WO2022144021A1

WO2022144021A1 - Pharmaceutical composition containing dorzagliatin and glucagon-like peptide-1 analog

Info

Publication number: WO2022144021A1
Application number: PCT/CN2022/070063
Authority: WO
Inventors: 陈力; 汤福兴; 宋浩亮; 单永强; 富欣
Original assignee: 华领医药技术（上海）有限公司
Priority date: 2021-01-04
Filing date: 2022-01-04
Publication date: 2022-07-07
Also published as: TW202228680A; CN114712488A; TWI817307B; CN114712488B

Abstract

The present invention relates to a pharmaceutical composition, comprising (a) Dorzagliatin, or an isotopic marker, enantiomer, diastereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof; and (b) a GLP-1 analog, or a pharmaceutically acceptable salt thereof. The present invention further relates to a kit and pharmaceutical composition containing (a) and (b), and uses thereof, etc.

Description

Pharmaceutical composition of Dorzagliatin and glucagon-like peptide-1 analogs

Related applications

This application claims the priority of Chinese patent application CN202110004096.9 filed on January 4, 2021 and Chinese patent application CN202111505931.3 filed on December 10, 2021, the contents of which are incorporated herein by reference.

technical field

The present invention relates to a pharmaceutical combination of a glucokinase activator (Glucokinase Activator, GKA) and a partner drug, a pharmaceutical composition, a kit and the use thereof. More specifically, the present invention relates to pharmaceutical combinations, pharmaceutical compositions, kits and uses of Dorzagliatin and glucagon-like peptide-1 (glucagon-like peptide-1, GLP-1) analogs.

Background technique

Diabetes has become a common disease worldwide, and the number of global patients is now 425 million, and the number of Chinese patients is as high as 116 million (International Diabetes Federation, Diabetes Atlas, 2015). Type 2 diabetes is non-insulin dependent diabetes mellitus (NIDDM), which accounts for more than 90% of diabetic patients. Type 2 diabetes is a chronic metabolic disorder of hyperglycemia caused by the imbalance of blood glucose homeostasis caused by insulin secretion disorders and insulin resistance. The balance of blood sugar in the human body is mainly completed by the coordination of two glucose-controlling hormones, insulin and glucagon. Glucagon-like peptide-1 (GLP-1) is involved in the regulation of insulin secretion. GLP-1 is also a drug for the treatment of diabetes and plays an important role in the balance of blood sugar in the human body. Insulin and GLP-1 analogs have become important drugs for the treatment of diabetes.

Glucokinase (GK) plays a central role in stabilizing the blood sugar balance in the human body. As a glucose sensor in blood glucose homeostasis, GK senses blood glucose changes, regulates the secretion of messenger glucose control hormones, insulin and glucagon, and GLP-1, and constitutes a sensing system for the regulation of blood glucose homeostasis in the human body. GK is mainly distributed in the liver, where it rapidly converts glucose into hepatic glycogen for storage in response to rising blood sugar levels, while lowering blood glucose levels. Glucose reserve during glucose intake and glucose supply during fasting controlled by glucose control hormones constitute the regulation of blood glucose homeostasis in the human body. The organs involved in glucose storage mainly include liver, muscle and fat. Under the action of blood sugar and insulin, glucose is taken up and converted into liver glycogen, muscle glycogen and triglyceride. The main organ involved in the supply of glucose is the liver. Under the action of blood sugar and glucagon, it supplies sugar to the human body through hepatic glucose synthesis and hepatic glucose output. Insulin can also effectively regulate the activity of the sodium-glucose co-transporter SGLT-2. When blood sugar rises, the glucose excreted by the kidneys is reabsorbed and used for the body's glucose reserve. Glucose uptake and hepatic glucose output, as well as the use of glucose by various organs, constitute the operating system for the homeostasis of blood glucose in the human body. The coordinated operation of the glucose sensing system and the operating system constitutes the random regulation of the blood glucose homeostasis of the human body.

In diabetic patients, due to the impaired function and expression of glucokinase (GK) and the dysfunction of the sensor, the early phase secretion of glucose-controlling hormones is disturbed, which affects the uptake and output of glucose, resulting in postprandial hyperglycemia and preprandial hypoglycemia. Abnormal signal instructions of glucose control hormone cause abnormal function and expression of key proteins in the execution system of glucose uptake and output operation, resulting in abnormal operation and type 2 diabetes.

As a progressive degenerative disease, type 2 diabetes requires progressive intensification of treatment over time to adequately control blood sugar as beta cells progressively fail. Treatment resistance is a common and major challenge in the treatment of type 2 diabetes. Although metformin, DPP-4 inhibitors, SGLT-2 inhibitors, and sulfonylureas can be administered alone or in combination, a large number of patients with type 2 diabetes have poor glycemic control. Therefore, there is an unmet clinical need in the field of diabetes, especially in the treatment of refractory type 2 diabetes.

Purpose of invention

The present invention relates to a drug combination of a glucokinase activator (Glucokinase Activator, GKA) and a combination drug (partner drug), wherein GKA is Dorzagliatin (also known as HMS5552), the Chinese name is Dorzagliatin, and the structure is as follows:

The present invention provides a pharmaceutical combination comprising:

(a) Dorzagliatin, or an isotopic label, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof; and

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical composition comprising:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

The present invention provides a kit comprising:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

The inventors found that the above-mentioned pharmaceutical combination, pharmaceutical composition and kit can effectively control blood sugar and improve the hypoglycemic efficacy of Dorzagliatin or the existing hypoglycemic drug GLP-1 analogs.

An object of the present invention is to provide pharmaceutical combinations, pharmaceutical compositions, uses of kits, and/or methods for preventing, slowing, and treating metabolic disorders (eg, type 2 diabetes).

Specifically, it is an object of the present invention to provide a pharmaceutical combination, pharmaceutical composition, use of a kit, and/or method for improving glycemic control in a patient in need thereof, and/or treating the patient's glycemic control.

Another object of the present invention is to provide improved glycemic control in patients with poor glycemic control despite an anti-diabetic monotherapy regimen (eg monotherapy), or a combination of two or three anti-diabetic drugs, and/or use of a pharmaceutical combination, pharmaceutical composition, kit, and/or method for treating glycemic control in a patient.

Another object of the present invention is to provide a pharmaceutical combination, pharmaceutical composition and kit for preventing, delaying or delaying the progression of impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome into type II diabetes uses, and/or methods.

Another object of the present invention is to provide the use of pharmaceutical combinations, pharmaceutical compositions, kits, and or methods for preventing a condition or disorder selected from diabetic complications, slowing the progression of the condition or disorder, delaying or treating the condition or disorder.

Combined with the context of the present invention and common knowledge in the art, other objects of the present invention can be easily understood by those skilled in the art.

SUMMARY OF THE INVENTION

A first aspect of the present invention provides a pharmaceutical combination comprising:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

In some embodiments, wherein said (a) and (b) are used simultaneously, separately or sequentially.

A second aspect of the present invention provides a pharmaceutical composition comprising:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

A third aspect of the present invention provides a kit comprising:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

In some embodiments, the kit may contain one pharmaceutical composition or may contain two single formulations of (a) and (b).

The fourth aspect of the present invention provides a pharmaceutical combination and the use of the pharmaceutical composition in the preparation of a medicament for the treatment of diabetes and related symptoms.

In some embodiments, the medicament is a kit.

A fifth aspect of the present invention provides a method of treating diabetes and its associated symptoms in a subject, comprising administering to said subject simultaneously, separately or sequentially:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

definition

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

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

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

All numerical values or expressions referring to component amounts used in the specification and claims should be understood to be modified by "about" in all instances. The term "about" when referring to an amount or numerical range means that the indicated amount or numerical range is an approximation within experimental variability (or within statistical experimental error) and thus the amount or numerical range may be within the stated amount or numerical range The example varies between ±5.

All ranges referring to the same component or property are inclusive of the endpoints, which endpoints are independently combinable. Since these ranges are continuous, they include every value between the minimum and maximum values. It is also to be understood that any numerical range recited herein is intended to include all subranges within that range.

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

As used in this specification and in the claims, "and/or" should be understood to mean "either or both" of the associated components, ie, the components exist jointly in some cases and separately in other cases. Multiple components listed with "and/or" should be construed in the same fashion, ie, "one or more" of the associated component. Other components may optionally be present other than the components specifically identified by the "and/or" clause, whether related or unrelated to those specifically identified components. Thus, by way of non-limiting example, reference to "A and/or B", when used in conjunction with an open-ended word such as "includes," may in one embodiment refer to only A (optionally including in addition to B In another embodiment, it may refer to only B (optionally including components other than A); in yet another embodiment, refer to A and B (optionally including other components), etc.

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

Abbreviations used herein have their usual meanings in the fields of chemistry, biology and formulation.

Term Dorzagliatin (or HMS5552), chemical name (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4- Methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide, originally disclosed in WO2009127546A1.

Compounds that are active ingredients in the pharmaceutical combinations, pharmaceutical compositions, kits of the present invention containing Dorzagliatin and/or GLP-1 analogs may form salts. Unless otherwise stated, references in this application to having Dorzagliatin or GLP-1 analogs are understood to include references to their salts. As used herein, the term "salt(s)" refers to acid salts with inorganic and/or organic acids and base salts with inorganic and/or organic bases. Additionally, when the compound contains a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), a zwitterion ("inner salt") can be formed and the zwitterion ( "Internal salt") is included in the term "salt(s)" as used herein. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds can be formed, for example, by reacting the compounds with an amount (eg, an equal amount) of an acid or base in a medium, such as a medium in which the salt precipitates or an aqueous medium ( lyophilized after the reaction).

Particular salts include those salts which, within the scope of sound medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergy, etc., and which are commensurate with a reasonable benefit/hazard ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or salts formed with organic acids such as acetic, oxalic, Maleic, tartaric, citric, succinic or malonic acid. Also included are salts formed using methods conventional in the art, eg, ion exchange methods. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor acid salt, camphorsulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate , malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, Pectin Acetate, Persulfate, 3-Phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Stearate, Succinate, Sulfate, Tartrate, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl _{) 4} _salts . Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations with counter ions such as halides, hydroxide, formate, sulfate, phosphate, Nitrates, lower alkyl sulfonates and aryl sulfonates.

Dorzagliatin, a compound of the present invention, contains one or more asymmetric centers, and thus may exist in various stereoisomeric, eg, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (eg, cis and trans isomers), or may be in the form of a mixture of stereoisomers, Include racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers can be separated by prepared by asymmetric synthesis.

Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The present invention covers all solvates of Dorzagliatin, the compound of the present invention.

The term "solvate" refers to a solvent-bound compound or salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that is combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general _formula RxH2O, wherein R is the compound, and x is a number greater than zero. A given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R.0.5H2 ₎ O)) and polyhydrates (x is a number greater than 1, eg, dihydrate ( _R.2H2O ) and hexahydrate ( _R.6H2O )).

The compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

The present invention also includes isotopically-labeled compounds which are equivalent to Dorzagliatin but with one or more atoms replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of ^hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, ^3H , ^13C , ^11C , ^14C , ^15N , ¹⁸ , respectively O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, such as those into which radioactive isotopes (eg, ^3H ^and14C ) have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, ie ³ H, and carbon-14, ie ¹⁴ C isotopes are particularly preferred because of their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium, ie, 2H, may be preferred in some circumstances because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half ^- life or reduced dosage requirements. Isotopically labeled Dorzagliatin compounds of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in carrying out the processes disclosed in the following Schemes and/or Examples and Preparations .

A "GLP-1 analog" is an analog of glucagon-like peptide-1 (GLP-1). GLP-1, an incretin, is mainly secreted by L cells in the small intestine. It stimulates GLP-1 receptors, increases insulin secretion from pancreatic beta cells, inhibits postprandial glucagon, inhibits gastric emptying, and suppresses appetite. Other effects include inhibiting the production of glucose by the liver and improving the uptake of glucose by tissues outside the liver. All of these tend to lower blood sugar levels after meals. GLP-1 is rapidly degraded and destroyed by an enzyme called DPP-4. A variety of GLP-1-like chemicals, termed GLP-1 analogs, are available in the prior art, which bind to the GLP-1 receptor and resist degradation by DPP-4 enzymes. They behave essentially like GLP-1, and they act for longer. The effects of GLP-1 depend on blood sugar levels. If blood sugar is not elevated, GLP-1 is not working properly. From a practical standpoint, this means that GLP-1-based therapies rarely cause hypoglycemia. Currently listed GLP-1 analogs mainly include liraglutide, exenatide, albiglutide, dulaglutide, semaglutide, lixisenatide, benaglutide and loxenatide.

"Pharmaceutically acceptable" or "pharmaceutically acceptable" refers to a substance that is not biologically or otherwise substantially undesirable, ie, the substance can be administered to an individual without causing any undesirable biological function or interact in a detrimental manner with any other component of a composition containing such a substance.

The term "simultaneous" is used to refer to the simultaneous administration of two drugs. If not administered simultaneously, they are administered "sequentially" within a time frame such that both are therapeutically effective within the same time frame. Thus, "sequential" administration may allow for administration of one drug within 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, or hours of the other drug, provided that the first is administered The circulating half-life of the drug is such that a therapeutically effective amount of both exists at the same time. The time delay between administration of the ingredients will vary depending on the precise nature of the ingredients, the interactions therebetween, and their respective half-lives.

Unlike "simultaneously" or "sequentially", the term "separately" means that there is a significant interval between the administration of one drug and the other, i.e., when the second drug is administered, the first drug administered may be is no longer present in the bloodstream in a therapeutically effective amount.

The term "pharmaceutically acceptable carrier" refers to an inactive ingredient that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound. As used herein, "carrier" and "excipient" have the same meaning.

The term "therapeutically effective amount" refers to an amount of an agent sufficient to provide the desired biological result. The result may be a reduction and/or alleviation of a sign, symptom or cause of a disease, or any other desired change in a biological system. For example, a "therapeutically effective amount" for therapeutic use refers to the amount of a composition comprising a compound as the active ingredient of the present invention required to clinically reduce a disease. In any case, the appropriate "therapeutically effective amount" can be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression "therapeutically effective amount" generally refers to the amount of active substance at which it has a therapeutic effect.

As used herein, the term "treat" is synonymous with the terms "prevent", "alleviation" and is intended to mean delaying disease progression, preventing disease progression and/or reducing said disease that will develop or is expected to develop severity of symptoms. Thus, these terms include amelioration of existing disease symptoms, prevention of additional symptoms, amelioration or prevention of underlying metabolic causes of symptoms, inhibition of a disorder or disease, eg, preventing the development of a disorder or disease, alleviating a disorder or disease, enabling a disorder or disease Regression, alleviation of symptoms caused by a disease or disorder, or cessation of symptoms of a disease or disorder.

The term "subject" as used herein includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, Dogs and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention, the mammal is a human. The term "subject" includes a confirmed patient, but the "subject" does not need to have any special identity to the hospital, clinic, or research facility (eg, as a confirmed patient, study participant, etc.).

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

Description of drawings

Figure 1 is a graph of the effect of Dorzagliatin combined with liraglutide on fasting blood glucose concentration compared to single drug.

Figure 2 is a graph showing the effect of Dorzagliatin in combination with liraglutide on the area under the blood glucose curve compared to single drug.

Figure 3 is a graph showing the effect of Dorzagliatin combined with liraglutide on fasting HbA1C compared to single drug.

Figure 4 is a graph showing the effect of Dorzagliatin combined with liraglutide on fasting total GLP-1 compared to single drug.

Figure 5 is a graph of the effect of Dorzagliatin combined with liraglutide on fasting insulin compared with single drug.

Figure 6 is a graph showing the effect of Dorzagliatin in combination with liraglutide on fasting C-peptide compared to single drug.

Figure 7 is a graph showing the effect of Dorzagliatin combined with liraglutide on fasting glucagon compared to single drug.

In the figure, *p<0.05, **p<0.01.

Detailed description of the invention

In one embodiment, the present invention relates to a pharmaceutical combination comprising:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

In a specific embodiment, the pharmaceutical combination of the present invention, wherein said (a) and (b) are used simultaneously, separately or sequentially.

In another specific embodiment, the pharmaceutical combination of the present invention, wherein the weight ratio of Dorzagliatin to GLP-1 analog is about 30000:1 to 2:1, preferably about 30000:1, 15000:1, 7500:1 1, 5000:1, 3750:1, 3000:1, 2500:1, 2150:1, 1800:1, 1600:1, 1500:1, 1000:1, 750:1, 600:1, 500:1, 375:1, 300:1, 250:1, 215:1, 200:1, 190:1, 170:1, 150:1, 125:1, 100:1, 90:1, 80:1, 75: 1, 50:1, 40:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1 or 3:1.

In another specific embodiment of the present invention, the pharmaceutical combination of the present invention, wherein said Dorzagliatin is present in a dose (preferably unit dose) range of about 1 mg to about 200 mg, preferably a dose of about 25 mg to about 150 mg A (preferred unit dose) range exists; more preferably, wherein the dose (preferred unit dose) of said Dorzagliatin is about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg or 150 mg. In a preferred embodiment, Dorzagliatin is administered orally twice daily, more preferably twice daily.

In another specific embodiment of the present invention, the pharmaceutical combination of the present invention, wherein said GLP-1 analog is present in a dose (preferably unit dose) range of about 0.0001 mg to about 100 mg, preferably about 0.001 mg to about A dose (preferably unit dose) range of 50 mg exists; more preferably, wherein the dose (preferably a unit dose) of the GLP-1 analog is about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg , 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.8 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 10 mg, 12 mg, 14 mg, 30 mg, or 50 mg.

In another specific embodiment of the present invention, the pharmaceutical combination of the present invention, wherein the GLP-1 analog is selected from the group consisting of liraglutide, exenatide, albiglutide, dulaglutide, semaglutide peptides, lixisenatide, benaglutide and loxenatide; preferably, the GLP-1 analog is liraglutide.

In another specific embodiment of the present invention, possible combinations include, but are not limited to:

Dorzagliatin in combination with liraglutide; Dorzagliatin in combination with exenatide; Dorzagliatin in combination with albiglutide; Dorzagliatin in combination with dulaglutide; Oral dosage form combination; Dorzagliatin in combination with lixisenatide; Dorzagliatin in combination with benaglutide; Dorzagliatin in combination with loxenatide.

The main active components and specifications/usages of the marketed GLP-1 analogs are shown in Table 1.

Table 1 Main active components and specifications/usage of GLP-1 analogues on the market

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is liraglutide, and the dose (preferably a unit dose) is about 0.6 mg, 1.2 mg or 1.8 mg. In a preferred embodiment, liraglutide is administered once daily, more preferably by subcutaneous injection once daily.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is exenatide, and its dose (preferably a unit dose) is about 0.005 mg, 0.01 mg or 0.02 mg; preferably, wherein The dose of exenatide, preferably a unit dose, is about 0.005 mg or 0.01 mg. In a preferred embodiment, exenatide is administered twice daily, more preferably by subcutaneous injection twice daily.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is exenatide microspheres, and its dose (preferably a unit dose) is about 0.03 mg, 1 mg or 2 mg; preferably , wherein the dose (preferably a unit dose) of the exenatide microspheres is about 2 mg. In a preferred embodiment, exenatide microspheres are administered once a week, more preferably once a week by subcutaneous injection.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is albiglutide, and its dose (preferably a unit dose) is about 4 mg, 7 mg, 30 mg or 50 mg; preferably , wherein the dose (preferably a unit dose) of said albiglutide is about 30 mg or 50 mg. In a preferred embodiment, albiglutide is administered once a week, more preferably by a subcutaneous injection once a week.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is dulaglutide, and its dose (preferably a unit dose) is about 0.1 mg, 0.2 mg, 0.75 mg, 1.5 mg, 3.0 mg mg or 4.5 mg; preferably, wherein the dose (preferably a unit dose) of said dulaglutide is about 0.75 mg or 1.5 mg. Preferably, wherein the dose (preferably a unit dose) of said dulaglutide is about 3.0 mg or 4.5 mg. In a preferred embodiment, the dulaglutide is administered once a week, more preferably by a subcutaneous injection once a week.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is an injection dosage form of semaglutide, and its dose (preferably a unit dose) is about 0.04 mg, 0.07 mg, 0.15 mg, 0.25 mg mg, 0.5 mg, 1.0 mg or 2.0 mg; preferably, wherein the dose (preferably a unit dose) of said semaglutide is about 0.25 mg, 0.5 mg or 1 mg. Preferably, wherein the dose (preferably a unit dose) of said semaglutide is about 2.0 mg. In a preferred embodiment, semaglutide is administered once a week, more preferably by subcutaneous injection once a week.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is an oral dosage form of semaglutide, and its dose (preferably a unit dose) is about 3 mg, 7 mg or 14 mg; preferably Preferably, wherein the dose (preferably a unit dose) of the semaglutide tablet is about 3 mg, 7 mg or 14 mg. In a preferred embodiment, the semaglutide tablet is administered once daily, more preferably orally once daily.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is lixisenatide, and its dose (preferably a unit dose) is about 0.01 mg or 0.02 mg; preferably, wherein the lixisenatide The dose of senatide (preferably a unit dose) is about 0.01 mg or 0.02 mg. In a preferred embodiment, lixisenatide is administered once daily, more preferably by subcutaneous injection once daily.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is benaglutide, and its dose (preferably a unit dose) is about 0.1 mg, 0.2 mg, 0.3 mg or 0.6 mg; preferably , wherein the dose (preferably a unit dose) of said benaglutide is about 0.1 mg or 0.2 mg. In a preferred embodiment, benaglutide is administered three times daily, more preferably by subcutaneous injection three times daily.

In another specific embodiment, in the pharmaceutical combination of the present invention, the GLP-1 analog is loxenatide, and its dose (preferably a unit dose) is about 0.01 mg, 0.03 mg, 0.1 mg or 0.2 mg; preferably , wherein the dose (preferably a unit dose) of said loxenatide is about 0.1 mg or 0.2 mg. In a preferred embodiment, loxenatide is administered once a week, more preferably once a week by subcutaneous injection.

The pharmaceutical combination of the present invention includes, but is not limited to, the combination of Dorzagliatin and the GLP-1 analog in a compound dosage form (eg, a tablet, capsule or injection), or the combination of Dorzagliatin and the GLP-1 analog in a single dosage form . Those skilled in the art can flexibly configure different combined usage modes according to actual needs. According to the dosage of Dorzagliatin and different GLP-1 analogs, it is flexible to choose to use a combination dosage form for simultaneous administration, or to use a single dosage form for simultaneous, sequential or separate use.

The dose administered is also individualized according to the characteristics of the subject, such as symptoms, treatment expectations, body weight, age, severity of disease, route of administration, etc. In one embodiment of the invention, a subtherapeutic dose of Dorzagliatin, or an isotopic label, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate thereof, is administered to a subject (eg, a human) , solvate or crystalline forms and/or subtherapeutic doses of a GLP-1 analog or a pharmaceutically acceptable salt thereof.

Subtherapeutic doses contemplated herein are lower than treatment as monotherapy in a typical subject (eg, a human) or a subject (eg, a human) with type 2 diabetes or in a subject (eg, a human) in need of glycemic control an effective amount. The therapeutically effective amount of the monotherapy is individualized according to the characteristics of the subject, such as symptoms, treatment expectations, body weight, age, severity of disease, route of administration, and the like.

In one embodiment, the present invention relates to a pharmaceutical composition comprising:

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.

In another specific embodiment, the pharmaceutical composition of the present invention, wherein the weight ratio of Dorzagliatin to GLP-1 analog is about 30000:1 to 2:1, preferably about 30000:1, 15000:1, 7500 :1, 5000:1, 3750:1, 3000:1, 2500:1, 2150:1, 1800:1, 1600:1, 1500:1, 1000:1, 750:1, 600:1, 500:1 , 375:1, 300:1, 250:1, 215:1, 200:1, 190:1, 170:1, 150:1, 125:1, 100:1, 90:1, 80:1, 75 :1, 50:1, 40:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1, or 3:1.

In another specific embodiment of the present invention, the pharmaceutical composition of the present invention, wherein said Dorzagliatin is present in a dose (preferably unit dose) range of about 1 mg to about 200 mg, preferably about 25 mg to about 150 mg Dosage (preferably unit dose) ranges exist; more preferably, wherein the dose (preferably unit dose) of said Dorzagliatin is about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg or 150 mg. In a preferred embodiment, Dorzagliatin is administered orally twice daily, more preferably twice daily.

In another specific embodiment of the present invention, the pharmaceutical composition of the present invention, wherein said GLP-1 analog is present in a dose (preferably unit dose) range of about 0.0001 mg to about 100 mg, preferably about 0.001 mg to about 100 mg A dose (preferably unit dose) range of about 50 mg exists; more preferably, wherein the dose (preferably a unit dose) of the GLP-1 analog is about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.8 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 10 mg, 12 mg, 14 mg, 30 mg, or 50 mg.

In another specific embodiment of the present invention, the pharmaceutical composition of the present invention, wherein the GLP-1 analog is selected from liraglutide, exenatide, albiglutide, dulaglutide, sema Glutide, lixisenatide, benaglutide and loxenatide; preferably, the GLP-1 analog is liraglutide.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is liraglutide, and the dose (preferably a unit dose) is about 0.6 mg, 1.2 mg or 1.8 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is exenatide, and its dose (preferably a unit dose) is about 0.005 mg, 0.01 mg or 0.02 mg; preferably, wherein the dosage of exenatide (preferably a unit dosage) is about 0.005 mg or 0.01 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is exenatide microspheres, and its dose (preferably a unit dose) is about 0.03 mg, 1 mg or 2 mg; preferably Ground, wherein the dose (preferably a unit dose) of the exenatide microspheres is about 2 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is albiglutide, and its dose (preferably a unit dose) is about 4 mg, 7 mg, 30 mg or 50 mg; Preferably, wherein the dose (preferably a unit dose) of said albiglutide is about 30 mg or 50 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is dulaglutide, and its dose (preferably a unit dose) is about 0.1 mg, 0.2 mg, 0.75 mg, 1.5 mg, 3.0 mg or 4.5 mg; preferably, wherein the dose (preferably a unit dose) of said dulaglutide is about 0.75 mg or 1.5 mg. Preferably, wherein the dose (preferably a unit dose) of said dulaglutide is about 3.0 mg or 4.5 mg.

In another specific embodiment, the GLP-1 analog in the pharmaceutical composition of the present invention is an injection dosage form of semaglutide, and its dose (preferably a unit dose) is about 0.04 mg, 0.07 mg, 0.15 mg, 0.25 mg mg, 0.5 mg, 1.0 mg or 2.0 mg; preferably, wherein the dose (preferably a unit dose) of said semaglutide is about 0.25 mg, 0.5 mg or 1 mg. Preferably, wherein the dose (preferably a unit dose) of said semaglutide is about 2.0 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is an oral dosage form of semaglutide, and its dose (preferably a unit dose) is about 3 mg, 7 mg or 14 mg; Preferably, wherein the dose (preferably a unit dose) of the semaglutide tablet is about 3 mg, 7 mg or 14 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is lixisenatide, and its dose (preferably a unit dose) is about 0.01 mg or 0.02 mg; preferably, wherein the The dose of lixisenatide (preferably a unit dose) is about 0.01 mg or 0.02 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is benaglutide, and its dose (preferably a unit dose) is about 0.1 mg, 0.2 mg, 0.3 mg or 0.6 mg; Preferably, wherein the dose (preferably a unit dose) of said benaglutide is about 0.1 mg or 0.2 mg.

In another specific embodiment, in the pharmaceutical composition of the present invention, the GLP-1 analog is loxenatide, and its dose (preferably a unit dose) is about 0.01 mg, 0.03 mg, 0.1 mg or 0.2 mg; Preferably, wherein the dose (preferably a unit dose) of said loxenatide is about 0.1 mg or 0.2 mg.

In one embodiment, the pharmaceutical compositions of the present invention further comprise one or more pharmaceutically acceptable carriers/excipients.

In one embodiment, the Dorzagliatin and GLP-1 analogs are carried by different carriers/excipients, respectively, and in one embodiment, the Dorzagliatin and GLP-1 analogs are carried by the same carrier/excipient .

Preferably, the excipient is selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agent.

In one embodiment, the pharmaceutical composition of the present invention optionally contains one or more fillers (diluents). Examples of fillers include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose (including microcrystalline cellulose and silicified microcrystalline cellulose), lactose, lactose anhydrous or monohydrate, sucrose, starch, pregels starch, dextrose, mannitol (including mannitol Pearlitol SD 200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate , dextrin/glucose binders, maltodextrins, compressible sugars and other known extenders or fillers and/or mixtures of two or more of them.

Examples of preferred fillers (diluents) include microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose, mannitol, sorbitol, calcium dihydrogen phosphate (dihydrate), corn starch, pre- Gelatinized starch and powdered cellulose. More preferred fillers (diluents) are microcrystalline cellulose and silicified microcrystalline cellulose. Microcrystalline cellulose is available from several suppliers 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 composition of the present invention contains optional one or more binders. Examples include, but are not limited to, carboxymethyl cellulose (including sodium carboxymethyl cellulose), hydroxypropyl cellulose (including hydroxypropyl cellulose EXF), corn starch, pregelatinized starch, modified corn starch, polyethylene pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) (including hydroxypropyl methylcellulose 2208), lactose, sucrose, acacia, ethyl cellulose, cellulose acetate, and wax binders such as Brazil Carnauba wax, paraffin wax, spermaceti, polyethylene or microcrystalline waxes and other conventional binders and/or mixtures of two or more of them. Further, in addition to the above-mentioned binders, binders suitable for the present invention also include, but are not limited to, alginic acid, microcrystalline cellulose, dextrin, gelatin, pullulan, liquid glucose, guar gum, methylcellulose , polyethylene oxide, povidone and syrup and combinations thereof.

Preferred embodiments of binders include hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HMPC), polyvinyl pyrrolidone (Povidone), hydroxyethyl cellulose, starch 1500, and copolyvinypyrone . More preferred binders are hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.

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

Preferably, the disintegrant is selected from one or more of modified starch, modified cellulose polymer or polycarboxylic acid, specifically selected from croscarmellose sodium, crospovidone, hydroxyl Sodium Starch Acetate, Polacrilin Potassium and Carboxymethylcellulose Calcium (CMC Calcium). In one embodiment, the disintegrant is crospovidone. In another embodiment, the disintegrant is sodium starch glycolate. In another embodiment, the disintegrant is croscarmellose sodium. Croscarmellose sodium NF type A is commercially available under the trade name "Ac-di-sol".

In one embodiment, one or more lubricants are included in the pharmaceutical compositions of the present invention. Examples of lubricants suitable for use in the present invention include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, lauryl Sodium sulfate, glyceryl palmitostearate, palmitic acid, myristic acid and hydrogenated vegetable oils (including hydrogenated castor oil) and fats and other known lubricants and/or mixtures of two or more of them.

Preferred embodiments of lubricants include magnesium stearate, calcium stearate, stearic acid, sodium stearoyl fumarate, hydrogenated castor oil, and mixtures thereof. More preferred lubricants are magnesium stearate, or sodium stearyl fumarate, or mixtures thereof.

In one embodiment, one or more glidants and/or antiadherents are included in the pharmaceutical compositions of the present invention. Examples of glidants and/or anti-adherents 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 dioxide Silicones such as aggregated silicates and hydrated silica.

Preferred embodiments of glidants include colloidal silicon dioxide, calcium phosphate, magnesium silicate and talc, or mixtures thereof. The preferred glidant is colloidal silica.

In one embodiment, the pharmaceutical composition of the present invention may optionally contain one or more surfactants or wetting agents. Surfactants can be anionic, cationic or neutral surfactants. Anionic surfactants include sodium lauryl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, and sodium laurate mixed with stearate and talc. Cationic surfactants include benzalkonium chloride and alkyltrimethylammonium bromide. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol, and sorbitan ester. Embodiments of wetting agents include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene stearate.

In one embodiment, optional antioxidants may also be included in the pharmaceutical compositions of the present invention to impart chemical stability. Examples of antioxidants suitable for use in the present invention include, but are not limited to, tocopherol, ascorbic acid, ascorbyl palmitate, gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), thioglycerol, potassium metabisulfite , propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite, and combinations thereof.

Preferably, the antioxidant is selected from the group consisting of alpha-tocopherol, gamma-tocopherol, delta-tocopherol, extracts from natural sources enriched in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitic acid ester, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene and butylated hydroxyanisole.

In one embodiment, the antioxidant is BHT or BHA.

In one embodiment, the pharmaceutical composition of the present invention may also add sweeteners and/or flavoring agents as required.

There are many types of sweeteners, which can be divided into natural sweeteners and synthetic sweeteners; nutritious sweeteners and non-nutritive sweeteners according to their nutritional value; sugars according to their chemical structure and properties and non-sugar sweeteners. Specific examples include sugars such as glucose, fructose, sucrose, maltose, starch sugar and lactose, natural sweeteners such as stevia, licorice, disodium glycyrrhizinate, tripotassium and trisodium glycyrrhizinate, saccharin, sodium saccharin, cyclohexyl Synthetic sweeteners such as sodium sulfamate, aspartame and alitame.

Flavor enhancers, also known as flavor enhancers, refer to substances that can significantly enhance or improve the original flavor of food. For example, sweet flavors are included to simulate flavors such as strawberry, apple, and peach.

Colorants include red iron oxide (iron trioxide), yellow iron oxide, and the like.

Preferable examples of the coating agent include sugar coating agents, water-soluble film coating agents, enteric film coating agents and the like.

The sugar coating agent uses sucrose. In addition, one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, amylopectin, carnauba wax and the like may also be used in combination.

Examples of water-soluble film coating agents include cellulosic polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, and the like; synthetic polymers such as poly Vinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, etc.

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

Preferred examples of coating additives include: plasticizers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), propylene glycol, triethyl citrate, castor oil, polysorbate, etc. or two or more thereof Opacifying agents such as titanium dioxide, etc.; colorants, dyes and lakes such as red iron oxide (iron trioxide), yellow iron oxide, etc.; glidants such as talc and the like.

In one embodiment, a commercially available coating agent such as Opadry as a pre-formulated powder mix supplied by Colorcon

In the pharmaceutical composition, the formulations are conventional dosage forms in the prior art, such as tablets, capsules, granules, pills, oral solutions, syrups, sugar-coated tablets, drops, suspensions and the like. In the present invention, Dorzagliatin can be included in any suitable dosage form.

The pharmaceutical composition can be prepared by any feasible formulation method in the prior art. The GLP-1 analog can be an oral formulation (eg, semaglutide tablets).

In a specific embodiment, the pharmaceutical compositions of the present invention are prepared by dry granulation or wet granulation (high shear and/or fluid bed).

Dry granulation involves direct compression of the active material with suitable excipients. Alternatively, the active substance powders can be mixed and granulated to prepare capsules.

Wet granulation is a method of adding a binder into a solvent to prepare a binder solution, and then adding or directly adding it into a granulator to make wet granules.

Dorzagliatin can also be prepared as a solid dispersion or as a combination tablet. For the preparation of solid dispersions and compound tablets of Dorzagliatin, please refer to CN107854435B, CN110548148A, CN110548026A, CN110548027A, CN110548146A, CN110548147A and CN110548149A. These patents/patent applications are incorporated herein by reference.

According to a preferred embodiment of the present invention, the present invention also provides a kit to meet the individualized treatment needs of different subjects.

The kit includes:

(a) Dorzagliatin or an isotopic label, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof; and

(b) A GLP-1 analog or a pharmaceutically acceptable salt thereof.

According to another preferred version of the present invention, the kit further includes:

(c) optionally at least one pharmaceutically acceptable carrier for dissolving or dispersing (a) and (b).

Wherein, the kit of the present invention may include the pharmaceutical composition, and in this case, the kit includes a container for accommodating the pharmaceutical composition. Alternatively, the (a) and (b) are separately contained in a single preparation as the active ingredients, in which case the kit of the present invention comprises two single preparation containers for containing (a) and (b), respectively of a single preparation. When the single preparation containing (b) as the active ingredient is in the form of an injection, the kit is also used to contain an injection device.

Preferably, the kit further includes instructions for use.

Those skilled in the art can easily understand the dosage range of the specific GLP-1 analog in the kit based on the prior art. The dosage range of the specific marketed GLP-1 analog in the above-mentioned pharmaceutical combination is preferred.

Use for the treatment and/or prevention of disease

Another embodiment of the present invention relates to a pharmaceutical combination and the use of the pharmaceutical composition in the preparation of a medicine. in particular:

A specific embodiment of the present invention relates to the use of the pharmaceutical combination and pharmaceutical composition of the present invention in the preparation of treatment and/or prevention of the following diseases and medical conditions, especially one or more selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance , Abnormal fasting glucose, hyperglycemia, postprandial hyperglycemia, hypertension, overweight, obesity, insulin resistance and the use of the drug for the metabolic syndrome. The uses of the above embodiments include the simultaneous, separate or sequential use of (a) and (b) in the pharmaceutical combination, pharmaceutical composition.

Yet another embodiment of the present invention relates to the kit of the present invention for the treatment and/or prevention of the following diseases and medical conditions, especially one or more selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, abnormal fasting glucose , hyperglycemia, postprandial hyperglycemia, hypertension, overweight, obesity, insulin resistance and metabolic syndrome.

Methods of treating and/or preventing disease

Yet another embodiment of the present invention involves administering to said subject simultaneously, separately or sequentially: (a) Dorzagliatin, or an isotopic label, enantiomer, diastereomer, pharmaceutically acceptable A salt, hydrate, solvate or crystalline form; and (b) a GLP-1 analog, or a pharmaceutically acceptable salt thereof, for use in a method of treating and/or preventing a disease.

According to a specific embodiment, in the method for treating and/or preventing diseases of the present invention, the weight ratio of Dorzagliatin to GLP-1 analog is about 30000:1 to 2:1, preferably about 30000:1, 15000:1 1, 7500:1, 5000:1, 3750:1, 3000:1, 2500:1, 2150:1, 1800:1, 1600:1, 1500:1, 1000:1, 750:1, 600:1, 500:1, 375:1, 300:1, 250:1, 215:1, 200:1, 190:1, 170:1, 150:1, 125:1, 100:1, 90:1, 80: 1, 75:1, 50:1, 40:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1 or 3:1.

According to a specific embodiment, in the method of treating and/or preventing a disease of the present invention, the Dorzagliatin is present in a dose (preferably a unit dose) ranging from about 1 mg to about 200 mg, preferably from about 25 mg to about 150 mg Dosage (preferably unit dose) ranges exist; more preferably, wherein the dose (preferably unit dose) of said Dorzagliatin is about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg or 150 mg.

According to a specific embodiment, in the method of treating and/or preventing disease of the present invention, the GLP-1 analog is present in a dose (preferably a unit dose) ranging from about 0.0001 mg to about 100 mg, preferably about 0.001 mg to about 100 mg. A dose (preferably unit dose) range of about 50 mg exists; more preferably, wherein the dose (preferably a unit dose) of the GLP-1 analog is about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.8 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 10 mg, 12 mg, 14 mg, 30 mg, or 50 mg.

In the method for treating and/or preventing disease of the present invention:

- preventing, slowing the progression, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, hyperglycemia Hypertension, overweight, obesity, insulin resistance and metabolic syndrome; or

-Improved glycemic control and/or decreased fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; or

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

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

- reduce weight and/or body fat, or prevent weight and/or body fat gain, or promote weight and/or body fat loss; or

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

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

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

- preventing, slowing the progression, delaying or treating of post-transplant new-onset diabetes mellitus (NODAT) and/or post-transplant metabolic syndrome (PTMS); or - preventing, delaying or reducing NODAT and/or PTMS-related complications, including microvascular and macrovascular disease and events, transplant rejection, infection and death; or

-Treatment of hyperuricemia and hyperuricemia-related conditions.

In a preferred embodiment of the present invention, the diseases include type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance and metabolic syndrome.

According to another embodiment, the present invention also provides a method of treating Type II diabetes by orally administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the present invention. In one embodiment, the subject in need of such treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet.

The pharmaceutical compositions of the present invention may be administered once daily (QD), twice daily (BID) or three times daily (TID).

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

Example 1. Pharmacodynamic study of Dorzagliatin combined with liraglutide

The efficacy of Dorzagliatin in combination with GLP-1 analogs (eg, liraglutide) in GK rats was investigated.

1. Experimental procedure

74 male GK rats (about 9-11 weeks old) and 10 male Wistar rats (about 9 weeks old) were obtained from Shanghai SLAC Laboratory Animal Co.LTD. Each rat was housed individually in a cage with a unique number for each cage.

Before the experiment, all rats were allowed to adapt to the environment and gavage mode for 1 week, that is, PO Acclimation. Two days before the end of the gavage adaptation period (-2 days), the rats were fasted for 8 hours, and the fasting blood glucose of the rats was detected. One day before the start of the 42-day efficacy study (day 0), 32 male GK rats, and 8 male Wistar rats were selected based on day 0 body weight, food intake, and -2 day fasting blood glucose data. Thirty-two male GK rats were randomly divided into 4 groups, with 8 rats in each group, respectively as group 2-Vehicle group, group 3-Dorzagliatin single-use group, group 4-liraglutide single-use group and group 5 -Dorzagliatin+liraglutide group. Eight male Wistar rats were used as group 1 - normal control group. The specific groups are shown in Table 1.

Table 1: Rats Grouping Scheme

Wherein, the solvent is: the double distilled water solution of 0.5% HPC+0.1% Tween 80; the concentration of liraglutide is 0.081mg/ml, the dose is 2.5ml/kg, that is, 0.2mg/kg, and the concentration of Dorzagliatin is 4.000mg/ml , the dose is 5mL/kg, that is, 20mg/kg. Body weight measurement: once a day; food intake measurement: once a day. Fasting blood glucose measurement: once a week.

In the experiment, liraglutide was purchased from Shanghai Bide Medical Technology Co., Ltd., and Dorzagliatin was obtained from: Hua Medicine Technology (Shanghai) Co., Ltd.

42-day efficacy research experiment

From days 1 to 6, all rats had free access to food and water before 9:00 a.m. every day, and their body weight and food intake were measured at 9:00 a.m. every day.

Group 2 was intragastrically administered with vehicle at 9:00 am and 17:00 pm, group 3 was intragastrically administered 2.5 mL/kg of Dorzagliatin at 9:00 am and 17:00 pm, respectively, and group 4 was injected subcutaneously with 0.2 mg/kg of liraglutide, group 5 was given 2.5 mL/kg of Dorzagliatin by gavage at 9:00 am and 17:00 pm, respectively, and at the same time, 0.2 mg/kg of liraglutide was subcutaneously injected at 9:00 am.

On the 7th day, the body weight and food intake of the rats in each group were measured at 9:00 in the morning. Groups 2 to 5 were given the vehicle or test drugs at around 9:00 in the morning and 16:00 in the afternoon, respectively, at 17:00 in the afternoon (ie Fasting for 8 hours) to measure fasting blood glucose.

After that, the experiment of week 1 was repeated (except days 33 and 42), and fasting blood glucose was detected on days 14, 21, 28 and 35, respectively.

On the 33rd day, all rats had free access to food and water before 7:00 am, the body weight and food intake of the rats in each group were measured at 7:00 am, and then fasted from 7:00 am to 12:00 am. Fasting blood glucose was measured at 12:00 (t=-60 min), then group 2 was gavaged with vehicle, and all rats in groups 3 to 5 were administered the test drugs. After 1 hour, blood glucose was measured (t=0 min); and glucose tolerance test was performed by oral gavage of glucose (2 g/kg, 5 ml/kg), and then blood glucose was measured 15, 30, 60 and 120 min after glucose administration. Blood was drawn from the tail at each time point -10 ul, and blood glucose levels were then tested by a blood glucose meter. Meanwhile, an additional 50 ul of blood was collected at t=0 min and t=30 min to separate plasma by anticoagulant 0.1 M EDTA-K2 for insulin and C-peptide testing. At the same time, an additional 120ul of blood was collected at t=0min and t=30min to separate plasma by anticoagulant 0.1M EDTA-K2 and aprotinin for glucagon testing. At the end of the study, food was placed in the cage and the rats were returned to the animal room.

On the 42nd day at the end of the study, all rats had free access to food and water before 7:00 am, and the body weight and food intake of the rats in each group were measured at 7:00 am, and then fasted from 7:00 am, and all animals were given Gastric vehicle or administration of test drug. At 12:00, Dorzagliatin was administered to all rats in groups 3 and 5. At 13:00 pm (ie, fasting for 6 hours), fasting blood glucose was measured. Rats were then euthanized with _CO and blood was collected via cardiac puncture, and plasma was isolated and collected for testing of fasting total GLP-1, fasting insulin, fasting glucagon and fasting C-peptide. 50uL of whole blood was collected for fasting HbA1C testing.

2. Experimental results

Analyze the fasting blood glucose data of animals in each group after fasting for 8 hours on days -2, 7, 14, 21, 28, and 35, and fasting blood glucose data after fasting for 6 hours on day 42, as shown in Figure 1 .

The data of fasting HbA1C, fasting insulin, fasting total GLP-1, fasting C-peptide and fasting glucagon on the 42nd day of each group of animals were analyzed. The results are shown in Figures 3 to 7. The -10mpk group represents the Dorzagliatin single-use group, the liraglutide-0.2mpk group represents the liraglutide single-use group, and the dozagliatin-10mpk+liraglutide-0.2mpk group represents the Dorzagliatin+liraglutide group.

2.1. Fasting blood glucose and OGTT

Fasting blood glucose data are shown in Table 3 in tabular form and in Figure 1 in graph form.

Table 3 Fasting blood glucose data on days -2, 7, 14, 21, 28, 35 and 42

Combined with Table 3 and Figure 1, it can be seen that Dorzagliatin combined with liraglutide can control fasting blood glucose better and faster than Dorzagliatin alone or liraglutide alone.

As shown in Figure 2, in the OGTT experiment, Dorzagliatin combined with liraglutide further reduced the area under the blood glucose curve compared to Dorzagliatin alone or liraglutide alone. And the combined effect was significantly different from that of Dorzagliatin alone or liraglutide alone.

Specifically: compared with Dorzagliatin alone, the AUC of the Wistar rat normal control group was 16161 mg/dL.min, the AUC of the vehicle group was 44148 mg/dL.min, the Dorzagliatin alone group was 37328 mg/dL.min, and the liraglutide was 37328 mg/dL.min. The single-use group was 37763 mg/dL.min, and the Dorzagliatin and liraglutide combination group was 29962 mg/dL.min.

Combining Figure 1, Figure 2 and Table 3, it can be seen that Dorzagliatin combined with liraglutide has a significant synergistic effect.

2.2. Fasting HbA1C, fasting total GLP-1, fasting insulin, fasting C-peptide and fasting glucagon

Figures 3 to 7 show the synergistic effect of Dorzagliatin combined with liraglutide on fasting HbA1C, fasting total GLP-1, fasting insulin, fasting C-peptide and fasting glucagon indicators, respectively.

2.2.1. Fasting HbA1C

As shown in Figure 3, Dorzagliatin combined with liraglutide can reduce fasting HbA1C better than Dorzagliatin or liraglutide alone, and the effect of the combination is significantly different than that of liraglutide alone.

Specifically, the fasting HbA1C of the Wistar rat normal control group was 3.2%, the fasting HbA1C of the vehicle group was 4.7%, the Dorzagliatin single group was 3.6%, the liraglutide single group was 3.8%, Dorzagliatin and liraglutide were The combination group was 3.4%.

2.2.2. Fasting total GLP-1

As shown in Figure 4, Dorzagliatin combined with liraglutide can improve fasting total GLP-1 better than Dorzagliatin or liraglutide alone, and the combined effect is significantly different from Dorzagliatin alone.

Specifically, the fasting total GLP-1 of the Wistar rat normal control group was 19.1 pM, the fasting total GLP-1 of the vehicle group was 16.1 pM, the Dorzagliatin single-use group was 16.0 pM, and the liraglutide single-use group was 32.6 pM, Dorzagliatin combined with liraglutide was 33.8 pM.

2.2.3. Fasting insulin

As shown in Figure 5, Dorzagliatin combined with liraglutide can reduce fasting insulin and improve insulin resistance better than Dorzagliatin or liraglutide alone.

Specifically, the fasting insulin of the Wistar rat normal control group was 4.17 ng/mL, the fasting insulin of the vehicle group was 6.28 ng/mL, the Dorzagliatin single-use group was 4.97 ng/mL, and the liraglutide single-use group was 4.86 ng/mL. mL, Dorzagliatin combined with liraglutide group was 3.82ng/mL.

2.2.4. Fasting C-peptide

As shown in Figure 6, Dorzagliatin combined with liraglutide can better reduce fasting C-peptide and improve insulin resistance than Dorzagliatin or liraglutide alone.

Specifically, the fasting C-peptide of the Wistar rat normal control group was 1042 pmol/L, the fasting C-peptide of the vehicle group was 1223 pmol/L, the Dorzagliatin single-use group was 1129 pmol/L, and the liraglutide single-use group was 1036 pmol/L. L, Dorzagliatin combined with liraglutide group was 935pmol/L.

2.2.5. Fasting glucagon

As shown in Figure 7, Dorzagliatin combined with liraglutide reduced fasting glucagon better than either Dorzagliatin or liraglutide alone. Specifically, the fasting glucagon of the Wistar rat normal control group was 122.7 pg/mL, the fasting glucagon of the vehicle group was 124.46 pg/mL, the Dorzagliatin single group was 112.39 pg/mL, and the liraglutide single group was 112.39 pg/mL. The group was 121.74pg/mL, and the group that used Dorzagliatin in combination with liraglutide was 112.19pg/mL.

The test results show that the combination of 10mg/kg Dorzagliatin (gavage, twice a day) and 0.2mg/kg liraglutide (subcutaneous injection, once a day) has a significantly better hypoglycemic effect than 10mg/kg Dorzagliatin (gavage). , twice a day) or 0.2 mg/kg liraglutide (subcutaneous injection, once a day) monotherapy.

The above-mentioned pharmacodynamic efficacy study of Dorzagliatin in combination with existing diabetes drugs shows that the combined use can improve the efficacy of Dorzagliatin or GLP-1 analogs of existing hypoglycemic drugs, improve insulin resistance, and reduce safety risks.

Claims

A drug combination comprising:

(a) Dorzagliatin, or an isotopic label, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof; and

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.
The pharmaceutical combination of claim 1, wherein said (a) and (b) are used simultaneously, separately or sequentially.
The pharmaceutical combination of claim 1 or 2, wherein the weight ratio of Dorzagliatin to GLP-1 analog is about 30000:1 to 2:1, preferably about 30000:1, 15000:1, 7500:1, 5000:1 , 3750:1, 3000:1, 2500:1, 2150:1, 1800:1, 1600:1, 1500:1, 1000:1, 750:1, 600:1, 500:1, 375:1, 300 :1, 250:1, 215:1, 200:1, 190:1, 170:1, 150:1, 125:1, 100:1, 90:1, 80:1, 75:1, 50:1 , 40:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1, or 3:1.
The pharmaceutical combination of any one of claims 1-3, wherein the Dorzagliatin is present in a dose (preferably unit dose) range of about 1 mg to about 200 mg, preferably a dose (preferably a unit dose) of about 25 mg to about 150 mg ) range exists; more preferably, wherein the dose (preferably a unit dose) of said Dorzagliatin is about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg or 150 mg.
The pharmaceutical combination of any one of claims 1-4, wherein the GLP-1 analog is present in a dose (preferably unit dose) range of about 0.0001 mg to about 100 mg, preferably a dose of about 0.001 mg to about 50 mg (preferably unit dose) ranges exist; more preferably, wherein the dose (preferably unit dose) of the GLP-1 analog is about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg , 1.5 mg, 1.6 mg, 1.8 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 10 mg, 12 mg, 14 mg, 30 mg, or 50 mg.
The pharmaceutical combination of any one of claims 1-5, wherein the GLP-1 analog is selected from the group consisting of liraglutide, exenatide, albiglutide, dulaglutide, semaglutide, lixisenatide Natide, Benaglutide and Loxenatide; preferably, the GLP-1 analog is liraglutide.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is liraglutide in a dose (preferably a unit dose) of about 0.6 mg, 1.2 mg or 1.8 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is exenatide in a dose (preferably a unit dose) of about 0.005 mg, 0.01 mg, or 0.02 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is exenatide microspheres in a dose (preferably a unit dose) of about 0.03 mg, 1 mg or 2 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is albiglutide in a dose (preferably a unit dose) of about 4 mg, 7 mg, 30 mg or 50 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is dulaglutide in a dose (preferably a unit dose) of about 0.1 mg, 0.2 mg, 0.75 mg or 1.5 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is dulaglutide in a dose (preferably a unit dose) of about 3.0 mg or 4.5 mg.
The pharmaceutical combination of claim 6, wherein the GLP-1 analog is an injectable formulation of semaglutide in a dose (preferably a unit dose) of about 0.04 mg, 0.07 mg, 0.15 mg, 0.25 mg, 0.5 mg or 1.0 mg .
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is an injectable formulation of semaglutide in a dose (preferably a unit dose) of 2.0 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is an oral formulation of semaglutide in a dose (preferably a unit dose) of about 3 mg, 7 mg or 14 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is lixisenatide in a dose (preferably a unit dose) of about 0.01 mg or 0.02 mg.
6. The pharmaceutical combination of claim 6, wherein the GLP-1 analog is benaglutide in a dose (preferably a unit dose) of about 0.1 mg, 0.2 mg, 0.3 mg or 0.6 mg.
The pharmaceutical combination of claim 6, wherein the GLP-1 analog is loxenatide in a dose (preferably a unit dose) of about 0.01 mg, 0.03 mg, 0.1 mg or 0.2 mg; preferably, the loxenatide The dose (preferably a unit dose) of the peptide is 0.1 mg or 0.2 mg.
A pharmaceutical composition comprising:

(a) Dorzagliatin, or an isotopic label, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof; and

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition of claim 19, wherein the weight ratio of Dorzagliatin to GLP-1 analog is about 30000:1 to 2:1, preferably about 30000:1, 15000:1, 7500:1, 5000:1, 3750:1, 3000:1, 2500:1, 2150:1, 1800:1, 1600:1, 1500:1, 1000:1, 750:1, 600:1, 500:1, 375:1, 300:1 1, 250:1, 215:1, 200:1, 190:1, 170:1, 150:1, 125:1, 100:1, 90:1, 80:1, 75:1, 50:1, 40:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1 or 3:1.
The pharmaceutical composition of any one of claims 19-20, wherein the Dorzagliatin is present in a dose (preferably unit dose) range of about 1 mg to about 200 mg, preferably a dose (preferably a unit dose) of about 25 mg to about 150 mg dose) range exists; more preferably, wherein the dose (preferably a unit dose) of said Dorzagliatin is about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg or 150 mg.
The pharmaceutical composition of any one of claims 19-21, wherein the GLP-1 analog is present in a dose (preferably unit dose) range of about 0.0001 mg to about 100 mg, preferably about 0.001 mg to about 50 mg Dosage (preferably unit dose) ranges exist; more preferably, wherein the dose (preferably unit dose) of the GLP-1 analog is about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg , 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.8 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 10 mg, 12 mg, 14 mg, 30 mg, or 50 mg.
The pharmaceutical composition of any one of claims 19-22, wherein the GLP-1 analog is selected from the group consisting of liraglutide, exenatide, albiglutide, dulaglutide, semaglutide, Senatide, Benaglutide and Loxenatide; preferably, the GLP-1 analog is liraglutide.
24. The pharmaceutical composition of claim 23, wherein the GLP-1 analog is liraglutide in a dose (preferably a unit dose) of about 0.6 mg, 1.2 mg or 1.8 mg.
The pharmaceutical composition of any one of claims 19-24, further comprising one or more pharmaceutically acceptable excipients.
A kit comprising:

(a) Dorzagliatin, or an isotopic label, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof;

(b) A GLP-1 analog, or a pharmaceutically acceptable salt thereof.
Use of the pharmaceutical combination of any one of claims 1-18, or the pharmaceutical composition of any one of claims 19-25, in the manufacture of a medicament.
28. The use of claim 27, wherein the medicament is a kit.
28. The use of claim 27 or 28, wherein in the medicament, (a) and (b) are used simultaneously, separately or sequentially.
29. The use of any one of claims 27-29, wherein the medicament is for the treatment of diabetes and its associated symptoms.
The purposes of claim 30, wherein the diabetes and its associated symptoms are selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension , insulin resistance and metabolic syndrome.
A method of treating a disease in a subject comprising administering to the subject the pharmaceutical composition of any one of claims 1-18, or the pharmaceutical composition of any one of claims 19-25, or The kit of claim 26.
The method of claim 32, wherein the disease comprises type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance and metabolism syndrome.
The pharmaceutical combination of any one of claims 1-18, or the pharmaceutical composition of any one of claims 19-25, or the kit of claim 26, for the treatment of a disease; preferably, the disease comprises I Type 2 diabetes, type 2 diabetes, impaired glucose tolerance, abnormal fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance and metabolic syndrome.