HK40018819B - Pharmaceutical combination, comprising glucokinase activator and sglt-2 inhibitor and preparation methods and uses thereof - Google Patents

Description

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

Priority claim

This application claims priority to Chinese invention patent application No. 201810556685.6, filed on May 31, 2018, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

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, as well as a preparation method and use thereof for treating certain diseases.

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

Background Art

Diabetes has become a common disease worldwide, with 425 million patients worldwide and 120 million in China (International Diabetes Federation, Diabetes Atlas, 2015). Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), accounts for over 90% of diabetic patients. Type 2 diabetes is a chronic metabolic disorder characterized by hyperglycemia caused by impaired insulin secretion and insulin resistance, leading to an imbalance in blood glucose homeostasis. Blood glucose homeostasis is primarily controlled by the coordinated production of two glucose-regulating hormones, insulin and glucagon.

The glucose sensor glucokinase (GK) senses changes in blood glucose and regulates the secretion of the glucose-controlling messenger hormones insulin, glucagon, and GLP-1 (glucagon-like peptide-1), forming the sensor system for regulating blood glucose homeostasis. Glucose-controlling hormones regulate glucose uptake, glucose storage, and glucose supply during fasting, which together form the body's glucose homeostasis. Organs primarily involved in glucose storage include the liver, muscle, and adipose tissue. These organs, under the influence of blood glucose and insulin, take up glucose and convert it into liver glycogen, muscle glycogen, and triglycerides. The liver is the primary organ involved in glucose supply. Under the influence of blood glucose and glucagon, it supplies glucose to the body through glycogen synthesis and export. Insulin also effectively regulates the activity of the sodium-glucose cotransporter SGLT-2, allowing glucose excreted by the kidneys to be reabsorbed when blood glucose levels rise, thus replenishing the body's glucose reserves. Glucose uptake, glycogen export, and glucose utilization by various organs constitute the operational system for maintaining glucose homeostasis. The coordinated operation of the glucose sensing and operational systems contributes to the stochastic regulation of blood glucose homeostasis.

In diabetic patients, impaired glucokinase function and expression lead to sensor dysfunction, resulting in dysregulation of early-phase secretion of glucose-controlling hormones, affecting glucose uptake and output, leading to postprandial hyperglycemia and pre-meal hypoglycemia. Abnormal glucose-controlling hormone signaling leads to abnormal function and expression of key proteins in the glucose uptake and output execution system, resulting in abnormal operation and the development of type 2 diabetes.

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

Summary of the Invention

Diabetic patients often encounter the situation that SGLT-2 inhibitors alone are ineffective in controlling blood sugar at ideal levels, especially after a period of use. In response to this, the present inventors have discovered that combining an SGLT-2 inhibitor with a glucokinase activator can significantly enhance the glucose-lowering effect of the SGLT-2 inhibitor and reduce safety risks. Consequently, the present invention has developed a pharmaceutical combination, composition, and compound preparation containing a glucokinase activator and an SGLT-2 inhibitor.

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

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

The present invention provides a pharmaceutical combination, a pharmaceutical composition, a 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 structure shown below, or an isotope-labeled product thereof, or a pharmaceutically acceptable salt thereof, and other oral hypoglycemic drugs.

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

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

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

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

The present invention also provides a pharmaceutical combination, pharmaceutical composition, or fixed-dose combination preparation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients) prepared by a dry or wet processing method. The pharmaceutical combination, pharmaceutical composition, or fixed-dose combination preparation of the present invention releases the two or more active pharmaceutical ingredients in a rapid manner.

The present invention also provides a pharmaceutical formulation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients), which has a short disintegration time, 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 formulation of a fixed-dose combination of a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients, such as empagliflozin, dapagliflozin, or canagliflozin) by a dry or wet processing method. Dry processing methods include dry compression (tableting) and dry granulation; wet processing methods include wet granulation.

The present invention also provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients), as well as a method for preventing metabolic disorders (especially type 2 diabetes), slowing their progression, delaying or treating the metabolic disorders.

The present invention also provides pharmaceutical combinations, pharmaceutical compositions or pharmaceutical preparations comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredients), as well as methods for improving glycemic control in patients in need thereof (especially patients with type 2 diabetes).

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

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

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

Those skilled in the art will find other objects of the present invention clear from the above description and from the embodiments.

SUMMARY OF THE INVENTION

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

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

(b) SGLT-2 inhibitors; and

(c) one or more excipients.

Another aspect of the present invention provides a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation comprising the following components, as well as a method for preparing the same and use thereof in treating diabetes and related diseases:

(a) a glucokinase activator selected from the group consisting of HMS5552, or a pharmaceutically acceptable salt, isotope-labeled substance, crystalline form, hydrate, solvate, diastereomer or enantiomeric form thereof; preferably, the glucokinase activator is HMS5552;

More preferably, HMS5552 is in the form of a solid dispersion;

(b) empagliflozin, dapagliflozin, canagliflozin, or pharmaceutically acceptable salts, isotopically labeled substances, crystalline forms, hydrates, solvates, diastereomers or enantiomeric forms thereof;

and

(c) one or more excipients.

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

definition

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

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

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

All numerical values or expressions used in the specification and claims referring to amounts of ingredients, process conditions, and the like are to be understood as modified in all instances by "about." The term "about," when referring to an amount or a range of values, means that the amount or range of values referred to is an approximation within the experimental variability (or within the statistical experimental error), and thus the amount or range of values may vary, for example, by +5 of the stated amount or range of values.

All ranges relating to the same component or property include the endpoints, which are independently combinable. 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 herein is intended to include all subranges within that range.

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

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

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

The abbreviations used herein have their usual meanings in the fields of chemistry, biology and pharmaceuticals.

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

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

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

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

EUDRAGIT is the trade name for synthetic pharmaceutical excipients, including methacrylic acid copolymers and methacrylate copolymers, commonly known as polyacrylic resins. Polyacrylic resin excipients are classified into different grades based on their composition, ratio, and degree of polymerization. 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 ratio of 1:1; and Eudragit S is a polymer of methacrylic acid and methyl methacrylate, with a free carboxyl group:ester ratio of 1:2.

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

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

As used herein, 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 symptoms that will develop or are expected to develop. Thus, these terms include ameliorating existing disease symptoms, preventing additional symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting the disorder or disease, e.g., preventing the development of a disorder or disease, alleviating a disorder or disease, regressing a disorder or disease, alleviating a condition caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

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

As used herein, 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, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the present invention, the mammal is a human.

The compounds used as active ingredients in the pharmaceutical combinations, compositions, or formulations (e.g., fixed-dose combination formulations) of the present invention containing a glucokinase activator may form salts. Unless otherwise indicated, reference to a compound herein is to be understood as including reference to its salts. As used herein, the term "salt(s)" refers to acidic salts formed with inorganic and/or organic acids and basic salts formed with inorganic and/or organic bases. In addition, when the compound contains a basic moiety (e.g., but not limited to, pyridine or imidazole) and an acidic moiety (e.g., but not limited to, a carboxylic acid), zwitterions ("inner salts") may form, and such zwitterions ("inner salts") are encompassed by the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful. Salts of the compounds can be formed, for example, by reacting the compound with an amount (e.g., an equal amount) of an acid or base in a medium, such as a medium in which the salt precipitates or an aqueous medium (followed by lyophilization).

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

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

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the effects of empagliflozin alone and HMS5552 and empagliflozin combined on blood glucose after glucose loading in normal mice (n=10);

Figure 2 shows the effects of a single dose of empagliflozin alone and a single dose of HMS5552 and empagliflozin combined on AUC _0-120min after glucose load in normal mice (n=10; ***, P<0.001).

Detailed Description of the Invention

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

In a particular aspect of the present invention, the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation comprises:

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

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

(3) fillers; and/or

(4) adhesive; and/or

(5) disintegrant; and/or

(6) lubricants or glidants; and/or

(7) Coating agent.

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

Pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation

Glucokinase activator + SGLT-2 inhibitor

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

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

(b) SGLT-2 inhibitors;

Preferably, examples of the SGLT-2 inhibitor include, but are not limited to, canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin, or pharmaceutically acceptable salts thereof;

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

(c) one or more excipients;

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

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

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

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

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

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

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

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

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

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

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 label or a pharmaceutically acceptable salt thereof, which is prepared together with a polymer carrier by spray drying, hot melt or freeze drying to obtain a solid dispersion.

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

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

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

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

In one embodiment, the polymer carrier is selected from:

Eudragit E100, a 1:2:1 copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate, including Eudragit E PO;

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

Eudragit S100, a 1:2 copolymer of methacrylic acid and methyl methacrylate;

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

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

In one embodiment, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed-dose combination formulation), 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.

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

In one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) and empagliflozin, the dosage (preferably unit dosage) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dosage (preferably unit dosage) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dosage (preferably unit dosage) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween. More preferred dosages (preferably unit doses) of the glucokinase activator (preferably HMS5552 or an isotope-labeled form thereof or a pharmaceutically acceptable salt thereof) are about 25 mg, about 50 mg, about 75 mg, or about 100 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (preferably a fixed-dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination) of the above-mentioned glucokinase activator (HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) and empagliflozin, the dose (preferably unit dose) of empagliflozin is about 0.5 mg to about 50 mg, in particular about 1 mg to about 25 mg. Preferred doses (preferably unit doses) of empagliflozin are about 5 mg, about 10 mg, about 12.5 mg and about 25 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination), HMS5552 is present in the form of a solid dispersion.

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

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

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

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

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

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

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

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

(8) approximately 25 mg of HMS5552 and approximately 25 mg of empagliflozin;

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

(10) approximately 100 mg of HMS5552 and approximately 10 mg of empagliflozin;

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

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

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 pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention is preferably in the form of a tablet.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 dapagliflozin (or dapagliflozin propylene glycol monohydrate). The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of the above-mentioned glucokinase activator (HMS5552 or its isotope-labeled product or pharmaceutically acceptable salt) and dapagliflozin (or dapagliflozin propylene glycol monohydrate) comprises, by weight, about 1 to 98% of glucokinase activator (preferably HMS5552 or its isotope-labeled product or pharmaceutically acceptable salt); about 0.1 to 30% of dapagliflozin or dapagliflozin propylene glycol monohydrate; about 0 to 85% of a filler; about 1 to 25% of a binder; about 1 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. 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.

In one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed-dose combination) of the above-mentioned glucokinase activator (HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) and dapagliflozin or dapagliflozin propylene glycol monohydrate, the dosage (preferably 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 dosage (preferably unit dose) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dosage (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 dosage (preferably unit dose) of the glucokinase activator (preferably HMS5552 or an isotope-labeled form thereof or a pharmaceutically acceptable salt thereof) is about 25 mg, about 50 mg, about 75 mg, or about 100 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, the pharmaceutical 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 dapagliflozin or dapagliflozin propylene glycol monohydrate is calculated based on the content of dapagliflozin. The dosage (preferably unit dose) is about 1 mg to about 50 mg, especially about 2.5 mg, about 5 mg, about 10 mg and about 25 mg. Preferably, the dosage (preferably unit dose) is about 2.5 mg, about 5 mg and about 10 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 is present in the form of a solid dispersion.

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

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

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

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

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

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

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

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

(8) approximately 100 mg of HMS5552 and approximately 10 mg of dapagliflozin (or approximately 12.3 mg of dapagliflozin propylene glycol monohydrate);

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 pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention is preferably in the form of a tablet.

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

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

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

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

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

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

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

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

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

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

In one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the above-mentioned glucokinase activator (HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) and canagliflozin (or canagliflozin hemihydrate), the dosage (preferably unit dosage) of the glucokinase activator (preferably HMS5552 or its isotope-labeled substance or pharmaceutically acceptable salt) is about 1 mg to 200 mg. The preferred dosage (preferably unit dosage) of the glucokinase activator is about 5 mg to 100 mg. Preferably, the dosage (preferably unit dosage) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, or any range therebetween. More preferred dosages (preferably unit doses) of the glucokinase activator (preferably HMS5552 or an isotope-labeled form thereof or a pharmaceutically acceptable salt thereof) are about 25 mg, about 50 mg, about 75 mg, or about 100 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (preferably a fixed-dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, the pharmaceutical 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 canagliflozin (or canagliflozin hemihydrate) is, calculated based on the content of canagliflozin, in a dosage (preferably a unit dose) of about 50 mg to about 500 mg, preferably, about 100 mg or about 300 mg. Preferably, in the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation), HMS5552 is present in the form of a solid dispersion.

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

(1) approximately 25 mg of HMS5552 and approximately 100 mg of canagliflozin (or approximately 101.93 mg of canagliflozin hemihydrate);

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

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

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

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

(6) approximately 50 mg of HMS5552 and approximately 300 mg of canagliflozin (or approximately 305.78 mg of canagliflozin hemihydrate);

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

(8) approximately 100 mg of HMS5552 and approximately 300 mg of canagliflozin (or approximately 305.78 mg of canagliflozin hemihydrate);

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

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

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

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

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

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

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

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

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

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

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

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

The example of preferred filler (diluent) comprises microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose, mannitol, sorbitol, monocalcium phosphate (dihydrate), corn starch, pregelatinized starch and powdered cellulose.Preferred filler (diluent) is microcrystalline cellulose, silicified microcrystalline cellulose.Microcrystalline cellulose can derive from several suppliers, comprises Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH105 and Avicel PH 200 that FMC Corporation manufactures.

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

Preferred embodiments of the binder include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HMPC), polyvinyl pyrrolidone (povidone), hydroxyethyl cellulose, starch 1500 and co-polyvinylpyrrolidone. More preferred binders are hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone.

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

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

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed-dose combination) contains one or more lubricants. Examples of lubricants suitable for use in 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, palmitostearin, palmitic acid, myristic acid, hydrogenated vegetable oils (including hydrogenated castor oil) and fats, and other known lubricants and/or mixtures of two or more thereof.

In one embodiment, the lubricant includes magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil, and mixtures thereof. More preferably, the lubricant is magnesium stearate, or sodium stearyl fumarate, or mixtures thereof.

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

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

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 may be anionic, cationic or neutral surfactants. Anionic surfactants include sodium lauryl sulfate, sodium lauryl sulfate, sodium oleyl sulfate and sodium laurate mixed with stearate and talc. Cationic surfactants include benzalkonium chloride and alkyltrimethylammonium bromide. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol and sorbitan esters. Embodiments of wetting agents include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives and polyoxyethylene stearate.

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

In one embodiment, the antioxidant is selected from the group consisting of α-tocopherol, γ-tocopherol, δ-tocopherol, extracts of natural sources enriched with tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, lauryl gallate, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA). In one embodiment, the antioxidant is BHT or BHA.

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

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

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

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

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

In one embodiment, the tablets can be coated with, for example, a mixture of hydroxypropylcellulose and hydroxypropylmethylcellulose containing 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 finished tablet. A commercially available coating material is Opadry () supplied by Colorcon as a preformulated powder mixture, such as Opadry 03K12429.

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

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

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

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

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

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

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

Preparation method

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

(1) Adding the active pharmaceutical ingredient glucokinase activator (preferably HMS5552) and the combination drug (preferably empagliflozin, dapagliflozin, or canagliflozin) into a granulator;

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

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

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

(5) the obtained wet granules are sized by a suitable granulator to obtain wet granules of suitable size;

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

(7) granulating on a suitable grinder to obtain dry granules of suitable size;

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

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

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

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

(12) Optionally, the resulting tablet is film-coated.

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

(1) Add the active pharmaceutical ingredient glucokinase activator (preferably HMS5552) into a granulator;

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

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

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

(5) The obtained wet granules are granulated in a suitable granulator to obtain wet granules of suitable size;

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

(7) granulating on a suitable grinder to obtain dry granules of suitable size;

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

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

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

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

(12) Optionally, the resulting tablet is film-coated.

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

(1) Add the active pharmaceutical ingredient glucokinase activator (preferably HMS5552) and the combination drug (preferably empagliflozin, dapagliflozin, or canagliflozin) into a mixing tank;

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

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

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

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

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

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

(8) adding an optional disintegrant (e.g., croscarmellose sodium, crospovidone, sodium starch glycolate) to step (7);

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

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

(11) Optionally, the tablets obtained in step (5) or step (10) can be film-coated.

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 a method selected from spray drying, fluidized bed drying, solvent method, melt extrusion, etc.

One embodiment of the present invention is a method for preparing a solid dispersion of a glucokinase activator by spray drying, comprising the steps of:

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

(2) Spray drying: control the inlet air temperature, air volume, atomizing air flow rate and pressure, and solution spraying speed, etc.

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

Methods and uses for treating and/or preventing diseases

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

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

- Improved glycemic control and/or reductions in fasting plasma glucose, postprandial plasma glucose and/or glycosylated haemoglobin HbA1c; or

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

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

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

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

-Prevent, slow, delay or treat diseases or conditions caused by abnormal accumulation of fat in the liver or ectopic fat; or

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

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

-Treatment of hyperuricemia and hyperuricemia-related diseases; or

-Diabetic nephropathy, decreased renal function.

The present invention also provides a method for treating type 2 diabetes by orally administering a therapeutically effective amount of a pharmaceutical composition or formulation (preferably a fixed-dose combination pharmaceutical composition or fixed-dose combination formulation) containing a glucokinase activator and a combination drug of the present invention to a subject in need of such treatment. In one embodiment, the subject in need of such treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet. The composition or formulation (preferably a fixed-dose combination pharmaceutical composition or fixed-dose combination formulation) containing a glucokinase activator of the present invention can be administered once daily (QD), twice daily (BID), or three times daily (TID).

Specifically, the present invention relates to the following specific embodiments.

Embodiment 1 - Glucokinase activator + SGLT-2 inhibitor (e.g., empagliflozin)

Solution 1. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation comprising:

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

(b) SGLT-2 inhibitors;

(c) one or more excipients;

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

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

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

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

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

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 (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

7. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of 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.

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

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

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

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

Option 12. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Option 1 to Option 11, which is a tablet.

Option 13. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Option 12, which is a coated tablet.

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

a film coating substrate, such as hypromellose, hydroxypropyl methylcellulose, or a mixture thereof;

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

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

Optional sunscreens, such as titanium dioxide, and

Optional glidant.

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

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

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

About 0.1-50% empagliflozin;

About 0-80% filler;

About 1 to 25% binder;

About 0-15% disintegrant;

About 0.1-10% lubricant;

about 0-3% of a glidant; and

About 0-5% coating agent.

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

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

About 1-35% empagliflozin;

About 0-90% filler;

About 1-10% binder;

about 1-10% disintegrant;

About 0.1-5% lubricant;

about 0-3% of a glidant; and

About 0-5% coating agent.

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

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

about 5 mg, about 10 mg, about 12.5 mg, and about 25 mg of empagliflozin;

About 0-80% filler;

About 1 to 25% binder;

About 0-15% disintegrant;

About 0.1-10% lubricant;

about 0-3% of a glidant; and

About 0-5% coating agent.

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

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

- Approximately 5 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

- approximately 12.5 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

- Approximately 10 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

- Approximately 25 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

- Approximately 25 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

- Approximately 10 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

- Approximately 10 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

- Approximately 25 mg of empagliflozin;

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1-5% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

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

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

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

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

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

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

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

Scheme 38. The method for preparing a pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 35-37, 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).

Option 39. The drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Options 1 to 34, for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and/or metabolic syndrome; or improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications.

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

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

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

Solution 1. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation comprising:

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

(b) SGLT-2 inhibitors;

(c) one or more excipients;

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

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

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

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

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

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 (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

7. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of 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.

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

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

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

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

Option 12. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Option 1 to Option 11, which is a tablet.

Option 13. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Option 12, which is a coated tablet.

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

a film coating substrate, such as hypromellose, hydroxypropyl methylcellulose, or a mixture thereof;

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

optional colorant, such as red iron oxide, yellow iron oxide, or mixtures thereof;

Optional sunscreens, such as titanium dioxide, and

Optional glidant.

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

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

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

approximately 0.1-30% dapagliflozin or dapagliflozin propylene glycol monohydrate;

About 0-85% filler;

About 1 to 25% binder;

About 0-15% disintegrant;

About 0.1-10% lubricant;

about 0-3% of a glidant; and

About 0-5% coating agent.

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

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

approximately 0.5-20% dapagliflozin or dapagliflozin propylene glycol monohydrate;

About 0-90% filler;

About 1-10% binder;

about 1-10% disintegrant;

About 0.1-5% lubricant; and

About 0-5% coating agent.

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

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

about 2.5 mg, about 5 mg, and about 10 mg of dapagliflozin or an amount of dapagliflozin propylene glycol monohydrate to achieve such dosages;

About 0-85% filler;

About 1 to 25% binder;

About 0-15% disintegrant;

About 0.1-10% lubricant;

about 0-3% of a glidant; and

About 0-5% coating agent.

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

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

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

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1 to 8% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1 to 8% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1 to 8% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1 to 8% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1 to 8% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

- about 0 to 70% filler;

- about 2 to 8% binder;

- about 1 to 8% disintegrant;

- About 0.5-3% lubricant;

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

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

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

Scheme 31. A method for the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 30, comprising blending the active ingredient with one or more excipients for granulation, preferably further filling the obtained granular mixture into vials, sachets or capsules or compressing into a desired tablet shape; more preferably further coating the obtained tablet.

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

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

Scheme 34. The method for preparing a pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 31-33, 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).

Option 35. The drug combination, pharmaceutical composition or fixed-dose combination preparation of any one of Options 1 to 30, for treating or preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and/or metabolic syndrome; or improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications.

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

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

Embodiment III - Glucokinase activator + SGLT-2 inhibitor (e.g., canagliflozin)

Solution 1. A pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation comprising:

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

(b) SGLT-2 inhibitors;

(c) one or more excipients;

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

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

Scheme 3. The drug combination, pharmaceutical composition or fixed-dose combination preparation of Scheme 1 or 2, wherein the glucokinase activator is approximately 1 to 80% by weight; and the SGLT-2 inhibitor is approximately 10 to 80% by weight.

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

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

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 (anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, and more preferably Eudragit L100.

7. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of 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.

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

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

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

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

Option 12. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Option 1 to Option 11, which is a tablet.

Option 13. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of Option 12, which is a coated tablet.

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

a film coating substrate, such as hypromellose, hydroxypropyl methylcellulose, or a mixture thereof;

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

optional colorant, such as red iron oxide, yellow iron oxide, or mixtures thereof;

Optional sunscreens, such as titanium dioxide, and

Optional glidant.

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

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

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

About 10-80% canagliflozin or canagliflozin hemihydrate;

About 0-85% filler;

About 1 to 25% binder;

About 0-15% disintegrant;

About 0.1-10% lubricant;

about 0-3% of a glidant; and

About 0-5% coating agent.

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

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

About 10-80% canagliflozin or canagliflozin hemihydrate;

About 0-85% filler;

About 1-10% binder;

about 1-10% disintegrant;

About 0.1-10% lubricant;

About 0-5% coating agent.

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

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

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

About 0-85% filler;

About 1 to 25% binder;

About 0-15% disintegrant;

About 0.1-10% lubricant;

about 0-3% of a glidant; and

About 0-5% coating agent.

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

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

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

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

- about 2-8% of a binder, such as hydroxypropyl cellulose;

- about 1-5% disintegrant, such as croscarmellose sodium;

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

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

- about 2-8% of a binder, such as hydroxypropyl cellulose;

- about 1-5% disintegrant, such as croscarmellose sodium;

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

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

- about 2-8% of a binder, such as hydroxypropyl cellulose;

- about 1-5% disintegrant, such as croscarmellose sodium;

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

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

- about 2-8% of a binder, such as hydroxypropyl cellulose;

- about 1-5% disintegrant, such as croscarmellose sodium;

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

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

- about 2-8% of a binder, such as hydroxypropyl cellulose;

- about 1-5% disintegrant, such as croscarmellose sodium;

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

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

- about 2-8% of a binder, such as hydroxypropyl cellulose;

- about 1-5% disintegrant, such as croscarmellose sodium;

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

- about 0-0.5% glidant; and

- About 0-5% coating agent.

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

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

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

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

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

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

Scheme 31. A method for the pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Schemes 1 to 30, comprising blending the active ingredient with one or more excipients for granulation, preferably further filling the obtained granular mixture into vials, sachets or capsules or compressing into a desired tablet shape; more preferably further coating the obtained tablet.

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

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

Scheme 34. The method for preparing a pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation according to any one of Schemes 31-33, 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).

Option 35. The pharmaceutical combination, pharmaceutical composition or fixed-dose combination preparation of any one of Options 1 to 30, for preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and/or metabolic syndrome; or improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing diabetic complications.

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

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

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 modifications and replacements based on the technology of the present invention fall within the scope of protection of the present invention.

Example

Preparation of compound tablets of glucokinase activator

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, and Zhenxing Reagent. Production equipment and analytical testing instruments 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; and Mettler Toledo Instrument Newark, DE.

I. Preparation of Solid Dispersion of Glucokinase Activator

1.1 Preparation of solid dispersion solution before spray drying

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

6.75 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker) under stirring. After complete dissolution, 0.75 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and stirred continuously to obtain 50 ml of solution.

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

5.25 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker) under stirring. After complete dissolution, 2.25 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and stirred continuously to obtain 50 ml of solution.

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

3.75 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker/) under stirring. After complete dissolution, 3.75 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and continued to stir to obtain 50 ml of solution.

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

2.25 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker) under stirring. After complete dissolution, 5.25 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and continued to stir to obtain 50 ml of solution.

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

1.5 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker) under stirring. After complete dissolution, 6 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and stirred continuously to obtain 50 ml of solution.

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

0.75 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker) under stirring. After complete dissolution, 6.75 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and continued to stir to obtain 50 ml of solution.

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

3.0 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker) under stirring. After complete dissolution, 4.5 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and stirred continuously to obtain 50 ml of solution.

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

4.5 g of Eudragit L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T.Baker) under stirring. After complete dissolution, 3.0 g of compound HMS5552 was added. Sufficient anhydrous ethanol was added and stirred continuously to obtain 50 ml of solution.

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

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

1.2 Preparation of solid dispersion of glucokinase activator

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

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

Solid dispersions were prepared by spray drying the solutions prepared in Examples 1A-8A. The spray dryer was set at an inlet air temperature of 90-150°C, an inlet air flow rate of 0.3-0.5 ^{m 3} /min, and an air flow rate of 15-30 L/min. The solutions were sprayed at a rate of 5-7 mL/min, and solid dispersions 1-8 were obtained by spray drying.

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

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

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

II. Preparation of compound tablets

2.1 Preparation of compound tablets by high shear wet granulation

The HMS5552 solid dispersion prepared according to the above-mentioned preparation example of the solid dispersion of the glucokinase activator and the combination drug are added to a high-shear wet granulator. A filler (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, or lactose) and a disintegrant (e.g., croscarmellose sodium, crospovidone, or sodium starch glycolate) are also added. A portion of the binder powder is added and mixed under high shear stirring for 5 minutes. A prepared binder solution (e.g., hydroxypropyl cellulose, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose) is added to the dry blend under high shear stirring over a period of 1-6 minutes to granulate. The wet granules are granulated on a Comil granulator to obtain wet granules of appropriate size. The wet granules are dried in a tray oven at approximately 60°C or in a fluidized bed dryer (inlet air temperature 40-60°C) for 20-40 minutes. The dried material is then ground using a grinder to obtain granules of appropriate size. After milling, microcrystalline cellulose or silicified microcrystalline cellulose (for fillers with an external portion) and a disintegrant (e.g., croscarmellose sodium, crospovidone, or sodium starch glycolate) are added to the granules and mixed in a drum mixer. A lubricant (magnesium stearate or sodium stearyl fumarate) and/or an optional glidant (micronized silica gel) are then added and mixed thoroughly. The lubricated mixture is compressed using a rotary tablet press to produce tablets of various weights and shapes (plain tablets, uncoated core tablets) corresponding to different specifications. The resulting tablets are optionally film-coated with II to increase their weight by approximately 3%, thereby producing film-coated tablets.

Example 1B HMS5552 + Empagliflozin Compound Tablets (Dosage Specifications 75 mg/5 mg)

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

Example 2B HMS5552 + Empagliflozin Compound Tablets (Dosage Specifications 75 mg/12.5 mg)

Prescription composition Unit prescription amount/mg %(w/w) Empagliflozin 12.50 4.46 HMS5552 solid dispersion* 150.00 53.57 microcrystalline cellulose 99.30 35.47 Hydroxypropyl cellulose 8.40 3.00 Croscarmellose sodium 7.00 2.50 magnesium stearate 2.80 1.00 Total weight of core 280.00 100.0 Obaday 8.40 3.00 Total weight of coated tablets 288.40 --

*150.0 mg of HMS5552 solid dispersion is equivalent to 75 mg of HMS5552.

Example 3B HMS5552 + Empagliflozin Compound Tablets (Dosage Specifications 75 mg/10 mg)

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

Example 4B HMS5552 + Empagliflozin Compound Tablets (Dosage Specifications 75 mg/25 mg)

Prescription composition Unit prescription amount/mg %(w/w) Empagliflozin 25.00 8.92 HMS5552 solid dispersion* 150.00 53.58 microcrystalline cellulose 88.20 31.50 Hydroxypropyl cellulose 8.40 3.00 Croscarmellose sodium 5.60 2.00 magnesium stearate 2.80 1.00 Total weight of core 280.00 100.00 Obaday 8.40 3.00 Total weight of coated tablets 288.40 --

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

Example 5B HMS5552 + Empagliflozin Compound Tablets (Dosage Specifications 100 mg/10 mg)

Prescription composition Unit prescription amount/mg %(w/w) Empagliflozin 10.00 3.33 HMS5552 solid dispersion* 200.00 66.67 microcrystalline cellulose 72.00 24.00 Hydroxypropyl cellulose 9.00 3.00 Croscarmellose sodium 6.00 2.00 magnesium stearate 3.00 1.00 Total weight of core 300.00 100.00 Obaday 9.00 3.00 Total weight of coated tablets 309.00 --

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

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

Prescription composition Unit prescription amount/mg %(w/w) Dapagliflozin propylene glycol monohydrate** 6.15 2.36 MS5552 solid dispersion* 150.00 57.70 microcrystalline cellulose 88.25 33.94 Hydroxypropyl cellulose 7.80 3.00 Croscarmellose sodium 5.20 2.00 magnesium stearate 2.60 1.00 Total weight of core 260.00 100.00 Obaday 7.80 3.00 Total weight of coated tablets 267.80 --

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

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

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

Prescription composition Unit prescription amount/mg %(w/w) Dapagliflozin propylene glycol monohydrate** 6.15 2.80 HMS5552 solid dispersion* 100.00 45.45 microcrystalline cellulose 100.65 45.75 Hydroxypropyl cellulose 6.60 3.00 Croscarmellose sodium 4.40 2.00 magnesium stearate 2.20 1.00 Total weight of core 220.00 100.00 Obaday 6.60 3.00 Total weight of coated tablets 266.60 --

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

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

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

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

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

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

Prescription composition Unit prescription amount/mg %(w/w) Dapagliflozin propylene glycol monohydrate** 6.15 2.05 HMS5552 solid dispersion* 200.00 66.67 microcrystalline cellulose 75.55 25.18 Hydroxypropyl cellulose 9.00 3.00 Croscarmellose sodium 6.30 2.00 magnesium stearate 3.00 1.00 Total weight of core 300.00 100.00 Obaday 9.00 3.00 Total weight of coated tablets 309.00 --

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

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

Example 10B HMS5552 + Canagliflozin Compound Tablets (Dosage Specifications 75 mg/100 mg)

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

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

Example 11B HMS5552 + Canagliflozin Compound Tablets (Dosage Specification 50 mg/100 mg)

Prescription composition Unit prescription amount/mg %(w/w) Canagliflozin hemihydrate** 101.93 16.99 HMS5552 solid dispersion* 100.00 16.67 microcrystalline cellulose 344.07 57.35 Hydroxypropyl cellulose 18.00 3.00 Croscarmellose sodium 30.00 5.00 magnesium stearate 6.00 1.00 Total weight of core 600.0 100.00 Obaday 18.00 3.00 Total weight of coated tablets 618.00 --

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

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

Example 12B HMS5552 + Canagliflozin Compound Tablets (Dosage Specification 100 mg/100 mg)

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

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

Example 13B HMS5552 + Canagliflozin Compound Tablets (Dosage Specifications 75 mg/300 mg)

Prescription composition Unit prescription amount/mg %(w/w) Canagliflozin hemihydrate** 305.78 40.77 HMS5552 solid dispersion* 150.00 20.00 microcrystalline cellulose 226.72 30.23 Hydroxypropyl cellulose 22.50 3.00 Croscarmellose sodium 37.50 5.00 magnesium stearate 7.50 1.00 Total weight of core 750.00 100.00 Obaday 22.50 3.00 Total weight of coated tablets 772.50 --

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

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

Example 14B HMS5552 + Canagliflozin Compound Tablets (Dosage Specifications 50 mg/300 mg)

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

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

Example 15B HMS5552 + Canagliflozin Compound Tablets (Dosage Specifications 25 mg/300 mg)

Prescription composition Unit prescription amount/mg %(w/w) Canagliflozin hemihydrate** 305.78 40.77 HMS5552 solid dispersion* 50.00 6.67 microcrystalline cellulose 326.72 43.56 Hydroxypropyl cellulose 22.50 3.00 Croscarmellose sodium 37.50 5.00 magnesium stearate 7.50 1.00 Total weight of core 750.00 100.00 Obaday 22.50 3.00 Total weight of coated tablets 772.50 --

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

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

2.2 Preparation of compound tablets by fluidized bed wet granulation

The HMS5552 solid dispersion prepared according to the above-mentioned preparation example of the solid dispersion of a glucokinase activator and the drug combination are added to a fluidized bed granulator, along with an optional filler (e.g., microcrystalline cellulose). A prepared binder solution (e.g., polyvinyl pyrrolidone) is sprayed into the mixture in the fluidized bed for 20-60 minutes for granulation, followed by further drying in a fluidized bed dryer (inlet air temperature 40-60°C). The dried material is then ground using a grinder to obtain granules of appropriate size. Following grinding, microcrystalline cellulose or silicified microcrystalline cellulose (for formulations with an additional filler) is added to the granules and mixed in a drum mixer. A lubricant (magnesium stearate) and/or an optional glidant (microsilica gel) are then added and mixed thoroughly. The lubricated mixture is compressed using a rotary tablet press to produce tablets (plain tablets, uncoated core tablets) of varying weights and shapes corresponding to various specifications. The obtained tablets are optionally film-coated with a solid dispersion prepared according to the above-mentioned method for preparing a glucokinase activator to increase the weight by about 3%, thereby obtaining film-coated tablets.

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

Prescription composition Unit prescription amount/mg %(w/w) Empagliflozin 10.00 4.50 HMS5552 solid dispersion* 100.00 45.50 microcrystalline cellulose 96.80 44.00 Povidone 6.60 3.00 Croscarmellose sodium 4.40 2.00 magnesium stearate 2.20 1.00 Total weight of core 220.00 100.0 Obaday 6.60 3.00 Total weight of coated tablets 226.60 --

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

2.3 Preparation of compound tablets by dry compaction granulation

The HMS5552 solid dispersion prepared according to the above-mentioned preparation example of the solid dispersion of a glucokinase activator and the combination drug are added to a mixing drum. A filler (e.g., microcrystalline cellulose) and a binder (e.g., hydroxypropyl cellulose) are added and mixed thoroughly. The mixture is then rolled using a roller granulator to obtain a slurry, which is then pulverized in a grinder to obtain granules of appropriate size. After grinding, optional microcrystalline cellulose or silicified microcrystalline cellulose (for fillers with an external component) and a disintegrant (e.g., croscarmellose sodium) are added to the granules and mixed in a drum mixer. A lubricant (magnesium stearate or sodium stearyl fumarate) and/or an optional glidant (micropowdered silica gel) are then added and mixed thoroughly. The lubricated mixture is compressed using a rotary tablet press to produce tablets of varying weights and shapes (plain tablets, uncoated core tablets) corresponding to different specifications. The resulting tablets are optionally film-coated with II to increase their weight by approximately 3%, thereby producing film-coated tablets.

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

Prescription composition Unit prescription amount/mg %(w/w) Dapagliflozin propylene glycol monohydrate** 12.30 5.13 HMS5552 solid dispersion* 100.00 41.67 microcrystalline cellulose 113.06 47.11 Hydroxypropyl cellulose 7.20 3.00 Croscarmellose sodium 5.04 2.10 magnesium stearate 2.40 1.00 Total weight of core 240.00 100.00 Obaday 7.20 3.00 Total weight of coated tablets 247.20 --

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

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

Example 18B HMS5552 + Empagliflozin Compound Tablets (Dosage Specifications 50 mg/25 mg)

Prescription composition Unit prescription amount/mg %(w/w) Empagliflozin 25.00 10.40 HMS5552 solid dispersion* 100.00 41.70 microcrystalline cellulose 100.30 41.80 Hydroxypropyl cellulose 7.20 3.00 Croscarmellose sodium 5.10 2.13 magnesium stearate 2.40 1.00 Total weight of core 240.00 100.00 Obaday 7.20 3.00 Total weight of coated tablets 247.20 --

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

2.4 Preparation of compound tablets by direct compression of powder mixing

The HMS5552 solid dispersion prepared according to the preparation example of the solid dispersion of the glucokinase activator and the combination drug are premixed uniformly according to the principle of geometric increase and added to a mixing barrel. A filler (e.g., microcrystalline cellulose), a disintegrant (e.g., cross-linked sodium carboxymethyl cellulose) and an optional glidant (microsilica gel) are added to the granules and mixed in a barrel mixer. Then, a lubricant (magnesium stearate or sodium stearyl fumarate) is added and further mixed uniformly. The lubricated mixture is tableted using a rotary tablet press to obtain tablets (plain tablets, uncoated core tablets) of different tablet weights and tablet shapes corresponding to different specifications. The resulting tablets are optionally film-coated with II to increase the weight by approximately 3%, thereby obtaining film-coated tablets.

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

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

Prescription composition Unit prescription amount/mg %(w/w) Empagliflozin 25.00 6.25 HMS5552 solid dispersion* 50.00 12.50 microcrystalline cellulose 309.00 77.25 Croscarmellose sodium 8.00 2.00 Micro-powder silica gel 4.00 1.00 magnesium stearate 4.00 1.00 Total weight of core 400.00 100.00 Obaday 12.00 3.00 Total weight of coated tablets 412.00 --

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

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

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

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

III. In vitro dissolution testing of compound preparations containing glucokinase activators

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

According to the above test method, the dissolution results of the above-mentioned fixed-dose tablets and their corresponding single-ingredient tablets are as follows.

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

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

Table 3 Dissolution results of fixed-dose combination tablets prepared in Example 5B

Table 4 Dissolution results of fixed-dose combination tablets prepared in Example 7B

Table 5 Dissolution results of fixed-dose combination tablets prepared in Example 8B

Table 6 Dissolution results of fixed-dose combination tablets prepared in Example 9B

Table 7 Dissolution results of fixed-dose combination tablets prepared in Example 19B

Table 8 Dissolution results of fixed-dose combination tablets prepared in Example 20B

From the dissolution results of the above fixed-dose combination preparations, it can be seen that the dissolution of the fixed-dose combination preparations of the present invention meets the requirements of a rapid-release preparation.

IV. Physical Properties of Compound Preparations Containing Glucokinase Activators

The physical properties of the above-mentioned fixed-dose tablets were tested using pharmacopoeial instruments and methods, and the results are described below.

Table 9 Physical properties of fixed-dose compound tablet cores prepared in different examples

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

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

Table 12 Physical properties of fixed-dose compound tablet cores prepared in different examples

V. Pharmacodynamic studies of compound preparations containing glucokinase activators

Example 1C

Effects of glucokinase activators and combination drugs on glucose/sucrose tolerance in normal mice

Normal male C57BL/6J mice were fasted for 6 hours and then orally administered with a solvent control, 10 mg/kg empagliflozin, or 10 mg/kg HMS5552 combined with 10 mg/kg empagliflozin. One hour later, 2 g/kg of glucose was administered orally. Blood was collected from the tail vein before (-60 minutes), before glucose administration (0 minutes), and 15, 30, 60, and 120 minutes after glucose administration for whole blood glucose measurement. Analysis of the area under the blood glucose curve (AUC0-120min, mmol/L*min) from 0 to 120 minutes compared to the solvent control revealed that the glucose-lowering effect of 10 mg/kg HMS5552 combined with 10 mg/kg empagliflozin was significantly superior to that of 10 mg/kg empagliflozin alone, with statistically significant differences (P<0.001).

Empagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, lowers blood sugar by reducing renal glucose reabsorption, lowering the renal glucose threshold, and promoting glucose excretion in the urine. It can also reduce cardiovascular risk and cardiovascular mortality and is used for type 2 diabetes patients with concurrent cardiovascular disease. HMS5552, a novel glucokinase activator, can improve pancreatic islet function, promote incretin secretion, and reduce insulin resistance in patients with type 2 diabetes. It has the dual therapeutic effect of reducing fasting and postprandial blood sugar. The combination of an SGLT-2 inhibitor and HMS5552 has better blood sugar control efficacy and reduces the risk of diabetic complications in patients whose blood sugar control fails to be controlled by SGLT-2 inhibitors, obese patients, and diabetic patients with concurrent cardiovascular disease.

The aforementioned efficacy study of HMS5552 in combination with existing oral diabetes medications (SGLT-2 inhibitors) demonstrates that combined use can enhance the efficacy of HMS5552 or existing glucose-lowering drugs, reduce safety risks, and improve medical outcomes. Developing an oral fixed-dose combination of HMS5552 and existing oral diabetes medications is the most promising combination diabetes treatment to address these clinical needs.

Claims (58)

1. A combination of drugs, comprising: (a) A glucokinase activator, wherein the glucokinase activator is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, its crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof: (b) SGLT-2 inhibitors, namely empagliflozin and its pharmaceutically acceptable salts. 2. The pharmaceutical combination of claim 1, wherein the glucokinase activator is a compound HMS5552 represented by the following formula, or an isotopic label thereof, or a pharmaceutically acceptable salt thereof. 3. The pharmaceutical combination of claim 1, wherein the glucokinase activator is in solid dispersion form. 4. The pharmaceutical combination of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is a type A methacrylic acid copolymer. 5. The pharmaceutical combination of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is a 1:1 anionic copolymer of methacrylic acid and methyl methacrylate. 6. The pharmaceutical combination of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is Eudragit. 7. The pharmaceutical combination of claim 1, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is Eudragit L100. 8. The pharmaceutical combination of any one of claims 4-7, wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, 4:5 to 5:4, or 5:6 to 6:5. 9. The pharmaceutical combination of any one of claims 4-7, wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:1, 2:3, 3:4, 4:5 or 5:6. 10. The pharmaceutical combination of claim 1, wherein the glucokinase activator is present in a dose range of 1 mg to 200 mg. 11. The pharmaceutical combination of claim 1, wherein the glucokinase activator is present in a dose range of 25 mg to 100 mg. 12. The pharmaceutical combination of claim 1, wherein the dose of said glucokinase activator is 25 mg, 50 mg, 75 mg or 100 mg. 13. The pharmaceutical combination of claim 1, wherein the SGLT-2 inhibitor is empagliflozin, in a dose of 0.5 mg to 50 mg. 14. The pharmaceutical combination of claim 1, wherein the SGLT-2 inhibitor is empagliflozin, in a dose of 1 mg to 25 mg. 15. The pharmaceutical combination of claim 1, wherein the SGLT-2 inhibitor is empagliflozin in a dose of 5 mg, 10 mg, 12.5 mg or 25 mg. 16. The pharmaceutical combination of any one of claims 11-15, wherein the dose is a unit dose. 17. A pharmaceutical composition comprising any one of the pharmaceutical compositions according to claims 1-16. 18. The pharmaceutical composition of claim 17, comprising a solid dispersion of a glucokinase activator and an SGLT-2 inhibitor, wherein the solid dispersion of the glucokinase activator comprises 1 to 96% by weight. 19. The pharmaceutical composition of claim 17, further comprising one or more excipients, wherein the excipients are selected from binders, fillers, disintegrants, lubricants, flow aids, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, coloring agents, or coating agents. 20. The pharmaceutical composition of claim 17, wherein it is in the form of tablets or capsules. 21. The pharmaceutical composition of claim 17, wherein it is a coated tablet. 22. A fixed-dose compound preparation comprising: (a) A glucokinase activator, which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, its crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof: (b) SGLT-2 inhibitors, namely empagliflozin and its pharmaceutically acceptable salts; (c) One or more excipients. 23. The fixed-dose combination preparation of claim 22, wherein the glucokinase activator comprises 1-96% by weight. 24. The fixed-dose combination formulation of claim 22, wherein the glucokinase activator is compound HMS5552 represented by the following formula, or an isotopic label thereof, or a pharmaceutically acceptable salt thereof. 25. The fixed-dose compound preparation of claim 22, wherein the glucokinase activator is in solid dispersion form. 26. The fixed-dose combination formulation of claim 22, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is a type A methacrylic acid copolymer. 27. The fixed-dose combination formulation of claim 22, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is a 1:1 anionic copolymer of methacrylic acid and methyl methacrylate. 28. The fixed-dose combination formulation of claim 22, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is Eudragit. 29. The fixed-dose combination formulation of claim 22, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymer carrier, wherein the polymer carrier is Eudragit L100. 30. A fixed-dose combination formulation of any one of claims 26-29, wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, 4:5 to 5:4, or 5:6 to 6:5. 31. A fixed-dose combination formulation according to any one of claims 26-29, wherein the weight ratio of the glucokinase activator to the polymer carrier is 1:1, 2:3, 3:4, 4:5 or 5:6. 32. The fixed-dose combination formulation of claim 22, wherein the glucokinase activator is present in a dose range of 1 mg to 200 mg. 33. The fixed-dose combination formulation of claim 22, wherein the glucokinase activator is present in a dose range of 25 mg to 100 mg. 34. The fixed-dose combination preparation of claim 22, wherein the dose of the glucokinase activator is 25 mg, 50 mg, 75 mg or 100 mg. 35. The fixed-dose combination preparation of claim 22, wherein the SGLT-2 inhibitor is empagliflozin, and the dose is 0.5 mg to 50 mg. 36. The fixed-dose combination preparation of claim 22, wherein the SGLT-2 inhibitor is empagliflozin, and the dose is 1 mg to 25 mg. 37. The fixed-dose combination formulation of claim 22, wherein the SGLT-2 inhibitor is empagliflozin, in a dose of 5 mg, 10 mg, 12.5 mg or 25 mg. 38. The fixed-dose combination formulation of claim 22, comprising a solid dispersion of a glucokinase activator and an SGLT-2 inhibitor, wherein the solid dispersion of the glucokinase activator comprises 1 to 96% by weight. 39. The fixed-dose compound preparation of claim 22, wherein the one or more excipients are selected from binders, fillers, disintegrants, lubricants, flow aids, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, coloring agents, or coating agents. 40. The fixed-dose compound formulation of claim 39, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose; the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch, or pregelatinized starch; the disintegrant is selected from croscarmellose sodium, croscarmellose, or glycolic acid starch sodium; the lubricant is selected from magnesium stearate or sodium stearoyl fumarate; and the flow aid is selected from colloidal silica or talc. 41. The fixed-dose compound preparation of claim 22, wherein it is a tablet. 42. The fixed-dose compound preparation of claim 41, wherein it is a coated tablet. 43. The fixed-dose combination formulation of claim 42, wherein the coated tablet is a film-coated tablet, wherein the film-coating agent comprises: The film coating substrate is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or mixtures thereof; Optional plasticizers are selected from polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or mixtures thereof; The optional colorant is selected from iron oxide red, iron oxide yellow, or mixtures thereof; Optional light-blocking agent, selected from titanium dioxide, and Optional glialization agent. 44. The fixed-dose compound preparation of claim 43, wherein the coated tablet is a film-coated tablet, wherein the film coating agent is Opadry. 45. The fixed-dose compound preparation of claim 22, wherein the dosage of the active ingredient by weight is: HMS5552 in 25mg, 50mg, 75mg or 100mg; Empagliflozin in doses of 5 mg, 10 mg, 12.5 mg, or 25 mg. 46. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 75 mg HMS5552/5 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -75 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -5mg of empagliflozin. 47. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 75 mg HMS5552/12.5 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -75 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -12.5 mg of empagliflozin. 48. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 75 mg HMS5552/10 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -75 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -10mg of empagliflozin. 49. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 75 mg HMS5552/25 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -75 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -25mg of empagliflozin. 50. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 50 mg HMS5552/25 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -50 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -25mg of empagliflozin. 51. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 50 mg HMS5552/10 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -50 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -10mg of empagliflozin. 52. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 100 mg HMS5552/10 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -100 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -10mg of empagliflozin. 53. The fixed-dose combination formulation of claim 45, wherein the fixed-dose combination formulation is a 25 mg HMS5552/25 mg empagliflozin tablet, comprising, by weight, the following components in the following amounts: -25 mg of HMS5552, which is a solid dispersion containing HMS5552 and Eudragit L100 in a 1:1 ratio; and -25mg of empagliflozin. 54. The fixed-dose combination formulation of claim 45, comprising 150 mg of a solid dispersion, 5.00 mg of empagliflozin, 88.10 mg of microcrystalline cellulose, 7.80 mg of hydroxypropyl cellulose, 6.50 mg of croscarmellose sodium, 2.60 mg of magnesium stearate and 7.80 mg of eupadic, wherein the solid dispersion contains 1:1 HMS5552 and Eudragit L100 and contains 75 mg of HMS5552. 55. The fixed-dose combination formulation of claim 45, comprising 150 mg of a solid dispersion, 12.50 mg of empagliflozin, 99.30 mg of microcrystalline cellulose, 8.40 mg of hydroxypropyl cellulose, 7.00 mg of croscarmellose sodium, 2.80 mg of magnesium stearate and 8.40 mg of eupadic, wherein the solid dispersion contains 1:1 HMS5552 and Eudragit L100 and contains 75 mg of HMS5552. 56. The fixed-dose combination formulation of claim 45, comprising 100 mg of a solid dispersion, 25.00 mg of empagliflozin, 100.30 mg of microcrystalline cellulose, 7.20 mg of hydroxypropyl cellulose, 5.10 mg of croscarmellose sodium, 2.40 mg of magnesium stearate and 7.20 mg of eupadic, wherein the solid dispersion contains 1:1 HMS5552 and Eudragit L100 and contains 50 mg of HMS5552. 57. Use of any pharmaceutical composition of claims 1-16 or any pharmaceutical composition of claims 17-21 in the preparation of a medicament for preventing, slowing the progression of, delaying or treating, or preventing, slowing, delaying or reversing complications of diabetes, selected from: type 1 diabetes, type 2 diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, impaired renal function and/or metabolic syndrome; or for improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c. 58. Use of any pharmaceutical composition of claims 1-16 or any pharmaceutical composition of claims 17-21 in the preparation of a medicament for preventing one or more metabolic disorders selected from the group consisting of, slowing the progression of, delaying or treating, or preventing, slowing, delaying or reversing complications of diabetes: postprandial hyperglycemia.