RU2781638C2 - Pharmaceutical combination, composition, and combined composition, containing glucokinase activator and ppar receptor activator, and their preparation method, and their use - Google Patents

Abstract

FIELD: medicine; therapy.

SUBSTANCE: group of inventions relates to the field of medicine, namely to therapy; it is intended for prevention, slowing down the progression, delay, or treatment of metabolic disorders. A hypoglycemic pharmaceutical combination contains a glucokinase activator, which is a compound HMS5552, PPAR receptor activator selected from a group consisting of rosiglitazone, pioglitazone, and their pharmaceutically acceptable salts. The mass ratio of the glucokinase activator to PPAR receptor activator is from 50:1 to 1:10. The glucokinase activator is present in a dose in the range from 1 mg to 200 mg, and PPAR receptor activator is present in a dose in the range from 1 mg to 50 mg. In another embodiments, a hypoglycemic pharmaceutical composition and a hypoglycemic combined combination with a fixed dose are provided. A method for prevention, slowing down the progression, delay, or treatment of one or several metabolic disorders is also presented, including administration to a subject of therapeutically effective amount of the specified hypoglycemic pharmaceutical combination, or the specified hypoglycemic pharmaceutical composition, or the specified hypoglycemic combined composition with a fixed dose.

EFFECT: use of the group of inventions provides excellent hypoglycemic effect.

82 cl, 2 dwg, 4 tbl, 30 ex

Description

Priority Application

The present application claims priority over Chinese Patent Application No. 201810556685.6, filed May 31, 2018, the disclosure of which is incorporated herein by reference in its entirety.

The technical field to which the invention belongs

The present invention relates to a pharmaceutical combination, composition and fixed dose combination (FDC) comprising a glucokinase activator (GKA) drug and a partner drug, a method for their preparation, and their use in the treatment of certain diseases.

More specifically, the present disclosure relates to a pharmaceutical combination, a pharmaceutical composition, or a fixed dose combination oral solid formulation containing a glucokinase activator drug and a partner drug, and a method for their preparation. The present invention also relates to the use of a pharmaceutical combination, a pharmaceutical composition, or a fixed dose combination formulation containing a glucokinase activator for the treatment and/or prevention of one or more diseases and medical disorders, including type I diabetes, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, impaired glucose tolerance, impaired fasting blood glucose, obesity and hypertension. In addition, the present invention also relates to a method for the treatment and/or prevention of one or more diseases and medical disorders, comprising the application of a therapeutically effective amount of a pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation disclosed in this application, in a subject in need of it. .

Prior Art

Diabetes mellitus has become a common disease worldwide, with 425 million patients worldwide and 120 million patients in China (International Diabetes Federation, Diabetes Atlas, 2015). Type II diabetes, i.e. non-insulin dependent diabetes mellitus (NIDDM), occurs in more than 90% of diabetic patients. Type II diabetes is a hyperglycemic chronic metabolic dysfunction resulting from an imbalance in blood glucose homeostasis in the human body caused by impaired insulin secretion and insulin resistance. The human body's blood glucose balance is mainly coordinated by two hormones that control blood glucose levels, including insulin and glucagon.

Glucosensor glucokinase (GC) senses changes in blood glucose, regulates the secretion of the glucose-controlling messenger hormones insulin and glucagon, as well as GLP-1 (glucagon-like peptide-1), and is a sensory system for regulating the equilibrium level of glucose in human blood. Glucose control hormones control the accumulation of glucose during glucose uptake and the supply of glucose during fasting, ensuring that an individual's blood glucose levels are balanced. The organs involved in the storage of glucose are mainly the liver, muscles, and adipose tissue. Under the action of glucose and insulin in the blood, glucose is taken up and converted into liver glycogen, muscle glycogen and triglycerides. The main organ responsible for the supply of glucose is the liver. Through the action of glucose and glucagon in the blood, the liver delivers glucose to the human body through glucose synthesis in the liver and the removal of glucose from the liver. Insulin can also effectively regulate the activity of the sodium glucose co-transporter SGLT-2. When blood glucose levels rise, glucose excreted by the kidneys is reabsorbed to store glucose in the body. Glucose uptake and glucose output from the liver, as well as the use of glucose by various organs, constitute the operating system for maintaining the balance of glucose in human blood. The coordinated work of the sensory system and the operating system of glucose is the selective regulation of the equilibrium of glucose in human blood.

In diabetic patients, impaired glucokinase function and expression, as well as sensor dysfunction, lead to dysfunction in the early phase of secretion of glucose-controlling hormones, affecting glucose uptake and production and leading to postprandial and fasting hyperglycemia. Abnormal glucose-control hormone signaling induces abnormal function and expression of key proteins in the glucose uptake and excretion executive system, creating an abnormal operating condition leading to type II diabetes.

Existing oral hypoglycemic agents for the treatment of diabetes usually act on a single glucose control organ and cannot effectively treat the problem of unbalanced blood glucose homeostasis. Glucokinase activators are a class of new drugs developed to treat or improve the pathological condition of patients with type II diabetes. For example, ((S)-2-[4((2-chlorophenoxy)-2-oxo-2,5-dihydropyrrol-1-yl]-4-methylpentanoic acid [1-((R)-2,3-dihydroxypropyl )-1H-pyrazol-3-yl]-amide (hereinafter referred to as HMS5552) can effectively improve glucose sensor function in diabetic patients, and is currently the most promising agent for the treatment of diabetes in order to solve the above clinical problems.

Brief summary of the invention

Patients with diabetes during treatment are often faced with a situation where PPAR receptor activators are not effective on their own, and blood glucose levels cannot be controlled to ideal levels, especially after a period of use. In this regard, the inventors found that the combination of a PPAR receptor activator and a glucokinase activator can significantly improve the hypoglycemic effect of the PPAR receptor activator and reduce the safety risk; thus, a pharmaceutical combination, composition and combination formulation containing a glucokinase activator and a PPAR receptor activator disclosed in the present application was obtained.

More specifically, the combination of a PPAR receptor activator and a glucokinase activator can improve the function of multiple organs of patients in the middle and advanced stages, and treat diabetes and comorbidities and complications well. The number of tablets taken by patients was reduced and patient compliance was improved, the total dose of drugs providing the same therapeutic effect was reduced, and maximum efficacy was achieved at the lowest dose. This has a good effect and is of practical value for the treatment or prevention of one or more of type I diabetes, type II diabetes, hyperglycemia, glucose intolerance, obesity and other symptoms.

On the other hand, the fixed dose combination formulation containing a glucokinase activator and a drug partner (the second active pharmaceutical ingredient or several such ingredients) described in the present application not only has better therapeutic effects than when using a single application of each of these two or more drugs, but also solves the technical problems that usually exist for combination formulations. The fixed dose combination formulation disclosed herein can provide simultaneous release of two or more active ingredients at a uniform content and allows optimization of the dissolution rate of the active ingredients contained in the formulation, in particular by accelerating the release of the active ingredients contained in the formulation at medium pH. small intestine. It promotes timely or simultaneous delivery of drugs to target organs - intestine, pancreatic islets and liver, achieving the clinical benefits of multi-organ targeting and synergistic hypoglycemic effect, as well as demonstrating better therapeutic effect and reduction of toxic or side effects. In addition, the fixed dose combination formulation containing a glucokinase activator and a drug partner (a second active pharmaceutical ingredient or several such ingredients) described in this application also has a short disintegration time and good dissolution characteristics and/or provides high bioavailability of the glucokinase activator. in patients.

The present invention provides a pharmaceutical combination, a pharmaceutical composition and a fixed dose combination formulation comprising a glucokinase activator such as HMS5552 with the following structure, or an isotopically labeled analog thereof, or a pharmaceutically acceptable salt thereof, and another oral hypoglycemic agent, especially a solid formulation such as a solid oral formulation such as a tablet,

In particular, the present invention also provides a pharmaceutical combination, a pharmaceutical composition or a fixed dose combination formulation containing a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof, and a PPAR receptor activator. Examples of a PPAR receptor activator include rosiglitazone, pioglitazone, chiglitazar, and a pharmaceutically acceptable salt thereof.

More specifically, the present disclosure also provides a fixed dose combination solid formulation containing a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a partner drug such as rosiglitazone. The solid formulation is preferably a tablet, or preferably a coated tablet. In one embodiment, the HMS5552 glucokinase activator is in the form of a solid dispersion containing a polymeric carrier.

More specifically, the present disclosure also provides a fixed dose combination solid formulation containing a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a partner drug such as pioglitazone. The solid formulation is preferably a tablet, and preferably a coated tablet. In one embodiment, the HMS5552 glucokinase activator is in the form of a solid dispersion containing a polymeric carrier.

The present invention also provides a pharmaceutical combination, a pharmaceutical composition or a fixed dose combination formulation of a glucokinase activator drug and a partner drug (a second active pharmaceutical ingredient or more of such ingredients) prepared by a dry or wet processing method. The release mode of a pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation disclosed herein is a rapid release of two or more active pharmaceutical ingredients.

The present invention also provides a pharmaceutical composition comprising a glucokinase activator drug and a partner drug (a second active pharmaceutical ingredient or more of such ingredients) that has a short disintegration time and good dissolution characteristics and/or provides high bioavailability of the glucokinase activator in patients. The present disclosure also provides a method for preparing a pharmaceutical composition or pharmaceutical formulation from a fixed dose combination of a glucokinase activator drug and a partner drug (a second active pharmaceutical ingredient or multiple such ingredients such as rosiglitazone and pioglitazone) via a dry or wet processing method. The dry processing method includes dry pressing (tabletting) and dry granulation; and the wet processing method includes wet granulation.

The present invention also provides a pharmaceutical combination, a pharmaceutical composition, or a pharmaceutical formulation comprising a glucokinase activator drug and a partner drug (a second active pharmaceutical ingredient or more of such ingredients), and a method for preventing, slowing, delaying, or treating a metabolic disorder (especially diabetes II). type).

The present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical formulation comprising a glucokinase activator drug and a partner drug (a second active pharmaceutical ingredient or more of such ingredients), and a method for improving blood glucose control in patients in need thereof, especially patients with type II diabetes.

The present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical composition containing a glucokinase activator drug and a partner drug, and a method for improving blood glucose control in patients with poor blood glucose control.

The present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical composition comprising a glucokinase activator drug and a partner drug, and a method for preventing, slowing or delaying impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hypertension, insulin resistance and/or progression of the metabolic syndrome to type II diabetes.

The present invention also provides a pharmaceutical combination, a pharmaceutical composition and a pharmaceutical composition containing a glucokinase activator drug and a partner drug, and a method for preventing, slowing, delaying, or treating a disease or disorder, including complications of diabetes.

Other aspects of the present invention will be apparent to those skilled in the art from the description and examples.

Brief description of the embodiments of the invention

The first aspect of the present invention provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical composition containing the following components, a process for their preparation and their use in the treatment of diabetes and related diseases:

(a) a glucokinase activator which is a compound selected from the following formula, or a pharmaceutically acceptable salt thereof, an isotopically labeled analogue thereof, a crystalline form, a hydrate, a solvate, or a diastereomeric or enantiomeric form; preferably the glucokinase activator is HMS5552; or preferably HMS5552 is present in the form of a solid dispersion,

;

;

(b) a PPAR receptor activator; and

(c) one or more excipients.

Another aspect of the present invention provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical composition containing the following components, a process for their preparation and their use in the treatment of diabetes and related diseases:

(a) a glucokinase activator, which is the compound HMS5552, or a pharmaceutically acceptable salt thereof, an isotopically labeled analog thereof, a crystalline form, hydrate, solvate, diastereomeric or enantiomeric form; preferably the glucokinase activator is HMS5552; also alternatively, HMS5552 is present in the form of a solid dispersion;

(b) rosiglitazone, pioglitazone, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, or diastereomeric or enantiomeric form thereof; and

(c) one or more excipients.

In particular, one aspect of the present invention also relates to a pharmaceutical combination, a pharmaceutical composition, and a pharmaceutical formulation comprising a fixed dose combination of HMS5552 solid dispersion and a drug partner (eg, rosiglitazone, pioglitazone); as well as to the method of their preparation and to their use.

Definitions

Unless otherwise indicated, all technical and scientific terms used in this application have the same meanings as commonly understood by experts in the field of technology to which the present invention belongs, but in case of conflict, the definitions in this description shall prevail.

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

Unless otherwise indicated, all percentages (%) in the description are weight percent (% by weight).

All numerical values or expressions relating to the number of components, process conditions, etc., used in the description and claims, should be understood as modified by the term "about" in all cases. The term "about" when referring to an amount or range of numerical values means that said amount or range of numerical values is an approximate value within experimental variability (or within statistical experimental error). Therefore, the number or range of numerical values may vary, for example, within ±5 percent of the number or range of numerical values.

All ranges that include the same components or properties include endpoints that can be independently combined. Because 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 a range is used in the present disclosure to define physical properties such as molecular weight or chemical properties, it should include all combinations and subcombinations of the range and particular embodiments therein. The term "comprising" (and related terms such as "comprising" or "comprising" or "having") includes embodiments that are, for example, any combination of substances, compositions, methods or processes, etc., and "consisting of the functions described" or "essentially consisting of the functions described".

As used in the description and claims, the term "and/or" should be understood as "alternative or both" of the associated components, that is, the components exist together in some cases, and exist separately in other cases. Multiple components listed using the term "and/or" should be understood equally, that is, "one or more" related components. In addition to the components specifically identified in the "and/or" section, other components may be present as needed, whether or not related to those specifically identified components. Therefore, as a non-limiting example, when "A and/or B" is used to connect a public end word such as "comprising", in one embodiment, it can only refer to A (optionally containing components other than B); in another embodiment, it may refer only to B (optionally containing components other than A); in yet another embodiment, it refers to A and B (if necessary, containing other components), etc.

It should be understood that, unless expressly stated otherwise, in any method that includes more than one step or one act claimed in this application, the order of the steps and acts of the method is not necessarily limited to the order of the steps and acts of the described method.

The abbreviations used in the present description have general meanings in the fields of chemistry, biology and formulation.

Unless otherwise indicated, the term "PPAR receptor activator" or any substances representing it (such as, for example, "rosiglitazone, pioglitazone") in the context of the present invention also includes any pharmaceutically acceptable salt, crystalline form, hydrate, solvate, diastereomer or enantiomer.

HMS5552 (formerly RO5305552 and English name Dorzagliatin) has the chemical name (S)-2-[4-(2-chlorophenoxy)-2-oxo-2,5-dihydropyrrol-1-yl]-4-methyl- pentanoic acid [1-((R)-2,3-dihydroxypropyl)-1H-pyrazol-3-yl]-amide.

Unless otherwise indicated, percentages by weight (wt%) are percentages of the total weight of the pharmaceutical combination, pharmaceutical composition, or pharmaceutical composition.

Solid dispersion (SD) refers to a solid dispersion system formed by highly dispersed treatment of one or more active pharmaceutical ingredients with inactive adjuvants or carriers.

EUDRAGIT is the trade name for a synthetic pharmaceutical adjuvant. It includes methacrylic acid copolymers and methacrylate ester copolymers, collectively referred to as polyacrylic resins. Polyacrylic resin adjuvants are divided into different models according to their composition, proportion and degree of polymerization. Among them, Eudragit-E is a polymer of dimethylaminoethyl methacrylate and methacrylate; Eudragit-L is a polymer of methacrylic acid and methyl methacrylate with a free carboxyl:ester ratio of 1:1; and Eudragit-S is a polymer of methacrylic acid and methyl methacrylate with a free carboxyl:ester ratio of 1:2.

Used in this application, the term "tablet" includes compressed pharmaceutical compositions of all shapes and sizes, coated or uncoated.

The terms "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to provide the desired biological result. The biological outcome may be to reduce and/or alleviate the signs, symptoms, or causes of a disease, or any other necessary alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as an active ingredient, as disclosed herein, to provide a clinically significant reduction in disease. A suitable "effective" amount in any individual embodiment can be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression "effective amount" usually refers to the amount at which the active substance has a therapeutic effect.

As used herein, the terms "treat" or "treatment" are synonymous with "prevent" and are intended to mean delaying the development of diseases, preventing the development of diseases, and/or reducing the severity of such symptoms that are present or about to develop. Thus, these terms include alleviating existing symptoms of a disease, preventing additional symptoms, alleviating or preventing the underlying metabolic causes of symptoms, inhibiting a disorder or disease, such as preventing the development of a disorder or disease, alleviating a disorder or disease, inducing regression of a disorder or disease, alleviating a condition, caused by a disease or disorder, or the cessation of symptoms of the disease or disorder.

By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable, i. a material that can be administered to an individual without exhibiting a minimum of undesirable biological effects or without adverse interaction with any other components of the composition in which it is contained.

Used in this application, the term "subject" includes mammals and animals that are not mammals. Examples of mammals include any member of the mammalian class: humans, non-human primates such as chimpanzees, and other primate and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals, including but not limited to rodents such as rats, mice, guinea pigs, and the like. 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.

A compound as an active ingredient in a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (eg, fixed dose combination formulation) containing the glucokinase activator described herein may form a salt. By reference to a compound disclosed in this application is meant a reference to its salts, unless otherwise indicated. The term "salt(s)", as used in this application, means acid salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when the compound contains both a basic component such as, but not limited to, pyridine or imidazole, and an acidic component, such as, but not limited to, carboxylic acid; zwitterions ("internal salts") may be formed, and are included in the term "salt(s)" as used herein. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also applicable. Salts of a compound may be formed, for example, by reacting the compound with such an amount as an equivalent amount of an acid or base in a medium such as the medium from which the salt precipitates or in an aqueous medium (post-reaction lyophilization).

Various compounds and salts, solvates, esters and prodrugs, as well as their polymorphs are intended to be included in the description.

It should be understood that the terminology used in this application is intended to describe specific embodiments and is not intended to be limiting. In addition, while any methods, devices, and materials similar or equivalent to those described herein may be used in the practice or testing of the invention, preferred methods, devices, and materials are described below.

Brief description of the drawings

n = 10) с применением росиглитазона отдельно и комбинации HMS5552 и росиглитазона; иIn FIG. 1 shows the effect on blood glucose after a glucose load in normal mice (

n = 10) using rosiglitazone alone and a combination of HMS5552 and rosiglitazone; and

n = 10; ***, P < 0,001) с применением росиглитазона отдельно и комбинации HMS5552 и росиглитазона.in fig. 2 shows the effect on AUC _{0-120 min} (area under the pharmacokinetic curve describing the "concentration/time" relationship over a period of 0-120 min) after a glucose load in normal mice (

n = 10; ***, P < 0.001) with rosiglitazone alone and with the combination of HMS5552 and rosiglitazone.

Detailed description of embodiments 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 formulation of a glucokinase activator (alternatively, HMS5552 or an isotopically labeled analogue or a pharmaceutically acceptable salt thereof) and a drug partner (e.g., rosiglitazone, pioglitazone). The formulation may be a powder, granule, tablet, capsule, sachet, or other solid form. In particular, one aspect of the present disclosure relates to a tablet containing a fixed dose combination of a glucokinase activator and a drug partner (eg, rosiglitazone, pioglitazone).

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

(1) a glucokinase activator or a pharmaceutically acceptable salt thereof, or an isotopically labeled analog thereof, its crystalline form, hydrate, solvate, diastereomeric or enantiomeric form; preferably the glucokinase activator is HMS5552; more alternatively, HMS5552 is present in the form of a solid dispersion, such as a solid dispersion (eg, spray-dried powder) containing a polymeric carrier;

(2) a PPAR receptor activator; preferably selected from rosiglitazone, pioglitazone, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, diastereomeric or enantiomeric form thereof; and/or

(3) filler(s); and/or

(4) binding agent(s); and/or

(5) disintegrant(s); and/or

(6) lubricant(s) or glidant(s); and/or

(7) coating agent(s).

In one embodiment disclosed in this application, the pharmaceutical combination, pharmaceutical composition or pharmaceutical composition may also contain one or more excipients selected from the group consisting of one or more binding agents; one or more diluents (fillers); one or more disintegrants; one or more lubricants; one or more glidants; one or more surfactants or wetting agents; one or more antioxidants; and one or more coating agent(s).

Pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation

Glucokinase activator + PPAR receptor activator

In one embodiment, the present invention relates to a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) that includes:

(a) a glucokinase activator, which is a compound represented by the following formulas, or a pharmaceutically acceptable salt thereof, an isotopically labeled analog thereof, a crystalline form, a hydrate, a solvate, or a diastereomeric or enantiomeric form:

HMS5552

HMS5552

(b) a PPAR receptor activator;

alternatively, the PPAR receptor activator is selected from the group consisting of rosiglitazone or rosiglitazone maleate, pioglitazone or pioglitazone hydrochloride, and chiglitazar; and

(c) one or more excipients;

while the aforementioned drugs (a) and (b) are used simultaneously, separately or sequentially.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the weight ratio of glucokinase activator to PPAR receptor activator is about 50:1 to about 1:10, alternatively, about 25:1 to 1:5, or alternatively, about 1:10, about 1:5, about 1:2, about 1.67:1, about 3.33:1, about 5:1, about 6 .25:1, about 6.67:1, about 12.5:1, about 18.75:1, or about 25:1.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the glucokinase activator is present at a dose (alternatively, a single dose) in the range of about 1 mg to 200 mg, or, alternatively, from about 25 mg to 100 mg, alternatively, where the dose (preferably a single dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg, or about 100 mg.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical composition, the PPAR receptor activator is present at a dose (optionally, unit dose) in the range of about 1 to 50 mg, or alternatively, about 4 mg to 15 mg. , alternatively, wherein the dose (optionally, unit dose) of the PPAR receptor activator is about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 12 mg, about 14 mg, or about 15 mg , or, alternatively, about 4 mg or about 15 mg; alternatively, the PPAR receptor activator is rosiglitazone or pioglitazone.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the aforementioned glucokinase activator is HMS5552, or an isotopically labeled analog thereof, or a pharmaceutically acceptable salt,

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the glucokinase activator is present in the form of a solid dispersion.

In one embodiment, a solid dispersion is obtained by spray drying, hot melting, or lyophilization of a glucokinase activator, or its isotopically labeled analog, or a pharmaceutically acceptable salt thereof, together with a polymeric carrier.

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

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

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the glucokinase activator is present in the form of a solid dispersion and the weight ratio of the solid dispersion of glucokinase activator to PPAR receptor activator is from about 100:1 to 1:5, alternatively, about 50:1 to 2:5, or alternatively, about 1:5, about 2:5, about 1:1, about 3.33:1, about 6 .67:1, about 10:1, about 12.5:1, about 13.3:1, about 25:1, about 37.5:1, or about 50:1.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the glucokinase activator is an HMS5552 compound, an isotopically labeled analog thereof, or a pharmaceutically acceptable salt thereof, which are combined with a polymeric carrier to form a solid dispersion by spray drying, hot melting or lyophilization, etc.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the solid dispersion polymer carrier is selected from a polypropylene resin based polymer, which is a polymer compound obtained by polymerizing acrylic acid. (or methacrylic acid and its esters such as methyl ester, ethyl esters, etc.) (as a monomer), or obtained by polymerizing two monomers (binary polymerization) or three monomers (triple polymerization) in a certain ratio with using acrylic acid and methacrylic acid (or its ester such as methyl ester, ethyl ester, dimethylaminoethyl ether, etc.).

In one embodiment, the polymeric carrier used in the solid dispersion in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) is selected from the group consisting of a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate; a copolymer of methacrylic acid and ethyl acrylate; a copolymer of methacrylic acid and methyl methacrylate; a copolymer of ethyl acrylate, methyl methacrylate and chlorotrimethylaminoethyl methacrylate; 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 aforementioned polymeric carrier is selected from the group consisting of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (1:2:1) copolymer, methacrylic acid-ethyl acrylate (1:1) copolymer, methacrylic acid-methyl methacrylate (1:2) copolymer, copolymer ethyl acrylate, methyl methacrylate and chlorotrimethylaminoethyl methacrylate (1:2:0.2), copolymer of ethyl acrylate, methyl methacrylate and chlorotrimethylaminoethyl methacrylate (1:2:0.1), copolymer of ethyl acrylate and methyl methacrylate (2:1), copolymer of methacrylic acid and butyl acrylate (35:65 ), a copolymer of methacrylic acid and methyl methacrylate (1:1), a copolymer of methacrylic acid and methyl methacrylate (35:65).

In one embodiment, the aforementioned polymeric carrier is Eudragit, including Eudragit-E, Eudragit-L, Eudragit-S, Eudragit-RL, and Eudragit-RS, wherein Eudragit-E is prepared by polymerization of dimethylaminomethacrylate and other neutral methacrylates, including copolymers of dimethylaminoethylmethacrylate and methacrylate ; Eudragit-L and Eudragit-S are prepared by polymerization of methacrylic acid and methacrylates in various ratios, including a copolymer of methacrylic acid and methyl methacrylate with 1:1 free carboxyl:ester or a copolymer of methacrylic acid and methyl methacrylate with 1:2 free carboxyl:ester; Eudragit-RL and Eudragit-RS types are an acrylic acid copolymer containing several quaternary amine and methacrylate groups, including an acrylic acid copolymer containing 10% of a quaternary amine and methacrylate group, and an acrylic acid copolymer containing 5% of a quaternary amine and methacrylate group.

In one embodiment, the polymeric carrier mentioned above is selected from the group consisting of:

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

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

Eudragit-S100, which is a copolymer of methacrylic acid and methyl methacrylate (1:2).

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), the HMS5552 solid dispersion polymeric carrier is type A copolymer of methacrylic acid (anionic copolymer of methacrylic acid and methyl methacrylate (1:1) ), alternatively Eudragit or alternatively Eudragit-L100.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) (alternatively, the weight ratio of HMS5552 to Eudragit-L100 in 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; alternatively, 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; alternatively, about 2:3 to 7:3, about 3:4 to 7:3, about 4:5 to 7:3, about 5:3 6 to 7:3, or about 1:1 to 7:3; alternatively, 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; alternatively, 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 in between.

Alternatively, in one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, fixed dose combination formulation), the weight ratio of HMS5552 to Eudragit-L100 in 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 , approximately 3:7, approximately 1:9, approximately 9:1, or any range in between.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (alternatively a fixed dose combination formulation), the second active ingredient is rosiglitazone (or rosiglitazone maleate). The aforementioned pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of a glucokinase activator (HMS5552 or an isotopically labeled analogue thereof or a pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate) contains (by weight): about 1-98% glucokinase activator (as alternatively, HMS5552 or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof); about 0.1-25% rosiglitazone or rosiglitazone maleate; about 0-90% filler(s); about 1-25% binding agent(s); about 0-15% disintegrant(s); about 0.1-10% lubricant(s), about 0-3% glidant(s), and about 0-5% coating agent(s). The pharmaceutical composition or pharmaceutical formulation (optionally a fixed dose combination formulation) is prepared by a wet granulation process or a dry granulation process, alternatively a wet granulation process.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) of a glucokinase activator (HMS5552 or an isotopically labeled analog thereof or a pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate), the dose ( optionally, a unit dose) of a glucokinase activator (optionally HMS5552 or an isotopically labeled analogue thereof or a pharmaceutically acceptable salt thereof) is from about 1 mg to 200 mg. An alternative dose (alternatively, a single dose) of the glucokinase activator is 5 mg to 100 mg. Alternatively, the dose (optionally, 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 in between. Alternatively, the dose (optionally, unit dose) of the glucokinase activator (optionally HMS5552 or an isotopically labeled analog thereof or a pharmaceutically acceptable salt thereof) is about 25 mg, about 50 mg, about 75 mg, or about 100 mg. Alternatively, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) of a glucokinase activator (HMS5552 or an isotopically labeled analog or pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate), based on the amount rosiglitazone, the dose (alternatively, a single dose) of rosiglitazone (or rosiglitazone maleate) is from about 2 mg to 8 mg, or, alternatively, the dose (alternatively, a single dose) is about 2 mg, about 4 mg, or about 8 mg. Alternatively, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, fixed dose combination formulation) of the present invention, specific dosage embodiments (alternatively, single doses) of HMS5552 and rosiglitazone (or rosiglitazone maleate) are as follows:

(1) about 25 mg HMS5552 and about 4 mg rosiglitazone (or about 5.30 mg rosiglitazone maleate);

(2) about 50 mg HMS5552 and about 4 mg rosiglitazone (or about 5.30 mg rosiglitazone maleate);

(3) about 75 mg HMS5552 and about 4 mg rosiglitazone (or about 5.30 mg rosiglitazone maleate); and

(4) about 100 mg HMS5552 and about 4 mg rosiglitazone (or about 5.30 mg rosiglitazone maleate);

alternatively, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, fixed dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, an alternative dosage form of a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) of the present invention is a tablet.

In one embodiment, said tablet is a fixed dose combination tablet of a glucokinase activator (HMS5552 or its isotopically labeled analogue or a pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate).

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination tablet that is a glucokinase activator 25 mg tablet (optionally, HMS5552 or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof)/4 mg of rosiglitazone (or the amount of rosiglitazone maleate from which the indicated amount of rosiglitazone can be obtained)), contains components in the following amounts (by weight): about 25 mg of glucokinase activator (alternatively, HMS5552 or its isotopically labeled analogue or its pharmaceutically acceptable salt) ; about 4 mg of rosiglitazone (or such amount of rosiglitazone maleate that allows you to get the specified amount of rosiglitazone); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 0.5-3% lubricant(s); about 0-0.5% glidant(s), and about 0-5% coating agent(s); alternatively, the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or, alternatively, the solid dispersion contains a glucokinase activator and a polymeric carrier, or, alternatively, contains about 1:1 of a glucokinase activator and Eudragit-L100.

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (preferably a fixed dose combination tablet that is a 50 mg glucokinase activator tablet (preferably HMS5552 or an isotopically labeled analogue thereof or a pharmaceutically acceptable salt thereof)/4 mg rosiglitazone (or an amount of rosiglitazone maleate, from which the indicated amount of rosiglitazone can be obtained)) contains components in the following amounts (by weight): about 50 mg of glucokinase activator (preferably HMS5552 or its isotopically labeled analogue or its pharmaceutically acceptable salt); about 4 mg of rosiglitazone (or such amount of rosiglitazone maleate that allows you to get the specified amount of rosiglitazone); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 0.5-3% lubricant(s); about 0-0.5% glidant(s), and about 0-5% coating agent(s); preferably the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or preferably the solid dispersion contains a glucokinase activator and a polymeric carrier, or preferably contains about 1:1 of a glucokinase activator and Eudragit-L100.

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination tablet that is a glucokinase activator 75 mg tablet (optionally, HMS5552 or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof)/4 mg of rosiglitazone (or the amount of rosiglitazone maleate from which the indicated amount of rosiglitazone can be obtained)), contains components in the following amounts (by weight): about 75 mg of glucokinase activator (alternatively, HMS5552 or its isotopically labeled analogue or its pharmaceutically acceptable salt) ; about 4 mg of rosiglitazone (or such amount of rosiglitazone maleate that allows you to get the specified amount of rosiglitazone); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 0.5-3% lubricant(s); about 0-0.5% glidant(s), and about 0-5% coating agent(s); alternatively, the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or, alternatively, the solid dispersion contains a glucokinase activator and a polymeric carrier, or, alternatively, contains about 1:1 of a glucokinase activator and Eudragit-L100.

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination tablet that is a glucokinase activator 100 mg tablet (optionally, HMS5552 or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof)/4 mg of rosiglitazone (or the amount of rosiglitazone maleate from which the indicated amount of rosiglitazone can be obtained)) contains components in the following amounts (by weight): about 100 mg of glucokinase activator (alternatively, HMS5552 or its isotopically labeled analogue or its pharmaceutically acceptable salt); about 4 mg of rosiglitazone (or such amount of rosiglitazone maleate that allows you to get the specified amount of rosiglitazone); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 0.5-3% lubricant(s); about 0-0.5% glidant(s), and about 0-5% coating agent(s); alternatively, the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or, alternatively, the solid dispersion contains a glucokinase activator and a polymeric carrier, or, alternatively, contains about 1:1 of a glucokinase activator and Eudragit-L100.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (alternatively a fixed dose combination formulation), the second active ingredient is pioglitazone (or pioglitazone hydrochloride). The aforementioned pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of a glucokinase activator (HMS5552 or an isotopically labeled analogue thereof or a pharmaceutically acceptable salt thereof and pioglitazone (or pioglitazone hydrochloride) contains (by weight): about 1-85% glucokinase activator (as an option , HMS5552, or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof); about 0.1-25% pioglitazone (or pioglitazone hydrochloride); about 0-90% excipient(s); about 1-25% coupling agent(s); about 0-15% disintegrant(s), about 0.1-10% lubricant(s), about 0-3% glidant(s), and about 0-5% coating agent(s). (optionally a fixed dose combination formulation) is prepared by a wet granulation process or a dry granulation process, alternatively with wet granulation method.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) of a glucokinase activator (HMS5552 or an isotopically labeled analog thereof or a pharmaceutically acceptable salt thereof) and pioglitazone (or pioglitazone hydrochloride), the dose ( optionally, a unit dose) of a glucokinase activator (optionally HMS5552 or an isotopically labeled analogue thereof or a pharmaceutically acceptable salt thereof) is from about 1 mg to 200 mg. Alternatively, the dose (optionally, 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 in between. Alternatively, the dose (optionally, unit dose) of the glucokinase activator (optionally HMS5552 or an isotopically labeled analog thereof or a pharmaceutically acceptable salt thereof) is about 25 mg, about 50 mg, about 75 mg, or about 100 mg. Alternatively, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) of a glucokinase activator (HMS5552 or an isotopically labeled analog thereof or a pharmaceutically acceptable salt thereof) and pioglitazone (or pioglitazone hydrochloride), the dose ( alternatively, a single dose) of pioglitazone (or pioglitazone hydrochloride) is from about 15 mg to 45 mg, or alternatively, the dose (alternatively, a single dose) is about 15 mg, about 30 mg, or about 45 mg. Alternatively, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, fixed dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In the pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of the present invention, specific dosage embodiments (alternatively, unit doses) of HMS5552 and pioglitazone (or pioglitazone hydrochloride) are as follows:

(1) about 25 mg HMS5552 and about 15 mg pioglitazone (or about 15.91 mg pioglitazone hydrochloride);

(2) about 50 mg HMS5552 and about 15 mg pioglitazone (or about 15.91 mg pioglitazone hydrochloride);

(3) about 75 mg HMS5552 and about 15 mg pioglitazone (or about 15.91 mg pioglitazone hydrochloride);

(4) about 100 mg HMS5552 and about 15 mg pioglitazone (or about 15.91 mg pioglitazone hydrochloride);

alternatively, in the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, fixed dose combination formulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, the preferred dosage form of the pharmaceutical combination, pharmaceutical composition, or pharmaceutical composition (alternatively, a fixed dose combination dosage form) of the present invention is a tablet.

In one embodiment, said tablet is a fixed dose combination tablet of a glucokinase activator (HMS5552 or its isotopically labeled analogue or a pharmaceutically acceptable salt thereof) and pioglitazone (or pioglitazone hydrochloride).

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination tablet that is a glucokinase activator 25 mg tablet (optionally, HMS5552 or an isotopically labeled analog thereof, or a pharmaceutically acceptable salt thereof)/15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the indicated amount of pioglitazone can be obtained)) contains components in the following amounts (by weight): approximately 25 mg of glucokinase activator (alternatively, HMS5552 or its isotopically labeled analogue, or its pharmaceutically acceptable salt) ; about 15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the indicated amount of pioglitazone can be obtained); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 1-10% lubricant(s); about 0-3% glidant(s) and about 0-5% coating agent(s); alternatively, the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or alternatively, the solid dispersion contains a glucokinase activator and a polymeric carrier, or alternatively, contains about 1:1 glucokinase activator and Eudragit-L100.

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination tablet that is a glucokinase activator 50 mg tablet (optionally, HMS5552 or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof)/15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the specified amount of pioglitazone can be obtained)) contains components in the following amounts (by weight): about 50 mg of glucokinase activator (alternatively, HMS5552 or its isotopically labeled analogue, or its pharmaceutically acceptable salt) ; about 15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the indicated amount of pioglitazone can be obtained); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 1-10% lubricant(s); about 0-3% glidant(s) and about 0-5% coating agent(s); alternatively, the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or alternatively, the solid dispersion contains a glucokinase activator and a polymeric carrier, or alternatively contains about 1:1 glucokinase activator and Eudragit-L100.

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination tablet that is a glucokinase activator 75 mg tablet (alternatively, HMS5552 or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof)/15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the indicated amount of pioglitazone can be obtained)) contains components in the following amounts (by weight): about 75 mg of glucokinase activator (alternatively, HMS5552 or its isotopically labeled analogue, or its pharmaceutically acceptable salt) ; about 15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the indicated amount of pioglitazone can be obtained); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 1-10% lubricant(s); about 0-3% glidant(s) and about 0-5% coating agent(s); alternatively, the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or, alternatively, the solid dispersion contains a glucokinase activator and a polymeric carrier, or, alternatively, contains about 1:1 of a glucokinase activator and Eudragit-L100.

In one embodiment, a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination tablet that is a glucokinase activator 100 mg tablet (optionally, HMS5552 or an isotopically labeled analogue thereof, or a pharmaceutically acceptable salt thereof)/15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the indicated amount of pioglitazone can be obtained)) contains components in the following amounts (by weight): about 100 mg of glucokinase activator (alternatively, HMS5552 or its isotopically labeled analogue, or its pharmaceutically acceptable salt) ; about 15 mg of pioglitazone (or the amount of pioglitazone hydrochloride from which the indicated amount of pioglitazone can be obtained); about 0-75% optional filler(s); about 2-8% binding agent(s); about 1-15% disintegrant(s); about 1-10% lubricant(s); about 0-3% glidant(s) and about 0-5% coating agent(s); alternatively, the aforementioned glucokinase activator is in the form of a solid dispersion as described above, or, alternatively, the solid dispersion contains a glucokinase activator and a polymeric carrier, or, alternatively, contains about 1:1 of a glucokinase activator and Eudragit-L100.

In one embodiment, the aforementioned pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (optionally, a fixed dose combination formulation) further comprises other excipients, which include, but are not limited to, one or a mixture of diluents, flavoring agents (flavors), sweeteners, and colors. them.

In one embodiment, the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) disclosed herein optionally contains one or more excipients (diluents). Examples of excipients include cellulose derivatives such as microcrystalline cellulose or lignocellulose (including microcrystalline cellulose and siliconized microcrystalline cellulose), lactose, lactose anhydrous or lactose monohydrate, sucrose, starch, pregelatinized starch, dextrose, mannitol (including Pearlitol SD 200 mannitol), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/glucose binder, maltodextrin, compressed sugar, and other known compatible agents or excipients, or a mixture of the two or more of them, but are not limited to them.

Examples of preferred fillers (diluents) include microcrystalline cellulose (MCC), siliconized microcrystalline cellulose (SMCC), lactose, mannitol, sorbitol, calcium dihydrogen phosphate (dihydrate), corn starch, pregelatinized starch and powdered cellulose. Other preferred fillers (diluents) are microcrystalline cellulose and siliconized microcrystalline cellulose. Microcrystalline cellulose is available from several vendors including Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200 manufactured by FMC Corporation.

In one embodiment, the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) disclosed herein optionally contains one or more coupling agents. Examples include carboxymethyl cellulose (including sodium carboxymethyl cellulose), hydroxypropyl cellulose (including hydroxypropyl cellulose EXF), corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC) (including hydroxypropyl methyl cellulose 2208), lactose, sucrose, gum arabic, ethyl cellulose, cellulose acetate; and wax binders such as carnauba wax, paraffin wax, cetyl wax, polyethylene or microcrystalline wax, and other conventional binder and/or a mixture of two or more of them, but are not limited to. Furthermore, in addition to the above binders, binders suitable for use in the present invention include alginic acid, microcrystalline cellulose, dextrin, gelatin, amylopectin, liquid glucose, guar gum, methylcellulose, polyethylene oxide, povidone, and syrup, and a combination thereof. , but are not limited to them.

Alternative embodiments of the coupling agent include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HMPC), polyvinylpyrrolidone (povidone), hydroxyethyl cellulose, starch 1500, and polyvidone. Other alternative binders are hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.

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

In one embodiment, the disintegrant is selected from one or more of a modified starch, a modified cellulose polymer, or a polycarboxylic acid, specifically selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, potassium polacrilin, and calcium CMC. In one embodiment, the disintegrant is crospovidone. In another embodiment, the disintegrant is sodium starch glycolate. In another embodiment, the disintegrant is croscarmellose sodium. Croscarmellose sodium NF type A is available commercially under the trade name "Ac-di-sol".

In one embodiment, the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) disclosed herein contains one or more lubricants. Examples of lubricants suitable for use herein include magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitate stearate, palmitic acid, myristic acid, and hydrogenated vegetable oils ( including but not limited to hydrogenated castor oil) and fats, and other known lubricants and/or a mixture of two or more of them.

In one embodiment, lubricant embodiments include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil, and mixtures thereof. Another possible lubricant is magnesium stearate, sodium stearyl fumarate, or a mixture thereof.

In one embodiment, the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) disclosed herein 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, silica, colloidal silica, magnesium silicate, calcium phosphate, magnesium trisilicate, talc, and other forms of silica such as aggregated silicate and hydrated silica gel. them.

In one embodiment, embodiments of glidant include colloidal silicon dioxide, calcium phosphate, magnesium silicate, and talc, or a mixture thereof. A possible variant of glidant is colloidal silicon dioxide.

In one embodiment, the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively, a fixed dose combination formulation) disclosed herein may also optionally contain one or more surfactants or wetting agents. The surfactant may be an anionic, cationic or neutral surfactant. The anionic surfactant includes sodium lauryl sulfate, sodium lauryl sulfonate, sodium oleyl sulfate and sodium laurate mixed with stearate and talc. The cationic surfactant includes benzalkonium chloride and alkyltrimethylammonium bromide. The neutral surfactant includes glycerol monooleate, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol sorbitan ester. Wetting agent options include poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, and polyoxyethylene stearate.

In one embodiment, the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (alternatively a fixed dose combination formulation) disclosed herein may also optionally contain an antioxidant to provide chemical stability. Examples of an antioxidant suitable for use in the present invention include tocopherol, ascorbic acid, gallic acid ester, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerin, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. and a combination thereof, but are not limited to.

In one embodiment, the antioxidant is selected from the group consisting of α-tocopherol, γ-tocopherol, δ-tocopherol, natural extracts enriched with tocopherol, L-ascorbic acid and its sodium or calcium salt, 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 formulation disclosed herein is a tablet obtained by compression. The tablet may be coated, and alternative examples of coating substrates include sugar coating substrates, water soluble film coating substrates, enteric film coating substrates, and the like.

Sucrose is used as a sugar-based coating substrate. In addition, one or more selected from talc powder, precipitated calcium carbonate, gelatin, gum arabic, amylopectin, carnauba wax, and the like can also be used in combination.

Examples of the water-soluble film coating substrate include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, and the like.

Examples of the enteric film coating substrate include cellulose polymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, and the like; an acrylic polymer 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. P.

Alternative examples of coating additives include plasticizers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), propylene glycol, triethyl citrate, castor oil, polysorbate, and the like, or a mixture of two or more of them; opacifiers such as titanium dioxide and the like; dyes, pigments and varnishes such as red iron oxide (iron oxide), yellow iron oxide, and the like; and glidants such as talc and the like.

In one embodiment, the tablet may be coated, for example, with a mixture of hydroxypropylcellulose and hydroxypropylmethylcellulose, where the mixture contains titanium dioxide and/or other colorants such as iron oxide, colorants and varnishes; a mixture of polyvinyl alcohol (PVA) and polyethylene glycol (PEG); or any other suitable immediate release coating agent. The coating provides flavor masking and additional stability to the final tablet. A commercially available coating material is Opadry®, such as Opadry 03K12429, which is a pre-blended powder mixture supplied by Colorcon.

In one embodiment, sweeteners and/or flavors may also be added to the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (preferably a fixed dose combination formulation) disclosed herein, if desired.

In one embodiment, the aforementioned coupling agent is polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose; the aforementioned filler is microcrystalline cellulose, siliconized microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch or pregelatinized starch; the above disintegrant is croscarmellose sodium, crospovidone or sodium starch glycolate, the above lubricant is magnesium stearate or sodium stearyl fumarate, and the above glidant is colloidal silicon dioxide.

In one embodiment, said coupling agent is hydroxypropyl cellulose, said excipient is microcrystalline cellulose, siliconized microcrystalline cellulose, or lactose, said disintegrant is croscarmellose sodium, crospovidone, or sodium starch glycolate, said lubricant is magnesium stearate or sodium stearyl fumarate, and said glidant is colloidal silica.

In one embodiment, said coupling agent is polyvinylpyrrolidone, said filler is microcrystalline cellulose or siliconized microcrystalline cellulose, said disintegrant is croscarmellose sodium or crospovidone, said lubricant is magnesium stearate or sodium stearyl fumarate, and said glidant is colloidal silicon dioxide.

In one embodiment, said coupling agent is hydroxypropyl methylcellulose, said excipient is microcrystalline cellulose, siliconized microcrystalline cellulose, or lactose, said disintegrant is croscarmellose sodium, crospovidone, or sodium starch glycolate, said lubricant is magnesium stearate or sodium stearyl fumarate, and said glidant is colloidal silica.

In one embodiment, said coupling agent is hydroxypropyl cellulose, said filler is microcrystalline cellulose, siliconized microcrystalline cellulose or lactose, said disintegrant is croscarmellose sodium, and said lubricant is magnesium stearate or sodium stearyl fumarate.

In one embodiment, said coupling agent is polyvinylpyrrolidone, said lubricant is magnesium stearate, and said glidant is colloidal silicon dioxide.

Cooking method

In one embodiment, the pharmaceutical composition or fixed dose combination formulation disclosed herein is prepared by wet granulation (high shear and/or fluid bed). Granulation is a method in which the binding agent(s) are added to a solvent to prepare a solution of the binding agent, and then added to or directly applied to the granulator to obtain wet granules. The wet granulation method includes the following steps:

(1) adding a glucokinase activator active pharmaceutical ingredient (optionally HMS5552) and a partner drug (optionally rosiglitazone or pioglitazone) to the granulator;

(2) adding optional filler(s) (eg, microcrystalline cellulose, siliconized microcrystalline cellulose or lactose) to the mixture obtained in step (1);

(3) adding an optional disintegrant(s) (eg, croscarmellose sodium, crospovidone, or sodium starch glycolate) to the mixture obtained in step (1) or (2);

(4) for high shear granulation, adding the binding agent(s) (for example, hydroxypropyl cellulose, polyvinylpyrrolidone or hydroxypropyl methylcellulose) to pure water to prepare a solution of the binding agent, and then adding it to the granulating granulator with stirring. For fluid bed granulation, two active pharmaceutical ingredients are added to the fluid bed, and the binder solution, which is an aqueous solution prepared from the binder(s) and pure water, is sprayed into the fluid bed with compressed air;

(5) sizing the obtained wet granules in a suitable mill to obtain wet granules of a suitable size;

(6) for granules obtained by high shear granulation, drying on a tray in an oven or drying in a fluid bed dryer; and for granules obtained by granulation in a fluidized bed, drying in a fluidized bed;

(7) grinding the granules in a suitable grinder to obtain dry granules of a suitable size;

(8) adding in a suitable mixer the optional excipient(s) (diluent(s) such as microcrystalline cellulose) and the optional disintegrant(s) (eg croscarmellose sodium) and mixing with the dry granules;

(9) adding lubricant(s) (eg, magnesium stearate and sodium stearyl fumarate) to the mixture from step (8);

(10) adding optional glidant(s) (eg, colloidal silicon dioxide) to the mixture from step (9);

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

(12) if necessary, applying a film coating on the obtained tablets.

In another embodiment, the pharmaceutical composition disclosed in this application, prepared by wet granulation (high shear and/or in a fluidized bed). Granulation is a method in which the binding agent(s) and the second active ingredient are added to a solvent to prepare a solution (or suspension) of the binding agent, and then added to a granulator to obtain wet granules. The wet granulation method includes the following steps:

(1) adding a glucokinase activator active pharmaceutical ingredient (optionally HMS5552) to the granulator;

(2) adding optional filler(s) (eg, microcrystalline cellulose, siliconized microcrystalline cellulose, or lactose) to the mixture from step (1);

(3) adding an optional disintegrant(s) (eg, croscarmellose sodium, crospovidone, or sodium starch glycolate) to the mixture obtained in step (1) or (2);

(4) for high shear granulation, adding the binder(s) (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, or hydroxypropyl methylcellulose) to the solvent to uniformly disperse or dissolve, and then add the second active ingredient (preferably rosiglitazone or pioglitazone) in a certain amount to disperse or dissolution to form a homogeneous binder system. The system is added to the granulator for granulation with stirring. For fluid bed granulation, an active pharmaceutical ingredient such as HMS5552 is added to the fluid bed, and the binder system, which is a solution or suspension prepared from the binder(s) and pure water or an organic solvent (such as ethanol), is sprayed into fluidized bed with compressed air;

(5) sizing the obtained wet granules in a suitable mill to obtain wet granules of a suitable size;

(6) for granules obtained by high shear granulation, drying on a tray in an oven or drying in a fluid bed dryer; and for granules obtained by granulation in a fluidized bed, drying in a fluidized bed;

(7) grinding the granules in a suitable grinder to obtain dry granules of a suitable size;

(8) in a suitable mixer, adding optional filler(s) (diluent(s) such as microcrystalline cellulose) and optional disintegrant(s) (eg croscarmellose sodium), and mixing with dry granules;

(9) adding lubricant(s) (eg, magnesium stearate and sodium stearyl fumarate) to the mixture from step (8);

(10) optionally adding optional glidant(s) (eg colloidal silica) to the mixture from step (9);

(11) filling the mixture of lubricated granules from steps (9) or (10) into vials, pouches or capsules, or compressing them into a tablet of the desired shape; and

(12) if necessary, applying a film coating on the obtained tablets.

The dry processing method (direct pressing or dry granulation) includes the following steps:

(1) adding a glucokinase activator active pharmaceutical ingredient (optionally HMS5552) and a partner drug (preferably rosiglitazone or pioglitazone) to a mixing tank;

(2) adding optional filler(s) (eg, microcrystalline cellulose, siliconized microcrystalline cellulose, or lactose) to the mixture in step (1);

(3) adding optional binding agent(s) (eg, hydroxypropylcellulose, polyvinylpyrrolidone, or hydroxypropylmethylcellulose) to the mixture obtained in step (1) or (2);

(4) adding lubricant(s) or glidant(s) to the mixture from step (3), and mixing;

(5) filling the mixture from step (4) into vials, bags or capsules, compressing the mixture from step (4) into a tablet of the desired shape, or processing the mixture from step (4) with a roller compressor;

(6) pre-mixing the mixture from step (3) followed by roller rolling if the mixture was treated in step (4) with a roller compressor; if necessary, grinding the granules in a suitable mill to obtain granules of the required size;

(7) in a suitable mixer, adding optional diluent(s) to the granules obtained in step (6) to improve compaction characteristics;

(8) adding optional disintegrant(s) (eg, croscarmellose sodium, crospovidone, or sodium starch glycolate) to the mixture from step (7);

(9) adding optional lubricant(s) or glidant(s) to the mixture from step (8);

(10) filling the mixture of lubricated granules from step (9) into vials, sachets or capsules, or compressing it into a tablet of the desired shape; and

(11) if necessary, applying a film coating to the tablets obtained in step (5) or step (10).

In one embodiment disclosed herein, the glucokinase activator in the pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation disclosed herein is in the form of a solid dispersion which can be prepared by a process selected from the group consisting of a spray drying process. , a fluidized bed drying method, a solvent method, a melt extrusion method, and the like.

One of the embodiments disclosed in this application is a process for preparing a solid dispersion of a glucokinase activator by a spray drying process, which includes the steps of:

(1) preparing a solution for spray drying, including dissolving the polymeric carrier and glucokinase activator (as an option, HMS5552) in a solvent;

(2) spray drying, including adjusting the temperature of the inlet air, the amount of inlet air, the flow rate and pressure of the atomized air stream, the spray rate of the solution, and the like.

In the embodiment disclosed herein, the solvent used to prepare the solid dispersion of the glucokinase activator includes, but is not limited to, alkanols, esters, nitriles, cycloalkanes, aromatic hydrocarbons, ketones, and the like. In particular, the solvent is selected from the group consisting of 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 the treatment and/or prevention of diseases

Another embodiment disclosed in this application relates to a method or use of a composition or formulation (preferably a fixed dose combination pharmaceutical composition or a fixed dose combination formulation) containing a glucokinase activator described in this application for the treatment and/or prevention of the following diseases and medical disorders, especially one or more diseases selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose and hyperglycemia; comprising administering to a subject a therapeutically effective amount of a composition or formulation (preferably a fixed dose combination pharmaceutical composition or a fixed dose combination formulation) disclosed herein:

- prevention, retardation of progression, delay or treatment of a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight , obesity and metabolic syndrome; or

- improvement in glycemic control and/or reduction in fasting plasma glucose, postprandial plasma glucose and/or plasma glycated hemoglobin HbA1c; or

- preventing, slowing down, delaying or canceling the progression from impaired glucose tolerance, insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus; or

- prevention, retardation of progression, delay or treatment of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts, as well as micro- and macrovascular diseases such as nephropathy, retinopathy, neuropathy, learning and memory dysfunction, neurodegenerative or cognitive impairment, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcers, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusion, cardiomyopathy, heart failure, heart failure rhythm and vascular restenosis; or

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

- preventing, slowing down, delaying or treating degeneration of pancreatic beta cells and/or reduction in the functionality of pancreatic beta cells and/or improving and/or restoring or protecting the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion; or

- to prevent, slow down, delay or treat diseases or conditions associated with abnormal accumulation of hepatic or ectopic fat; or

- maintaining and/or improving insulin sensitivity and/or for the treatment or prevention of hyperinsulinemia and/or insulin resistance; or

- to prevent, slow down the progression, delay or treat diabetes for the first time after transplantation (NODAT) and / or post-transplant metabolic syndrome (PTMS); or

- to prevent, delay or reduce complications associated with NODAT and/or PTMS, including micro- and macrovascular disease and events, graft rejection, infection and death; or

- for the treatment of hyperuricemia and conditions associated with hyperuricemia; or

- non-alcoholic fatty liver disease, non-alcoholic steatohepatitis.

The present invention also provides a method of treating type II diabetes by oral administration of a therapeutically effective amount of a pharmaceutical composition or formulation (alternatively a fixed dose combination pharmaceutical composition or a fixed dose combination formulation) comprising a glucokinase activator and a drug partner described herein. application, for a subject in need of treatment. In one embodiment, the subject in need of treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet. A composition or formulation (alternatively, a fixed dose combination pharmaceutical composition or a fixed dose combination formulation) containing the glucokinase activator described herein can be administered once daily (QD), twice daily (BID), or three times a day (TID).

In particular, the present invention relates to the following specific embodiments.

Embodiment I: Glucokinase activator + PPAR receptor activator (eg, rosiglitazone)

Solution 1. Pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation containing:

(a) a glucokinase activator, which is a compound represented by the following formulas, or a pharmaceutically acceptable salt thereof, an isotopically labeled analog thereof, a crystalline form, a hydrate, a solvate, or a diastereomeric or enantiomeric form,

HMS5552

HMS5552

(b) a PPAR receptor activator; and

(c) one or more excipients;

while the aforementioned drugs (a) and (b) are used simultaneously, separately or sequentially.

Solution 2 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 1, wherein the weight ratio of glucokinase activator to PPAR receptor activator is from about 50:1 to 1:10, preferably from about 25:1 to 1:5, or more preferably about 1:10, about 1:5, about 1:2, about 1.67:1, about 3.33:1, about 5:1, about 6.25:1, about 6.67:1, about 12.5:1, about 18.75:1, or about 25:1.

Solution 3. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 1 or 2, wherein the glucokinase activator is about 1-98% by weight; and the PPAR receptor activator is about 1-25 wt%.

Solution 4. Pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation according to any of solutions 1-3, wherein the glucokinase activator is a compound HMS5552 represented by the following formula, or a pharmaceutically acceptable salt, isotopically labeled analog, its crystalline form, hydrate, solvate , diastereomeric or enantiomeric form,

.

.

Solution 5 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-4, wherein the glucokinase activator is in the form of a solid dispersion.

Solution 6 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 5, wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier and the polymeric carrier is a copolymer of methacrylic acid type A (anionic copolymer of methacrylic acid and methyl methacrylate (1 :1)), preferably Eudragit or alternatively Eudragit-L100.

Solution 7. Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 6, wherein the weight ratio of glucokinase activator to polymeric carrier is from about 1:10 to 10:1, alternatively from 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 about 6:5, or alternatively about 1:1, about 2:3, about 3:4, about 4:5, or about 5:6, or any range in between.

Solution 8. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-7, wherein the PPAR receptor activator is selected from the group consisting of rosiglitazone (or rosiglitazone maleate), pioglitazone (or pioglitazone hydrochloride), chiglitazar, and their pharmaceutically acceptable salt.

Solution 9. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-8, wherein the glucokinase activator is present at a dose (optionally, a single dose) in the range of about 1 mg to 200 mg, alternatively, about 25 mg to about 100 mg, and preferably the dose (alternatively, a single dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg, or about 100 mg.

Solution 10 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-9, wherein the PPAR receptor activator is present at a dose (alternatively, a single dose) in the range of about 1 mg to 50 mg, or as variant, from about 4 mg to 15 mg, alternatively, the dose (alternatively, a single dose) of the PPAR receptor activator is about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 12 mg , about 14 mg or about 15 mg, or more alternatively, about 4 mg or about 15 mg; alternatively, the PPAR receptor activator is rosiglitazone or pioglitazone.

Solution 11. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-10, wherein one or more of the excipients is selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavors, sweeteners, colorants and coating agent(s).

Solution 12 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-11, which is a tablet.

Solution 13 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 12, which is a coated tablet.

Solution 14 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 13, wherein the coated tablet is a film-coated tablet and the film-forming agent comprises:

film-forming substrate(s) such as hypromellose, hydroxypropyl methylcellulose, or a mixture thereof;

optional plasticizer(s) such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or a mixture thereof;

optional dye(s) such as iron oxide red, iron oxide yellow, or a mixture thereof;

an optional opacifying agent(s) such as titanium dioxide, and

optional glidant(s).

Solution 15 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 14, wherein the coated tablet is a film-coated tablet and the film-forming agent is Opadry.

Solution 16 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-15, comprising (by weight):

about 1 to 98% glucokinase activator (as a carianth, HMS5552 or an isotopically labeled analog thereof, or a pharmaceutically acceptable salt thereof), as a carianth, HMS5552, as a carianth, a solid dispersion of HMS5552, as a carianth, a solid dispersion containing HMS5552, and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

about 0.1-25% rosiglitazone;

about 0-90% filler(s);

about 1-25% binding agent(s);

about 0-15% disintegrant(s);

about 0.1-10% lubricant(s);

about 0-3% glidant(s); and

about 0-5% agent(s) for coating.

Solution 17. Pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of Solution 16, comprising (by weight):

- about 1-75% glucokinase activator (as a carianth, HMS5552 or its isotopically labeled analogue, or a pharmaceutically acceptable salt), as a carianth, HMS5552, as a carianth, a solid dispersion of HMS5552, as a carianth, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 0.1-15% rosiglitazone;

- about 0-90% filler(s);

- about 1-10% binding agent(s);

- about 1-10% disintegrant(s);

- about 0.1-5% lubricant(s);

- about 0-3% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 18 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 16, where the doses (as carianth, unit doses) of the ingredients are (by weight):

- about 25 mg, about 50 mg, about 75 mg or about 100 mg of glucokinase activator, or, as a carian, HMS5552;

- about 2 mg, about 4 mg or about 8 mg of rosiglitazone;

- about 0-90% filler(s);

- about 1-25% of the binding agent (agents);

- about 1-15% disintegrant(s);

- about 0.1-10% lubricant(s);

- about 0-3% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 19. The pharmaceutical combination, pharmaceutical composition, or fixed-dose combination formulation from Solution 18 (the fixed-dose combination formulation as a carianth is a 25 mg HMS5552/4 mg rosiglitazone tablet or an appropriate amount of rosiglitazone maleate) comprising the components in the following amounts ( by weight):

- about 25 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate;

- about 0-75% filler(s);

- about 2-8% binding agent(s);

- about 1-5% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 20: The pharmaceutical combination, pharmaceutical composition, or fixed-dose combination formulation from Solution 18 (the fixed-dose combination formulation as a carianth is a 50 mg HMS5552/4 mg rosiglitazone tablet or an appropriate amount of rosiglitazone maleate) comprising the components in the following amounts ( by weight):

- about 50 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate;

- about 0-75% filler(s);

- about 2-8% binding agent(s);

- about 1-5% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 21. The pharmaceutical combination, pharmaceutical composition, or fixed-dose combination formulation from Solution 18 (the fixed-dose combination formulation as a carianth is a 75 mg HMS5552/4 mg rosiglitazone tablet or an appropriate amount of rosiglitazone maleate) comprising the components in the following amounts ( by weight):

- about 75 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate;

- about 0-75% filler(s);

- about 2-8% binding agent(s);

- about 1-5% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 22. The pharmaceutical combination, pharmaceutical composition, or fixed-dose combination formulation from Solution 18 (the fixed-dose combination formulation as a carianth is a 100 mg HMS5552/4 mg rosiglitazone tablet or an appropriate amount of rosiglitazone maleate) comprising the components in the following amounts ( by weight):

- about 100 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate;

- about 0-75% filler(s);

- about 2-8% binding agent(s);

- about 1-5% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 23 Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 18 containing about 50 mg of solid dispersion, about 5.30 mg of rosiglitazone maleate, about 177.20 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7 .50 mg of croscarmellose sodium, about 2.50 mg of magnesium stearate and about 7.50 mg of Opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit-L100 and contains about 25 mg of HMS5552.

Solution 24 Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 18 containing about 100 mg of solid dispersion, about 5.30 mg of rosiglitazone maleate, about 127.20 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7 .50 mg of croscarmellose sodium, about 2.50 mg of magnesium stearate and about 7.50 mg of Opadry, while the solid dispersion includes about 1:1 of HMS5552 and Eudragit-L100 and contains about 50 mg of HMS5552.

Solution 25 Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 18 containing about 150 mg of solid dispersion, about 5.30 mg of rosiglitazone maleate, about 123.70 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 9 00 mg croscarmellose sodium, about 3.00 mg magnesium stearate, and about 9.00 mg Opadry, wherein the solid dispersion includes about 1:1 HMS5552 and Eudragit-L100 and contains about 75 mg HMS5552.

Solution 26 Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 18 containing about 200 mg of solid dispersion, about 5.30 mg of rosiglitazone maleate, about 63.09 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 9 00 mg croscarmellose sodium, about 3.00 mg magnesium stearate and about 9.00 mg Opadry, wherein the solid dispersion comprises about 1:1 HMS5552 and Eudragit-L100 and contains about 100 mg HMS5552.

Solution 27 Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 18 containing about 50 mg of solid dispersion, about 5.30 mg of rosiglitazone maleate, about 177.20 mg of microcrystalline cellulose, about 7.50 mg of polyvinylpyrrolidone, about 7 .50 mg of croscarmellose sodium, about 2.50 mg of magnesium stearate and about 7.50 mg of Opadry, while the solid dispersion includes about 1:1 HMS5552 and Eudragit-L100 and contains about 25 mg of HMS5552.

Solution 28. A method of preparing a pharmaceutical combination, a pharmaceutical composition or a fixed dose combination formulation according to any of Solutions 1-27, including adding active ingredients to one or more granulation excipients, as a carian, followed by filling the resulting mixture of granules into a vial, sachet or capsule, or compression into a tablet of the desired shape; or, alternatively, further coating the resulting tablet.

Solution 29 A process for preparing a pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation according to Solution 28, wherein the preparation is carried out by wet granulation (high shear and/or fluid bed) or dry processing (direct compression or dry granulation).

Solution 30 A method of preparing a pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation according to any of Solutions 28-29, wherein the glucokinase activator is prepared in the form of a solid dispersion.

Solution 31 A process for preparing a pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation according to any of Solutions 28-30, wherein the glucokinase activator and the second or more active ingredients can also be formulated together in the form of a combined solid dispersion (i.e., a solid dispersion containing two or more active ingredients).

Solution 32 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-27, which is used to prevent, retard the progression, delay, or treat one or more metabolic disorders selected from the group consisting of type I diabetes, type II diabetes type, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or aggravating the complications of diabetes mellitus.

Solution 33: A method of preventing, slowing progression, 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, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or aggravating complications of diabetes mellitus, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any one of Solutions 1-27.

Solution 34 Use of the pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-27 in the manufacture of a medicament for the prevention, retardation of progression, delay, or treatment of 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, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c.

Embodiment II: Glucokinase activator + PPAR receptor activator (eg pioglitazone)

Solution 1. Pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation containing:

(a) a glucokinase activator, which is a compound represented by the following formulas, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, diastereomeric or enantiomeric form thereof,

HMS5552

HMS5552

(b) a PPAR receptor activator; and

(c) one or more excipients;

while the aforementioned drugs (a) and (b) are used simultaneously, separately or sequentially.

Solution 2 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 1, wherein the weight ratio of glucokinase activator to PPAR receptor activator is from about 50:1 to 1:10, as a carian, from about 25:1 to 1: 5, or, still as a carian, about 1:10, about 1:5, about 1:2, about 1.67:1, about 3.33:1, about 5:1, about 6.25:1, about 6.67:1, about 12.5:1, about 18.75:1, or about 25:1.

Solution 3. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 1 or 2, wherein the glucokinase activator is about 1-95% by weight; and the PPAR receptor activator is about 0.1-25 wt%.

Solution 4 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any one of Solutions 1-3, wherein the glucokinase activator is HMS5552 compound represented by the following formula, or a pharmaceutically acceptable salt, isotopically labeled analogue thereof, crystalline form, hydrate, solvate, or diastereomeric or enantiomeric form,

.

.

Solution 5 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-4, wherein the glucokinase activator is in the form of a solid dispersion.

Solution 6 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 5, wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier and the polymeric carrier is a copolymer of methacrylic acid type A (anionic copolymer of methacrylic acid and methyl methacrylate (1 :1)), as a carian, Eudragit or, as a carian, Eudragit-L100.

Solution 7. Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 6, wherein the weight ratio of glucokinase activator to polymeric carrier is about 1:10 to about 10:1, as a carian, about 1:9 to about 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 about 6:5, or, as a carian, about 1:1, about 2:3, about 3:4, about 4:5, or about 5:6, or any range in between.

Solution 8. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-7, wherein the PPAR receptor activator is selected from the group consisting of rosiglitazone (or rosiglitazone maleate), pioglitazone (or pioglitazone hydrochloride), chiglitazar, and their pharmaceutically acceptable salt.

Solution 9. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any one of Solutions 1-8, wherein the glucokinase activator is present at a dose (as carant, unit dose) in the range of about 1 mg to about 200 mg, as carian, about 25 mg to about 100 mg, or, as a carian, wherein the dose (as a carian, unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg, or about 100 mg.

Solution 10. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any one of Solutions 1-9, wherein the PPAR receptor activator is present at a dose (as carianth, unit dose) in the range of about 1 mg to 50 mg, or, in as a carian, about 4 mg to 15 mg, as a carian, the dose (as a carian, unit dose) of a PPAR receptor activator is about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 12 mg, about 14 mg, or about 15 mg, or, alternatively, about 4 mg, or about 15 mg; as a carian, the PPAR receptor activator is rosiglitazone or pioglitazone.

Solution 11. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-10, wherein one or more of the excipients is selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavors, sweeteners, colors and coating agents.

Solution 12 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-11, which is a tablet.

Solution 13 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 12, which is a coated tablet.

Solution 14 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 13, wherein the coated tablet is a film-coated tablet and the film-forming agent contains:

film-forming substrate(s) such as hypromellose, hydroxypropyl methylcellulose, or a mixture thereof;

optional plasticizer(s) such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or a mixture thereof;

optional dye(s) such as iron oxide red, iron oxide yellow, or a mixture thereof;

an optional opacifying agent(s) such as titanium dioxide, and

optional glidant(s).

Solution 15 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 14, wherein the coated tablet is a film-coated tablet and the film-forming agent is Opadry.

Solution 16 The pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of any of Solutions 1-15, comprising (by weight):

about 1 to 95% glucokinase activator, as a carian, HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

about 1-65% pioglitazone or pioglitazone hydrochloride;

about 0-80% filler(s);

about 1-25% binding agent(s);

about 0-15% disintegrant(s);

about 0.1-10% lubricant(s);

about 0-3% glidant(s); and

about 0-5% agent(s) for coating.

Solution 17. Pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of Solution 16, containing (by weight):

about 1-85% glucokinase activator (as a carianth, HMS5552 or its isotopically labeled analogue, or a pharmaceutically acceptable salt), as a carianth, HMS5552, as a carianth, a solid dispersion of HMS5552, as a carianth, a solid dispersion containing HMS5552 and a polymeric a carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

about 5-25% pioglitazone or pioglitazone hydrochloride;

about 0-90% filler(s);

about 1-25% binding agent(s);

about 0-15% disintegrant(s);

about 0.1-10% lubricant(s), and

approximately 0-3% glidant(s).

Solution 18 The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 16, where the doses (as carianth, unit doses) of the ingredients are (by weight):

- about 25 mg, about 50 mg, about 75 mg or about 100 mg of glucokinase activator, or, as a carian, HMS5552;

- about 15 mg, about 30 mg or about 45 mg of pioglitazone, or an amount of pioglitazone hydrochloride that allows you to get the specified amount of pioglitazone;

- about 0-90% filler(s);

- about 1-25% of the binding agent (agents);

- about 0-15% disintegrant(s);

- about 0.1-10% lubricant(s);

- about 0-3% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 19. Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation from Solution 18 (fixed dose combination formulation as a carianth, is a 25 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride) comprising the components in the following amounts ( by weight):

- about 25 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride;

- about 0-90% filler(s);

- about 1-25% of the binding agent (agents);

- about 1-8% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 20. Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation from Solution 18 (fixed dose combination formulation as carianth, is a 50 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride) comprising the components in the following amounts ( by weight):

- about 50 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride;

- about 0-90% filler(s);

- about 1-25% of the binding agent (agents);

- about 1-8% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 21. Pharmaceutical combination, pharmaceutical composition, or fixed-dose combination formulation from Solution 18 (fixed-dose combination formulation as carianth, is a 75 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride), comprising the components in the following amounts ( by weight):

- about 75 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride;

- about 0-90% filler(s);

- about 1-25% of the binding agent (agents);

- about 1-8% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 22. Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation from Solution 18 (fixed dose combination formulation as a carianth, is a 100 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride) comprising the components in the following amounts ( by weight):

- about 100 mg of HMS5552, as a carian, a solid dispersion of HMS5552, as a carian, a solid dispersion containing HMS5552 and a polymeric carrier, or, as a carian, a solid dispersion containing about 1:1 HMS5552 and Eudragit-L100;

- about 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride;

- about 0-90% filler(s);

- about 1-25% of the binding agent (agents);

- about 1-8% disintegrant(s);

- about 0.5-3% lubricant(s);

- about 0-0.5% glidant(s); and

- about 0-5% agent(s) for coating.

Solution 23 Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 18 containing about 150 mg of solid dispersion, about 15.91 mg of pioglitazone hydrochloride, about 113.09 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 9 00 mg croscarmellose sodium, about 3.00 mg magnesium stearate, and about 9.00 mg Opadry, wherein the solid dispersion includes about 1:1 HMS5552 and Eudragit-L100 and contains about 75 mg HMS5552.

Solution 24 Pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of Solution 18 containing about 200 mg solid dispersion, about 15.91 mg pioglitazone hydrochloride, about 73.09 mg microcrystalline cellulose, about 9.00 mg hydroxypropyl cellulose, about 9 00 mg croscarmellose sodium, about 3.00 mg magnesium stearate and about 9.00 mg Opadry, wherein the solid dispersion comprises about 1:1 HMS5552 and Eudragit-L100 and contains about 100 mg HMS5552.

Solution 25 Pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of Solution 18 containing about 100 mg solid dispersion, about 15.91 mg pioglitazone hydrochloride, about 260.09 mg microcrystalline cellulose, about 12.00 mg hydroxypropyl cellulose, about 8 00 mg croscarmellose sodium, about 4.00 mg magnesium stearate and about 12.00 mg Opadry, wherein the solid dispersion comprises about 1:1 HMS5552 and Eudragit-L100 and contains about 50 mg HMS5552.

Solution 26 Pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of Solution 18 containing about 50 mg solid dispersion, about 15.91 mg pioglitazone hydrochloride, about 216.09 mg microcrystalline cellulose, about 9.00 mg hydroxypropyl cellulose, about 6 00 mg croscarmellose sodium, about 3.00 mg magnesium stearate and about 9.00 mg Opadry, with the solid dispersion comprising about 1:1 HMS5552 and Eudragit-L100 and containing about 25 mg HMS5552.

Solution 27. A method of preparing a pharmaceutical combination, a pharmaceutical composition or a fixed dose combination formulation according to any of solutions 1-26, including adding active ingredients to one or more granulation excipients, as an option, further filling the resulting mixture of granules into a vial, sachet or capsule, or compression into a tablet of the desired shape; still, as an option, further coating on the resulting tablet.

Solution 28 A process for preparing a pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation according to Solution 27, wherein preparation is carried out by wet granulation (high shear and/or fluid bed) or dry processing (direct compression or dry granulation).

Solution 29 A method of preparing a pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation according to any of Solutions 27-28, wherein the glucokinase activator is prepared in the form of a solid dispersion.

Solution 30 A method of preparing a pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation according to any of Solutions 27-29, wherein the glucokinase activator and the second or more active ingredients can also be formulated together in the form of a combined solid dispersion (i.e., a solid dispersion containing two or more active ingredients).

Solution 31. The pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-26, which is used to treat or prevent, slow the progression, delay, or treat 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, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or to improve blood glucose control and/or reduce fasting plasma glucose, postprandial plasma glucose and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or aggravating the complications of diabetes mellitus.

Solution 32. A method of treating or preventing, slowing the progression, 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, hyperglycemia after food intake, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or aggravating the complications of diabetes mellitus, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any one of Solutions 1-26.

Solution 33 Use of the pharmaceutical combination, pharmaceutical composition, or fixed dose combination formulation of any of Solutions 1-26 in the manufacture of a medicament for the treatment or prevention, retardation of progression, delay, or treatment of one or more metabolic disorders selected from the group consisting of diabetes type I, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma 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 various modifications and substitutions made based on the technology disclosed in this application are within the protection scope of the present invention.

Examples

Preparation of the glucokinase activator combination tablet

The chemicals used in this specification are available from companies such as Shin-Etsu, Japan; Evonik, Germany; J.T. Baker, USA; SCR, China; Ashland, USA; US FMC; JRS, Germany; Colorcon, USA; Capsugel, BASF, Zhenxing, China; etc. Production equipment, analytical testing tools, etc. available from companies such as Sartorius, Nikon, Sympatec, Bruker, Gea Niro, Korsch, Erweka, Agilent, Quadro Engineering, Canada; Waters, USA; TA, USA; SOTAX, Switzerland; Mettler Toledo Instrument, Newark, Delaware.

I. Preparation of a solid dispersion of glucokinase activator.

1.1 Preparation of solid dispersion solution for spray drying

Example 1A (weight ratio of active ingredients to polymeric carriers is 1:9)

6.75 g of Eudragit-L100 (Evonik, Germany) was weighed out and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 0.75 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 2A (weight ratio of active ingredients to polymeric carriers is 3:7)

5.25 g Eudragit-L100 (Evonik, Germany) was weighed out and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 2.25 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 3A (weight ratio of active ingredients to polymeric carriers is 5:5)

3.75 g Eudragit-L100 (Evonik, Germany) was weighed out and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 3.75 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 4A (weight ratio of active ingredients to polymeric carriers is 7:3).

2.25 g Eudragit-L100 (Evonik, Germany) was weighed out and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 5.25 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 5A (weight ratio of active ingredients to polymeric carriers is 8:2)

1.5 g Eudragit-L100 (Evonik, Germany) was weighed out and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 6 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 6A (weight ratio of active ingredients to polymeric carriers is 9:1)

0.75 g of Eudragit-L100 (Evonik, Germany) was weighed out and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 6.75 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 7A (weight ratio of active ingredients to polymeric carriers is 6:4)

3.0 g Eudragit-L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 4.5 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 8A (weight ratio of active ingredients to polymeric carriers is 4:6)

4.5 g Eudragit-L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (J.T. Baker) with stirring. After complete dissolution, 3.0 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 50 ml solution.

Example 9A (weight ratio of active ingredients to polymeric carriers is 5:5)

187.5 g Eudragit-L100 (Evonik, Germany) was weighed and added to anhydrous ethanol (Zhenxing, China). After complete dissolution, 187.5 g of HMS5552 was added. Stirring was continued after sufficient anhydrous ethanol was added to obtain a 2500 ml solution.

1.2 Preparation of a solid dispersion of glucokinase activator

A solid dispersion of the glucokinase activator was prepared by spray drying the solution prepared above. The numbering of the obtained solid dispersion corresponds to the numbering of the above examples. Spray dryers that are suitable herein include, but are not limited to, spray dryers manufactured by Niro GEA Process Engineering Inc., Buchi Labortechnik AG, ProCept, and SPX ANHYDROUS. Spray drying can be accomplished by selecting an appropriate dry gas inlet temperature, inlet quantity, feed rate, and spray pressure so that the droplets are sufficiently dried when they reach the device wall. This can ensure that the dried droplets are substantially solid and in the form of a fine powder which will not adhere to the wall and which will not be difficult to collect in the cyclone. The resulting powder is subjected to secondary drying to ensure that the product meets the quality requirements.

Description of the manufacturing process for the preparation of a solid dispersion of glucokinase activator by spray drying.

Solid dispersions were prepared by spray drying the solution obtained in the above examples 1A-8A, where the air temperature at the inlet of the spray dryer was 90-150°C, the inlet air flow rate was 0.3-0.5 m ³ /min, the air velocity the flow rate was 15-30 l/min, and the spraying rate of the above solutions was 5-7 ml/min. Solid dispersions 1-8 were obtained by spray drying.

A solid dispersion was prepared by spray drying the solution obtained in the above example 9A, where the air temperature at the inlet of the spray dryer was 90-150°C, the flow rate of the incoming air was 20-30 kg/h, the air flow rate was 3-30 kg/ h, and the spraying rate of the above solutions was 5-200 ml/min. Solid dispersion 9 was obtained by spray drying.

Solid dispersions 1-9 were prepared in accordance with the method described above, in which:

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

II. Preparation of the combination tablet

2.1 Preparation of the combination tablet by the high shear wet granulation process

The solid dispersion of HMS5552 prepared according to the above preparation examples of the solid dispersion of glucokinase activator and partner drug was added to the high shear wet granulator. A filler (eg, microcrystalline cellulose, siliconized microcrystalline cellulose, or lactose) and a disintegrant (eg, croscarmellose sodium, crospovidone, or sodium starch glycolate) are added. A portion of the binder powder was added and mixed for 5 minutes with high shear mixing. The prepared binder solution (eg, hydroxypropylcellulose, polyvinylpyrrolidone, or hydroxypropylmethylcellulose) was added to the above dry mix with high shear mixing for 1-6 minutes to granulate. The wet granules were ground in a Comil mill to obtain wet granules of suitable size. The wet granules were dried on a tray in an oven at a temperature of about 60°C or in a fluidized bed dryer (at an inlet air temperature of 40-60°C) for 20-40 minutes. The dried material was then crushed with a grinder to obtain granules of suitable size. After milling, microcrystalline cellulose or siliconized microcrystalline cellulose (for the filler including the extragranular portion) and a disintegrant (eg croscarmellose sodium, crospovidone or sodium starch glycolate) were added to the granules and the mixture was tumbled. A lubricant (magnesium stearate or sodium stearyl fumarate) and/or optionally glidant (micronized silica gel) was then added to the mixture and thoroughly mixed. The lubricant mixture was compressed on a rotary tablet press to produce tablets (plain tablets, uncoated tablet cores) of various tablet weights and shapes corresponding to different strengths. If necessary, the resulting tablets were film-coated with Opadry® II and the weight increased by about 3%, resulting in film-coated tablets.

Example 1B: HMS5552 + rosiglitazone combination tablet (dosage: 25 mg/4 mg).

The composition of the composition Single dose, amount/mg wt.% Rosiglitazone maleate* 5.30 2.12 HMS5552 solid dispersion** 50.00 20.00 Microcrystalline cellulose 177.20 70.88 Hydroxypropylcellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00 magnesium stearate 2.50 1.00 Total weight of tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of coated tablet 257.50 -

*5.30 mg of rosiglitazone maleate is equivalent to 4 mg of rosiglitazone free base anhydrate.

** 50.00 mg HMS5552 solid dispersion contained 25 mg HMS5552.

Example 2B: HMS5552 + rosiglitazone combination tablet (dosage: 50 mg/4 mg).

The composition of the composition Single dose, amount/mg wt.% Rosiglitazone maleate* 5.30 2.12 HMS5552 solid dispersion ** 100.00 40.00 Microcrystalline cellulose 127.20 50.88 Hydroxypropylcellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00 magnesium stearate 2.50 1.00 Total weight of tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of coated tablet 257.5 -

*5.30 mg of rosiglitazone maleate is equivalent to 4 mg of rosiglitazone free base anhydride.

** 100.00 mg HMS5552 solid dispersion contained 50 mg HMS5552.

Example 3B: HMS5552 + rosiglitazone combination tablet (dosage: 75 mg/4 mg).

The composition of the composition Single dose, amount/mg wt.% Rosiglitazone maleate* 5.30 1.77 HMS5552 solid dispersion** 150.00 50.00 Microcrystalline cellulose 123.70 41.23 Hydroxypropylcellulose 9.00 3.00 Croscarmellose sodium 9.00 3.00 magnesium stearate 3.00 1.00 Total weight of tablet core 300.00 100.00 Opadry 9.00 3.00 Total weight of coated tablet 309.00 -

* 5.30 mg of rosiglitazone maleate is equivalent to 4 mg of rosiglitazone free base anhydrate.

**150.00 mg HMS5552 solid dispersion contained 75 mg HMS5552.

Example 4B: HMS5552 + rosiglitazone combination tablet (dosage: 100 mg/4 mg).

The composition of the composition Single dose, amount/mg wt.% Rosiglitazone maleate* 5.30 1.77 HMS5552 solid dispersion** 200.00 66.67 Microcrystalline cellulose 73.70 24.57 Hydroxypropylcellulose 9.00 3.00 Croscarmellose sodium 9.00 3.00 magnesium stearate 3.00 1.00 Total weight of tablet core 300.00 100.00 Opadry 9.00 3.00 Total weight of coated tablets 309.00 -

*5.30 mg of rosiglitazone maleate is equivalent to 4 mg of rosiglitazone free base anhydrate.

** 200.00 mg HMS5552 solid dispersion contained 100 mg HMS5552.

Example 5B: HMS5552 + pioglitazone combination tablet (dosage: 75 mg/15 mg).

The composition of the composition Single dose, amount/mg wt.% Pioglitazone Hydrochloride* 15.91 5.30 HMS5552 solid dispersion** 150.00 50.00 Microcrystalline cellulose 113.09 37.70 Hydroxypropylcellulose 9.00 3.00 Croscarmellose sodium 9.00 3.00 magnesium stearate 3.00 1.00 Total weight of tablet core 300.00 100.00 Opadry 9.00 3.00 Total weight of coated tablet 309.00 -

* 15.91 mg pioglitazone hydrochloride is equivalent to 15 mg pioglitazone free base anhydrate.

** 150.00 mg HMS5552 solid dispersion contained 75 mg HMS5552.

Example 6B: HMS5552 + pioglitazone combination tablet (100 mg/15 mg dosage).

The composition of the composition Single dose, amount/mg wt.% Pioglitazone Hydrochloride* 15.91 5.30 HMS5552 solid dispersion** 200.00 66.67 Microcrystalline cellulose 63.09 21.03 Hydroxypropylcellulose 9.00 3.00 Croscarmellose sodium 9.00 3.00 magnesium stearate 3.00 1.00 Total weight of tablet core 300.00 100.00 Opadry 9.00 3.00 Total weight of coated tablet 309.00

* 15.91 mg pioglitazone hydrochloride is equivalent to 15 mg pioglitazone free base anhydrate.

** 200.00 mg HMS5552 solid dispersion contained 100 mg HMS5552;

2.2 Preparation of the combination tablet by wet granulation in a fluidized bed.

The solid dispersion of HMS5552 prepared according to the above preparation examples of the solid dispersion of the glucokinase activator and partner drug was added to the fluid bed granulator. An optional filler (eg, microcrystalline cellulose) was added. The prepared binder solution (for example, polyvinylpyrrolidone) was sprayed into the mixture in a fluidized bed for 20-60 minutes to granulate, and then drying was continued in a fluidized bed dryer (with an air inlet temperature of 40-60°C). The dried material was then crushed with a grinder to obtain granules of suitable size. After milling, microcrystalline cellulose or siliconized microcrystalline cellulose (for formulation containing extragranular filler) was added to the granules, and the mixture was mixed in a drum mixer. Lubricant (magnesium stearate) and/or if necessary, glidant (micronized silica gel) was then added to the mixture and thoroughly mixed. The lubricant mixture was compressed in a rotary tablet press to produce tablets (plain tablets, uncoated tablet cores) of various tablet weights and shapes corresponding to different strengths. If necessary, the obtained tablets were film-coated and the weight increased by about 3%, resulting in film-coated tablets.

Example 7B: HMS5552 + rosiglitazone combination tablet (dosage: 25 mg/4 mg).

The composition of the composition Single dose, amount/mg wt.% Rosiglitazone maleate* 5.30 2.12 HMS5552 solid dispersion** 50.0 20.0 Microcrystalline cellulose 177.20 70.88 Polyvinylpyrrolidone 7.50 3.00 Croscarmellose sodium 7.50 3.00 magnesium stearate 2.50 1.00 Total weight of tablet core 250.0 100.0 Opadry 7.50 3.00 Total weight of coated tablet 257.50 -

* 5.30 mg of rosiglitazone maleate is equivalent to 4 mg of rosiglitazone free base anhydrate.

** 50.00 mg HMS5552 solid dispersion contained 25 mg HMS5552.

2.3 Obtaining a combined tablet by the dry granulation method.

The solid dispersion of HMS5552 prepared according to the above preparation examples of the solid dispersion of glucokinase activator and partner drug was added to the mixing tank. Filler (eg microcrystalline cellulose) and binder (eg hydroxypropyl cellulose) were added and mixed thoroughly. The mixture was then rolled out on a roller granulator for compaction, and the resulting bar was broken and crushed in a crusher to obtain granules of a suitable size. After milling, optional microcrystalline cellulose or siliconized microcrystalline cellulose (for extragranular filler) and a disintegrant (eg, croscarmellose sodium) were added to the granules and the mixture was tumbled. A lubricant (magnesium stearate or sodium stearyl fumarate) and/or, if necessary, glidant (micronized silica gel) was then added to the mixture and thoroughly mixed. The lubricant mixture was compressed in a rotary tablet press to produce tablets (plain tablets, uncoated tablet cores) of various tablet weights and shapes corresponding to different strengths. If necessary, the resulting tablets were film-coated with Opadry® II and the weight increased by about 3%, resulting in film-coated tablets.

Example 8B: HMS5552 + pioglitazone combination tablet (dosage: 50 mg/15 mg).

The composition of the composition Single dose, amount/mg wt.% Pioglitazone Hydrochloride* 15.91 3.98 HMS5552 solid dispersion** 100.0 25.00 Microcrystalline cellulose 260.09 65.02 Hydroxypropylcellulose 12.00 3.00 Croscarmellose sodium 8.00 2.00 magnesium stearate 4.00 1.00 Total weight of tablet core 400.00 100.00 Opadry 12.00 3.00 Total weight of coated tablet 412.00 -

* 15.91 mg pioglitazone hydrochloride is equivalent to 15 mg pioglitazone free base anhydrate.

** 100.00 mg HMS5552 solid dispersion contained 50 mg HMS5552.

2.4 Preparation of the combined tablet by direct compression of the powder mixture.

The solid dispersion of HMS5552, prepared according to the above preparation examples of the solid dispersion of glucokinase activator and partner drug, was premixed until homogeneous according to the principle of geometric progression, and then added to the mixing tank. The filler (eg, microcrystalline cellulose), disintegrant (eg, croscarmellose sodium) and optional glidant (micronized silica gel) were added to the granules and mixed in a drum mixer. Then, a lubricant (magnesium stearate or sodium stearyl fumarate) was added to the mixture and further mixed thoroughly. The lubricant mixture was compressed in a rotary tablet press to produce tablets (plain tablets, uncoated tablet cores) of various tablet weights and shapes corresponding to different strengths. If necessary, the resulting tablets were film-coated with Opadry® II and the weight increased by about 3%, resulting in film-coated tablets.

The composition of the composition of the combination tablet described in the above preparation process was as follows:

Example 9B: HMS5552 + pioglitazone combination tablet (dosage: 25 mg/15 mg).

The composition of the composition Single dose, amount/mg wt.% Pioglitazone Hydrochloride* 15.91 5.30 HMS5552 solid dispersion** 50.00 16.67 Microcrystalline cellulose 216.09 72.03 Hydroxypropylcellulose 9.00 3.00 Croscarmellose sodium 6.00 2.00 magnesium stearate 3.00 1.00 Total weight of tablet core 300.00 100.00 Opadry 9.00 3.00 Total weight of coated tablet 309.00 -

* 15.91 mg pioglitazone hydrochloride is equivalent to 15 mg pioglitazone free base anhydrate.

** 50.00 mg HMS5552 solid dispersion contained 25 mg HMS5552.

III. In vitro dissolution test of a combined formulation containing a glucokinase activator.

The dissolution rate of the tablet was tested by the paddle method from the Chinese Pharmacopoeia (2015 edition). The dissolution of HMS5552 and another drug partner was tested in pH 6.8 media, respectively. After 5 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes, respectively, 5 ml samples were taken for HPLC analysis.

According to the above test procedure, several tablets with the above fixed doses and their respective individual tablets were tested for their dissolution, and the results are shown below.

Table 1 Dissolution results of the fixed dose combination tablets prepared in Example 2B. Moment of time Dissolution rate (%) 5 minutes 15 minutes 30 minutes 45 min 60 min Example 2B-HMS5552 50 mg 80.2 97.4 100.1 100.8 101.9 Example 2B-rosiglitazone 4 mg 47.1 80.4 88.5 92.3 94.0

Table 2 Dissolution results of the fixed dose combination tablets prepared in Example 3B. Moment of time Dissolution rate (%) 5 minutes 15 minutes 30 minutes 45 min 60 min Example 3B-HMS5552 75 mg 67.2 91.4 99.5 101.7 102.6 Example 3B-rosiglitazone, 4 mg 58.8 81.9 94.2 95.7 96.7

From the above dissolution results of the fixed dose combination formulations, it can be seen that the dissolution of the fixed dose combination formulations disclosed herein satisfies the requirement for an immediate release formulation.

IV. Physical properties of combination formulations containing glucokinase activator

According to the relevant instruments and methods described in the Pharmacopoeia, the physical properties of several tablets with the above fixed doses were tested. The results are described below.

Table 3. Physical properties of the fixed dose combination tablet cores prepared in the various examples. Ingredient Dosage (HMS5552 / rosiglitazone), mg 25/4 50/4 75/4 100/4 25/4 Relevant example Example 1B Example 2B Example 3B Example 4B Example 7B Tablet form Round, doubly convex Round, doubly convex Round, doubly convex Round, doubly convex Round, doubly convex Tablet core size, mm 9.00 9.00 9.00 9.00 9.00 Color White White White White White Mass / mg 250 250 300 300 250 Strength / CR (average value) ≥ 7 ≥ 7 ≥ 7 ≥ 7 ≥7 Disintegration time (min) ≤10 ≤10 ≤10 ≤10 ≤10 Abrasion, % ≤0.5 ≤0.5 ≤0.5 ≤0.5 ≤0.5

Table 4. Physical properties of fixed dose combination tablet cores prepared in various examples Ingredient Dosage (HMS5552 / pioglitazone), mg 75/15 100/15 50/15 25/15 Relevant example Example 5B Example 6B Example 8B Example 9B Tablet form Round, doubly convex Round, doubly convex Round, doubly convex Round, doubly convex Tablet core size, mm 9.00 9.00 9.00 9.00 Color White White White White Mass / mg 300 300 400 300 Strength / CR (average value) ≥10 ≥10 ≥10 ≥10 Disintegration time (min) ≤10 ≤10 ≤10 ≤10 Abrasion, % ≤0.5 ≤0.5 ≤0.5 ≤0.5

V. Study of the pharmacodynamics of combined formulations containing a glucokinase activator.

Example 1C

Investigation of the effect of a combination of glucokinase activator and partner drug on glucose/sucrose tolerance in normal mice.

In normal male C57BL/6J mice, after fasting for 6 hours, the vehicle control, 20 mg/kg rosiglitazone, or a combination of 10 mg/kg HMS5552 and 20 mg/kg rosiglitazone, respectively, was administered orally; and 1 hour later, 2 g/kg glucose was administered orally. Blood was taken from the tail vein before drug administration (-60 minutes), before glucose administration (0 minutes), and 15, 30, 60 and 120 minutes after glucose administration, and whole blood glucose was determined. Analyzed the area under the curve of glucose from 0 to 120 minutes (AUC0-120 min, mmol/l*m), and compared with the group, which was given a control solvent. The results showed that the hypoglycemic effect of the combination of 10 mg/kg HMS5552 and 20 mg/kg rosiglitazone significantly exceeded the effect of 20 mg/kg rosiglitazone alone, with a statistically significant difference with P<0.001.

Rosiglitazone, an insulin sensitizer belonging to the thiazolidinedione class, is a peroxisome proliferator-activated receptor (PPAR) activator that has the effect of lowering blood glucose by increasing the sensitivity of skeletal muscle, liver, and adipose tissue to insulin, and has a good clinical effect in non-alcoholic steatohepatitis. HMS5552, a novel glucokinase activator, improves pancreatic islet function in patients with type 2 diabetes, promotes incretin secretion, reduces insulin resistance, and has a dual therapeutic effect on lowering fasting and postprandial blood glucose. For patients who fail to control blood glucose with a PPAR activator and patients with diabetes mellitus with non-alcoholic steatohepatitis, the combination of a PPAR receptor activator and HMS5552 may provide better blood glucose control, reduce the risk of diabetic complications, and has the effect of treating non-alcoholic steatohepatitis.

The above study on the efficacy of HMS5552 in combination with existing oral diabetes medications indicates that combined use can improve the efficacy of HMS5552 or existing hypoglycemic agents, reduce safety risks, and improve medical effects. Oral fixed dose combination formulations developed with HMS5552 and existing oral diabetes drugs are currently the most promising combination diabetes treatments for the above clinical challenges.

Claims (124)

1. Hypoglycemic pharmaceutical combination containing: (a) a glucokinase activator, which is the compound HMS5552 represented by the following formula

; and (b) a PPAR receptor activator selected from the group consisting of rosiglitazone, pioglitazone, and pharmaceutically acceptable salts thereof; where the mass ratio of glucokinase activator to PPAR receptor activator is from 50:1 to 1:10; the glucokinase activator is present in a dose ranging from 1 mg to 200 mg; the PPAR receptor activator is present at a dose in the range of 1 mg to 50 mg. 2. The hypoglycemic pharmaceutical combination according to claim 1, wherein the weight ratio of glucokinase activator to PPAR receptor activator is from 25:1 to 1:5. 3. Hypoglycemic pharmaceutical combination according to claim 1, where the mass ratio of glucokinase activator to PPAR receptor activator is 1:10, 1:5, 1:2, 1.67:1, 3.33:1, 5:1, 6, 25:1, 6.67:1, 12.5:1, 18.75:1 or 25:1. 4. Hypoglycemic pharmaceutical combination according to any one of paragraphs. 1-3, where the glucokinase activator is in the form of a solid dispersion. 5. Hypoglycemic pharmaceutical combination according to claim 1, where the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier, where the polymeric carrier is a type A methacrylic acid copolymer. 6. Hypoglycemic pharmaceutical combination according to claim 1, where the glucokinase activator is in the form of a solid dispersion containing a polymer carrier, where the polymer carrier is an anionic copolymer of methacrylic acid and methyl methacrylate 1:1. 7. The hypoglycemic pharmaceutical combination according to claim 1, wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier, wherein the polymeric carrier is Eudragit. 8. The hypoglycemic pharmaceutical combination according to claim 1, wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier, wherein the polymeric carrier is Eudragit-L100. 9. Hypoglycemic pharmaceutical combination according to any one of paragraphs. 5-8, where the weight ratio of glucokinase activator to polymer carrier is from 1:10 to 10:1. 10. Hypoglycemic pharmaceutical combination according to any one of paragraphs. 5-8, where the mass ratio of the glucokinase activator to the polymer carrier is from 1:9 to 9:1, from 1:4 to 4:1, from 3:7 to 7:3, from 2:3 to 3:2, from 3:4 to 4:3, 4:5 to 5:4, or 5:6 to 6:5. 11. Hypoglycemic pharmaceutical combination according to any one of paragraphs. 5-8, wherein the weight ratio of glucokinase activator to polymer carrier is 1:1, 2:3, 3:4, 4:5, or 5:6. 12. The hypoglycemic pharmaceutical combination according to claim 1, wherein the glucokinase activator is present at a dose in the range of 25 mg to 100 mg. 13. Hypoglycemic pharmaceutical combination according to claim 1, where the dose of glucokinase activator is 25 mg, 50 mg, 75 mg or 100 mg. 14. The hypoglycemic pharmaceutical combination according to claim 1, wherein the PPAR receptor activator is present in a dose of 4 mg to 15 mg. 15. The hypoglycemic pharmaceutical combination according to claim 1, wherein the dose of the PPAR receptor activator is 1 mg, 2 mg, 4 mg, 5 mg, 10 mg, 12 mg, 14 mg, or 15 mg. 16. The hypoglycemic pharmaceutical combination according to claim 1, wherein the dose of the PPAR receptor activator is 4 mg or 15 mg. 17. The hypoglycemic pharmaceutical combination of claim 1 wherein the PPAR receptor activator is rosiglitazone maleate or pioglitazone hydrochloride. 18. Hypoglycemic pharmaceutical combination according to any one of paragraphs. 12-17, where the indicated dose is a single dose. 19. Hypoglycemic pharmaceutical composition containing hypoglycemic pharmaceutical combination according to any one of paragraphs. 1-18. 20. A hypoglycemic pharmaceutical composition according to claim 19, comprising a PPAR receptor activator and a glucokinase activator solid dispersion, wherein the weight ratio of the glucokinase activator solid dispersion to the PPAR receptor activator is from 100:1 to 1:5. 21. The hypoglycemic pharmaceutical composition according to claim 20, wherein the weight ratio of the solid dispersion of the glucokinase activator and the PPAR receptor activator is from 50:1 to 2:5. 22. The hypoglycemic pharmaceutical composition according to claim 20, where the mass ratio of the solid dispersion of the glucokinase activator and the PPAR receptor activator is 1:5, 2:5, 1:1, 3.33:1, 6.67:1, 10:1, 12.5:1, 13.3:1, 25:1, 37.5:1 or 50:1. 23. Hypoglycemic pharmaceutical composition according to claim 20, where the solid dispersion of the glucokinase activator is 1-98 wt.%; and the PPAR receptor activator is 0.1-25 wt%. 24. Hypoglycemic pharmaceutical composition according to claim 19, additionally containing one or more excipients selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavors, sweeteners, colorants and agents for forming the coating. 25. The hypoglycemic pharmaceutical composition according to claim 19, which is in a form selected from the group consisting of a tablet or capsule. 26. The hypoglycemic pharmaceutical composition according to claim 19, which is in the form of a coated tablet. 27. Fixed dose hypoglycemic combination formulation, comprising: (a) a glucokinase activator, which is an HMS5552 compound represented by the following formula

(b) a PPAR receptor activator selected from the group consisting of rosiglitazone, pioglitazone, and pharmaceutically acceptable salts thereof; and (c) one or more excipients; where the mass ratio of glucokinase activator to PPAR receptor activator is from 50:1 to 1:10; the glucokinase activator is present in a dose ranging from 1 mg to 200 mg; the PPAR receptor activator is present at a dose in the range of 1 mg to 50 mg. 28. The fixed dose hypoglycemic combination formulation of claim 27 wherein the weight ratio of glucokinase activator to PPAR receptor activator is between 25:1 and 1:5. 29. The fixed dose hypoglycemic combination formulation of claim 27 wherein the weight ratio of glucokinase activator to PPAR receptor activator is 1:10, 1:5, 1:2, 1.67:1, 3.33:1, 5:1 , 6.25:1, 6.67:1, 12.5:1, 18.75:1 or 25:1. 30. Hypoglycemic combination composition with a fixed dose according to claim 27, where the glucokinase activator is 1-98 wt.%; and the PPAR receptor activator is 0.1-25 wt%. 31. Hypoglycemic combination composition with a fixed dose according to any one of paragraphs. 27-30 wherein the glucokinase activator is in the form of a solid dispersion. 32. The fixed dose hypoglycemic combination formulation of claim 27, wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier that is a type A methacrylic acid copolymer. 33. The fixed dose hypoglycemic combination formulation of claim 27, wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier that is a 1:1 anionic copolymer of methacrylic acid and methyl methacrylate. 34. The fixed dose hypoglycemic combination formulation of claim 27 wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier which is Eudragit. 35. The fixed dose hypoglycemic combination formulation of claim 27 wherein the glucokinase activator is in the form of a solid dispersion containing a polymeric carrier which is Eudragit-L100. 36. Hypoglycemic combination composition with a fixed dose according to any one of paragraphs. 32-35, where the mass ratio of glucokinase activator to polymer carrier is from 1:10 to 10:1. 37. Hypoglycemic combination composition with a fixed dose according to any one of paragraphs. 32-35, where the mass ratio of glucokinase activator to polymeric carrier is from 1:9 to 9:1, from 1:4 to 4:1, from 3:7 to 7:3, from 2:3 to 3:2, from 3:4 to 4:3, 4:5 to 5:4, or 5:6 to 6:5. 38. Hypoglycemic combination composition with a fixed dose according to any one of paragraphs. 32-35, wherein the weight ratio of glucokinase activator to polymer carrier is 1:1, 2:3, 3:4, 4:5, or 5:6. 39. The fixed dose hypoglycemic combination formulation of claim 27, wherein the glucokinase activator is present at a dose in the range of 25 mg to 100 mg. 40. The fixed dose hypoglycemic combination formulation of claim 27, wherein the dose of glucokinase activator is 25 mg, 50 mg, 75 mg, or 100 mg. 41. The fixed dose hypoglycemic combination formulation of claim 27, wherein the PPAR receptor activator is present at a dose in the range of 4 mg to 15 mg. 42. The fixed dose hypoglycemic combination formulation of claim 27, wherein the PPAR receptor activator dose is 1 mg, 2 mg, 4 mg, 5 mg, 10 mg, 12 mg, 14 mg, or 15 mg. 43. The fixed dose hypoglycemic combination formulation of claim 27, wherein the PPAR receptor activator dose is 4 mg or 15 mg. 44. The fixed dose hypoglycemic combination formulation of claim 27 wherein the PPAR receptor activator is rosiglitazone maleate or pioglitazone hydrochloride. 45. The fixed dose hypoglycemic combination formulation of claim 27 wherein the weight ratio of the solid dispersion of glucokinase activator and PPAR receptor activator is between 100:1 and 1:5. 46. The fixed dose hypoglycemic combination formulation of claim 27 wherein the weight ratio of the solid dispersion of glucokinase activator and PPAR receptor activator is between 50:1 and 2:5. 47. The fixed dose hypoglycemic combination formulation of claim 27 wherein the weight ratio of the solid dispersion of glucokinase activator and PPAR receptor activator is 1:5, 2:5, 1:1, 3.33:1, 6.67:1, 10 :1, 12.5:1, 13.3:1, 25:1, 37.5:1 or 50:1. 48. Hypoglycemic combination composition with a fixed dose according to claim 27, where the glucokinase activator is 1-98 wt.%; and the PPAR receptor activator is 0.1-25% by weight. 49. A fixed dose hypoglycemic combination formulation according to claim 27, wherein one or more excipients is selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavors, sweeteners, dyes and agents for forming the coating. 50. Hypoglycemic combination formulation with a fixed dose according to claim 49, where the binding agent is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose; the filler is selected from the group consisting of microcrystalline cellulose, siliconized microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch and pregelatinized starch; the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate; the lubricant is selected from the group consisting of magnesium stearate and sodium stearyl fumarate; and glidant is selected from the group consisting of colloidal silicon dioxide and talc. 51. The fixed dose hypoglycemic combination formulation of claim 27, which is a tablet. 52. The fixed dose hypoglycemic combination formulation of claim 51, which is a coated tablet. 53. The fixed dose hypoglycemic combination formulation of claim 52, wherein the coated tablet is a film coated tablet. 54. The fixed dose hypoglycemic combination formulation of claim 52, wherein the coated tablet is a film-coated tablet and the film-forming agent is Opadry. 55. Fixed dose hypoglycemic combination formulation according to claim 27, containing (by weight): - 1-98% glucokinase activator, which is HMS5552; - 0.1-15% PPAR receptor activator; - 0-80% filler(s); - 1-25% binding agent(s); - 0-15% disintegrant(s); - 0.1-10% lubricant(s); and - 0-3% glidant(s). 56. The fixed dose hypoglycemic combination formulation of claim 55 wherein the glucokinase activator is a solid dispersion containing HMS5552. 57. The fixed dose hypoglycemic combination formulation of claim 55, wherein the glucokinase activator is a solid dispersion containing HMS5552 and a polymeric carrier. 58. The fixed dose hypoglycemic combination formulation of claim 55, wherein the glucokinase activator is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100. 59. Hypoglycemic combination formulation with a fixed dose according to claim 27, where the doses of the active ingredients are (by weight): 25 mg, 50 mg, 75 mg or 100 mg HMS5552; and 2 mg, 4 mg or 8 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate. 60. Fixed dose hypoglycemic combination formulation according to claim 59, which is a 25 mg HMS5552/4 mg tablet of rosiglitazone or an appropriate amount of rosiglitazone maleate and includes components in the following amounts (by weight): - 25 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate. 61. Fixed dose hypoglycemic combination formulation according to claim 59, which is a 50 mg HMS5552/4 mg tablet of rosiglitazone or an appropriate amount of rosiglitazone maleate and includes components in the following amounts (by weight): - 50 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate. 62. Fixed dose hypoglycemic combination formulation according to claim 59, which is a 75 mg HMS5552/4 mg tablet of rosiglitazone or an appropriate amount of rosiglitazone maleate and includes components in the following amounts (by weight): - 75 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate. 63. Fixed dose hypoglycemic combination formulation according to claim 59, which is a 100 mg HMS5552/4 mg tablet of rosiglitazone or an appropriate amount of rosiglitazone maleate and contains the components in the following amounts (by weight): - 100 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 4 mg of rosiglitazone or the corresponding amount of rosiglitazone maleate. 64. Fixed dose hypoglycemic combination formulation according to claim 59, containing 50 mg solid dispersion, 5.30 mg rosiglitazone maleate, 177.20 mg microcrystalline cellulose, 7.50 mg hydroxypropyl cellulose, 7.50 mg croscarmellose sodium, 2.50 mg magnesium stearate and 7.50 mg Opadry, where the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 25 mg HMS5552. 65. Fixed dose hypoglycemic combination formulation according to claim 59, containing 100 mg solid dispersion, 5.30 mg rosiglitazone maleate, 127.20 mg microcrystalline cellulose, 7.50 mg hydroxypropyl cellulose, 7.50 mg croscarmellose sodium, 2.50 mg magnesium stearate and 7.50 mg Opadry, where the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 50 mg HMS5552. 66. Fixed dose hypoglycemic combination formulation according to claim 59 containing 150 mg solid dispersion, 5.30 mg rosiglitazone maleate, 123.70 mg microcrystalline cellulose, 9.00 mg hydroxypropyl cellulose, 9.00 mg croscarmellose sodium, 3.00 mg magnesium stearate and 9.00 mg Opadry, where the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 75 mg HMS5552. 67. Fixed dose hypoglycemic combination formulation according to claim 59 containing 200 mg solid dispersion, 5.30 mg rosiglitazone maleate, 73.7 mg microcrystalline cellulose, 9.00 mg hydroxypropyl cellulose, 9.00 mg croscarmellose sodium, 3.00 mg magnesium stearate and 9.00 mg Opadry, where the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 100 mg HMS5552. 68. Fixed dose hypoglycemic combination formulation according to claim 59, containing 50 mg solid dispersion, 5.30 mg rosiglitazone maleate, 177.20 mg microcrystalline cellulose, 7.50 mg hydroxypropyl cellulose, 7.50 mg croscarmellose sodium, 2.50 mg magnesium stearate and 7.50 mg Opadry, where the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 25 mg HMS5552. 69. Hypoglycemic combination formulation with a fixed dose according to claim 27, where the doses of the active ingredients are (by weight): 25 mg, 50 mg, 75 mg or 100 mg HMS5552; and 15 mg, 30 mg or 45 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride. 70. Fixed dose hypoglycemic combination formulation according to claim 69, which is a 25 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride and includes components in the following quantities (by weight): - 25 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride. 71. Fixed dose hypoglycemic combination formulation according to claim 69, which is a 50 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride and contains the components in the following quantities (by weight): - 50 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride. 72. Fixed dose hypoglycemic combination formulation according to claim 69, which is a 75 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride and contains the components in the following amounts (by weight): - 75 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride. 73. Fixed dose hypoglycemic combination formulation according to claim 69, which is a 100 mg HMS5552/15 mg pioglitazone tablet or an appropriate amount of pioglitazone hydrochloride and contains the components in the following amounts (by weight): - 100 mg HMS5552, which is a solid dispersion containing 1:1 HMS5552 and Eudragit-L100; - 15 mg of pioglitazone or the corresponding amount of pioglitazone hydrochloride. 74. Fixed dose hypoglycemic combination formulation according to claim 69 containing 150 mg solid dispersion, 15.91 mg pioglitazone hydrochloride, 113.09 mg microcrystalline cellulose, 9.00 mg hydroxypropyl cellulose, 9.00 mg croscarmellose sodium, 3.00 mg magnesium stearate and 9.00 mg Opadry, while the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 75 mg HMS5552. 75. Fixed dose hypoglycemic combination formulation according to claim 69 containing 200 mg solid dispersion, 15.91 mg pioglitazone hydrochloride, 63.09 mg microcrystalline cellulose, 9.00 mg hydroxypropyl cellulose, 9.00 mg croscarmellose sodium, 3.00 mg magnesium stearate and 9.00 mg Opadry, while the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 100 mg HMS5552. 76. Fixed dose hypoglycemic combination formulation according to claim 69 containing 100 mg solid dispersion, 15.91 mg pioglitazone hydrochloride, 260.09 mg microcrystalline cellulose, 12.00 mg hydroxypropyl cellulose, 8.00 mg croscarmellose sodium, 4.00 mg magnesium stearate and 12.00 mg Opadry, while the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 50 mg HMS5552. 77. Fixed dose hypoglycemic combination formulation according to claim 69 containing 50 mg solid dispersion, 15.91 mg pioglitazone hydrochloride, 216.09 mg microcrystalline cellulose, 9.00 mg hydroxypropyl cellulose, 6.00 mg croscarmellose sodium, 3.00 mg magnesium stearate and 9.00 mg Opadry, while the solid dispersion includes 1:1 HMS5552 and Eudragit-L100 and contains 25 mg HMS5552. 78. Hypoglycemic pharmaceutical combination according to any one of paragraphs. 1-18, which is used to prevent, slow the progression, delay or treat 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, hyperglycemia after eating, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and / or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing the complications of diabetes. 79. Hypoglycemic pharmaceutical composition according to any one of paragraphs. 19-26, which is used to prevent, slow the progression, delay or treat 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, hyperglycemia after eating, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and / or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing the complications of diabetes mellitus. 80. Hypoglycemic combination composition with a fixed dose according to any one of paragraphs. 27-77, which is used to prevent, slow the progression, delay or treat 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, hyperglycemia after eating, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and / or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing the complications of diabetes. 81. A method for preventing, slowing the progression, 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, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or reversing the complications of diabetes mellitus, comprising administering to a subject a therapeutically effective amount of a hypoglycemic pharmaceutical combination according to any one of paragraphs. 1-18 or hypoglycemic pharmaceutical composition according to any one of paragraphs. 19-26 or a fixed dose hypoglycemic combination formulation according to any one of paragraphs. 27-77. 82. The use of a hypoglycemic pharmaceutical combination according to any one of paragraphs. 1-18 or hypoglycemic pharmaceutical composition according to any one of paragraphs. 19-26 in the manufacture of a medicament for preventing, slowing the progression, 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, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving blood glucose control and/or lowering fasting plasma glucose, postprandial plasma glucose, and/or plasma glycosylated hemoglobin HbA1c.

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