate);

[0114] (4) about 100 mg of HMS5552 and about 50 mg of sitagliptin (or about 64.25 mg of sitagliptin phosphate monohydrate);

[0115] (5) about 25 mg of HMS5552 and about 100 mg of sitagliptin (or about 128.5 mg of sitagliptin phosphate monohydrate);

[0116] (6) about 50 mg of HMS5552 and about 100 mg of sitagliptin (or about 128.5 mg of sitagliptin phosphate monohydrate);

[0117] (7) about 75 mg of HMS5552 and about 100 mg of sitagliptin (or about 128.5 mg of sitagliptin phosphate monohydrate);

[0118] (8) about 100 mg of HMS5552 and about 100 mg of sitagliptin (or about 128.5 mg of sitagliptin phosphate monohydrate);

[0119] Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion. In one embodiment, the preferred dosage form of the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation is a tablet.

[0120] In one embodiment, the above-mentioned tablet is a fixed-dose combination tablet of a glucokinase activator (HMS5552 and its isotopically labeled compound or pharmaceutically acceptable salt) and sitagliptin or sitagliptin phosphate monohydrate.

[0121] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 25 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0-50% 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 0-5% of a coating agent; preferably, the above 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 containing about 1:1 of the glucokinase activator and Eudragit L100.

[0122] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 50 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0-50% 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 0-5% of a coating agent; preferably, the above 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 containing about 1:1 of the glucokinase activator and Eudragit L100.

[0123] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet which is a tablet of 75 mg of a glucokinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 75 mg of a glucokinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0 to 50% 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 0 to 5% of a coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0124] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet which is a tablet of 100 mg of a glucokinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 100 mg of a glucokinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 50 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0 to 50% 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 0 to 5% of a coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0125] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 25 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0-50% 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 0-5% of a coating agent; preferably, the above glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymeric carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0126] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 50 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0-50% 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 0-5% of a coating agent; preferably, the above glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymeric carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0127] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet which is a tablet of 75 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 75 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0 to 50% 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 0 to 5% of a coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0128] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet which is a tablet of 100 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose)), by weight, comprises the following components in the following amounts: about 100 mg of a glucokinase activator (preferably HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or sitagliptin phosphate monohydrate in an amount obtainable at this dose); about 0 to 50% 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 0 to 5% of a coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0129] In one embodiment, in the above drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the second active ingredient is saxagliptin or saxagliptin monohydrate, and by weight it comprises: about 1 to 80% of a glucokinase activator (or its isotopically labeled compound or pharmaceutically acceptable salt); about 0.5 to 20% of saxagliptin (or saxagliptin monohydrate); about 0 to 90% of a filler; about 1 to 25% of a binder; about 0 to 15% of a disintegrant; about 0.1 to 10% of a lubricant, about 0 to 3% of a glidant and about 0 to 5% of a coating agent.

[0130] 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 saxagliptin (or saxagliptin monohydrate), and by weight, it comprises: about 1-80% of a glucokinase activator (preferably HMS5552 or its isotope-labeled substance or a pharmaceutically acceptable salt); about 0.5-20% of saxagliptin (or saxagliptin monohydrate); about 0-90% of a filler; about 1-25% of a binder; about 0-15% of a disintegrant; about 0.1-10% of a lubricant, about 0-3% of a glidant and about 0-5% of a 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.

[0131] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the dose (preferably unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or a pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dose (preferably unit dose) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dose (preferably unit dose) 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 dose (preferably unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or a 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 combination preparation), HMS5552 exists in the form of a solid dispersion.

[0132] 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 saxagliptin (or saxagliptin monohydrate), and calculated by the content of saxagliptin, its dose (preferably unit dose) is about 1 mg to about 50 mg, preferably about 2.5 mg, about 5 mg, about 7.5 mg and about 10 mg, and most preferably about 2.5 mg and about 5 mg. Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion.

[0133] In the pharmaceutical composition or fixed-dose combination preparation of the present invention, specific embodiments of the doses (preferably unit doses) of HMS5552 (or its isotope-labeled substance or a pharmaceutically acceptable salt) and saxagliptin (or saxagliptin monohydrate) are as follows:

[0134] (1) About 25 mg of HMS5552 and about 2.5 mg of saxagliptin (or about 2.64 mg of saxagliptin monohydrate);

[0135] (2) About 50 mg of HMS5552 and about 2.5 mg of saxagliptin (or about 2.64 mg of saxagliptin monohydrate);

[0136] (3) About 75 mg of HMS5552 and about 2.5 mg of saxagliptin (or about 2.64 mg of saxagliptin monohydrate);

[0137] (4) About 100 mg of HMS5552 and about 2.5 mg of saxagliptin (or about 2.64 mg of saxagliptin monohydrate);

[0138] (5) About 25 mg of HMS5552 and about 5 mg of saxagliptin (or about 5.29 mg of saxagliptin monohydrate);

[0139] (6) About 50 mg of HMS5552 and about 5 mg of saxagliptin (or about 5.29 mg of saxagliptin monohydrate);

[0140] (7) About 75 mg of HMS5552 and about 5 mg of saxagliptin (or about 5.29 mg of saxagliptin monohydrate);

[0141] (8) About 100 mg of HMS5552 and about 5 mg of saxagliptin (or about 5.29 mg of saxagliptin monohydrate);

[0142] Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion.

[0143] In one embodiment, the preferred dosage form of the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is a tablet.

[0144] In one embodiment, the above-mentioned tablet is a fixed-dose combination tablet of a glucokinase activator (HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) and saxagliptin (or saxagliptin monohydrate).

[0145] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 2.5 mg saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, contains the following components in the following amounts: about 25 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% filler; about 2 to 8% binder; about 1 to 5% disintegrant; about 0.5 to 3% lubricant; about 0 to 0.5% glidant and about 0 to 5% coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymeric carrier, preferably containing about 1:1 glucokinase activator and Eudragit L100.

[0146] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 2.5 mg saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, contains the following components in the following amounts: about 50 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% filler; about 2 to 8% binder; about 1 to 5% disintegrant; about 0.5 to 3% lubricant; about 0 to 0.5% glidant and about 0 to 5% coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymeric carrier, preferably containing about 1:1 glucokinase activator and Eudragit L100.

[0147] 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 (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 2.5 mg saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, comprises the following components in the following amounts: about 75 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% filler; about 2 to 8% binder; about 1 to 5% disintegrant; about 0.5 to 3% lubricant; about 0 to 0.5% glidant and about 0 to 5% coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 glucokinase activator and Eudragit L100.

[0148] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 2.5 mg saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, comprises the following components in the following amounts: about 100 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% filler; about 2 to 8% binder; about 1 to 5% disintegrant; about 0.5 to 3% lubricant; about 0 to 0.5% glidant and about 0 to 5% coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 glucokinase activator and Eudragit L100.

[0149] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 5 mg saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, comprises the following components in the following amounts: about 25 mg of glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% filler; about 2 to 8% binder; about 1 to 5% disintegrant; about 0.5 to 3% lubricant; about 0 to 0.5% glidant and about 0 to 5% coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymeric carrier, preferably containing about 1:1 glucokinase activator and Eudragit L100.

[0150] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 5 mg saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, comprises the following components in the following amounts: about 50 mg of glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% filler; about 2 to 8% binder; about 1 to 5% disintegrant; about 0.5 to 3% lubricant; about 0 to 0.5% glidant and about 0 to 5% coating agent; preferably, the above glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymeric carrier, preferably containing about 1:1 glucokinase activator and Eudragit L100.

[0151] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet which is a tablet of 75 mg of a glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, contains the following components in the following amounts: about 75 mg of a glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% of a 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0152] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet which is a tablet of 100 mg of a glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose)), by weight, contains the following components in the following amounts: about 100 mg of a glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 5 mg of saxagliptin (or an amount of saxagliptin monohydrate that provides this dose); about 0 to 80% of a 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0153] 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 linagliptin. In the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotopically labeled substance or pharmaceutically acceptable salt) and linagliptin, by weight, it contains one or more of the following amounts of substances: about 1-90% of the glucokinase activator (HMS5552 or its isotopically labeled substance or pharmaceutically acceptable salt); about 1-20% of linagliptin; about 0-90% of a filler; about 1-25% of a binder; about 0-15% of a disintegrant; about 0.1-10% of a lubricant, about 0-3% of a glidant and about 0-5% of a coating agent.

[0154] 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 linagliptin. In the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotopically labeled substance or pharmaceutically acceptable salt) and linagliptin, by weight, it contains one or more of the following amounts of substances: about 1-80% of the glucokinase activator (HMS5552 or its isotopically labeled substance or pharmaceutically acceptable salt); about 1-20% of linagliptin; about 0-90% of a filler; about 1-25% of a binder; about 0-15% of a disintegrant; about 0.1-10% of a lubricant, about 0-3% of a glidant and about 0-5% of a 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.

[0155] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the dose (preferably the unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dose (preferably the unit dose) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dose (preferably the unit dose) 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 dose (preferably the unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance 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 combination preparation), HMS5552 exists in the form of a solid dispersion.

[0156] 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 linagliptin, and the dose (preferably the unit dose) of linagliptin is about 1 mg to about 50 mg, preferably about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg, and the most preferred dose (preferably the unit dose) of linagliptin is about 2.5 mg or about 5 mg. Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion.

[0157] In the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), the specific embodiments of the doses (preferably the unit doses) of HMS5552 (or its isotope-labeled substance or pharmaceutically acceptable salt) and saxagliptin are as follows:

[0158] (1) About 25 mg of HMS5552 and about 2.5 mg of linagliptin;

[0159] (2) About 25 mg of HMS5552 and about 5 mg of linagliptin;

[0160] (3) About 50 mg of HMS5552 and about 2.5 mg of linagliptin;

[0161] (4) About 50 mg of HMS5552 and about 5 mg of linagliptin;

[0162] (5) About 75 mg of HMS5552 and about 2.5 mg of linagliptin;

[0163] (6) About 75 mg of HMS5552 and about 5 mg of linagliptin;

[0164] (7) About 100 mg of HMS5552 and about 2.5 mg of linagliptin; and

[0165] (8) About 100 mg of HMS5552 and about 5 mg of linagliptin;

[0166] Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion.

[0167] In one embodiment, the preferred dosage form of the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is a tablet.

[0168] In one embodiment, the above-mentioned tablet is a fixed-dose combination tablet of a glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) and linagliptin.

[0169] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 5 mg linagliptin) contains the following components by weight: about 25 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 5 mg of linagliptin; about 0-90% 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 glucokinase activator is in the form of the solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0170] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 5 mg linagliptin), by weight, comprises the following components in the following amounts: about 50 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 5 mg of linagliptin; about 0-90% 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0171] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 5 mg linagliptin), by weight, comprises the following components in the following amounts: about 75 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 5 mg of linagliptin; about 0-90% 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0172] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt) / 5 mg linagliptin), by weight, comprises the following components in the following amounts: about 100 mg of glucokinase activator (HMS5552 or its isotopically labeled compound or pharmaceutically acceptable salt); about 5 mg of linagliptin; about 0-90% 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0173] 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 vildagliptin. 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-labeled substance or pharmaceutically acceptable salt) and vildagliptin, by weight, it contains about 1-80% of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt); about 1-50% of vildagliptin; about 0-55% of a filler; about 1-25% of a binder; about 0-15% of a disintegrant; about 0.1-10% of a lubricant, about 0-3% of a glidant and about 0-5% of a 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 dry granulation method.

[0174] 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-labeled substance or pharmaceutically acceptable salt) and vildagliptin, the dose (preferably the unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dose (preferably the unit dose) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dose (preferably the unit dose) 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 more preferred dose (preferably the unit dose) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance 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 combination preparation), HMS5552 exists in the form of a solid dispersion.

[0175] 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-labeled substance or pharmaceutically acceptable salt) and vildagliptin, the dose (preferably the unit dose) of vildagliptin is about 10 mg to about 150 mg, preferably about 50 mg and 100 mg, and the most preferred dose (preferably the unit dose) of vildagliptin is about 50 mg.

[0176] In one embodiment, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), specific embodiments of the dosages (preferably unit dosages) of HMS5552 (or its isotope-labeled substance or pharmaceutically acceptable salt) and vildagliptin are as follows:

[0177] (1) about 25 mg of HMS5552 and about 50 mg of vildagliptin;

[0178] (2) about 50 mg of HMS5552 and about 50 mg of vildagliptin;

[0179] (3) about 75 mg of HMS5552 and about 50 mg of vildagliptin; and

[0180] (4) about 100 mg of HMS5552 and about 50 mg of vildagliptin;

[0181] Preferably, in the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 exists in the form of a solid dispersion.

[0182] In one embodiment, the preferred dosage form of the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention is a tablet.

[0183] In one embodiment, the above-mentioned fixed-dose combination tablet is a tablet of a glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) and vildagliptin.

[0184] In one embodiment, the said drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 25 mg glucokinase activator (HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) / 50 mg vildagliptin), by weight, contains the following components in the following contents: about 25 mg of glucokinase activator (HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt); about 50 mg of vildagliptin; about 0 - 80% of a filler; about 2 - 8% of a binder; about 1 - 8% 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 glucokinase activator is in the form of the solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of the glucokinase activator and Eudragit L100.

[0185] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 50 mg glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 50 mg vildagliptin), by weight, comprises the following components in the following amounts: about 50 mg of glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 50 mg of vildagliptin; about 0-80% of a filler; about 2-8% of a binder; about 1-8% 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of glucokinase activator and Eudragit L100.

[0186] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 75 mg glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 50 mg vildagliptin), by weight, comprises the following components in the following amounts: about 75 mg of glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 50 mg of vildagliptin; about 0-80% of a filler; about 2-8% of a binder; about 1-8% 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of glucokinase activator and Eudragit L100.

[0187] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination tablet, which is a tablet of 100 mg glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt) / 50 mg vildagliptin), by weight, comprises the following components in the following amounts: about 100 mg of glucokinase activator (HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt); about 50 mg of vildagliptin; about 0-80% of a filler; about 2-8% of a binder; about 1-8% 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 glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, preferably containing about 1:1 of glucokinase activator and Eudragit L100.

[0188] In one embodiment, the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) further comprises an excipient, wherein the excipient includes, but is not limited to, one or more mixtures of diluents, binders, fillers, disintegrants, lubricants, glidants, flavoring agents (essences), sweeteners, colorants, and coating agents.

[0189] In one embodiment, the drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention optionally contains one or more 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, dibasic calcium phosphate, calcium sulfate, dextrin / glucose binder, maltodextrin, compressible sugar, and other known volume-increasing agents or fillers and / or mixtures of two or more of them.

[0190] 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. More 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.

[0191] In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention contains optionally one or more 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, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) (including hydroxypropyl methylcellulose 2208), lactose, sucrose, gum arabic, ethyl cellulose, cellulose acetate and wax binders such as carnauba wax, paraffin wax, cetyl wax, polyethylenes or microcrystalline waxes and other conventional binders and / or mixtures of two or more of them. Further, in addition to the above binders, binders suitable for the present invention include but are not limited to alginic acid, microcrystalline cellulose, dextrin, gelatin, amylopectin, liquid glucose, guar gum, methyl cellulose, polyethylene oxide, povidone and syrup and combinations thereof.

[0192] Preferred embodiments of the binder include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HMPC), polyvinylpyrrolidone (povidone), hydroxyethyl cellulose, starch 1500 and copolyvidone. More preferred binders are hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

[0193] In one embodiment, the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) contains optionally one or more disintegrants. Examples of disintegrants suitable for the present invention include but are not limited to croscarmellose sodium, crospovidone, lactose, sucrose, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, sodium starch glycolate, microcrystalline cellulose, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose and other known disintegrants.

[0194] Preferably, the disintegrant is selected from one or more of modified starch, modified cellulose polymer or polycarboxylic acid, specifically selected from croscarmellose sodium, crospovidone, sodium starch glycolate, potassium polacrilate and carboxymethylcellulose calcium (CMC Calcium). In one embodiment, the disintegrant is crospovidone. In another embodiment, the disintegrant is sodium starch glycolate. In another embodiment, the disintegrant is croscarmellose sodium. Croscarmellose sodium NF type A is available on the market under the trade name "Ac-di-sol".

[0195] In one embodiment, the above-mentioned drug 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, glyceryl palmitostearate, palmitic acid, myristic acid, and hydrogenated vegetable oils (including hydrogenated castor oil) and fats and other known lubricants and / or mixtures of two or more of them.

[0196] Preferably, 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 a mixture thereof.

[0197] In one embodiment, the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) contains one or more glidants and / or anti-adhesion agents. Examples of glidants and / or anti-adhesion agents suitable for the present invention include, but are not limited to, silica, colloidal silica, magnesium silicate, calcium phosphate, magnesium trisilicate, talc, and other forms of silica such as aggregated silicates and hydrated silica gel.

[0198] Preferably, embodiments of the glidant include colloidal silica, calcium phosphate, magnesium silicate, and talc, or mixtures thereof. A preferred glidant is colloidal silica.

[0199] In one embodiment, the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) may also optionally contain one or more surfactants or wetting agents. The surfactant can be anionic, cationic or neutral. Anionic surfactants include sodium lauryl sulfate, sodium dodecylsulfonate, sodium oleyl sulfate, and sodium laurate mixed with stearate and talc. Cationic surfactants include benzalkonium chloride and alkyltrimethylammonium bromide. Neutral surfactants include glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, and sorbitan esters. Embodiments of the wetting agent include poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivatives, and polyoxyethylene stearate.

[0200] In one embodiment, the above-mentioned drug combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) may also optionally contain one or more antioxidants to impart chemical stability thereto. Examples of antioxidants suitable for the present invention include, but are not limited to, tocopherol, ascorbic acid, gallate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite, and combinations thereof.

[0201] Preferably, the antioxidant is selected from α-tocopherol, γ-tocopherol, δ-tocopherol, extracts from natural sources enriched with tocopherols, 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.

[0202] In one embodiment, the preferred formulation of the above fixed-dose combination preparation is a tablet prepared by a compression method. The tablet can be coated, and preferred examples of the coating base material include sugar coating base materials, water-soluble film coating base materials, enteric film coating base materials, and the like.

[0203] The sugar coating base material uses sucrose. Additionally, one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, amylopectin, carnauba wax, etc. can be used in combination.

[0204] Examples of water-soluble film coating base materials include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc.; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, etc.

[0205] Examples of enteric film coating base materials include cellulose polymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, etc.; acrylic 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.

[0206] 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 of them; opacifiers such as titanium dioxide, etc.; colorants, dyes, and lakes such as iron oxide red (ferric oxide), iron oxide yellow, etc.; glidants such as talc, etc.

[0207] Preferably, the tablets can be coated with a mixture such as hydroxypropyl cellulose and hydroxypropyl methylcellulose, which contains titanium dioxide and / or other colorants such as iron oxide, 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 tablets. A commercially available coating material is Opadry provided by Colorcon, which is a pre-formulated powder mixture. For example, Opadry 03K12429.

[0208] In one embodiment, the above-mentioned drug combination, pharmaceutical composition, or pharmaceutical preparation (preferably a fixed-dose combination preparation) can also be added with a sweetening agent and / or a flavoring agent as needed.

[0209] In one embodiment, the above-mentioned binder is polyvinylpyrrolidone or hydroxypropyl cellulose or hydroxypropyl methylcellulose, the above-mentioned filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose or calcium dihydrogen phosphate or mannitol or corn starch and pregelatinized starch, the above-mentioned disintegrant is croscarmellose sodium or crospovidone or sodium starch glycolate, and the above-mentioned lubricant is magnesium stearate or sodium stearyl fumarate, and the above-mentioned glidant is colloidal silicon dioxide.

[0210] In one embodiment, the above-mentioned binder is hydroxypropyl cellulose, the above-mentioned filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose, the above-mentioned disintegrant is croscarmellose sodium or crospovidone or sodium starch glycolate, and the above-mentioned lubricant is magnesium stearate or sodium stearyl fumarate, and the above-mentioned glidant is colloidal silicon dioxide.

[0211] In one embodiment, the above-mentioned binder is polyvinylpyrrolidone, the above-mentioned filler is microcrystalline cellulose or silicified microcrystalline cellulose, the above-mentioned disintegrant is croscarmellose sodium or crospovidone, and the above-mentioned lubricant is magnesium stearate or sodium stearyl fumarate, and the above-mentioned glidant is colloidal silicon dioxide.

[0212] In one embodiment, the above-mentioned binder is hydroxypropyl methylcellulose, the above-mentioned filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose, the above-mentioned disintegrant is croscarmellose sodium or crospovidone or sodium starch glycolate, and the above-mentioned lubricant is magnesium stearate or sodium stearyl fumarate, and the above-mentioned glidant is colloidal silicon dioxide.

[0213] In one embodiment, the above-mentioned binder is hydroxypropyl cellulose, the above-mentioned filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose, the above-mentioned disintegrant is croscarmellose sodium, and the above-mentioned lubricant is magnesium stearate or sodium stearyl fumarate.

[0214] In one embodiment, the above-mentioned binder is polyvinylpyrrolidone, the above-mentioned lubricant is magnesium stearate, and the above-mentioned glidant is colloidal silica.

[0215] Preparation method

[0216] In one embodiment, the pharmaceutical composition or fixed-dose combination preparation of the present invention is prepared by wet granulation (high shear and / or fluidized bed). Granulation is a method of adding a binder to a solvent to prepare a binder solution, and then adding it or directly adding it to a granulator to form wet granules. The steps involved in the wet granulation method include the following:

[0217] (1) Add the active pharmaceutical ingredient glucose kinase activator (preferably HMS5552) and the combination drug (preferably sitagliptin, saxagliptin, vildagliptin, and linagliptin) to the granulator;

[0218] (2) Add the optional filler (such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to the mixture obtained in step (1);

[0219] (3) Add the optional disintegrant (such as croscarmellose sodium, crospovidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);

[0220] (4) For high-shear granulation, add the binder (such as hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methylcellulose) to pure water to prepare a binder solution, and then add it to the granulator for stirring granulation. For fluidized bed granulation, add the two active pharmaceutical ingredients to the fluidized bed, and spray the binder solution into it through compressed air. The binder solution is an aqueous solution prepared from a binder and pure water;

[0221] (5) The obtained wet granules are sized by passing through a suitable sieving machine to obtain wet granules of suitable size;

[0222] (6) The granules prepared by high-shear granulation are tray-dried in an oven or dried in a fluidized bed dryer. For the granules obtained by fluidized bed granulation, the granules are then dried in the fluidized bed;

[0223] (7) Size the granules on a suitable grinding machine to obtain dried granules of suitable size;

[0224] (8) In a suitable mixer, add the optional filler (diluent, such as microcrystalline cellulose) and the optional disintegrant (such as croscarmellose sodium) to mix with the dried granules;

[0225] (9) Add the lubricant (such as magnesium stearate and sodium stearyl fumarate) to the mixture in step (8);

[0226] (10) Add an optional glidant (such as colloidal silica) to the mixture of step (9);

[0227] (11) Fill the lubricated particulate mixture of step (9) or (10) into vials, sachets or capsules or compress into a desired tablet shape; and

[0228] (12) Optionally, film coat the resulting tablets.

[0229] In another embodiment, the pharmaceutical composition of the present invention is prepared by wet granulation (high shear and / or fluidized bed). Granulation is a method in which a binder and a second active ingredient are added to a solvent to prepare a binder solution (or suspension), and then added to a granulator to form wet granules. The steps involved in the wet granulation method include the following:

[0230] (1) Add the active pharmaceutical ingredient glucokinase activator (preferably HMS5552) to the granulator;

[0231] (2) Add an optional filler (such as microcrystalline cellulose, siliconized microcrystalline cellulose, lactose) to the mixture of step (1);

[0232] (3) Add an optional disintegrant (such as sodium carboxymethylcellulose cross-linked, crospovidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);

[0233] (4) For high shear granulation, add a binder (such as hydroxypropylcellulose or polyvinylpyrrolidone or hydroxypropylmethylcellulose) to a solvent to disperse or dissolve uniformly, and then add the prescribed amount of the second active ingredient (preferably sitagliptin, saxagliptin, vildagliptin and linagliptin) to disperse or dissolve to form a uniform binder system. Add this system to the granulator and stir to granulate. For fluidized bed granulation, add an active pharmaceutical ingredient such as HMS5552 to the fluidized bed, and spray the binder system into it through compressed air. The binder solution is a solution or suspension prepared from a binder and pure water or an organic solvent (such as ethanol);

[0234] (5) The resulting wet granules are sized in a suitable screening machine to obtain wet granules of suitable size;

[0235] (6) The granules prepared by high shear granulation are tray dried in an oven or dried in a fluidized bed dryer. For the granules obtained by fluidized bed granulation, the granules are then dried in the fluidized bed;

[0236] (7) Screen on a suitable grinder to obtain dried granules of suitable size;

[0237] (8) In a suitable mixer, add an optional filler (diluent, such as microcrystalline cellulose) and an optional disintegrant (such as croscarmellose sodium) to the dried granules and mix;

[0238] (9) Add a lubricant (such as magnesium stearate and sodium stearyl fumarate) to the mixture of step (8);

[0239] (10) Optionally, add a glidant (such as colloidal silicon dioxide) to the mixture of step (9);

[0240] (11) Fill the lubricated granule mixture of (9) or (10) into vials, sachets or capsules or compress it into the desired tablet shape; and

[0241] (12) Optionally, film coat the resulting tablets.

[0242] The steps involved in dry processing (direct compression or dry granulation) methods include:

[0243] (1) Add the active pharmaceutical ingredient glucose kinase activator (preferably HMS5552) and the combination drug (preferably sitagliptin, saxagliptin, vildagliptin and linagliptin) to the mixing barrel;

[0244] (2) Add an optional filler (such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to step (1);

[0245] (3) Add an optional binder (such as hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methylcellulose) to the mixture obtained in step (1) or (2);

[0246] (4) Add a lubricant or glidant to step (3) and mix;

[0247] (5) The mixture of step (4) can be filled into vials, sachets or capsules or compressed into the desired tablet shape, or processed by a roller compactor;

[0248] (6) If processed by a roller compactor, mix the mixture in step (3) beforehand and then perform roller rolling; if necessary, size the granules on a suitable grinder to obtain the desired size of granules;

[0249] (7) In a suitable mixer, an optional diluent can be added to the granules obtained in step (6) to improve the compression performance;

[0250] (8) Add an optional disintegrant (such as croscarmellose sodium, crospovidone, sodium starch glycolate) to step (7);

[0251] (9) Add an optional lubricant or glidant to the mixture of step (8);

[0252] (10) Fill the lubricated particulate mixture of (9) or (10) into vials, sachets or capsules or compress it into the desired tablet shape; and

[0253] (11) Optionally, the tablets obtained in step (5) or step (10) may be film-coated.

[0254] In one embodiment of the present invention, the glucokinase 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 methods selected from spray drying, fluidized bed drying, solvent method, melt extrusion method, etc.

[0255] One embodiment of the present invention is a method for preparing a solid dispersion of a glucokinase activator by spray drying, and the steps thereof include:

[0256] (1) Prepare a spray drying solution, including dissolving a polymer carrier and a glucokinase activator (preferably HMS5552) in a solvent;

[0257] (2) Spray drying, controlling the inlet air temperature, inlet air volume, flow rate and pressure of the atomizing gas stream, and the spraying speed of the solution, etc.

[0258] In the embodiments of the present invention, the solvents used in the preparation of the solid dispersion of the glucokinase activator include but are not limited to alkanols, esters, nitriles, cycloalkanes, aromatic hydrocarbons, ketones, etc. Specifically, the solvents are selected from the following solvents: absolute 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.

[0259] Methods and uses for treating and / or preventing diseases

[0260] Another embodiment of the present invention relates to a method or use for treating and / or preventing the following diseases and medical conditions using the composition or preparation containing a glucokinase activator of the present invention (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose combination preparation), especially one or more diseases selected from type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, and hyperglycemia, including administering to a subject a therapeutically effective amount of the composition or preparation of the present invention (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose combination preparation):

[0261] - Preventing a metabolic disorder selected from the following, slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder: type 1 diabetes, type 2 diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, and metabolic syndrome; or

[0262] - Improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose, and / or glycated hemoglobin HbA1c; or

[0263] - Preventing, slowing, delaying or reversing the progression of impaired glucose tolerance, insulin resistance and / or metabolic syndrome to type 2 diabetes; or

[0264] - Preventing a disease or disorder selected from the following, slowing the progression of the disease or disorder, delaying or treating the disease or disorder: diabetic complications such as cataracts and microvascular and macrovascular diseases such as nephropathy, retinopathy, neuropathy, impaired learning and memory, neurodegeneration or cognitive disorders, cardiovascular or cerebrovascular diseases, tissue ischemia, diabetic foot or ulcers, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial obstructive disease, cardiomyopathy, heart failure, arrhythmia, and vascular restenosis; or

[0265] - Reducing body weight and / or body fat, or preventing an increase in body weight and / or body fat, or promoting the reduction of body weight and / or body fat; or

[0266] - Preventing, slowing, delaying or treating pancreatic beta-cell degeneration and / or reduced pancreatic beta-cell function, and / or improving and / or restoring or protecting pancreatic beta-cell function and / or restoring pancreatic insulin secretion function; or

[0267] - Preventing, slowing, delaying or treating diseases or disorders caused by abnormal accumulation of hepatic or ectopic fat; or

[0268] - Maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance; or

[0269] - Preventing new-onset diabetes after transplantation (NODAT) and / or post-transplant metabolic syndrome (PTMS), slowing their progression, delaying or treating these conditions; or - Preventing, delaying or reducing NODAT- and / or PTMS-related complications, including microvascular and macrovascular diseases and events, transplant rejection, infection, and death; or

[0270] - Treating hyperuricemia and hyperuricemia-related conditions; or

[0271] - Diabetic cognitive dysfunction, memory dysfunction, Alzheimer's disease.

[0272] The present invention also provides a method for treating type II diabetes by orally administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition or formulation (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose compound preparation) of the present invention containing a glucokinase activator and a combination drug. In one embodiment, the subject in need of such treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet. The composition or formulation containing a glucokinase activator of the present invention (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose compound preparation) can be administered once daily (QD), twice daily (BID), or three times daily (TID).

[0273] Specifically, the present invention relates to the following specific embodiments.

[0274] Embodiment I - Glucokinase activator + DPP-IV inhibitor (e.g., sitagliptin)

[0275] Scheme 1. A drug combination, pharmaceutical composition or fixed-dose compound preparation, comprising:

[0276] (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, its isotope-labeled substance, crystalline form, hydrate, solvate, diastereoisomer or enantiomer form,

[0277]

[0278] (b) A DPP-IV inhibitor;

[0279] (c) One or more excipients;

[0280] wherein the above drugs (a) and (b) are used simultaneously, separately or successively.

[0281] Scheme 2. The drug combination, pharmaceutical composition or fixed-dose compound preparation of Scheme 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 100:1, preferably about 1:4 to 40:1, more preferably about 1:4, about 1:2, about 1:1, about 1.5:1, about 1.5:2, about 2:1, about 5:1, about 10:1, about 15:1, about 20:1 or about 40:1.

[0282] Scheme 3. The drug combination, pharmaceutical composition or fixed-dose compound preparation of Scheme 1 or 2, wherein the glucokinase activator is about 1 to 98% by weight; the DPP-IV inhibitor is about 0.2 to 80% by weight.

[0283] Scheme 4. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-3, wherein the glucokinase activator is the compound HMS5552 represented by the following formula or a pharmaceutically acceptable salt thereof, an isotopically labeled compound, a crystalline form, a hydrate, a solvate, a diastereoisomer or an enantiomer form,

[0284]

[0285] Scheme 5. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-4, wherein the glucokinase activator is in the form of a solid dispersion.

[0286] Scheme 6. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 5, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, and the polymer carrier is methacrylic acid copolymer type A (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, more preferably Eudragit L100.

[0287] Scheme 7. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 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.

[0288] Scheme 8. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-7, wherein the DPP-IV inhibitor is selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin, linagliptin, alogliptin, denagliptin, meglitinide, gosigliptin, terigliptin, dulaglutide, and pharmaceutically acceptable salts thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin and linagliptin, and pharmaceutically acceptable salts thereof.

[0289] Scheme 9. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-8, wherein the glucokinase activator is present in a dose range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg (preferably as a unit dose), and preferably, the dose of the glucokinase activator (preferably as a unit dose) is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0290] Embodiment 10. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-9, wherein the DPP-IV inhibitor is present in a dose range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg (preferably unit dose), preferably, wherein the dose of the DPP-IV inhibitor (preferably unit dose) is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg or about 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, more preferably about 25 mg, 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is linagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 5 mg or about 10 mg, more preferably about 5 mg; preferably, the DPP-IV inhibitor is saxagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 2.5 mg, about 5 mg or about 10 mg, more preferably about 2.5 mg or about 5 mg; preferably, the DPP-IV inhibitor is vildagliptin, and its dose (preferably unit dose) is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, most preferably about 50 mg.

[0291] Embodiment 11. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-10, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweetening agents, coloring agents or coating agents.

[0292] Embodiment 12. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-11, which is a tablet.

[0293] Embodiment 13. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Embodiment 12, which is a coated tablet.

[0294] Embodiment 14. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Embodiment 13, wherein the coated tablet is a film-coated tablet, and the film coating agent comprises:

[0295] A film coating substrate, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof;

[0296] An optional plasticizer, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or a mixture thereof;

[0297] Optional colorants, such as iron oxide red, iron oxide yellow or a mixture thereof;

[0298] Optional opacifying agents, such as titanium dioxide, and

[0299] Optional glidants.

[0300] Embodiment 15. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 14, wherein the coated tablet is a film-coated tablet and the film coating agent is Opadry.

[0301] Embodiment 16. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-15, which comprises, by weight:

[0302] About 1 to 80% glucose kinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;

[0303] About 1 to 80% sitagliptin or sitagliptin phosphate monohydrate;

[0304] About 0 to 55% filler;

[0305] About 1 to 25% binder;

[0306] About 0 to 15% disintegrant;

[0307] About 0.1 to 10% lubricant;

[0308] About 0 to 3% glidant; and

[0309] About 0 to 5% coating agent.

[0310] Embodiment 17. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 16, which comprises, by weight

[0311] About 5 to 70% glucose kinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;

[0312] About 5 to 75% sitagliptin or sitagliptin phosphate monohydrate;

[0313] About 0 to 50% filler (diluent);

[0314] About 1 to 10% binder;

[0315] About 1 to 10% disintegrant;

[0316] About 0.1 to 5% lubricant;

[0317] About 0 to 3% glidant; and

[0318] About 0 to 5% coating agent.

[0319] Embodiment 18. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 16, by weight, the dose of the active ingredient (preferably the unit dose) is:

[0320] About 25 mg, about 50 mg, about 75 mg or about 100 mg of glucokinase activator, preferably HMS5552;

[0321] About 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg of sitagliptin or an amount of sitagliptin phosphate monohydrate that can obtain this dose;

[0322] About 0 to 55% filler;

[0323] About 1 to 25% binder;

[0324] About 0 to 15% disintegrant;

[0325] About 0.1 to 10% lubricant;

[0326] About 0 to 3% glidant; and

[0327] About 0 to 5% coating agent.

[0328] Embodiment 19. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate), by weight, it contains the following components in the following contents:

[0329] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0330] - About 50 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0331] - About 0 to 50% filler;

[0332] - About 2 to 8% of a binder;

[0333] - About 1 to 5% of a disintegrant;

[0334] - About 0.5 to 3% of a lubricant;

[0335] - About 0 to 0.5% of a glidant; and

[0336] - About 0 to 5% of a coating agent.

[0337] Embodiment 20. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate), by weight, comprises the following components in the following contents:

[0338] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0339] - About 50 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0340] - About 0 to 50% of a filler;

[0341] - About 2 to 8% of a binder;

[0342] - About 1 to 5% of a disintegrant;

[0343] - About 0.5 to 3% of a lubricant; and

[0344] - About 0 to 0.5% of a glidant; and

[0345] - About 0 to 5% of a coating agent.

[0346] Embodiment 21. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate), by weight, comprises the following components in the following contents:

[0347] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0348] - About 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0349] - About 0 to 50% of a filler;

[0350] - About 2 to 8% of a binder;

[0351] - About 1 to 5% of a disintegrant;

[0352] - About 0.5 to 3% of a lubricant;

[0353] - About 0 to 0.5% of a glidant; and

[0354] - About 0 to 5% of a coating agent.

[0355] 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 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate), by weight, comprising the following components in the following contents:

[0356] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0357] - About 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0358] - About 0 to 50% of a filler;

[0359] - About 2 to 8% of a binder;

[0360] - About 1 to 5% of a disintegrant;

[0361] - About 0.5 to 3% of a lubricant;

[0362] - About 0 to 0.5% of a glidant; and

[0363] - About 0 to 5% of a coating agent.

[0364] 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 25 mg HMS5552 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate), by weight, comprising the following components in the following contents:

[0365] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0366] - About 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0367] - About 0 to 50% filler;

[0368] - About 2 to 8% binder;

[0369] - About 1 to 5% disintegrant;

[0370] - About 0.5 to 3% lubricant;

[0371] - About 0 to 0.5% glidant; and

[0372] - About 0 to 5% coating agent.

[0373] 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 100 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate), by weight, comprising the following components in the following contents:

[0374] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0375] - About 50 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0376] - About 0 to 50% filler;

[0377] - About 2 to 8% binder;

[0378] - About 1 to 5% disintegrant;

[0379] - About 0.5 to 3% lubricant;

[0380] - About 0 to 0.5% glidant; and

[0381] - About 0 to 5% coating agent.

[0382] Embodiment 25. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18, which contains about 100 mg of solid dispersion, about 64.25 mg of sitagliptin phosphate monohydrate, about 40.30 mg of microcrystalline cellulose, about 6.60 mg of hydroxypropyl cellulose, about 6.60 mg of croscarmellose 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.

[0383] Embodiment 26. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18, which contains about 150 mg of solid dispersion, about 64.25 mg of sitagliptin phosphate monohydrate, about 27.55 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 7.80 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.

[0384] Embodiment 27. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18, which contains about 100 mg of solid dispersion, about 128.50 mg of sitagliptin phosphate monohydrate, about 41.20 mg of microcrystalline cellulose, about 8.70 mg of hydroxypropyl cellulose, about 8.70 mg of croscarmellose sodium, about 2.90 mg of magnesium stearate and about 8.70 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.

[0385] Embodiment 28. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18, which contains about 150 mg of solid dispersion, about 128.50 mg of sitagliptin phosphate monohydrate, about 47.00 mg of microcrystalline cellulose, about 10.50 mg of hydroxypropyl cellulose, about 10.50 mg of croscarmellose sodium, about 3.50 mg of magnesium stearate and about 10.50 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.

[0386] Embodiment 29. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18, which comprises about 50 mg of solid dispersion, about 128.50 mg of sitagliptin phosphate monohydrate, about 100.50 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 9.00 mg of croscarmellose 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 25 mg of HMS5552.

[0387] Embodiment 30. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 18, which comprises about 200 mg of solid dispersion, about 64.25 mg of sitagliptin phosphate monohydrate, about 61.26 mg of microcrystalline cellulose, about 10.50 mg of hydroxypropyl cellulose, about 10.50 mg of croscarmellose sodium, about 3.50 mg of magnesium stearate and about 10.50 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.

[0388] Embodiment 31. A method for preparing the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-30, the method comprising granulating by incorporating the active ingredients into one or more excipients, preferably further filling the obtained granule mixture into vials, sachets or capsules or compressing it into a desired tablet shape; more preferably further coating the obtained tablets.

[0389] Embodiment 32. The method for preparing the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 31, which is prepared by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[0390] Embodiment 33. The method for preparing the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 31-32, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[0391] Embodiment 34. The method for preparing the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 31-33, wherein the glucokinase activator and the second or more active ingredients can also be prepared together in the form of a combined solid dispersion (i.e., a solid dispersion containing two or more active ingredients).

[0392] The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-30, which is used for treating or preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease 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 down, delaying or reversing diabetic complications.

[0393] Scheme 36. A method for treating or preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease 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 down, delaying or reversing diabetic complications, including administering to a subject a therapeutically effective amount of the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-30.

[0394] Scheme 37. Use of the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-30 in the preparation of a medicament for treating or preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder or preventing, slowing down, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

[0395] Embodiment II - Glucokinase activator + DPP-IV inhibitor (such as vildagliptin)

[0396] Scheme 1. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation, which comprises:

[0397] (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, its isotope-labeled substance, crystalline form, hydrate, solvate, diastereoisomer or enantiomer form,

[0398]

[0399] (b) DPP-IV inhibitor;

[0400] (c) one or more excipients;

[0401] wherein the above-mentioned drugs (a) and (b) are used simultaneously, separately or successively.

[0402] Scheme 2. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 50:1, preferably about 1:4 to 40:1, more preferably about 1:4, about 1:2, about 1:1, about 1.5:1, about 1.5:2, about 2:1, about 5:1, about 10:1, about 15:1, about 20:1 or about 40:1.

[0403] Scheme 3. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1 or 2, wherein the glucokinase activator is about 1 to 80% by weight; the DPP-IV inhibitor is about 1 to 50% by weight.

[0404] Scheme 4. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-3, 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 diastereoisomer or an enantiomer form,

[0405]

[0406] Scheme 5. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-4, wherein the glucokinase activator is in the form of a solid dispersion.

[0407] Scheme 6. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 5, 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 (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, more preferably Eudragit L100.

[0408] Embodiment 7. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to 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.

[0409] Embodiment 8. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin, linagliptin, alogliptin, denagliptin, meglitinide, goserelin, terelagliptin, dulaglutide, and pharmaceutically acceptable salts thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin and linagliptin, and pharmaceutically acceptable salts thereof.

[0410] Embodiment 9. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-8, wherein the glucokinase activator is present in a dose range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg (preferably in unit dose), preferably, wherein the dose of the glucokinase activator (preferably in unit dose) is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0411] Scheme 10. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-7, wherein the DPP-IV inhibitor is present in a dose (preferably unit dose) range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg, preferably, wherein the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg or about 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, more preferably about 25 mg, 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is linagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 5 mg or about 10 mg, more preferably about 5 mg; preferably, the DPP-IV inhibitor is saxagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 2.5 mg, about 5 mg or about 10 mg, more preferably about 2.5 mg or about 5 mg; preferably, the DPP-IV inhibitor is vildagliptin, and its dose (preferably unit dose) is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, most preferably about 50 mg.

[0412] Scheme 11. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-10, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweetening agents, coloring agents or coating agents.

[0413] Scheme 12. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-11, which is a tablet.

[0414] Scheme 13. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Scheme 12, which is a coated tablet.

[0415] Scheme 14. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Scheme 13, wherein the coated tablet is a film-coated tablet, and the film coating agent comprises:

[0416] A film coating substrate, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose or a mixture thereof;

[0417] An optional plasticizer, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or a mixture thereof;

[0418] Optional colorants, such as iron oxide red, iron oxide yellow or a mixture thereof;

[0419] Optional opacifying agents, such as titanium dioxide, and

[0420] Optional glidants.

[0421] Embodiment 15. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 14, wherein the coated tablet is a film-coated tablet and the film coating agent is Opadry.

[0422] Embodiment 16. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-15, which comprises, by weight:

[0423] About 1-80% of a glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;

[0424] About 1-50% of vildagliptin;

[0425] About 0-55% of a filler;

[0426] About 1-25% of a binder;

[0427] About 0-15% of a disintegrant;

[0428] About 0.1-10% of a lubricant;

[0429] About 0-3% of a glidant; and

[0430] About 0-5% of a coating agent.

[0431] Embodiment 17. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 16, wherein the dose of the active ingredient (preferably the unit dose), by weight, is:

[0432] About 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[0433] About 50 mg or about 100 mg of vildagliptin;

[0434] About 0-55% of a filler;

[0435] About 1-25% of a binder;

[0436] About 0-15% of a disintegrant;

[0437] About 0.1 to 10% lubricant;

[0438] About 0 to 3% glidant; and

[0439] About 0 to 5% coating agent.

[0440] Scheme 18. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 50 mg vildagliptin), by weight, comprises the following components in the following contents:

[0441] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0442] - About 50 mg of vildagliptin;

[0443] - About 0 to 80% filler;

[0444] - About 2 to 8% binder;

[0445] - About 1 to 8% disintegrant;

[0446] - About 0.5 to 3% lubricant;

[0447] - About 0 to 0.5% glidant; and

[0448] - About 0 to 5% coating agent.

[0449] Scheme 19. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 50 mg vildagliptin), by weight, comprises the following components in the following contents:

[0450] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0451] - About 50 mg of vildagliptin;

[0452] - About 0 to 80% filler;

[0453] - About 2 to 8% binder;

[0454] - About 1 to 8% disintegrant;

[0455] - About 0.5 to 3% of a lubricant;

[0456] - About 0 to 0.5% of a glidant; and

[0457] - About 0 to 5% of a coating agent.

[0458] Scheme 20. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 50 mg vildagliptin), by weight, comprises the following components in the following contents:

[0459] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0460] - About 50 mg of vildagliptin;

[0461] - About 0 to 80% of a filler;

[0462] - About 2 to 8% of a binder;

[0463] - About 1 to 8% of a disintegrant;

[0464] - About 0.5 to 3% of a lubricant;

[0465] - About 0 to 0.5% of a glidant; and

[0466] - About 0 to 5% of a coating agent.

[0467] Scheme 21. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17, which contains about 50 mg of solid dispersion, about 50.00 mg of vildagliptin, about 464.00 mg of microcrystalline cellulose, about 24.00 mg of croscarmellose sodium, about 6.00 mg of colloidal silicon dioxide, about 6.00 mg of magnesium stearate and about 18.00 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100 and contains about 25 mg of HMS5552.

[0468] Embodiment 22. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 100 mg of solid dispersion, about 50.00 mg of vildagliptin, about 414.00 mg of microcrystalline cellulose, about 24.00 mg of croscarmellose sodium, about 6.00 mg of colloidal silicon dioxide, 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.

[0469] Embodiment 23. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 150 mg of solid dispersion, about 50.00 mg of vildagliptin, about 512.50 mg of silicified microcrystalline cellulose, about 30.00 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate and about 21.50 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.

[0470] Embodiment 24. A method for preparing the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-23, the method comprising incorporating the active ingredients into one or more excipients for granulation, preferably further filling the obtained granule mixture into vials, sachets or capsules or compressing it into a desired tablet shape; more preferably further coating the obtained tablets.

[0471] Embodiment 25. The method for preparing the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 24, which is prepared by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[0472] Embodiment 26. The pharmaceutical combination, pharmaceutical composition or method for preparing a fixed-dose combination preparation according to any one of Embodiments 24-25, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[0473] Embodiment 27. The method for preparing the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 24-26, wherein the glucokinase activator and the 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).

[0474] Scheme 28. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-23, which is used for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c; or preventing, slowing down, delaying or reversing diabetic complications.

[0475] Scheme 29. A method for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c; or preventing, slowing down, delaying or reversing diabetic complications, including administering to a subject a therapeutically effective amount of the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-23.

[0476] Scheme 30. Use of the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-23 in the preparation of a medicament for treating or preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder or preventing, slowing down, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c.

[0477] Embodiment III - Glucokinase activator + DPP-IV inhibitor (such as saxagliptin)

[0478] Scheme 1. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation, which comprises:

[0479] (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, its isotope-labeled substance, crystalline form, hydrate, solvate, diastereoisomer or enantiomer form,

[0480]

[0481] (b) DPP-IV inhibitor;

[0482] (c) one or more excipients;

[0483] wherein the above-mentioned drugs (a) and (b) are used simultaneously, separately or successively.

[0484] 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 DPP-IV inhibitor is about 1:10 to 100:1, preferably about 1:4 to 40:1, more preferably about 1:4, about 1:2, about 1:1, about 1.5:1, about 1.5:2, about 2:1, about 5:1, about 10:1, about 15:1, about 20:1 or about 40:1.

[0485] Scheme 3. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1 or 2, wherein the glucokinase activator is about 1 to 80% by weight; the DPP-IV inhibitor is about 1 to 20% by weight.

[0486] Scheme 4. The drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-3, wherein the glucokinase activator is the compound HMS5552 represented by the following formula or its pharmaceutically acceptable salt, its isotope-labeled substance, crystalline form, hydrate, solvate, diastereoisomer or enantiomer form,

[0487]

[0488] Scheme 5. The drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-4, wherein the glucokinase activator is in the form of a solid dispersion.

[0489] Scheme 6. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 5, 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 (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, more preferably Eudragit L100.

[0490] 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.

[0491] Embodiment 8. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin, linagliptin, alogliptin, denagliptin, meglitinide, gosigliptin, teneligliptin, dulaglutide, and pharmaceutically acceptable salts thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin and linagliptin, and pharmaceutically acceptable salts thereof.

[0492] Embodiment 9. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-8, wherein the glucokinase activator is present in a dose range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg (preferably as a unit dose), preferably, wherein the dose of the glucokinase activator (preferably as a unit dose) is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0493] Embodiment 10. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-9, wherein the DPP-IV inhibitor is present in a dose (preferably unit dose) range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg, preferably, wherein the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg or about 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, more preferably about 25 mg, 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is linagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 5 mg or about 10 mg, more preferably about 5 mg; preferably, the DPP-IV inhibitor is saxagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 2.5 mg, about 5 mg or about 10 mg, more preferably about 2.5 mg or about 5 mg; preferably, the DPP-IV inhibitor is vildagliptin, and its dose (preferably unit dose) is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, most preferably about 50 mg.

[0494] Embodiment 11. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-10, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, coloring agents or coating agents.

[0495] Embodiment 12. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-11, which is a tablet.

[0496] Embodiment 13. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Embodiment 12, which is a coated tablet.

[0497] Embodiment 14. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Embodiment 13, wherein the coated tablet is a film-coated tablet, and the film coating agent comprises:

[0498] A film coating substrate, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose or a mixture thereof;

[0499] An optional plasticizer, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or a mixture thereof;

[0500] Optional colorants, such as iron oxide red, iron oxide yellow, or a mixture thereof;

[0501] Optional opacifying agents, such as titanium dioxide, and

[0502] Optional glidants.

[0503] Embodiment 15. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 14, wherein the coated tablet is a film-coated tablet, and the film coating agent is Opadry.

[0504] Embodiment 16. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-15, which comprises, by weight:

[0505] About 1 to 80% of a glucokinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;

[0506] About 1 to 20% of saxagliptin or saxagliptin monohydrate;

[0507] About 0 to 90% of a filler;

[0508] About 1 to 25% of a binder;

[0509] About 0 to 15% of a disintegrant;

[0510] About 0.1 to 10% of a lubricant;

[0511] About 0 to 3% of a glidant; and

[0512] About 0 to 5% of a coating agent.

[0513] Embodiment 17. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 16, wherein the dose of the active ingredient (preferably the unit dose), by weight, is:

[0514] About 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator (preferably HMS5552 or its isotope-labeled compound or pharmaceutically acceptable salt);

[0515] About 2.5 mg, about 5 mg, about 7.5 mg and about 10 mg of saxagliptin or an amount of saxagliptin monohydrate that can provide such a dose;

[0516] About 0 to 90% of a filler;

[0517] About 1 to 25% of a binder;

[0518] About 0 to 15% of a disintegrant;

[0519] About 0.1 to 10% of a lubricant;

[0520] About 0 to 3% of a glidant; and

[0521] About 0 to 5% of a coating agent.

[0522] Embodiment 18. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate), by weight, comprises the following components in the following contents:

[0523] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0524] - About 5 mg of saxagliptin or the corresponding amount of saxagliptin monohydrate;

[0525] - About 0 to 80% of a filler;

[0526] - About 2 to 8% of a binder;

[0527] - About 1 to 5% of a disintegrant;

[0528] - About 0.5 to 3% of a lubricant;

[0529] - About 0 to 0.5% of a glidant; and

[0530] - About 0 to 5% of a coating agent.

[0531] Embodiment 19. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 2.5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate), by weight, comprises the following components in the following contents:

[0532] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0533] - About 2.5 mg of saxagliptin or the corresponding amount of saxagliptin monohydrate;

[0534] - Approximately 0 to 80% filler;

[0535] - Approximately 2 to 8% binder;

[0536] - Approximately 1 to 5% disintegrant;

[0537] - Approximately 0.5 to 3% lubricant;

[0538] - Approximately 0 to 0.5% glidant; and

[0539] - Approximately 0 to 5% coating agent.

[0540] Embodiment 20. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate), by weight, contains the following components in the following contents:

[0541] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0542] - Approximately 5 mg of saxagliptin or the corresponding amount of saxagliptin monohydrate;

[0543] - Approximately 0 to 80% filler;

[0544] - Approximately 2 to 8% binder;

[0545] - Approximately 1 to 5% disintegrant;

[0546] - Approximately 0.5 to 3% lubricant;

[0547] - Approximately 0 to 0.5% glidant; and

[0548] - Approximately 0 to 5% coating agent.

[0549] Embodiment 21. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17 (the fixed-dose combination preparation is preferably a tablet of 100 mg HMS5552 / 2.5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate), by weight, contains the following components in the following contents:

[0550] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0551] - Saxagliptin at about 2.5 mg or the corresponding amount of saxagliptin monohydrate;

[0552] - About 0 to 80% filler;

[0553] - About 2 to 8% binder;

[0554] - About 1 to 5% disintegrant;

[0555] - About 0.5 to 3% lubricant;

[0556] - About 0 to 0.5% glidant; and

[0557] - About 0 to 5% coating agent.

[0558] Embodiment 22. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 150 mg of solid dispersion, about 5.29 mg of saxagliptin monohydrate, about 7.50 mg of hydroxypropyl cellulose, about 79.71 mg of microcrystalline cellulose, about 2.50 mg of magnesium stearate, about 5.00 mg of croscarmellose sodium and about 7.50 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.

[0559] Embodiment 23. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 100 mg of solid dispersion, about 2.64 mg of saxagliptin monohydrate, about 7.50 mg of hydroxypropyl cellulose, about 132.36 mg of microcrystalline cellulose, about 2.50 mg of magnesium stearate, about 5.00 mg of croscarmellose sodium and about 7.50 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.

[0560] Embodiment 24. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 200 mg of solid dispersion, about 2.64 mg of saxagliptin monohydrate, about 9.00 mg of polyvinylpyrrolidone, about 79.36 mg of microcrystalline cellulose, about 3.00 mg of magnesium stearate, about 6.00 mg of croscarmellose sodium 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.

[0561] Embodiment 25. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 50 mg of solid dispersion, about 5.29 mg of saxagliptin monohydrate, about 7.50 mg of povidone, about 179.71 mg of microcrystalline cellulose, about 2.50 mg of magnesium stearate, about 5.00 mg of croscarmellose sodium and about 7.50 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.

[0562] Embodiment 26. A method for preparing the drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-25, the method comprising granulating by incorporating the active ingredients into one or more excipients, preferably further filling the obtained granule mixture into vials, sachets or capsules or compressing it into a desired tablet shape; more preferably further coating the obtained tablets.

[0563] Embodiment 27. The method for preparing the drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 26, which is prepared by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[0564] Embodiment 28. The method for preparing the drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 26-27, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[0565] Embodiment 29. The method for preparing the drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 26-28, wherein the glucokinase activator and the second or more active ingredients can also be prepared together in the form of a combined solid dispersion (i.e., a solid dispersion containing 2 or more active ingredients).

[0566] Embodiment 30. The drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-25, which is used for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing down, delaying or reversing diabetic complications.

[0567] Method 31. A method for preventing one or more metabolic disorders selected from the following, slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications, including administering to a subject a therapeutically effective amount of the drug combination, pharmaceutical composition or fixed-dose combination preparation described in any one of Methods 1-25.

[0568] Method 32. Use of the drug combination, pharmaceutical composition or fixed-dose combination preparation described in any one of Methods 1-25 in the preparation of a drug 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 glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c.

[0569] Embodiment IV - Glucokinase activator + DPP-IV inhibitor (such as linagliptin)

[0570] Method 1. A drug combination, pharmaceutical composition or fixed-dose combination preparation, comprising:

[0571] (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, its isotope-labeled form, crystalline form, hydrate, solvate, diastereoisomer or enantiomer form,

[0572]

[0573] (b) A DPP-IV inhibitor;

[0574] (c) One or more excipients;

[0575] Wherein the above drugs (a) and (b) are used simultaneously, separately or successively.

[0576] Embodiment 2. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 50:1, preferably about 1:4 to 40:1, more preferably about 1:4, about 1:2, about 1:1, about 1.5:1, about 1.5:2, about 2:1, about 5:1, about 10:1, about 15:1, about 20:1 or about 40:1.

[0577] Embodiment 3. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 1 or 2, wherein the glucokinase activator is about 1 to 90% by weight; the DPP-IV inhibitor is about 1 to 20% by weight.

[0578] Embodiment 4. The drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-3, wherein the glucokinase activator is the compound HMS5552 represented by the following formula or its pharmaceutically acceptable salt, its isotope-labeled substance, crystalline form, hydrate, solvate, diastereoisomer or enantiomer form,

[0579]

[0580] Embodiment 5. The drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-4, wherein the glucokinase activator is in the form of a solid dispersion.

[0581] Embodiment 6. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 5, 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 (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, more preferably Eudragit L100.

[0582] Embodiment 7. The drug 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.

[0583] Embodiment 8. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin, linagliptin, alogliptin, denagliptin, megliptin, gosigliptin, teneligliptin, dulaglutide, and pharmaceutically acceptable salts thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin and linagliptin, and pharmaceutically acceptable salts thereof.

[0584] Embodiment 9. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-8, wherein the glucokinase activator is present in a dose range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg (preferably as a unit dose), preferably, the dose of the glucokinase activator (preferably as a unit dose) is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0585] Embodiment 10. A drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-9, wherein the DPP-IV inhibitor is present in a dose range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg (preferably as a unit dose), preferably, the dose of the DPP-IV inhibitor (preferably as a unit dose) is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg or about 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably as a unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, more preferably about 25 mg, 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is linagliptin, and its dose (preferably as a unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 5 mg or about 10 mg, more preferably about 5 mg; preferably, the DPP-IV inhibitor is saxagliptin, and its dose (preferably as a unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 2.5 mg, about 5 mg or about 10 mg, more preferably about 2.5 mg or about 5 mg; preferably, the DPP-IV inhibitor is vildagliptin, and its dose (preferably as a unit dose) is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, most preferably about 50 mg.

[0586] Scheme 11. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-10, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, coloring agents or coating agents.

[0587] Scheme 12. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-11, which is a tablet.

[0588] Scheme 13. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Scheme 12, which is a coated tablet.

[0589] Scheme 14. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Scheme 13, wherein the coated tablet is a film-coated tablet, and the film coating agent comprises:

[0590] A film coating base material, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose or a mixture thereof;

[0591] An optional plasticizer, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or a mixture thereof;

[0592] An optional coloring agent, such as iron oxide red, iron oxide yellow or a mixture thereof;

[0593] An optional opacifying agent, such as titanium dioxide, and

[0594] An optional glidant.

[0595] Scheme 15. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to Scheme 14, wherein the coated tablet is a film-coated tablet, and the film coating agent is Opadry.

[0596] Scheme 16. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 1-15, which comprises, by weight:

[0597] About 1-80% of a glucokinase activator (preferably HMS5552 or its isotope-labeled substance or a pharmaceutically acceptable salt), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;

[0598] About 1-20% of linagliptin;

[0599] About 0-90% of a filler;

[0600] About 1-25% of a binder;

[0601] About 0 to 15% of a disintegrant;

[0602] About 0.1 to 10% of a lubricant;

[0603] About 0 to 3% of a glidant; and

[0604] About 0 to 5% of a coating agent.

[0605] Scheme 17. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 16, by weight, the dose of the active ingredient (preferably the unit dose) is:

[0606] About 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator (preferably HMS5552 or its isotope-labeled substance or a pharmaceutically acceptable salt);

[0607] About 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of linagliptin;

[0608] About 0 to 90% of a filler;

[0609] About 1 to 25% of a binder;

[0610] About 0 to 15% of a disintegrant;

[0611] About 0.1 to 10% of a lubricant;

[0612] About 0 to 3% of a glidant; and

[0613] About 0 to 5% of a coating agent.

[0614] Scheme 18. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 5 mg linagliptin), by weight, it contains the following components in the following contents:

[0615] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0616] - About 5 mg of linagliptin;

[0617] - About 0 to 90% of a filler;

[0618] - About 2 to 8% of a binder;

[0619] - About 1 to 5% of a disintegrant;

[0620] - About 0.5 to 3% of a lubricant;

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

[0622] - about 0 to 5% of coating agent.

[0623] Scheme 19. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 5 mg linagliptin), by weight, comprises the following components in the following contents:

[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 about 1:1 of HMS5552 and Eudragit L100;

[0625] - about 5 mg of linagliptin;

[0626] - about 0 to 90% of filler;

[0627] - about 2 to 8% of binder;

[0628] - about 1 to 5% of disintegrant;

[0629] - about 0.5 to 3% of lubricant;

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

[0631] - about 0 to 5% of coating agent.

[0632] Scheme 20. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 5 mg linagliptin), by weight, comprises the following components in the following contents:

[0633] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0634] - about 5 mg of linagliptin;

[0635] - about 0 to 90% of filler;

[0636] - about 2 to 8% of binder;

[0637] - about 1 to 5% of disintegrant;

[0638] - about 0.5 to 3% of lubricant;

[0639] - About 0 to 0.5% glidant; and

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

[0641] Scheme 21. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 100 mg HMS5552 / 5 mg linagliptin), by weight, contains the following components in the following contents:

[0642] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0643] - About 5 mg of linagliptin;

[0644] - About 0 to 90% filler;

[0645] - About 2 to 8% binder;

[0646] - About 1 to 5% disintegrant;

[0647] - About 0.5 to 3% lubricant;

[0648] - About 0 to 0.5% glidant; and

[0649] - About 0 to 5% coating agent.

[0650] Scheme 22. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17, which contains about 50 mg solid dispersion, about 5.00 mg linagliptin, about 151.80 mg microcrystalline cellulose, about 6.60 mg hydroxypropyl cellulose, about 4.40 mg croscarmellose sodium, about 2.20 mg magnesium stearate and about 6.60 mg Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100 and contains about 25 mg HMS5552.

[0651] Scheme 23. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 17, which contains about 100 mg solid dispersion, about 5.00 mg linagliptin, about 120.60 mg microcrystalline cellulose, about 7.20 mg hydroxypropyl cellulose, about 4.80 mg croscarmellose sodium, about 2.40 mg magnesium stearate and about 7.20 mg Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100 and contains about 50 mg HMS5552.

[0652] Embodiment 24. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 150 mg of solid dispersion, about 5.00 mg of linagliptin, about 27.50 mg of microcrystalline cellulose, about 50.00 mg of mannitol, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of magnesium stearate and about 7.50 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.

[0653] Embodiment 25. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 50 mg of solid dispersion, about 5.00 mg of linagliptin, about 137.00 mg of microcrystalline cellulose, about 4.00 mg of croscarmellose sodium, about 2.00 mg of magnesium stearate, about 2.00 mg of colloidal silicon dioxide and about 6.00 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.

[0654] Embodiment 26. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Embodiment 17, which contains about 200 mg of solid dispersion, about 5.00 mg of linagliptin, about 77.0 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 contains HMS5552 and Eudragit L100 in a ratio of about 1:1, and contains about 100 mg of HMS5552.

[0655] Embodiment 27. A method for preparing the drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-26, the method comprising incorporating the active ingredients into one or more excipients for granulation, preferably further filling the obtained granule mixture into vials, sachets or capsules or compressing it into a desired tablet shape; more preferably further coating the obtained tablets.

[0656] Embodiment 28. The method for preparing the drug combination, pharmaceutical composition or fixed-dose combination preparation according to Embodiment 27, which is prepared by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[0657] Embodiment 29. The method for preparing the drug combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 27-28, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[0658] Embodiment 30. A method for preparing a pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 27-29, wherein the glucokinase activator and the second or more active ingredients can also be prepared together in the form of a combined solid dispersion (i.e., a solid dispersion containing two or more active ingredients).

[0659] Embodiment 31. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-26, which is used for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing down, delaying or reversing diabetic complications.

[0660] Embodiment 32. A method for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing down, delaying or reversing diabetic complications, including administering to a subject a therapeutically effective amount of a pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-26.

[0661] Embodiment 33. Use of a pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Embodiments 1-26 in the preparation of a medicament for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder or preventing, slowing down, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

[0662] The following examples further describe and illustrate 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 fall within the protection scope of the present invention. Example

[0663] Preparation of Compound Tablets of Glucokinase Activator

[0664] The chemicals used in the present invention can be purchased from companies such as Shin-Etsu Japan, Evonik Germany, J.T.Baker US, SCR China, Ashland US, FMC US, JRS Germany, Colorcon US, Capsugel, BASF, Zhenxing Reagent, etc. Production equipment, analytical and testing instruments, etc. can be purchased from companies such as Sartorius, Nikon, Sympatec, Bruker, Gea Niro, Korsch, Erweka, Agilent, Quadro Engineering, Canada; Warters, US; TA, US; SOTAX, Switzerland; Mettler Toledo Instrument Newark, DE.

[0665] I. Preparation of Solid Dispersion of Glucokinase Activator

[0666] 1.1 Preparation of Solution before Spray Drying of Solid Dispersion

[0667] Example 1A (weight ratio of active ingredient to polymer is 1:9)

[0668] Weigh 6.75 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to anhydrous ethanol (J.T.Baker) under stirring conditions. After complete dissolution, add 0.75 g of compound HMS5552, and continue stirring after adding sufficient anhydrous ethanol to obtain a 50 ml solution.

[0669] Example 2A (weight ratio of active ingredient to polymer is 3:7)

[0670] Weigh 5.25 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to anhydrous ethanol (J.T.Baker) under stirring conditions. After complete dissolution, add 2.25 g of compound HMS5552, and continue stirring after adding sufficient anhydrous ethanol to obtain a 50 ml solution.

[0671] Example 3A (weight ratio of active ingredient to polymer is 5:5)

[0672] Weigh 3.75 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to absolute ethanol (J.T.Baker / ) under stirring conditions. After complete dissolution, add 3.75 g of compound HMS5552, and continue stirring after adding sufficient absolute ethanol to obtain a 50 ml solution.

[0673] Example 4A (weight ratio of active ingredient to polymer is 7:3)

[0674] Weigh 2.25 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to absolute ethanol (J.T.Baker) under stirring conditions. After complete dissolution, add 5.25 g of compound HMS5552, and continue stirring after adding sufficient absolute ethanol to obtain a 50 ml solution.

[0675] Example 5A (weight ratio of active ingredient to polymer is 8:2)

[0676] Weigh 1.5 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to absolute ethanol (J.T.Baker) under stirring conditions. After complete dissolution, add 6 g of compound HMS5552, and continue stirring after adding sufficient absolute ethanol to obtain a 50 ml solution.

[0677] Example 6A (weight ratio of active ingredient to polymer is 9:1)

[0678] Weigh 0.75 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to absolute ethanol (J.T.Baker) under stirring conditions. After complete dissolution, add 6.75 g of compound HMS5552, and continue stirring after adding sufficient absolute ethanol to obtain a 50 ml solution.

[0679] Example 7A (weight ratio of active ingredient to polymer is 6:4)

[0680] Weigh 3.0 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to absolute ethanol (J.T.Baker) under stirring conditions. After complete dissolution, add 4.5 g of compound HMS5552, and continue stirring after adding sufficient absolute ethanol to obtain a 50 ml solution.

[0681] Example 8A (weight ratio of active ingredient to polymer is 4:6)

[0682] Weigh 4.5 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to anhydrous ethanol (J.T.Baker) under stirring conditions. After complete dissolution, add 3.0 g of compound HMS5552, and continue stirring after adding sufficient anhydrous ethanol to obtain a 50 ml solution.

[0683] Example 9A (weight ratio of active ingredient to polymer is 5:5)

[0684] Weigh 187.5 g of Eudragit L100 (Eudragit L100, Evonik Germany), add it to anhydrous ethanol (Zhenxing Reagent) under stirring conditions. After complete dissolution, add 187.5 g of compound HMS5552, and continue stirring to obtain a 2500 ml solution.

[0685] 1.2 Preparation of solid dispersion of glucokinase activator

[0686] Perform spray drying on the above-prepared solution to prepare a solid dispersion of glucokinase activator. The numbers of the obtained solid dispersions correspond to the numbers of the above examples. The spray drying equipment applicable to the present invention includes but is not limited to the spray drying equipment manufactured by Niro GEA Process Engineering Inc., Buchi Labortechnik AG, ProCept, and SPX ANHYDROUS. Spray drying can be carried out by selecting appropriate inlet air temperature of the drying gas, inlet air volume, liquid feeding speed, and atomization pressure, so that the liquid droplets are fully dried when they reach the device wall. This helps to ensure that the dried liquid droplets are basically solid, can form fine powder, and do not stick to the wall and are not difficult to collect in the cyclone. The obtained powder is subjected to secondary drying to ensure that the product meets the quality requirements.

[0687] Process Flow Description for the Preparation of Solid Dispersion of Glucokinase Activator by Spray Drying

[0688] Perform spray drying on the solutions prepared in the above Examples 1A - 8A to prepare solid dispersions, where the inlet air temperature set by the spray dryer is 90 - 150 °C, the inlet air flow rate is set to 0.3 - 0.5 m 3 / min, the air flow rate is 15 - 30 L / min, the liquid feeding speed of the above solution is 5 - 7 mL / min, and solid dispersions 1 - 8 are obtained by spray drying.

[0689] The solution prepared in Example 9A above was used to prepare a solid dispersion by spray drying, where the inlet air temperature of the spray dryer was set at 90 - 150 °C, the inlet air flow rate was set at 20 - 30 kg / h, the air flow rate was 3 - 30 kg / h, and the liquid spraying rate of the above solution was 5 - 200 mL / min. The solid dispersion 9 was obtained by spray drying.

[0690] In the above manner, solid dispersions 1 - 9 were prepared respectively, where:

[0691] The mass fraction of compound HMS5552 in solid dispersion 1 was 10%; the mass fraction of compound HMS5552 in solid dispersion 2 was 30%; the mass fraction of compound HMS5552 in solid dispersion 3 was 50%; the mass fraction of compound HMS5552 in solid dispersion 4 was 70%; the mass fraction of compound HMS5552 in solid dispersion 5 was 80%; the mass fraction of compound HMS5552 in solid dispersion 6 was 90%; the mass fraction of compound HMS5552 in solid dispersion 7 was 60%; the mass fraction of compound HMS5552 in solid dispersion 8 was 40%; the mass fraction of compound HMS5552 in solid dispersion 9 was 50%.

[0692] II. Preparation of compound tablets

[0693] 2.1 Preparation of compound tablets by high - shear wet granulation

[0694] The HMS5552 solid dispersion and the combination drug prepared according to the preparation examples of the solid dispersion of the above-mentioned glucokinase activator were added to a high-shear wet granulator, and a filler (such as microcrystalline cellulose, or silicified microcrystalline cellulose, or lactose) and a disintegrant (such as croscarmellose sodium, or crospovidone, or sodium starch glycolate) were added. Part of the binder powder was added, and high-shear stirring and mixing were carried out for 5 min. The prepared binder (such as hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methylcellulose) solution was added to the above dry mixture under high-shear stirring within 1 - 6 minutes for granulation. The wet granules were sized on a Comil granulator to obtain wet granules of appropriate size. The wet granules were 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 was milled using a grinder to obtain granules of a suitable size. After milling, microcrystalline cellulose or silicified microcrystalline cellulose (for the filler with an additional part) and a disintegrant (such as croscarmellose sodium, or crospovidone, or sodium starch glycolate) were added to the granules and mixed in a drum mixer. Then, a lubricant (magnesium stearate or sodium stearyl fumarate) and / or an optional glidant (colloidal silicon dioxide) were added and further mixed evenly. The lubricated mixture was compressed into tablets using a rotary tablet press to obtain tablets (plain tablets, uncoated tablet cores) with different tablet weights and tablet shapes corresponding to different specifications. The obtained tablets were optionally film-coated with II to increase the film coating weight by about 3% to obtain film-coated tablets.

[0695] Example 1B HMS5552 + Sitagliptin Compound Tablets (Dosage Specification 50 mg / 50 mg)

[0696] Prescription Composition Unit Prescription Quantity / mg %(w / w) Sitagliptin Phosphate Monohydrate* 64.25 29.20 HMS5552 Solid Dispersion 100.00 45.46 Microcrystalline Cellulose 40.35 18.34 Hydroxypropyl Cellulose 6.60 3.00 Croscarmellose Sodium 6.60 3.00 Magnesium Stearate 2.20 1.00 Total Weight of Tablet Core 220.00 100.00 Opadry 6.60 3.00 Total Weight of Coated Tablet 226.60 --

[0697] * 100.00 mg of HMS5552 solid dispersion is equivalent to 50 mg of HMS5552;

[0698] ** 64.25 mg of sitagliptin phosphate monohydrate is equivalent to 50.0 mg of sitagliptin free anhydride.

[0699] Example 2B HMS5552 + Sitagliptin Compound Tablets (Dosage Specification 75 mg / 50 mg)

[0700]

[0701]

[0702] * 150.00 mg of HMS5552 solid dispersion is equivalent to 75 mg of HMS5552;

[0703] **64.25 mg of sitagliptin phosphate monohydrate is equivalent to 50.0 mg of sitagliptin free anhydrate.

[0704] Example 3B HMS5552 + Sitagliptin Compound Tablets (Dosage Specification 50 mg / 100 mg)

[0705] Prescription Composition Unit Prescription Quantity / mg %(w / w) Sitagliptin Phosphate Monohydrate** 128.50 44.31 HMS5552 Solid Dispersion* 100.00 34.48 Microcrystalline Cellulose 41.20 14.21 Hydroxypropyl Cellulose 8.70 3.00 Croscarmellose Sodium 8.70 3.00 Magnesium Stearate 2.90 1.00 Total Weight of Tablet Core 290.0 100.00 Opadry 8.70 3.00 Total Weight of Coated Tablet 298.70 --

[0706] *100.00 mg of HMS5552 solid dispersion is equivalent to 50 mg of HMS5552;

[0707] **128.5 mg of sitagliptin phosphate monohydrate is equivalent to 100.0 mg of sitagliptin free anhydrate.

[0708] Example 4B HMS5552 + Sitagliptin Compound Tablets (Dosage Specification 75 mg / 100 mg)

[0709] Prescription Composition Unit Prescription Quantity / mg %(w / w) Sitagliptin Phosphate Monohydrate** 128.50 36.71 HMS5552 Solid Dispersion* 150.00 42.86 Microcrystalline Cellulose 47.00 13.43 Hydroxypropyl Cellulose 10.50 3.00 Croscarmellose Sodium 10.50 3.00 Magnesium Stearate 3.50 1.00 Total Weight of Tablet Core 350.00 100.00 Opadry 10.50 3.00 Total Weight of Coated Tablet 360.50 --

[0710] *150.00 mg of HMS5552 solid dispersion is equivalent to 75 mg of HMS5552;

[0711] **128.50 mg of sitagliptin phosphate monohydrate is equivalent to 100.0 mg of sitagliptin free anhydrate.

[0712] Example 5B HMS5552 + Sitagliptin Compound Tablets (Dosage Specification 25 mg / 100 mg)

[0713]

[0714]

[0715] *50.00 mg of HMS5552 solid dispersion is equivalent to 25 mg of HMS5552;

[0716] **128.50 mg of sitagliptin phosphate monohydrate is equivalent to 100.0 mg of sitagliptin free anhydrate.

[0717] Example 6B HMS5552 + Sitagliptin Compound Tablets (Dosage Specification 100 mg / 50 mg)

[0718] Prescription Composition Unit Prescription Quantity / mg %(w / w) Sitagliptin Phosphate Monohydrate* 64.25 18.36 HMS5552 Solid Dispersion 200.00 57.14 Microcrystalline Cellulose 61.26 17.50 Hydroxypropyl Cellulose 10.50 3.00 Croscarmellose Sodium 10.50 3.00 Magnesium Stearate 3.50 1.00 Total Weight of Tablet Core 350.00 100.00 Opadry 10.50 3.00 Total Weight of Coated Tablet 360.50

[0719] *200.00 mg of HMS5552 solid dispersion is equivalent to 100 mg of HMS5552;

[0720] **64.25 mg of sitagliptin phosphate monohydrate is equivalent to 50.0 mg of sitagliptin free anhydride.

[0721] Example 7B HMS5552 + linagliptin compound tablet (dose specification 25 mg / 5 mg)

[0722] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 50.00 22.73 Linagliptin 5.00 2.27 Microcrystalline Cellulose 151.80 69.00 Hydroxypropyl Cellulose 6.60 3.00 Croscarmellose Sodium 4.40 2.00 Magnesium Stearate 2.20 1.00 Total Weight of Tablet Core 220.00 100.00 Opadry 6.60 3.00 Total Weight of Coated Tablet 226.60 --

[0723] *50.00 mg of HMS5552 solid dispersion is equivalent to 25 mg of HMS5552.

[0724] Example 8B HMS5552 + linagliptin compound tablet (dose specification 50 mg / 5 mg)

[0725]

[0726]

[0727] *100.00 mg of HMS5552 solid dispersion is equivalent to 50 mg of HMS5552.

[0728] Example 9B HMS5552 + linagliptin compound tablet (dose specification 75 mg / 5 mg)

[0729] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 150.00 60.00 Linagliptin 5.00 2.00 Microcrystalline Cellulose 27.50 11.00 Mannitol 50.00 20.00 Hydroxypropyl Cellulose 7.50 3.00 Croscarmellose Sodium 7.50 3.00 Magnesium Stearate 2.50 1.00 Total Weight of Tablet Core 250.00 100.00 Opadry 7.50 3.00 Total Weight of Coated Tablet 257.50 --

[0730] *150.00 mg of HMS5552 solid dispersion is equivalent to 75 mg of HMS5552.

[0731] Example 10B HMS5552 + linagliptin compound tablet (dose specification 100 mg / 5 mg)

[0732] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 200.0 66.67 Linagliptin 5.0 1.67 Microcrystalline Cellulose 77.0 25.67 Hydroxypropyl Cellulose 9.00 3.00 Croscarmellose Sodium 6.00 2.00 Magnesium Stearate 3.00 1.00 Total Weight of Tablet Core 300.00 100.0 Opadry 9.00 3.00 Total Weight of Coated Tablet 309.00 --

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

[0734] Example 11B HMS5552 + saxagliptin compound tablet (dose specification 75 mg / 5 mg)

[0735]

[0736]

[0737] *150.00 mg of HMS5552 solid dispersion is equivalent to 75 mg of HMS5552;

[0738] **5.29 mg of saxagliptin monohydrate is equivalent to 5.0 mg of saxagliptin free anhydrate.

[0739] Example 12B HMS5552 + Saxagliptin Compound Tablets (Dosage Specification 50 mg / 2.5 mg)

[0740] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 100.00 40.00 Saxagliptin Monohydrate** 2.64 1.06 Hydroxypropyl Cellulose 7.50 3.00 Microcrystalline Cellulose 132.36 52.94 Magnesium Stearate 2.50 1.00 Croscarmellose Sodium 5.00 2.00 Total Weight of Tablet Core 250.00 100.00 Opadry 7.50 3.00 Total Weight of Coated Tablet 257.50 --

[0741] *100.00 mg of HMS5552 solid dispersion is equivalent to 50 mg of HMS5552;

[0742] **2.64 mg of saxagliptin monohydrate is equivalent to 2.5 mg of saxagliptin free anhydrate.

[0743] Example 13B HMS5552 + Saxagliptin Compound Tablets (Dosage Specification 100 mg / 2.5 mg)

[0744] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 200.00 66.67 Saxagliptin Monohydrate** 2.64 0.88 Povidone 9.00 3.00 Microcrystalline Cellulose 79.36 26.45 Magnesium Stearate 3.00 1.00 Croscarmellose Sodium 6.00 2.00 Total Weight of Tablet Core 300.00 100.00 Opadry 9.00 3.00 Total Weight of Coated Tablet 309.00 --

[0745] *200.00 mg of HMS5552 solid dispersion is equivalent to 100 mg of HMS5552;

[0746] **2.64 mg of saxagliptin monohydrate is equivalent to 2.5 mg of saxagliptin free anhydrate.

[0747] 2.2 Preparation of Compound Tablets by Fluidized Bed Wet Granulation

[0748] The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the above glucose kinase activator and the combined drug are added to a fluidized bed granulator, and an optional filler (such as microcrystalline cellulose) is added. The prepared binder (such as polyvinylpyrrolidone) solution is sprayed into the mixture in the fluidized bed within 20 - 60 minutes for granulation, and then continued to be dried in a fluidized bed dryer (inlet air temperature 40 - 60 °C). Then, the dried material is ground by a grinder to obtain particles of appropriate size. After grinding, microcrystalline cellulose or silicified microcrystalline cellulose (for the prescription with an externally added part of the filler) is added to the particles and mixed in a drum mixer. Then, a lubricant (magnesium stearate) and / or an optional glidant (aerosil) are added and further mixed evenly. The lubricated mixture is compressed into tablets of different tablet weights and tablet shapes corresponding to different specifications (plain tablets, uncoated tablet cores) using a rotary tablet press. The obtained tablets are optionally film-coated with a weight increase of about 3% using the method for preparing the solid dispersion of the above glucose kinase activator to obtain film-coated tablets.

[0749] Example 14B HMS5552 + Saxagliptin Compound Tablets (Dosage Specification 25mg / 5mg)

[0750] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 50.0 20.0 Saxagliptin Monohydrate** 5.29 2.12 Povidone 7.50 3.00 Microcrystalline Cellulose 179.71 71.88 Magnesium Stearate 2.50 1.00 Croscarmellose Sodium 5.00 2.00 Total Weight of Tablet Core 250.0 100.0 Opadry 7.50 3.00 Total Weight of Coated Tablet 257.50 --

[0751] *50.00mg of HMS5552 solid dispersion is equivalent to 25mg of HMS5552;

[0752] **5.29mg of saxagliptin monohydrate is equivalent to 5.0mg of free anhydrous saxagliptin.

[0753] 2.3 Preparation of Compound Tablets by Dry Granulation

[0754] The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the above-mentioned glucokinase activator and the combination drug are added to a mixing barrel, and a filler (such as microcrystalline cellulose) and a binder (such as hydroxypropyl cellulose) are added and mixed evenly. Then, it is rolled by a roller granulator, and the obtained strip is crushed and sized by a pulverizer to obtain granules of appropriate size. After grinding, optional microcrystalline cellulose or silicified microcrystalline cellulose (for the filler with an additional part) and a disintegrant (such as croscarmellose sodium) 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 (colloidal silicon dioxide) are added and further mixed evenly. The lubricated mixture is tabletted using a rotary tablet press to obtain tablets (plain tablets, uncoated tablet cores) with different tablet weights and tablet shapes corresponding to different specifications. The obtained tablets are optionally II Film-coated to increase the weight by about 3%, thus obtaining film-coated tablets.

[0755] Example 15B HMS5552 + Vildagliptin Compound Tablets (Dosage Specification 25mg / 50mg)

[0756]

[0757]

[0758] *100.00mg of HMS5552 solid dispersion is equivalent to 50mg of HMS5552.

[0759] Example 16B HMS5552 + Vildagliptin Compound Tablets (Dosage Specification 50mg / 50mg)

[0760] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 100.00 16.67 Vildagliptin 50.00 8.33 Microcrystalline Cellulose 414.00 69.00 Croscarmellose Sodium 24.00 4.00 Aerosil 6.00 1.00 Magnesium Stearate 6.00 1.00 Total Weight of Tablet Core 600.00 100.00 Opadry 18.00 3.00 Total Weight of Coated Tablet 618.00 --

[0761] *100.00mg of HMS5552 solid dispersion is equivalent to 50mg of HMS5552.

[0762] Example 17B HMS5552 + Vildagliptin Compound Tablets (Dosage Specification 75 mg / 50 mg)

[0763] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 150.00 20.00 Vildagliptin 50.00 6.67 Silicified Microcrystalline Cellulose 512.50 68.33 Croscarmellose Sodium 30.00 4.00 Magnesium Stearate 7.50 1.00 Total Weight of Tablet Core 750.00 100.00 Opadry 21.50 3.00 Total Weight of Coated Tablet 771.50 --

[0764] *150.00 mg of HMS5552 solid dispersion is equivalent to 75 mg of HMS5552.

[0765] 2.4 Preparation of Compound Tablets by Direct Compression of Powder Mixture

[0766] The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the glucokinase activator described above and the combination drug were premixed uniformly according to the geometric increment principle and then added to the mixing barrel. Filler (such as microcrystalline cellulose), disintegrant (such as croscarmellose sodium) and optional glidant (aerosil) were added to the granules and mixed in a barrel mixer. Then, lubricant (magnesium stearate or sodium stearyl fumarate) was added thereto and further mixed uniformly. The lubricated mixture was compressed into tablets using a rotary tablet press to obtain tablets (plain tablets, uncoated tablet cores) with different tablet weights and tablet shapes corresponding to different specifications. The obtained tablets were optionally II. Film-coated tablets were obtained by film coating with a weight increase of approximately 3% using

[0767] The formulation of the compound tablets described according to the above preparation process is as follows:

[0768] Example 18B HMS5552 + Linagliptin Compound Tablets (Dosage Specification 25 mg / 5 mg)

[0769] Prescription Composition Unit Prescription Quantity / mg %(w / w) HMS5552 Solid Dispersion* 50.00 25.00 Linagliptin 5.00 2.50 Microcrystalline Cellulose 137.00 68.50 Croscarmellose Sodium 4.00 2.00 Magnesium Stearate 2.00 1.00 Aerosil 2.00 1.00 Total Weight of Tablet Core 200.00 100.00 Opadry 6.00 3.00 Total Weight of Coated Tablet 206.00 --

[0770] *50.00 mg of HMS5552 solid dispersion is equivalent to 25 mg of HMS5552

[0771] III. In Vitro Dissolution Test of Compound Preparations Containing Glucokinase Activator

[0772] The dissolution of the tablets was tested by the paddle method of the Chinese Pharmacopoeia (2015 Edition), and the dissolution of HMS5552 and the other combination drug in a medium of pH 6.8 was tested respectively. At 5 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes, 5 ml of samples were taken respectively for HPLC analysis.

[0773] According to the above test method, the dissolution results of the above-mentioned tablets with several fixed dosage specifications and their corresponding single-component tablets are as follows.

[0774] Table 1 Dissolution Results of Fixed-Dose Compound Tablets Prepared in Example 1B

[0775]

[0776] Dissolution results of the fixed-dose combination tablets prepared in Example 4B, Table 2

[0777]

[0778] Dissolution results of the fixed-dose combination tablets prepared in Example 7B, Table 3

[0779]

[0780] Dissolution results of the fixed-dose combination tablets prepared in Example 9B, Table 4

[0781]

[0782] Dissolution results of the fixed-dose combination tablets prepared in Example 11B, Table 5

[0783]

[0784] Dissolution results of the fixed-dose combination tablets prepared in Example 14B, Table 6

[0785]

[0786] Dissolution results of the fixed-dose combination tablets prepared in Example 17B, Table 7

[0787]

[0788] It can be seen from the dissolution results of the above fixed-dose combination preparations that the dissolution of the fixed combination preparation of the present invention meets the requirements of a rapid-release preparation.

[0789] IV. Physical properties of the combination preparation containing a glucokinase activator

[0790] According to the relevant instruments and methods of the pharmacopoeia, the physical properties of the tablets of the above several fixed-dose specifications were tested, and the results are described as follows.

[0791] Table 8 Physical properties of the fixed-dose combination tablets prepared in different examples

[0792]

[0793]

[0794] Table 9 Physical properties of the fixed-dose combination tablet cores prepared in different examples

[0795]

[0796] Table 10 Physical properties of fixed-dose compound tablet cores prepared in different examples

[0797]

[0798] Table 11 Physical properties of fixed-dose compound tablet cores prepared in different examples

[0799]

[0800]

[0801] V. Pharmacodynamic study of compound preparations containing glucokinase activators

[0802] Example 1C

[0803] Pharmacodynamic animal study of HMS5552 combined with sitagliptin in type 2 diabetic model rats

[0804] SD obese rats were induced to form type 2 diabetic model rats by STZ. They were orally administered lysosome, 10 mg / kg HMS5552, 30 mg / kg HMS5552, 10 mg / kg sitagliptin, 30 mg / kg sitagliptin, 10 mg / kg HMS5552 combined with 10 mg / kg sitagliptin, or 10 mg / kg HMS5552 combined with 30 mg / kg sitagliptin once a day. After 30 days of treatment, through oral glucose tolerance test (OGTT), the area under the blood glucose curve (AUEC0-4hr, hr*mg / dL) from 0 to 4 hours was analyzed for the change compared with the baseline before treatment (AUEC). The results showed that the combination of 10 mg / kg HMS5552 and 30 mg / kg sitagliptin had the best hypoglycemic effect, which was better than the high-dose monotherapy of HMS5552 and sitagliptin (30 mg / kg), with statistically significant differences.

[0805] Sitagliptin, a dipeptidyl peptidase-4 (DPP-IV) inhibitor, improves glycemic control by inhibiting the degradation of incretin GLP-1, increasing the level of active incretin, and reducing postprandial blood glucose, and is used to treat type 2 diabetes. HMS5552, a novel glucokinase activator, can improve the pancreatic islet function of type 2 diabetic patients, promote the secretion of incretin, and reduce insulin resistance, with dual therapeutic effects of reducing fasting and postprandial blood glucose. The combination of DPP-IV inhibitor and HMS5552 has better glycemic control efficacy and reduces the risk of diabetic complications for patients with ineffective glycemic control with DPP-IV inhibitors, obese patients, and diabetic patients with cardiovascular diseases.

[0806] The above-mentioned efficacy study on the combination of HMS5552 and existing oral diabetes drugs shows that the combination 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.

[0807] In summary, the present invention relates to the following technical solutions:

[0808] 1. A drug combination, comprising:

[0809] (a) A glucokinase activator, wherein the glucokinase activator is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopically labeled form thereof, a crystalline form thereof, a hydrate, a solvate, a diastereoisomer or an enantiomeric form:

[0810]

[0811]

[0812] (b) A DPP-IV inhibitor;

[0813] wherein the above drugs (a) and (b) are used simultaneously, separately or successively.

[0814] 2. The drug combination of technical solution 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 100:1, preferably about 1:4 to 40:1, more preferably about 1:4, about 1:2, about 1:1, about 1.5:1, about 1.5:2, about 2:1, about 5:1, about 10:1, about 15:1, about 20:1 or about 40:1.

[0815] 3. The drug combination of technical solution 1 or 2, wherein the glucokinase activator is the compound HMS5552 represented by the following formula, or an isotopically labeled form thereof or a pharmaceutically acceptable salt thereof,

[0816]

[0817] 4. The drug combination of any one of technical solutions 1-3, wherein the glucokinase activator is in the form of a solid dispersion; preferably, the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is methacrylic acid copolymer type A (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, more preferably Eudragit L100.

[0818] 5. The pharmaceutical combination of Technical Solution 4, wherein the weight ratio of the glucokinase activator to the polymer carrier is from about 1:10 to 10:1, preferably from about 1:9 to 9:1, from about 1:4 to 4:1, from about 3:7 to 7:3, from about 2:3 to 3:2, from about 3:4 to 4:3, from about 4:5 to 5:4 or from about 5:6 to 6:5, more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6.

[0819] 6. The pharmaceutical combination according to any one of Technical Solutions 1-5, wherein the DPP-IV inhibitor is selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin, linagliptin, alogliptin, denagliptin, meglitinide, gosogliptin, teragliptin, dulaglutide, and pharmaceutically acceptable salts thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin and linagliptin, and pharmaceutically acceptable salts thereof.

[0820] 7. The pharmaceutical combination according to any one of Technical Solutions 1-6, wherein the glucokinase activator is present in a dosage (preferably unit dosage) range of from about 1 mg to about 200 mg, preferably from about 25 mg to about 100 mg, preferably, wherein the dosage (preferably unit dosage) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0821] 8. The pharmaceutical combination according to any one of technical solutions 1-7, wherein the DPP-IV inhibitor is present in a dose (preferably unit dose) range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg. Preferably, the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg or about 100 mg, and most preferably is about 2.5 mg, about 5 mg, about 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, more preferably about 25 mg, 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is linagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 5 mg or about 10 mg, more preferably about 5 mg; preferably, the DPP-IV inhibitor is saxagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 2.5 mg, about 5 mg or about 10 mg, more preferably about 2.5 mg or about 5 mg; preferably, the DPP-IV inhibitor is vildagliptin, and its dose (preferably unit dose) is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, most preferably about 50 mg.

[0822] 9. The pharmaceutical combination according to any one of technical solutions 1-8, which is in the form of a pharmaceutical composition.

[0823] 10. The pharmaceutical composition according to technical solution 9, which comprises a solid dispersion of a glucokinase activator and a DPP-IV inhibitor. Preferably, the weight ratio of the solid dispersion of the glucokinase activator to the DPP-IV inhibitor is about 1:5 to 100:1, preferably about 1:2 to 80:1, more preferably about 1:2, about 1:1, about 2:1, about 3:1, about 3:2, about 4:1, about 10:1, about 20:1, about 30:1, about 40:1 or about 80:1.

[0824] 11. The pharmaceutical composition according to technical solution 9 or 10, wherein the solid dispersion of the glucokinase activator is about 1 to 98% by weight; the DPP-IV inhibitor is about 0.2 to 80% by weight.

[0825] 12. The pharmaceutical composition according to any one of technical solutions 9-11, which further comprises 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.

[0826] 13. The pharmaceutical composition according to any one of technical solutions 9-12, which is in a form selected from tablets, capsules, pills and lozenges, preferably tablets, more preferably coated tablets.

[0827] 14. A fixed-dose combination preparation, which comprises:

[0828] (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, its isotope-labeled substance, its crystalline form, hydrate, solvate, diastereoisomer or enantiomer form:

[0829]

[0830] (b) A DPP-IV inhibitor;

[0831] (c) One or more excipients.

[0832] 15. The fixed-dose combination preparation according to technical solution 14, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 100:1, preferably about 1:4 to 40:1, more preferably about 1:4, about 1:2, about 1:1, about 1.5:1, about 1.5:2, about 2:1, about 5:1, about 10:1, about 15:1, about 20:1 or about 40:1.

[0833] 16. The fixed-dose combination preparation according to technical solution 14 or 15, wherein the glucokinase activator is about 1 to 98% by weight; the DPP-IV inhibitor is about 0.2 to 80% by weight.

[0834] 17. The fixed-dose combination preparation according to any one of technical solutions 14-16, wherein the glucokinase activator is the compound HMS5552 represented by the following formula, or its isotope-labeled substance or its pharmaceutically acceptable salt,

[0835]

[0836] 18. A fixed-dose combination preparation according to any one of technical solutions 14-17, wherein the glucokinase activator is in the form of a solid dispersion. Preferably, the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, and the polymer carrier is type A methacrylic acid copolymer (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, more preferably Eudragit L100.

[0837] 19. A fixed-dose combination preparation according to any one of technical solutions 14-18, 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.

[0838] 20. A fixed-dose combination preparation according to any one of technical solutions 14-19, wherein the DPP-IV inhibitor is selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vildagliptin, linagliptin, alogliptin, denagliptin, meglitinide, gosigliptin, terigliptin, dulaglutide, and pharmaceutically acceptable salts thereof. Preferably, it is selected from sitagliptin (or), saxagliptin (or saxagliptin monohydrate), vildagliptin and linagliptin, and pharmaceutically acceptable salts thereof.

[0839] 21. The fixed-dose combination preparation according to any one of technical solutions 14-20, wherein the glucokinase activator is present in a dose (preferably unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg. Preferably, the dose (preferably unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.

[0840] 22. The fixed-dose combination preparation according to any one of technical solutions 14-21, wherein the DPP-IV inhibitor is present in a dose (preferably unit dose) range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg. Preferably, the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg or about 100 mg, and most preferably is about 2.5 mg, about 5 mg, about 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg, more preferably about 25 mg, 50 mg or about 100 mg; preferably, the DPP-IV inhibitor is linagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 5 mg or about 10 mg, more preferably about 5 mg; preferably, the DPP-IV inhibitor is saxagliptin, and its dose (preferably unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about 2.5 mg, about 5 mg or about 10 mg, more preferably about 2.5 mg or about 5 mg; preferably, the DPP-IV inhibitor is vildagliptin, and its dose (preferably unit dose) is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, most preferably about 50 mg.

[0841] 23. The 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 DPP-IV inhibitor is about 1:5 to 100:1, preferably about 1:2 to 80:1, more preferably about 1:2, about 1:1, about 2:1, about 3:1, about 3:2, about 4:1, about 10:1, about 20:1, about 30:1, about 40:1 or about 80:1.

[0842] 24. The fixed-dose combination preparation according to technical solution 23, wherein the solid dispersion of the glucokinase activator is about 1 to 98% by weight; the DPP-IV inhibitor is about 0.2 to 80% by weight.

[0843] 25. The fixed-dose combination preparation according to 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.

[0844] 26. The fixed-dose combination preparation of Technical Solution 25, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose; the filler is selected from microcrystalline cellulose, siliconized microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch or pregelatinized starch; the disintegrant is selected from croscarmellose sodium, crospovidone or sodium starch glycolate; the lubricant is selected from magnesium stearate or sodium stearyl fumarate; the glidant is selected from colloidal silicon dioxide or talc.

[0845] 27. The fixed-dose combination preparation according to any one of Technical Solutions 14-26, which is a tablet.

[0846] 28. The fixed-dose combination preparation of Technical Solution 27, which is a coated tablet.

[0847] 29. The fixed-dose combination preparation of Technical Solution 28, wherein the coated tablet is a film-coated tablet, and the film coating agent comprises:

[0848] A film coating base material, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose or a mixture thereof;

[0849] An optional plasticizer, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or a mixture thereof;

[0850] An optional colorant, such as iron oxide red, iron oxide yellow or a mixture thereof;

[0851] An optional opacifier, such as titanium dioxide, and

[0852] An optional glidant.

[0853] 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.

[0854] 31. The fixed-dose combination preparation according to any one of Technical Solutions 14-30, by weight, comprises:

[0855] - About 1 to 80%, preferably about 5 to 75% 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 about 1:1 of HMS5552 and Eudragit L100;

[0856] - About 0.2 to 80%, preferably about 0.5 to 75% DPP-IV inhibitor;

[0857] - About 0 to 55% filler;

[0858] - About 1 to 25% binder;

[0859] - About 0 to 15% of a disintegrant;

[0860] - About 0.1 to 10% of a lubricant;

[0861] - About 0 to 3% of a glidant; and

[0862] - About 0 to 5% of a coating agent.

[0863] 32. The fixed-dose combination preparation of Technical Solution 31, by weight, the dose (preferably the unit dose) of the active ingredient is: about 25 mg, about 50 mg, about 75 mg or about 100 mg of a glucokinase activator, preferably HMS5552;

[0864] About 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate.

[0865] 33. The fixed-dose combination preparation of Technical Solution 32, the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, by weight, it contains the following components in the following contents:

[0866] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0867] - About 50 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0868] - About 0 to 50% of a filler;

[0869] - About 2 to 8% of a binder;

[0870] - About 1 to 5% of a disintegrant;

[0871] - About 0.5 to 3% of a lubricant;

[0872] - About 0 to 0.5% of a glidant; and

[0873] - About 0 to 5% of a coating agent.

[0874] 34. The fixed-dose combination preparation of Technical Solution 32, the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, by weight, it contains the following components in the following contents:

[0875] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0876] - About 50 mg of sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate;

[0877] - About 0 to 50% of a filler;

[0878] - About 2 to 8% of a binder;

[0879] - About 1 to 5% of a disintegrant;

[0880] - About 0.5 to 3% of a lubricant; and

[0881] - About 0 to 0.5% of a glidant; and

[0882] - About 0 to 5% of a coating agent.

[0883] 35. The fixed-dose combination preparation of Technical Solution 32, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 100 mg sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate, and by weight, it contains the following components in the following contents:

[0884] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0885] - About 100 mg of sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate;

[0886] - About 0 to 50% of a filler;

[0887] - About 2 to 8% of a binder;

[0888] - About 1 to 5% of a disintegrant;

[0889] - About 0.5 to 3% of a lubricant;

[0890] - About 0 to 0.5% of a glidant; and

[0891] - About 0 to 5% of a coating agent.

[0892] 36. The fixed-dose combination preparation of Technical Solution 32, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 100 mg sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate, and by weight, it contains the following components in the following contents:

[0893] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0894] - Approximately 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0895] - Approximately 0 to 50% of a filler;

[0896] - Approximately 2 to 8% of a binder;

[0897] - Approximately 1 to 5% of a disintegrant;

[0898] - Approximately 0.5 to 3% of a lubricant;

[0899] - Approximately 0 to 0.5% of a glidant; and

[0900] - Approximately 0 to 5% of a coating agent.

[0901] 37. The fixed-dose combination preparation of Technical Solution 32, wherein the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it contains the following components in the following contents:

[0902] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0903] - Approximately 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0904] - Approximately 0 to 50% of a filler;

[0905] - Approximately 2 to 8% of a binder;

[0906] - Approximately 1 to 5% of a disintegrant;

[0907] - Approximately 0.5 to 3% of a lubricant;

[0908] - Approximately 0 to 0.5% of a glidant; and

[0909] - Approximately 0 to 5% of a coating agent.

[0910] 38. The fixed-dose combination preparation of Technical Solution 32, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it contains the following components in the following contents:

[0911] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0912] - Approximately 50 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate;

[0913] - Approximately 0 to 50% of a filler;

[0914] - Approximately 2 to 8% of a binder;

[0915] - Approximately 1 to 5% of a disintegrant;

[0916] - Approximately 0.5 to 3% of a lubricant;

[0917] - Approximately 0 to 0.5% of a glidant; and

[0918] - Approximately 0 to 5% of a coating agent.

[0919] 39. The fixed-dose combination preparation of Technical Solution 32, which contains approximately 100 mg of solid dispersion, approximately 64.25 mg of sitagliptin phosphate monohydrate, approximately 40.35 mg of microcrystalline cellulose, approximately 6.60 mg of hydroxypropyl cellulose, approximately 6.60 mg of croscarmellose sodium, approximately 2.20 mg of magnesium stearate, and approximately 6.60 mg of Opadry, wherein the solid dispersion contains approximately 1:1 of HMS5552 and Eudragit L100 and contains approximately 50 mg of HMS5552.

[0920] 40. The fixed-dose combination preparation of Technical Solution 32, which contains approximately 150 mg of solid dispersion, approximately 64.25 mg of sitagliptin phosphate monohydrate, approximately 27.55 mg of microcrystalline cellulose, approximately 7.80 mg of hydroxypropyl cellulose, approximately 7.80 mg of croscarmellose sodium, approximately 2.60 mg of magnesium stearate, and approximately 7.80 mg of Opadry, wherein the solid dispersion contains approximately 1:1 of HMS5552 and Eudragit L100 and contains approximately 75 mg of HMS5552.

[0921] 41. The fixed-dose combination preparation of Technical Solution 32, which contains approximately 100 mg of solid dispersion, approximately 128.50 mg of sitagliptin phosphate monohydrate, approximately 41.20 mg of microcrystalline cellulose, approximately 8.70 mg of hydroxypropyl cellulose, approximately 8.70 mg of croscarmellose sodium, approximately 2.90 mg of magnesium stearate, and approximately 8.70 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1 and contains approximately 50 mg of HMS5552.

[0922] 42. The fixed-dose combination preparation of Technical Solution 32, which contains approximately 150 mg of solid dispersion, approximately 128.50 mg of sitagliptin phosphate monohydrate, approximately 47.00 mg of microcrystalline cellulose, approximately 10.50 mg of hydroxypropyl cellulose, approximately 10.50 mg of croscarmellose sodium, approximately 3.50 mg of magnesium stearate, and approximately 10.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1 and contains approximately 75 mg of HMS5552.

[0923] 43. The fixed-dose combination preparation of Technical Solution 32, which contains approximately 50 mg of solid dispersion, approximately 128.50 mg of sitagliptin phosphate monohydrate, approximately 100.50 mg of microcrystalline cellulose, approximately 9.00 mg of hydroxypropyl cellulose, approximately 9.00 mg of croscarmellose sodium, approximately 3.00 mg of magnesium stearate, and approximately 9.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1 and contains approximately 25 mg of HMS5552.

[0924] 44. The fixed-dose combination preparation of Technical Solution 32, which contains approximately 200 mg of solid dispersion, approximately 64.25 mg of sitagliptin phosphate monohydrate, approximately 61.26 mg of microcrystalline cellulose, approximately 10.50 mg of hydroxypropyl cellulose, approximately 10.50 mg of croscarmellose sodium, approximately 3.50 mg of magnesium stearate, and approximately 10.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1 and contains approximately 100 mg of HMS5552.

[0925] 45. The fixed-dose combination preparation of Technical Solution 31, by weight, the dose of the active ingredient (preferably the unit dose) is: approximately 25 mg, approximately 50 mg, approximately 75 mg, or approximately 100 mg of glucokinase activator, preferably HMS5552; approximately 50 mg or approximately 100 mg of vildagliptin.

[0926] 46. The fixed-dose combination preparation of Technical Solution 45, wherein the fixed-dose combination preparation is a tablet of 25 mg of HMS5552 / 50 mg of vildagliptin, and by weight, it contains the following components in the following contents:

[0927] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0928] - Approximately 50 mg of vildagliptin;

[0929] - Approximately 0 to 80% of a filler;

[0930] - Approximately 2 to 8% of a binder;

[0931] - Approximately 1 to 8% of a disintegrant;

[0932] - Approximately 0.5 to 3% of a lubricant;

[0933] - Approximately 0 to 0.5% of a glidant; and

[0934] - Approximately 0 to 5% of a coating agent.

[0935] 47. The fixed-dose combination preparation of Technical Solution 45, wherein the fixed-dose combination preparation is a tablet of 50 mg of HMS5552 / 50 mg of vildagliptin, and by weight, it contains the following components in the following contents:

[0936] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0937] - Approximately 50 mg of vildagliptin;

[0938] - Approximately 0 to 80% of a filler;

[0939] - Approximately 2 to 8% of a binder;

[0940] - Approximately 1 to 8% of a disintegrant;

[0941] - Approximately 0.5 to 3% of a lubricant;

[0942] - Approximately 0 to 0.5% of a glidant; and

[0943] - Approximately 0 to 5% of a coating agent.

[0944] 48. The fixed-dose combination preparation of Technical Solution 45, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 50 mg vildagliptin, and by weight, it contains the following components in the following contents:

[0945] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[0946] - Approximately 50 mg of vildagliptin;

[0947] - Approximately 0 to 80% of a filler;

[0948] - Approximately 2 to 8% of a binder;

[0949] - Approximately 1 to 8% of a disintegrant;

[0950] - Approximately 0.5 to 3% of a lubricant;

[0951] - Approximately 0 to 0.5% of a glidant; and

[0952] - Approximately 0 to 5% of a coating agent.

[0953] 49. The fixed-dose combination preparation of Technical Solution 45, which contains approximately 50 mg of solid dispersion, approximately 50.00 mg of vildagliptin, approximately 464.00 mg of microcrystalline cellulose, approximately 24.00 mg of croscarmellose sodium, approximately 6.00 mg of colloidal silicon dioxide, approximately 6.00 mg of magnesium stearate, and approximately 18.00 mg of Opadry, wherein the solid dispersion contains approximately 1:1 of HMS5552 and Eudragit L100 and contains approximately 25 mg of HMS5552.

[0954] 50. The fixed-dose combination preparation of Technical Solution 45, which contains approximately 100 mg of solid dispersion, approximately 50.00 mg of vildagliptin, approximately 414.00 mg of microcrystalline cellulose, approximately 24.00 mg of croscarmellose sodium, approximately 6.00 mg of colloidal silicon dioxide, approximately 6.00 mg of magnesium stearate, and approximately 18.00 mg of Opadry, wherein the solid dispersion contains approximately 1:1 of HMS5552 and Eudragit L100 and contains approximately 50 mg of HMS5552.

[0955] 51. The fixed-dose combination preparation of Technical Solution 45, which contains about 150 mg of solid dispersion, about 50.00 mg of vildagliptin, about 512.50 mg of silicified microcrystalline cellulose, about 30.00 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate and about 21.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 75 mg of HMS5552.

[0956] 52. The fixed-dose combination preparation of Technical Solution 31, by weight, the dose (preferably unit dose) of the active ingredient is: about 25 mg, about 50 mg, about 75 mg or about 100 mg of glucokinase activator, preferably HMS5552;

[0957] About 2.5 mg, about 5 mg, about 7.5 mg and about 10 mg of saxagliptin or the corresponding amount of saxagliptin monohydrate.

[0958] 53. The fixed-dose combination preparation of Technical Solution 52, the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate, by weight, it contains the following components in the following contents:

[0959] - About 25 mg of HMS5552, preferably the solid dispersion of HMS5552, preferably the solid dispersion containing HMS5552 and a polymer carrier, preferably the solid dispersion containing about 1:1 of HMS5552 and Eudragit L100;

[0960] - About 5 mg of saxagliptin or the corresponding amount of saxagliptin monohydrate;

[0961] - About 0 to 80% of a filler;

[0962] - About 2 to 8% of a binder;

[0963] - About 1 to 5% of a disintegrant;

[0964] - About 0.5 to 3% of a lubricant;

[0965] - About 0 to 0.5% of a glidant; and

[0966] - About 0 to 5% of a coating agent.

[0967] 54. The fixed-dose combination preparation of Technical Solution 52, the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 2.5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate, by weight, it contains the following components in the following contents:

[0968] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0969] - About 2.5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate;

[0970] - About 0 to 80% filler;

[0971] - About 2 to 8% binder;

[0972] - About 1 to 5% disintegrant;

[0973] - About 0.5 to 3% lubricant;

[0974] - About 0 to 0.5% glidant; and

[0975] - About 0 to 5% coating agent.

[0976] 55. The fixed-dose combination preparation of Technical Solution 52, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following contents:

[0977] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0978] - About 5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate;

[0979] - About 0 to 80% filler;

[0980] - About 2 to 8% binder;

[0981] - About 1 to 5% disintegrant;

[0982] - About 0.5 to 3% lubricant;

[0983] - About 0 to 0.5% glidant; and

[0984] - About 0 to 5% coating agent.

[0985] 56. The fixed-dose combination preparation of Technical Solution 52, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 2.5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following contents:

[0986] - 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 about 1:1 of HMS5552 and Eudragit L100;

[0987] - About 2.5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate;

[0988] - About 0 to 80% of a filler;

[0989] - About 2 to 8% of a binder;

[0990] - About 1 to 5% of a disintegrant;

[0991] - About 0.5 to 3% of a lubricant;

[0992] - About 0 to 0.5% of a glidant; and

[0993] - About 0 to 5% of a coating agent.

[0994] 57. The fixed-dose combination preparation of Technical Solution 52, which contains about 150 mg of solid dispersion, about 5.29 mg of saxagliptin monohydrate, about 7.50 mg of hydroxypropyl cellulose, about 79.71 mg of microcrystalline cellulose, about 2.50 mg of magnesium stearate, about 5.00 mg of croscarmellose sodium, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100 and contains about 75 mg of HMS5552.

[0995] 58. The fixed-dose combination preparation of Technical Solution 52, which contains about 100 mg of solid dispersion, about 2.64 mg of saxagliptin monohydrate, about 7.50 mg of hydroxypropyl cellulose, about 132.36 mg of microcrystalline cellulose, about 2.50 mg of magnesium stearate, about 5.00 mg of croscarmellose sodium, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100 and contains about 50 mg of HMS5552.

[0996] 59. The fixed-dose combination preparation of Technical Solution 52, which contains about 200 mg of solid dispersion, about 2.64 mg of saxagliptin monohydrate, about 9.00 mg of polyvinylpyrrolidone, about 79.36 mg of microcrystalline cellulose, about 3.00 mg of magnesium stearate, about 6.00 mg of croscarmellose sodium, and about 9.00 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100 and contains about 100 mg of HMS5552.

[0997] Fixed-dose combination preparation of Technical Solution 52, which contains approximately 50 mg of solid dispersion, approximately 5.29 mg of saxagliptin monohydrate, approximately 7.50 mg of povidone, approximately 179.71 mg of microcrystalline cellulose, approximately 2.50 mg of magnesium stearate, approximately 5.00 mg of croscarmellose sodium, and approximately 7.50 mg of Opadry, wherein the solid dispersion contains approximately 1:1 of HMS5552 and Eudragit L100, and contains approximately 25 mg of HMS5552.

[0998] 61. Fixed-dose combination preparation of Technical Solution 31. By weight, the dose (preferably unit dose) of the active ingredient is: approximately 25 mg, approximately 50 mg, approximately 75 mg, or approximately 100 mg of glucokinase activator, preferably HMS5552; approximately 2.5 mg, approximately 5 mg, approximately 7.5 mg, or approximately 10 mg of linagliptin.

[0999] 62. Fixed-dose combination preparation of Technical Solution 61. The fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 5 mg linagliptin. By weight, it contains the following components in the following amounts:

[1000] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[1001] - Approximately 5 mg of linagliptin;

[1002] - Approximately 0 - 90% filler;

[1003] - Approximately 2 - 8% binder;

[1004] - Approximately 1 - 5% disintegrant;

[1005] - Approximately 0.5 - 3% lubricant;

[1006] - Approximately 0 - 0.5% glidant; and

[1007] - Approximately 0 - 5% coating agent.

[1008] 63. Fixed-dose combination preparation of Technical Solution 61. The fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 5 mg linagliptin. By weight, it contains the following components in the following amounts:

[1009] - Approximately 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 approximately 1:1 of HMS5552 and Eudragit L100;

[1010] - About 5 mg of linagliptin;

[1011] - About 0 to 90% of a filler;

[1012] - About 2 to 8% of a binder;

[1013] - About 1 to 5% of a disintegrant;

[1014] - About 0.5 to 3% of a lubricant;

[1015] - About 0 to 0.5% of a glidant; and

[1016] - About 0 to 5% of a coating agent.

[1017] 64. The fixed-dose combination preparation of Technical Solution 61, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 5 mg linagliptin, and by weight, it comprises the following components in the following contents:

[1018] - 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 about 1:1 of HMS5552 and Eudragit L100;

[1019] - About 5 mg of linagliptin;

[1020] - About 0 to 90% of a filler;

[1021] - About 2 to 8% of a binder;

[1022] - About 1 to 5% of a disintegrant;

[1023] - About 0.5 to 3% of a lubricant;

[1024] - About 0 to 0.5% of a glidant; and

[1025] - About 0 to 5% of a coating agent.

[1026] 65. The fixed-dose combination preparation of Technical Solution 61, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 5 mg linagliptin, and by weight, it comprises the following components in the following contents:

[1027] - 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 about 1:1 of HMS5552 and Eudragit L100;

[1028] - About 5 mg of linagliptin;

[1029] - Approximately 0 to 90% filler;

[1030] - Approximately 2 to 8% binder;

[1031] - Approximately 1 to 5% disintegrant;

[1032] - Approximately 0.5 to 3% lubricant;

[1033] - Approximately 0 to 0.5% glidant; and

[1034] - Approximately 0 to 5% coating agent.

[1035] 66. The fixed-dose combination preparation of Technical Solution 61, which contains approximately 50 mg of solid dispersion, approximately 5.00 mg of linagliptin, approximately 151.80 mg of microcrystalline cellulose, approximately 6.60 mg of hydroxypropyl cellulose, approximately 4.40 mg of croscarmellose sodium, approximately 2.20 mg of magnesium stearate, and approximately 6.60 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1, and contains approximately 25 mg of HMS5552.

[1036] 67. The fixed-dose combination preparation of Technical Solution 61, which contains approximately 100 mg of solid dispersion, approximately 5.00 mg of linagliptin, approximately 120.60 mg of microcrystalline cellulose, approximately 7.20 mg of hydroxypropyl cellulose, approximately 4.80 mg of croscarmellose sodium, approximately 2.40 mg of magnesium stearate, and approximately 7.20 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1, and contains approximately 50 mg of HMS5552.

[1037] 68. The fixed-dose combination preparation of Technical Solution 61, which contains approximately 150 mg of solid dispersion, approximately 5.00 mg of linagliptin, approximately 27.50 mg of microcrystalline cellulose, approximately 50.00 mg of mannitol, approximately 7.50 mg of hydroxypropyl cellulose, approximately 7.50 mg of croscarmellose sodium, approximately 2.50 mg of magnesium stearate, and approximately 7.50 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1, and contains approximately 75 mg of HMS5552.

[1038] The fixed-dose combination preparation of Technical Solution 61, which contains approximately 50 mg of solid dispersion, approximately 5.00 mg of linagliptin, approximately 137.00 mg of microcrystalline cellulose, approximately 4.00 mg of croscarmellose sodium, approximately 2.00 mg of magnesium stearate, approximately 2.00 mg of colloidal silicon dioxide and approximately 6.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1 and contains approximately 25 mg of HMS5552.

[1039] The fixed-dose combination preparation of Technical Solution 61, which contains approximately 200 mg of solid dispersion, approximately 5.00 mg of linagliptin, approximately 77.0 mg of microcrystalline cellulose, approximately 9.00 mg of hydroxypropyl cellulose, approximately 6.00 mg of croscarmellose sodium, approximately 3.00 mg of magnesium stearate and approximately 9.00 mg of Opadry, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of approximately 1:1 and contains approximately 100 mg of HMS5552.

[1040] A method for preparing the fixed-dose combination preparation of any one of the foregoing technical solutions, the method comprising incorporating the active ingredient into one or more excipients for granulation, preferably further filling the obtained granule mixture into vials, sachets or capsules or compressing it into a desired tablet shape; more preferably further coating the obtained tablets.

[1041] The method for preparing the fixed-dose combination preparation of Technical Solution 71, which is prepared by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry granulation).

[1042] The method for preparing the fixed-dose combination preparation of any one of Technical Solutions 71-72, wherein the glucokinase activator is prepared in the form of a solid dispersion.

[1043] The method for preparing the fixed-dose combination preparation of any one of Technical Solutions 71-73, wherein the glucokinase activator and the second or more active ingredients are prepared together in the form of a compound solid dispersion.

[1044] 75. The pharmaceutical combination or pharmaceutical composition according to any one of Technical Solutions 1-13 or the fixed-dose combination preparation according to any one of Technical Solutions 14-70 is used for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing down, delaying or reversing diabetic complications.

[1045] 76. A method for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing down, delaying or reversing diabetic complications, including administering to a subject a therapeutically effective amount of the pharmaceutical combination or pharmaceutical composition according to any one of Technical Solutions 1-13 or the fixed-dose combination preparation according to any one of Technical Solutions 14-70.

[1046] 77. Use of the pharmaceutical combination or pharmaceutical composition according to any one of Technical Solutions 1-13 or the fixed-dose combination preparation according to any one of Technical Solutions 14-70 in the preparation of a medicament for preventing one or more metabolic disorders selected from the following, slowing down the progression of the metabolic disorder, delaying or treating the metabolic disorder or preventing, slowing down, delaying or reversing diabetic complications: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c.

Claims

1. A pharmaceutical combination product, comprising: (a) a glucokinase activator, wherein the glucokinase activator is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof: (b) a DPP-IV inhibitor selected from sitagliptin, saxagliptin or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical combination product of claim 1, wherein, The glucokinase activator is the compound HMS5552 represented by the following formula 3. The pharmaceutical combination product of claim 1, wherein the glucokinase activator is in the form of a solid dispersion.

4. The pharmaceutical combination product of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymeric carrier, and the polymeric carrier is copoly(methacrylic acid) type A.

5. The pharmaceutical combination product of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymeric carrier, and the polymeric carrier is an anionic copolymer of methacrylic acid and methyl methacrylate (1:1).

6. The pharmaceutical combination product of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymeric carrier, and the polymeric carrier is Eudragit.

7. The pharmaceutical combination product of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymeric carrier, and the polymeric carrier is Eudragit L100.

8. The pharmaceutical combination product of any one of claims 4-7, wherein the weight ratio of the glucokinase activator to the polymeric carrier is from 1:10 to 10:

1.

9. The pharmaceutical combination product of any one of claims 4-7, wherein the weight ratio of the glucokinase activator to the polymeric 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.

10. The pharmaceutical combination product of any one of claims 4-7, wherein the weight ratio of the glucokinase activator to the polymeric carrier is 1:1, 2:3, 3:4, 4:5 or 5:

6.

11. The pharmaceutical combination product of claim 1, wherein the DPP-IV inhibitor is selected from sitagliptin, sitagliptin phosphate monohydrate, saxagliptin or saxagliptin monohydrate.

12. The pharmaceutical combination product of claim 1, wherein the glucokinase activator is present in a dose range of 1 mg to 200 mg.

13. The pharmaceutical combination product of claim 1, wherein the glucokinase activator is present in a dose range of 25 mg to 100 mg.

14. The pharmaceutical combination product of claim 1, wherein the dose of the glucokinase activator is 25 mg, 50 mg, 75 mg or 100 mg.

15. The pharmaceutical combination product of claim 1, wherein the DPP-IV inhibitor is present in a dose range of 1 mg to 200 mg.

16. The pharmaceutical combination product of claim 1, wherein the DPP-IV inhibitor is present in a dose range of 2.5 mg to 100 mg.

17. The pharmaceutical combination product of claim 1, wherein the dose of the DPP-IV inhibitor is 2.5 mg, 5 mg, 10 mg, 20 mg, 50 mg or 100 mg.

18. The pharmaceutical combination product of claim 1, wherein the dose of the DPP-IV inhibitor is 2.5 mg, 5 mg, 50 mg or 100 mg.

19. The pharmaceutical combination product of claim 1, wherein the DPP-IV inhibitor is saxagliptin and its dose is 1 mg to 20 mg.

20. The pharmaceutical combination product of claim 1, wherein the DPP-IV inhibitor is saxagliptin and its dose is 1 mg, 2.5 mg, 5 mg or 10 mg.

21. The pharmaceutical combination product of claim 1, wherein the DPP-IV inhibitor is saxagliptin and its dose is 2.5 mg or 5 mg.

22. The pharmaceutical combination product of any one of claims 12 - 21, wherein the dose is a unit dose.

23. A pharmaceutical composition comprising the pharmaceutical combination product of any one of claims 1 - 22.

24. The pharmaceutical composition of claim 23, which comprises a solid dispersion of a glucokinase activator and a DPP-IV inhibitor.

25. The pharmaceutical composition of claim 23, wherein the weight ratio of the solid dispersion of the glucokinase activator to the DPP-IV inhibitor is 1:5 to 100:

1.

26. The pharmaceutical composition of claim 23, wherein the weight ratio of the solid dispersion of the glucokinase activator to the DPP-IV inhibitor is 1:2 to 80:

1.

27. The pharmaceutical composition of claim 23, wherein the weight ratio of the solid dispersion of the glucokinase activator to the DPP-IV inhibitor is 1:2, 1:1, 2:1, 3:1, 3:2, 4:1, 10:1, 20:1, 30:1, 40:1 or 80:

1.

28. The pharmaceutical composition of any one of claims 24 - 27, wherein the solid dispersion of the glucokinase activator is 1 - 98% by weight; the DPP-IV inhibitor is 0.2 - 80% by weight.

29. The pharmaceutical composition of claim 23, which further comprises one or more excipients.

30. The pharmaceutical composition of claim 29, wherein the excipients are selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, coloring agents or coating agents.

31. The pharmaceutical composition of claim 23, which is in a form selected from tablets, capsules, pills and lozenges.

32. The pharmaceutical composition of claim 23, which is a tablet.

33. The pharmaceutical composition of claim 23, which is a coated tablet.

34. A fixed-dose combination preparation, which comprises: (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof: (b) A DPP-IV inhibitor, which is selected from sitagliptin, saxagliptin or a pharmaceutically acceptable salt thereof; (c) One or more excipients.

35. The fixed-dose combination preparation according to claim 34, wherein, The glucokinase activator is 1 to 98% by weight; the DPP-IV inhibitor is 0.2 to 80% by weight.

36. The fixed-dose combination preparation of claim 34, wherein, The glucokinase activator is the compound HMS5552 represented by the following formula, 37. The fixed-dose combination preparation of claim 34, wherein the glucokinase activator is in the form of a solid dispersion.

38. The fixed-dose combination preparation of claim 34, wherein, The glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, and the polymer carrier is copoly(methacrylic acid) type A.

39. The fixed-dose combination preparation according to claim 34, wherein, The glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, and the polymer carrier is an anionic copolymer of methacrylic acid and methyl methacrylate (1:1). The fixed-dose combination preparation of claim 34, wherein, The glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, and the polymer carrier is Eudragit.

41. The fixed-dose combination preparation according to claim 34, wherein, The glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, and the polymer carrier is Eudragit L100.

42. The fixed-dose combination preparation of claim 34, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, and the weight ratio of the glucokinase activator to the polymer carrier is from 1:10 to 10:

1.

43. The fixed-dose combination preparation of claim 34, wherein the glucokinase activator is in the form of a solid dispersion comprising 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.

44. The fixed-dose combination preparation of claim 34, wherein the glucokinase activator is in the form of a solid dispersion comprising 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.

45. The fixed-dose combination preparation of claim 34, wherein the DPP-IV inhibitor is selected from sitagliptin, sitagliptin phosphate monohydrate, saxagliptin or saxagliptin monohydrate.

46. The fixed-dose combination preparation of claim 34, wherein the glucokinase activator is present in a dose range of 1 mg to 200 mg.

47. The fixed-dose combination preparation of claim 34, wherein the glucokinase activator is present in a dose range of 25 mg to 100 mg.

48. The fixed-dose combination preparation of claim 34, wherein the dose of the glucokinase activator is 25 mg, 50 mg, 75 mg or 100 mg.

49. The fixed-dose combination preparation of claim 34, wherein the DPP-IV inhibitor is from 1 mg to 200 mg.

50. The fixed-dose combination preparation of claim 34, wherein the DPP-IV inhibitor is present in a dose range of 2.5 mg to 100 mg.

51. The fixed-dose combination preparation of claim 34, wherein the dose of the DPP-IV inhibitor is 2.5 mg, 5 mg, 10 mg, 20 mg, 50 mg or 100 mg.

52. The fixed-dose combination preparation according to claim 34, wherein the dose of the DPP-IV inhibitor is 2.5 mg, 5 mg, 50 mg or 100 mg.

53. The fixed-dose combination preparation according to claim 34, wherein the DPP-IV inhibitor is saxagliptin and its dose is 1 mg to 20 mg.

54. The fixed-dose combination preparation according to claim 34, wherein the DPP-IV inhibitor is saxagliptin and its dose is 1 mg, 2.5 mg, 5 mg or 10 mg.

55. The fixed-dose combination preparation according to claim 34, wherein the DPP-IV inhibitor is saxagliptin and its dose is 2.5 mg or 5 mg.

56. The fixed-dose combination preparation according to claim 37, wherein the weight ratio of the solid dispersion of the glucokinase activator to the DPP-IV inhibitor is 1:5 to 100:

1.

57. The fixed-dose combination preparation according to claim 37, wherein the weight ratio of the solid dispersion of the glucokinase activator to the DPP-IV inhibitor is 1:2 to 80:

1.

58. The fixed-dose combination preparation according to claim 37, wherein the weight ratio of the solid dispersion of the glucokinase activator to the DPP-IV inhibitor is 1:2, 1:1, 2:1, 3:1, 3:2, 4:1, 10:1, 20:1, 30:1, 40:1 or 80:

1.

59. The fixed-dose combination preparation according to any one of claims 56-58, wherein the solid dispersion of the glucokinase activator is 1 to 98% by weight; the DPP-IV inhibitor is 0.2 to 80% by weight.

60. The fixed-dose combination preparation according to claim 34, 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.

61. The fixed-dose combination preparation according to claim 60, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methyl cellulose; the filler is selected from microcrystalline cellulose, siliconized microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch or pregelatinized starch; the disintegrant is selected from croscarmellose sodium, crospovidone or sodium starch glycolate; the lubricant is selected from magnesium stearate or sodium stearyl fumarate; the glidant is selected from colloidal silicon dioxide or talc.

62. The fixed-dose combination preparation according to claim 34, which is a tablet.

63. The fixed-dose combination preparation according to claim 62, which is a coated tablet.

64. The fixed-dose combination preparation according to claim 63, wherein the coated tablet is a film-coated tablet, and 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 a mixture thereof; An optional colorant selected from iron oxide red, iron oxide yellow or a mixture thereof; An optional opacifier selected from titanium dioxide, and An optional glidant.

65. The fixed-dose combination preparation of claim 64, wherein the coated tablet is a film-coated tablet, and the film coating agent is Opadry.

66. The fixed-dose combination preparation of claim 34, comprising, by weight: - 1 to 80% of a glucokinase activator; - 0.2 to 80% of a DPP-IV inhibitor; - 0 to 55% of a filler; - 1 to 25% of a binder; - 0 to 15% of a disintegrant; - 0.1 to 10% of a lubricant; - 0 to 3% of a glidant.

67. The fixed-dose combination preparation of claim 66, which comprises 5 to 75% of a glucokinase activator.

68. The fixed-dose combination preparation of claim 66, which comprises 0.5 to 75% of a DPP-IV inhibitor.

69. The fixed-dose combination preparation of claim 66, wherein the glucokinase activator is HMS5552.

70. The fixed-dose combination preparation of claim 66, wherein the glucokinase activator is a solid dispersion of HMS5552.

71. The fixed-dose combination preparation of claim 66, wherein the glucokinase activator is a solid dispersion containing HMS5552 and a polymer carrier.

72. The fixed-dose combination preparation of claim 66, wherein the glucokinase activator is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:

1.

73. The fixed-dose combination preparation of claim 66, wherein, by weight, the doses of the active ingredients are: 25 mg, 50 mg, 75 mg or 100 mg of a glucokinase activator; 25 mg, 50 mg, 75 mg, 100 mg, 150 mg or 200 mg of sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate.

74. The fixed-dose combination preparation of claim 73, which is a tablet of 50 mg HMS5552 / 50 mg sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate, and which, by weight, comprises the following components in the following contents: - 50 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 50 mg of sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate; - 0 to 50% of a filler; - 2 to 8% of a binder; - 1 to 5% of a disintegrant; - 0.5 to 3% of a lubricant; - 0 to 0.5% of a glidant.

75. The fixed-dose combination preparation of claim 73, which is a tablet of 75 mg HMS5552 / 50 mg sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate, and which, by weight, comprises the following components in the following contents: - 75 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 50 mg of sitagliptin or an equivalent amount of sitagliptin phosphate monohydrate; - 0 to 50% of a filler; - 2 to 8% of a binder; - 1 to 5% of a disintegrant; - 0.5 to 3% of a lubricant; and - 0 to 0.5% of a glidant.

76. The fixed-dose combination preparation of claim 73, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it comprises the following components in the following contents: - 50 mg of HMS5552, which is a solid dispersion containing 1:1 of HMS5552 and Eudragit L100; - 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate; - 0 to 50% of a filler; - 2 to 8% of a binder; - 1 to 5% of a disintegrant; - 0.5 to 3% of a lubricant; - 0 to 0.5% of a glidant.

77. The fixed-dose combination preparation of claim 73, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it comprises the following components in the following contents: - 75 mg of HMS5552, which is a solid dispersion containing 1:1 of HMS5552 and Eudragit L100; - 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate; - 0 to 50% of a filler; - 2 to 8% of a binder; - 1 to 5% of a disintegrant; - 0.5 to 3% of a lubricant; - 0 to 0.5% of a glidant.

78. The fixed-dose combination preparation of claim 73, wherein the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it comprises the following components in the following contents: - 25 mg of HMS5552, which is a solid dispersion containing 1:1 of HMS5552 and Eudragit L100; - 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate.

79. The fixed-dose combination preparation of claim 73, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it comprises the following components in the following contents: - 100 mg of HMS5552, which is a solid dispersion containing 1:1 of HMS5552 and Eudragit L100; - 50 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate.

80. The fixed-dose combination preparation of claim 73, wherein the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 50 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it comprises the following components in the following contents: - 25 mg of HMS5552, which is a solid dispersion containing 1:1 of HMS5552 and Eudragit L100; - 50 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate.

81. The fixed-dose combination preparation of claim 73, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 100 mg sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate, and by weight, it contains the following components in the following contents: - 100 mg of HMS5552, which is a solid dispersion containing 1:1 of HMS5552 and Eudragit L100; - 100 mg of sitagliptin or the corresponding amount of sitagliptin phosphate monohydrate.

82. The fixed-dose combination preparation of claim 73, which contains 100 mg of solid dispersion, 64.25 mg of sitagliptin phosphate monohydrate, 40.35 mg of microcrystalline cellulose, 6.60 mg of hydroxypropyl cellulose, 6.60 mg of croscarmellose sodium and 2.20 mg of magnesium stearate, wherein the solid dispersion contains 1:1 of HMS5552 and Eudragit L100 and contains 50 mg of HMS5552.

83. The fixed-dose combination preparation of claim 73, which contains 50 mg of solid dispersion, 128.50 mg of sitagliptin phosphate monohydrate, 100.50 mg of microcrystalline cellulose, 9.00 mg of hydroxypropyl cellulose, 9.00 mg of croscarmellose sodium and 3.00 mg of magnesium stearate, wherein the solid dispersion contains 1:1 of HMS5552 and Eudragit L100 and contains 25 mg of HMS5552.

84. The fixed-dose combination preparation of claim 73, which contains 200 mg of solid dispersion, 64.25 mg of sitagliptin phosphate monohydrate, 61.26 mg of microcrystalline cellulose, 10.50 mg of hydroxypropyl cellulose, 10.50 mg of croscarmellose sodium and 3.50 mg of magnesium stearate, wherein the solid dispersion contains 1:1 of HMS5552 and Eudragit L100 and contains 100 mg of HMS5552.

85. The fixed-dose combination preparation of claim 66, by weight, the dose of the active ingredient is: 25 mg, 50 mg, 75 mg or 100 mg of HMS5552; 2.5 mg, 5 mg, 7.5 mg or 10 mg of saxagliptin or the corresponding amount of saxagliptin monohydrate.

86. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate, and by weight, it contains the following components in the following contents: - 25 mg of HMS5552, which is a solid dispersion containing 1:1 of HMS5552 and Eudragit L100; - 5 mg of saxagliptin or the corresponding amount of saxagliptin monohydrate.

87. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 2.5 mg saxagliptin or the corresponding amount of saxagliptin monohydrate, and by weight, it contains the following components in the following contents: - 50 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 2.5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate.

88. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following amounts: - 75 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate.

89. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 2.5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following amounts: - 100 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 2.5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate.

90. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 25 mg HMS5552 / 2.5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following amounts: - 25 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 2.5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate.

91. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 75 mg HMS5552 / 2.5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following amounts: - 75 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 2.5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate.

92. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 50 mg HMS5552 / 5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following amounts: - 50 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate.

93. The fixed-dose combination preparation of claim 85, wherein the fixed-dose combination preparation is a tablet of 100 mg HMS5552 / 5 mg saxagliptin or an equivalent amount of saxagliptin monohydrate, and by weight, it contains the following components in the following amounts: - 100 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a ratio of 1:1; - 5 mg of saxagliptin or an equivalent amount of saxagliptin monohydrate.

94. The fixed-dose combination preparation of claim 85, which contains 150 mg of solid dispersion, 5.29 mg of saxagliptin monohydrate, 7.50 mg of hydroxypropyl cellulose, 79.71 mg of microcrystalline cellulose, 2.50 mg of magnesium stearate, and 5.00 mg of croscarmellose sodium, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of 1:1 and contains 75 mg of HMS5552.

95. The fixed-dose combination preparation of claim 85, which contains 100 mg of solid dispersion, 2.64 mg of saxagliptin monohydrate, 7.50 mg of hydroxypropyl cellulose, 132.36 mg of microcrystalline cellulose, 2.50 mg of magnesium stearate, and 5.00 mg of croscarmellose sodium, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of 1:1 and contains 50 mg of HMS5552.

96. The fixed-dose combination preparation of claim 85, which contains 200 mg of solid dispersion, 2.64 mg of saxagliptin monohydrate, 9.00 mg of povidone, 79.36 mg of microcrystalline cellulose, 3.00 mg of magnesium stearate, and 6.00 mg of croscarmellose sodium, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of 1:1 and contains 100 mg of HMS5552.

97. The fixed-dose combination preparation of claim 85, which contains 50 mg of solid dispersion, 5.29 mg of saxagliptin monohydrate, 7.50 mg of povidone, 179.71 mg of microcrystalline cellulose, 2.50 mg of magnesium stearate, and 5.00 mg of croscarmellose sodium, wherein the solid dispersion contains HMS5552 and Eudragit L100 in a ratio of 1:1 and contains 25 mg of HMS5552.

98. Use of the pharmaceutical combination product according to any one of claims 1-22 or the pharmaceutical composition according to any one of claims 23-33 in the preparation of a drug 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 glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory impairment, Alzheimer's disease, and / or metabolic syndrome; or improving blood glucose control and / or reducing fasting plasma glucose, postprandial plasma glucose, and / or glycated hemoglobin HbA1c. Use of the combination of a glucokinase activator and a DPP-IV inhibitor 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 glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory disorder, Alzheimer's disease and / or metabolic syndrome; or improving glycemic 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: Among them, The DPP-IV inhibitor is selected from sitagliptin, saxagliptin or a pharmaceutically acceptable salt thereof.

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