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WO2019228365A1 - 含有葡萄糖激酶激活剂和dpp-iv抑制剂的药物组合、组合物和复方制剂及其制备方法和用途 - Google Patents

含有葡萄糖激酶激活剂和dpp-iv抑制剂的药物组合、组合物和复方制剂及其制备方法和用途 Download PDF

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Publication number
WO2019228365A1
WO2019228365A1 PCT/CN2019/088864 CN2019088864W WO2019228365A1 WO 2019228365 A1 WO2019228365 A1 WO 2019228365A1 CN 2019088864 W CN2019088864 W CN 2019088864W WO 2019228365 A1 WO2019228365 A1 WO 2019228365A1
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WIPO (PCT)
Prior art keywords
hms5552
solid dispersion
dose
fixed
eudragit
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Ceased
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PCT/CN2019/088864
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English (en)
French (fr)
Inventor
陈力
李永国
王高森
高慧升
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Hua Medicine Shanghai Ltd
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Hua Medicine Shanghai Ltd
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Priority to RU2020143045A priority Critical patent/RU2770775C1/ru
Priority to CA3101831A priority patent/CA3101831A1/en
Priority to AU2019278016A priority patent/AU2019278016B2/en
Priority to HRP20250258TT priority patent/HRP20250258T1/hr
Priority to MX2020012965A priority patent/MX2020012965A/es
Priority to LTEPPCT/CN2019/088864T priority patent/LT3804715T/lt
Priority to IL279039A priority patent/IL279039B2/en
Priority to FIEP19811377.1T priority patent/FI3804715T3/fi
Priority to SM20250104T priority patent/SMT202500104T1/it
Priority to JP2020566718A priority patent/JP7565589B2/ja
Priority to US17/058,903 priority patent/US11963947B2/en
Priority to SG11202011881PA priority patent/SG11202011881PA/en
Priority to ES19811377T priority patent/ES3015131T3/es
Priority to EP19811377.1A priority patent/EP3804715B1/en
Priority to KR1020207037560A priority patent/KR102695135B1/ko
Priority to BR112020024125-3A priority patent/BR112020024125A2/pt
Priority to PL19811377.1T priority patent/PL3804715T3/pl
Priority to SI201930906T priority patent/SI3804715T1/sl
Priority to DK19811377.1T priority patent/DK3804715T3/da
Application filed by Hua Medicine Shanghai Ltd filed Critical Hua Medicine Shanghai Ltd
Priority to RS20250230A priority patent/RS66564B1/sr
Publication of WO2019228365A1 publication Critical patent/WO2019228365A1/zh
Anticipated expiration legal-status Critical
Priority to ZA2020/07681A priority patent/ZA202007681B/en
Priority to JP2022178385A priority patent/JP2022190170A/ja
Priority to US18/610,100 priority patent/US20240299357A1/en
Ceased legal-status Critical Current

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Definitions

  • the invention relates to a pharmaceutical combination, a composition and a fixed dose compound (FDC) preparation comprising a glucocokinase activator (GKA) drug and a partner drug, a preparation method thereof, and a method for treating the same.
  • FDC fixed dose compound
  • GKA glucocokinase activator
  • the present invention relates to a pharmaceutical combination, a pharmaceutical composition or a fixed-dose compound oral solid preparation comprising a glucokinase activator drug and a combination drug, and a method for preparing the same.
  • the invention also relates to the use of a pharmaceutical combination, a pharmaceutical composition or a fixed dose compound formulation comprising a glucokinase activator for the treatment and / or prevention of one or more diseases and medical conditions, including but not limited to type I diabetes, Type II diabetes, diabetic cognitive dysfunction, memory dysfunction, dementia, impaired glucose tolerance, abnormal fasting blood glucose, obesity, and hypertension.
  • the present invention also relates to a method of treating and / or preventing one or more diseases and medical conditions, which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical combination, a pharmaceutical composition or a fixed dose compound of the present invention preparation.
  • Type II diabetes or non-insulin dependent diabetes mellitus (NIDDM), accounts for more than 90% of diabetic patients.
  • Type II diabetes is a chronic metabolic disorder of hyperglycemia caused by impaired insulin secretion and insulin resistance caused by imbalance of human blood glucose homeostasis. Human blood glucose balance is mainly completed by the coordination of two glucose-controlling hormones, insulin and glucagon.
  • Glucose sensor Glucokinase senses changes in blood glucose and regulates the secretion of messenger-controlled hormones, insulin and glucagon, and GLP-1 (glucagon-like peptide-1), which constitutes the body's stable regulation of blood glucose Sense system.
  • Glucose hormone controlled glucose control during glucose uptake and fasting glucose supply constitute the steady state regulation of human blood glucose.
  • the organs involved in glucose reserve are mainly liver, muscle and fat, which are taken up by glucose and insulin and converted into liver glycogen, muscle glycogen and triglycerides.
  • the main organ involved in the supply of glucose is the liver. Under the action of blood glucose and glucagon, it supplies sugar to the human body through the synthesis of glucose and the output of glucose from the liver.
  • Insulin can also effectively regulate the activity of the sodium-glucose cotransporter SGLT-2.
  • the blood glucose rises, it can reabsorb the glucose excreted by the kidneys, which is used by the body for glucose reserve.
  • Glucose uptake and liver glucose output, as well as the use of glucose by various organs constitute an operating system for the steady-state balance of human blood glucose.
  • the coordinated operation of the glucose sensing system and the operation and operation system constitutes a random regulation of human blood glucose homeostasis.
  • glucose-controlling hormone signal instruction causes abnormal functions and expressions of key proteins in the glucose uptake and output operation execution system, resulting in abnormal operation and the formation of type II diabetes.
  • Glucokinase activators represent a new class of drugs developed to treat or improve the disease state of patients with type 2 diabetes.
  • ((S) -2- [4-((2-chloro-phenoxy) -2-oxo-2,5-dihydro-pyrrole-1-yl] -4-methyl-pentanoic acid [ 1-((R) -2,3-dihydroxy-propyl) -1H-pyrazol-3-yl] -amide (hereinafter referred to as HMS5552) can effectively improve the function of the glucose sensor in patients with diabetes. Hope to solve the above clinical needs of diabetes treatment drugs.
  • DPP-IV inhibitors alone is not effective, and blood glucose cannot be controlled at the desired level, especially after a period of use.
  • the present inventors found that the combination of a DPP-IV inhibitor and a glucokinase activator can significantly improve the hypoglycemic effect of the DPP-IV inhibitor and reduce the safety risk, and thus obtained the glucokinase activator and Pharmaceutical combination, composition and compound preparation of DPP-IV inhibitor.
  • the combined use of different oral medications for diabetes can improve the multi-organ function in patients with advanced stage and more effective treatment of diabetes and its associated diseases and complications. It can reduce the number of pills taken by the patient and improve the compliance of the patient; reduce the total dose of the drug to achieve the same effect, use the smallest dose to achieve the maximum drug effect, and treat or prevent one or more type I diabetes, type II
  • the symptoms of diabetes, hyperglycemia, impaired glucose tolerance, and obesity have good effects and practical significance.
  • the fixed-dose compound preparation containing a glucokinase activator and a combination drug (a second or more active pharmaceutical ingredient) of the present invention not only has a better therapeutic effect than the two or more drugs alone, It also solves the technical challenges commonly found in compound formulations.
  • the fixed-dose compound preparation of the present invention can solve the problems of simultaneous release and uniform content of two or more active ingredients, and can optimize the dissolution rate of the active ingredients contained in the preparation, especially to make the active ingredients contained in the preparation in the pH environment of the small intestine.
  • the rapid release of the drug is beneficial to the timely or simultaneous arrival of the drug in the intestinal tract, islet and liver target organs, to achieve the clinical advantage of multiple targets and synergistic hypoglycemia, and to exert better effects and reduce toxic and side effects.
  • the fixed-dose compound preparation containing a glucokinase activator and a combination drug (second or more active pharmaceutical ingredients) of the present invention also has a short disintegration time, and has good dissolution characteristics and / or makes glucokinase Activators are capable of high bioavailability in patients.
  • the present invention provides a glucokinase activator, for example, HMS5552 with the structure shown below, or its isotope label, or a pharmaceutically acceptable salt thereof, in combination with other oral hypoglycemic drugs, a pharmaceutical composition, a fixed dose compound , Especially solid preparations, such as oral solid preparations, such as tablets,
  • the present invention also provides a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose combination preparation comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a DPP-IV inhibitor.
  • DPP-IV inhibitors include, but are not limited to, sitagliptin, saxagliptin, vitagliptin, lidagliptin, alogliptin, denagliptin, meglitazone Ting, Goseliptin, Teligliptin, Duglitin, and their pharmaceutically acceptable salts.
  • sitagliptin, saxagliptin, vitagliptin, and lidagliptin are preferred.
  • the present invention also provides a fixed-dose solid preparation containing a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a combination drug such as sitagliptin.
  • the solid preparation is preferably a tablet, and more preferably a coated tablet.
  • the glucokinase activator such as HMS5552 is in the form of a solid dispersion.
  • the present invention also provides a fixed-dose compound solid preparation comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a combination drug such as vitagliptin.
  • the solid preparation is preferably a tablet, and more preferably a coated tablet.
  • the glucokinase activator such as HMS5552 is in the form of a solid dispersion.
  • the present invention also provides a fixed-dose combination solid preparation comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a combination drug such as saxagliptin.
  • the solid preparation is preferably a tablet, and more preferably a coated tablet.
  • the glucokinase activator such as HMS5552 is in the form of a solid dispersion.
  • the present invention also provides a fixed-dose solid preparation containing a glucokinase activator drug HMS5552 or a pharmaceutically acceptable salt thereof, and a combination drug such as ligagliptin.
  • the solid preparation is preferably a tablet, and more preferably a coated tablet.
  • the glucokinase activator such as HMS5552 is in the form of a solid dispersion.
  • the present invention also provides a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose combination preparation of a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredient) prepared by a dry or wet processing method.
  • the release mode of the pharmaceutical combination, pharmaceutical composition or fixed-dose compound preparation of the present invention is the rapid release of the two or more active pharmaceutical ingredients.
  • the present invention also provides a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredient), which has a short disintegration time, which has good dissolution characteristics and / or enables glucokinase activation
  • the agent is capable of high bioavailability in patients.
  • the present invention also provides preparation of glucokinase activator drugs and combination drugs (second or more active pharmaceutical ingredients, such as sitagliptin, saxagliptin, vitagliptin, and Ligliptin) method of fixed-dose combination pharmaceutical composition or pharmaceutical formulation.
  • Dry processing methods include dry compression (tablet) and dry granulation; wet processing methods include wet granulation.
  • the present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredient), and for preventing a metabolic disorder (especially type II diabetes).
  • a pharmaceutical combination especially type II diabetes.
  • the present invention also provides a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation comprising a glucokinase activator drug and a combination drug (a second or more active pharmaceutical ingredient), and for use in patients in need (especially those suffering from II To improve glycemic control in patients with type 2 diabetes).
  • the present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug, and a method for improving blood glucose control in a patient with insufficient blood glucose control.
  • the present invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug, and a method for preventing, slowing or delaying diabetic cognitive dysfunction, memory dysfunction, dementia, impaired glucose tolerance IGT), fasting blood glucose abnormalities (IFG), hypertension, insulin resistance, and / or a method of progressing to type 2 diabetes.
  • the present invention also provides a pharmaceutical combination, a pharmaceutical composition, and a pharmaceutical preparation comprising a glucokinase activator drug and a combination drug, and a method for preventing a disease or a condition including complications of diabetes, slowing its progression, delaying or treating the disease or Methods of illness.
  • a first aspect of the present invention provides a pharmaceutical combination, a pharmaceutical composition, or a pharmaceutical preparation comprising the following components, a method for preparing the same, and uses for treating diabetes and related diseases:
  • a glucokinase activator which is a compound selected from the following, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form thereof, a hydrate, a solvate, a diastereomer, or an enantiomer
  • the glucokinase activator is HMS5552; more preferably, HMS5552 is present in the form of a solid dispersion,
  • Another aspect of the present invention provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical preparation comprising the following components, a method for preparing the same, and use of the method for treating diabetes and related diseases:
  • a glucokinase activator which is selected from the group consisting of a HMS5552 compound, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form thereof, a hydrate, a solvate, a diastereomer or an enantiomer Form; preferably, the glucokinase activator is HMS5552; more preferably, HMS5552 is present in the form of a solid dispersion;
  • one aspect of the invention also relates to a fixed-dose combination drug combination, a drug comprising a HMS5552 solid dispersion and a combination drug (e.g., sitagliptin, vitagliptin, saxagliptin, lidagliptin) Composition or pharmaceutical preparation, and preparation method and use thereof.
  • a combination drug e.g., sitagliptin, vitagliptin, saxagliptin, lidagliptin
  • references to "A and / or B", when used in conjunction with an open ended text such as “include”, may in one embodiment refer only to A (optionally including other than B Components); in another embodiment, may refer only to B (optionally including components other than A); in yet another embodiment, refers to A and B (optionally including other components) and the like.
  • DPP-IV inhibitor or any of its species (eg, “sitagliptin, vitagliptin, saxagliptin, lidagliptin”) in the context of the present invention is also intended It includes any of its pharmaceutically acceptable salts, its crystalline form, hydrate, solvate, diastereomer or enantiomer.
  • HMS5552 which was previously named RO5305552, English name Dorzagliatin, and chemical name (S) -2- [4- (2-chloro-phenoxy) -2-oxo-2,5-dihydro-pyrrole- 1-yl] -4-methyl-pentanoic acid [1-((R) -2,3-dihydroxy-propyl) -1H-pyrazol-3-yl] -amide.
  • weight percent is expressed as a percentage of the total weight of a pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation.
  • a solid dispersion refers to a solid dispersion system in which one or more pharmaceutically active ingredients are highly dispersed into inactive excipients or carriers.
  • tablette as used herein is intended to include compressed pharmaceutical formulations of all shapes and sizes, whether coated or not.
  • an "effective amount” or “therapeutically effective amount” refers to an amount of an agent sufficient to provide a desired biological result.
  • the result may be a reduction and / or alleviation of signs, symptoms or causes of the disease, or any other desired change in the biological system.
  • an "effective amount” for therapeutic use refers to the amount of a composition required to clinically significantly reduce a disease comprising a compound as an active ingredient of the present invention.
  • an appropriate “effective” amount can be determined by one of ordinary skill in the art using routine experimentation. Therefore, the expression “effective amount” generally refers to the amount when the active substance has a therapeutic effect.
  • the term "treat” or “treatment” is synonymous with the term “prevent” and is intended to mean delaying the development of a disease, preventing the development of a disease, and / or reducing the development that is or is expected to develop The severity of the symptoms.
  • these terms include improving the symptoms of an existing disease, preventing additional symptoms, improving or preventing underlying metabolic causes of the symptoms, inhibiting a disorder or disease, for example, preventing the development of the disorder or disease, alleviating the disorder or disease, making the disorder or disease Degenerate, alleviate a condition caused by a disease or disorder, or stop the symptoms of a disease or disorder.
  • “Pharmaceutical” or “pharmacologically acceptable” refers to a substance that is not substantially biologically or otherwise undesirable, that is, the substance can be administered to an individual without causing any unwanted Biologically or without interacting in a harmful manner with any other component of a composition comprising such a substance.
  • subject includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; Dogs and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs.
  • non-mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • the compound that is an active ingredient in a glucokinase activator-containing pharmaceutical combination, pharmaceutical composition, or pharmaceutical preparation (for example, a fixed-dose combination preparation) of the present invention may form a salt.
  • salt as used herein refers to acid salts formed with inorganic and / or organic acids and basic salts formed with inorganic and / or organic bases.
  • a zwitterion 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, but other salts are also useful.
  • the salt of the compound can be formed, for example, by reacting the compound with a certain (e.g., equivalent) acid or base in a medium, such as the medium in which the salt precipitates or the aqueous medium ( Lyophilized after the reaction).
  • FIG. 1 is the dissolution result of Example 4B and the same-dose single-sided tablet
  • Figure 2 shows the results of pharmacodynamic animal studies of HMS5552 combined with sitagliptin in rats with type 2 diabetes.
  • One aspect of the invention relates to a glucokinase activator (preferably HMS5552 or its isotope marker or a pharmaceutically acceptable salt) and a combination drug (e.g., sitagliptin, vitagliptin, saxagliptin, ligag (Lentin), a pharmaceutical combination, a pharmaceutical composition, or a pharmaceutical preparation such as a fixed-dose combination.
  • a glucokinase activator preferably HMS5552 or its isotope marker or a pharmaceutically acceptable salt
  • a combination drug e.g., sitagliptin, vitagliptin, saxagliptin, ligag (Lentin)
  • the formulation may be in powder, granule, tablet, capsule, sachet, or other solid form.
  • one aspect of the invention relates to a fixed-dose combination tablet containing a glucokinase activator and a combination drug (eg, sitagliptin, vitagliptin, saxagliptin, lidagliptin).
  • a combination drug eg, sitagliptin, vitagliptin, saxagliptin, lidagliptin.
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation comprises:
  • glucokinase activator or a pharmaceutically acceptable salt thereof, or an isotopic label thereof, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof; preferably, said
  • the glucokinase activator is preferably HMS5552; more preferably, HMS5552 is present in the form of a solid dispersion, such as a solid dispersion comprising a polymer carrier (eg, a spray-dried powder);
  • DPP-IV inhibitor preferably, it is selected from the group consisting of: sitagliptin, vilagliptin, saxagliptin, lidagliptin, or a pharmaceutically acceptable salt thereof, an isotope marker thereof, and a crystal thereof Form, hydrate, solvate, diastereomer or enantiomeric form; and / or
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation may further contain one or more excipients, the excipients being selected from one or more binders; one or more A diluent (filler); one or more disintegrants; one or more lubricants; one or more glidants; one or more surfactants or wetting agents; and one Or multiple antioxidants; and one or more coating agents.
  • excipients being selected from one or more binders; one or more A diluent (filler); one or more disintegrants; one or more lubricants; one or more glidants; one or more surfactants or wetting agents; and one Or multiple antioxidants; and one or more coating agents.
  • the present invention relates to a pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed-dose combination formulation), which comprises:
  • a glucokinase activator which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystal form thereof, a hydrate, a solvate, a diastereomer, or an enantiomer Body form
  • sitagliptin is selected from the group consisting of sitagliptin, saxagliptin, vilagliptin, lidagliptin, alogliptin, dinaliptin, metagliptin, goselitin, teliliptin, Doxagliptin, and its pharmaceutically acceptable salts.
  • sitagliptin, saxagliptin, vitagliptin, and lidagliptin are preferred;
  • the above drugs (a) and (b) are used simultaneously, separately or sequentially.
  • the weight ratio of the glucokinase activator to the DPP-IV inhibitor in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation is about 1:10 to 100: 1 , Preferably about 1: 4 to 40: 1, more preferably about 1: 4, about 1: 2, about 1: 1, about 1.5: 1, about 1.5: 2, about 2: 1, and about 5: 1. About 10: 1, about 15: 1, about 20: 1, or about 40: 1.
  • the glucokinase activator ranges from about 1 mg to about 200 mg, preferably from about 25 mg to about 100 mg A range of doses (preferably unit doses) exists, preferably, wherein the dose (preferably unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg, or about 100 mg.
  • the DPP-IV inhibitor in a dose (preferably unit dose) range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg. Is present, preferably, wherein the dose (preferably a unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, or about 100 mg, and most preferably about 2.5 Mg, about 5 mg, about 50 mg, or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin, and its dose (preferably a unit dose) is about 25 mg to about 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, more preferably about 25 mg, 50 mg, or about 100 mg; preferably, said The DPP-IV inhibitor is lidagliptin, and its dosage (preferably a unit dose) is about 1 mg to about 20 mg, preferably about 1 mg, about
  • the aforementioned glucokinase activator is the compound HMS5552, or an isotope marker thereof, or a pharmaceutically acceptable salt thereof.
  • the glucokinase activator is present in the form of a solid dispersion.
  • the solid dispersion is obtained by a glucokinase activator, or an isotope label thereof, or a pharmaceutically acceptable salt thereof together with a polymer carrier by spray drying, hot melting or freeze drying.
  • the content of the glucokinase activator in the solid dispersion may vary from about 1% to about 99% by weight, preferably 10% to 90% by weight, based on the total weight of the solid dispersion. . In one embodiment, the content of glucokinase activator ranges from about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, approximately 9% by weight, approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, approximately 13% by weight, approximately 14% by weight, approximately 15% by weight, approximately 16% by weight, approximately 17% by weight, approximately 18% by weight, approximately 19% by weight, approximately 20% by weight, approximately 21% by weight, approximately 22% by weight, approximately 23% by weight, approximately 24% by weight, approximately 25% by weight, approximately 26% by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 3
  • the content of the glucokinase activator in the solid dispersion is about 1% to about 20% by weight, about 2% to about 40% by weight, and about 30% by weight based on the total weight of the solid dispersion. % To about 60% by weight, about 60% to about 80% by weight, about 70% to about 90% by weight, or about 80% to about 100% by weight.
  • the glucokinase activator is present in the form of a solid dispersion in which the glucose
  • the weight ratio of the kinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, About 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, About 3: 4, about 4: 5, or about 5: 6 or any range therebetween.
  • the glucokinase activator is the compound HMS5552, an isotopic label thereof, or a pharmaceutically acceptable salt thereof, which is polymerized with
  • the solid carrier is spray-dried, hot-melted or freeze-dried to obtain a solid dispersion.
  • the polymer carrier in the solid dispersion is selected from a polypropylene resin polymer, which is made of acrylic acid (or Methacrylic acid and their esters (such as methyl ester, ethyl ester, etc.) are polymerized in bulk (a monomer), or with methacrylic acid (or its esters such as: methyl ester, ethyl ester, and dimethylaminoethyl ester) Etc.) A polymer compound formed by copolymerizing two monomers (binary) or three monomers (ternary) at a certain ratio.
  • the polymer carrier used in the solid dispersion in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation is selected from the group consisting of butyl methacrylate, dimethyl methacrylate Copolymers of amine ethyl ester and methyl methacrylate, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methyl methacrylate, ethyl acrylate, methyl methacrylate and methyl Copolymer of trimethylaminoethyl acrylate, copolymer of ethyl acrylate and methyl methacrylate, copolymer of methacrylic acid, methyl acrylate and methyl methacrylate, copolymer of methacrylic acid and butyl acrylate Copolymer.
  • the polymer carrier is selected from the group consisting of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1: 2: 1) copolymer, methacrylic acid and ethyl acrylate (1: 1) copolymer, methacrylic acid and methyl methacrylate (1: 2) copolymer, ethyl acrylate, methyl methacrylate, and trimethylaminoethyl methacrylate chloride (1: 2: 0.2) Copolymer, copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate (1: 2: 0.1), copolymerization of ethyl acrylate and methyl methacrylate (2: 1) Copolymer, methacrylic acid and butyl acrylate (35:65) copolymer, methacrylic acid and methyl methacrylate (1: 1) copolymer, methacrylate, me
  • the above polymer carrier is Eudragit, including Eudragit E, Eudragit L, Eudragit S, Eudragit RL, and Eudragit RS, wherein Eudragit E is dimethylamino methacrylate and others.
  • Copolymers of methacrylic acid esters including polymers of dimethylaminoethyl methacrylate and methacrylates
  • Eudragit RL and Eudragit RS type contains some Copolymers of acrylic and methacrylic acid esters of quaternary amine genes, including copolymers of acrylic acid and methacrylates containing 10% quaternary amine groups and copolymers of acrylic acid and methacrylates containing
  • the aforementioned polymer carrier is selected from:
  • Eudragit E100 which is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1: 2: 1), including Eutech EPO;
  • Eudragit L100 is a type of methacrylic acid copolymer, which is an anionic copolymer of methacrylic acid and methyl methacrylate (1: 1);
  • Eudragit S100 a copolymer of methacrylic acid and methyl methacrylate (1: 2);
  • the polymer carrier in the HMS5552 solid dispersion is a methacrylic acid copolymer type A (methacrylic acid and methyl
  • the methyl acrylate (1: 1) anionic copolymer) is preferably Eudragit, and more preferably Eudragit L100.
  • the weight ratio of HMS5552 to Eudragit L100 in the HMS5552 solid dispersion in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation is from about 1:10 to 10: 1, about 1 : 9 to 9: 1, about 2: 3 to 9: 1, about 3: 4 to 9: 1, about 4: 5 to 9: 1, about 5: 6 to 9: 1, or about 1: 1 to 9: 1: about 2: 3 to 4: 1, about 3: 4 to 4: 1, about 4: 5 to 4: 1, about 5: 6 to 4: 1, or about 1: 1 to 4: 1; about 2: 3 to 7: 3, about 3: 4 to 7: 3, about 4: 5 to 7: 3, about 5: 6 to 7: 3, or about 1: 1 to 7: 3; about 2: 3 to 3: 2 , About 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5; about 1: 4 to 4: 1, about 3: 7 to 7: 3, and about 2: 3 To 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5
  • the weight ratio of HMS5552 to Eudragit L100 in the HMS5552 solid dispersion in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation is about 1: 1, about 2: 3, about 3: 2, about 1: 4, about 4: 1, about 3: 4, about 4: 3, about 4: 5, about 5: 4, about 5: 6, about 6: 5, about 7: 3, about 3: 7, about 1: 9, about 9: 1, or any range therebetween.
  • the second active ingredient is sitagliptin or sitagliptin phosphate monohydrate, by weight, Contains: about 1 to 80% of a glucokinase activator (preferably HMS5552 or its isotope marker or a pharmaceutically acceptable salt thereof); about 1 to 80% of sitagliptin (or sitagliptin phosphate monohydrate); about 0 to 55% of filler; about 1 to 25% of binder; about 0 to 15% of disintegrant; about 0.1 to 10% of lubricant; about 0 to 3% of glidant; and 0 to 5 % Coating agent.
  • a glucokinase activator preferably HMS5552 or its isotope marker or a pharmaceutically acceptable salt thereof
  • sitagliptin or sitagliptin phosphate monohydrate
  • about 0 to 55% of filler about 1 to 25% of binder; about 0 to 15% of disintegrant; about 0.1 to 10% of lubricant; about 0 to 3% of gli
  • the pharmaceutical preparation (preferably a fixed-dose combination preparation) comprises, by weight, about 5 to 45% of a glucokinase activator (preferably HMS5552 or an isotope marker thereof or a pharmaceutically acceptable salt thereof); and about 5 to 75% Siegel Lentin or sitagliptin phosphate monohydrate; about 0-50% filler; about 1-10% binder; about 1-10% disintegrant; about 0.1-5% lubricant; About 0 to 0.5% of glidant and 0 to 5% of coating agent.
  • the pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation) is prepared by a wet granulation method or a dry granulation method, and is preferably prepared by a wet granulation method
  • the dose of the glucokinase activator (preferably HMS5552 or its isotope marker or pharmaceutically acceptable salt) in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is from about 1 mg to 200 mg.
  • the preferred dose (preferably a unit dose) of a glucokinase activator is about 5 mg to 100 mg.
  • the dose (preferably a unit dose) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg , About 80 mg, about 90 mg, about 100 mg, or any range therebetween.
  • a more preferred dose (preferably a unit dose) of a glucokinase activator is about 25 mg, about 50 mg, about 75 mg, about 100 mg.
  • a glucokinase activator preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • the second active ingredient is sitagliptin (or sitagliptin phosphate monohydrate), and sitag Based on the content of Litin, its dose (preferably a unit dose) is about 25 mg to about 200 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, more Preferably it is about 25 mg, 50 mg or about 100 mg.
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • composition or pharmaceutical preparation preferably a fixed-dose combination preparation
  • HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof
  • sitagliptin or ciprostat
  • Specific embodiments of the dosage (preferably a unit dose) of glitatine monohydrate are as follows:
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • the aforementioned pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation preferably is a tablet.
  • the tablet is a fixed-dose compound tablet of glucokinase activator (HMS5552 and its isotope marker or pharmaceutically acceptable salt) and sitagliptin or sitagliptin phosphate monohydrate.
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation preferably a fixed-dose compound tablet, which is 25 mg of a glucokinase activator (preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof) / 50mg sitagliptin (or tablets of which sitagliptin phosphate monohydrate is available in this amount), by weight, containing the following components: about 25 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 50mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above,
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation preferably a fixed-dose compound tablet, which is a 50 mg glucokinase activator (preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof) / 50mg sitagliptin (or tablets of which sitagliptin phosphate monohydrate is available in this amount), by weight, containing the following components: about 50 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 50mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above,
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation preferably a fixed-dose compound tablet, which is 75 mg of a glucokinase activator (preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof) / 50mg sitagliptin (or tablets of which sitagliptin phosphate monohydrate is available in this amount), by weight, containing the following components: about 75 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 50mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above,
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation preferably a fixed-dose compound tablet, which is 100 mg of a glucokinase activator (preferably HMS5552 or an isotope marker thereof or a pharmaceutically acceptable salt) / 50mg sitagliptin (or tablets of which sitagliptin phosphate monohydrate is available in this amount), by weight, containing the following components: about 100 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 50mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above,
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation preferably a fixed-dose compound tablet, which is 25 mg of a glucokinase activator (preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof) / 100mg sitagliptin (or tablets of which sitagliptin phosphate monohydrate is available in this amount), by weight, containing the following components: about 25 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above,
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation preferably a fixed-dose compound tablet, which is a 50 mg glucokinase activator (preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof) / 100 mg sitagliptin (or tablets of sitagliptin phosphate monohydrate in the amount available), by weight, containing the following components: about 50 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dis
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation preferably a fixed-dose compound tablet, which is 75 mg of a glucokinase activator (preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof) / 100 mg sitagliptin (or tablets of which sitagliptin phosphate monohydrate is available in this amount), by weight, containing the following components: about 75 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above, preferably
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation preferably a fixed-dose compound tablet, which is 100 mg of a glucokinase activator (preferably HMS5552 or an isotope marker thereof or a pharmaceutically acceptable salt) / 100mg sitagliptin (or tablets of sitagliptin phosphate monohydrate in an amount available for this dose), by weight, containing the following components: about 100 mg of a glucokinase activator (preferably HMS5552 or its isotope label or pharmaceutically acceptable salt); about 100 mg of sitagliptin (or the amount of sitagliptin phosphate monohydrate available at this dose); about 0-50% optional About 2 to 8% of the binder; about 1 to 5% of the disintegrant; about 0.5 to 3% of the lubricant; about 0 to 0.5% of the glidant and 0 to 5% of the coating
  • the glucokinase activator is in the form of a solid dispersion as described above,
  • the second active ingredient is saxagliptin or saxagliptin monohydrate, comprising by weight: About 1 to 80% of glucokinase activator (or its isotope label or pharmaceutically acceptable salt); about 0.5 to 20% of saxagliptin (or saxagliptin monohydrate); about 0 to 90% Fillers; about 1 to 25% of binders; about 0 to 15% of disintegrants; about 0.1 to 10% of lubricants, about 0 to 3% of glidants and about 0 to 5% of coating agents .
  • the second active ingredient is saxagliptin (or saxagliptin monohydrate), by weight Contains: about 1 to 80% glucokinase activator (preferably HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 0.5 to 20% saxagliptin (or saxagliptin monohydrate); about 0 to 90% of filler; about 1 to 25% of binder; about 0 to 15% of disintegrant; about 0.1 to 10% of lubricant; about 0 to 3% of glidant; and about 0 to 5 % Coating agent.
  • the pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation) is prepared by a wet granulation method or a dry granulation method, and is preferably prepared by a wet granulation method.
  • the dose of the glucokinase activator (preferably HMS5552 or its isotope marker or pharmaceutically acceptable salt) in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is from about 1 mg to 200 mg.
  • the preferred dose (preferably a unit dose) of a glucokinase activator is about 5 mg to 100 mg.
  • the dose (preferably a unit dose) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg , About 80 mg, about 90 mg, about 100 mg, or any range therebetween.
  • a more preferred dose (preferably a unit dose) of a glucokinase activator is about 25 mg, about 50 mg, about 75 mg, about 100 mg.
  • a glucokinase activator preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • the second active ingredient is saxagliptin (or saxagliptin monohydrate), and sagliptin Calculating the content of Lentin, its dosage (preferably a unit dose) is about 1 mg to about 50 mg, preferably about 2.5 mg, about 5 mg, about 7.5 mg, and about 10 mg, and most preferably about 2.5 mg and about 5 mg.
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • the dose (preferably a unit dose) of HMS5552 (or its isotope marker or pharmaceutically acceptable salt) and saxagliptin (or saxagliptin monohydrate)
  • HMS5552 or its isotope marker or pharmaceutically acceptable salt
  • saxagliptin or saxagliptin monohydrate
  • HMS5552 exists in the form of a solid dispersion.
  • the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose compound preparation) is preferably in the form of a tablet.
  • the above tablets are fixed-dose compound tablets of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) and saxagliptin (or saxagliptin monohydrate).
  • HMS5552 glucokinase activator
  • saxagliptin or saxagliptin monohydrate
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed-dose compound tablet, which is 25 mg of a glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) /2.5 mg of saxagliptin (or a tablet of which sagliptin monohydrate can be obtained in this amount), by weight, containing the following components: about 25 mg of a glucokinase activator (HMS5552 or its Isotope label or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant and about 0 to 5% of coating agent; preferably, the above-mentioned glucose
  • the kinase activator is in the following
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is a 50 mg glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) /2.5 mg of saxagliptin (or a tablet in which the dose of saxagliptin monohydrate is available), by weight, containing the following components: about 50 mg of a glucokinase activator (HMS5552 or its Isotope label or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant and about 0 to 5% of coating agent; preferably, the above-mentioned glucose
  • the kinase activator is in the following
  • the pharmaceutical combination, pharmaceutical composition, or pharmaceutical formulation (preferably a fixed-dose compound tablet, which is 75 mg glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) /2.5 mg of saxagliptin (or a tablet of which sagliptin monohydrate is available in this amount), by weight, containing the following components: about 75 mg of a glucokinase activator (HMS5552 or its Isotope label or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant and about 0 to 5% of coating agent; preferably, the above-mentioned glucose
  • the kinase activator is in the form of
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is 100 mg of a glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) /2.5 mg of saxagliptin (or a tablet of which sagliptin monohydrate is available in this amount), by weight, containing the following components: about 100 mg of a glucokinase activator (HMS5552 or its Isotope label or pharmaceutically acceptable salt); about 2.5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant and about 0 to 5% of coating agent; preferably, the above-mentioned glucose
  • the kinase activator is in the form
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is 25 mg of a glucokinase activator (HMS5552 or its isotope marker or a pharmaceutically acceptable salt) / 5 mg Saxagliptin (or a tablet in which the dose of saxagliptin monohydrate is available), by weight, contains the following components: about 25 mg of a glucokinase activator (HMS5552 or its isotope) A marker or a pharmaceutically acceptable salt); about 5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% About 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokina
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is 50 mg of a glucokinase activator (HMS5552 or its isotope marker or a pharmaceutically acceptable salt) / 5 mg Saxagliptin (or a tablet in which the dose is available in the amount of saxagliptin monohydrate), by weight, contains the following components: about 50 mg of a glucokinase activator (HMS5552 or its isotope) A marker or a pharmaceutically acceptable salt); about 5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% About 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glu
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is 75 mg of a glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 5 mg Saxagliptin (or a tablet of which sagliptin monohydrate is available in this amount), by weight, contains each of the following components: about 75 mg of a glucokinase activator (HMS5552 or its isotope) A marker or a pharmaceutically acceptable salt); about 5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% About 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is 100 mg of a glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 5 mg Saxagliptin (or a tablet in which the amount of saxagliptin monohydrate is available), by weight, contains the following components: about 100 mg of a glucokinase activator (HMS5552 or its isotope) A marker or a pharmaceutically acceptable salt); about 5 mg of saxagliptin (or the amount of saxagliptin monohydrate available); about 0 to 80% of a bulking agent; about 2 to 8% About 1 to 5% of a disintegrant; about 0.5 to 3% of a lubricant; about 0 to 0.5% of a glidant and about 0 to 5% of a coating agent; preferably, the above-mentioned glucokinase
  • the second active ingredient is ligagliptin, and the aforementioned glucokinase activator (HMS5552 or its isotope marker) Or a pharmaceutically acceptable salt) and a pharmaceutical combination, pharmaceutical composition, or pharmaceutical preparation (preferably a fixed-dose combination preparation) of ligagliptin, comprising by weight one or more substances in an amount of about 1 ⁇ 90% glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt); about 1-20% lidagliptin; about 0-90% filler; about 1-25% adhesion About 0 to 15% of a disintegrant; about 0.1 to 10% of a lubricant; about 0 to 3% of a glidant; and about 0 to 5% of a coating agent.
  • HMS5552 or its isotope marker or a pharmaceutically acceptable salt
  • the second active ingredient is ligagliptin, and the aforementioned glucokinase activator (HMS5552 or its isotope marker) Or a pharmaceutically acceptable salt) and a pharmaceutical combination, pharmaceutical composition, or pharmaceutical preparation (preferably a fixed-dose combination preparation) of ligagliptin, comprising by weight one or more substances in an amount of about 1 ⁇ 80% glucokinase activator (HMS5552 or its isotope label or pharmaceutically acceptable salt); about 1-20% lidagliptin; about 0-90% filler; about 1-25% adhesion About 0 to 15% of a disintegrant; about 0.1 to 10% of a lubricant; about 0 to 3% of a glidant; and about 0 to 5% of a coating agent.
  • the pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation) is prepared by a wet granulation method or a dry
  • the dose of the glucokinase activator (preferably HMS5552 or its isotope marker or pharmaceutically acceptable salt) in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) is from about 1 mg to 200 mg.
  • the preferred dose (preferably a unit dose) of a glucokinase activator is about 5 mg to 100 mg.
  • the dose (preferably a unit dose) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg , About 80 mg, about 90 mg, about 100 mg, or any range therebetween.
  • a more preferred dose (preferably a unit dose) of a glucokinase activator is about 25 mg, about 50 mg, about 75 mg, about 100 mg.
  • a glucokinase activator preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • the second active ingredient is ligagliptin
  • the dose (preferably a unit dose) of ligagliptin is about 1 mg to about 50 mg, preferably about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg, and the most preferred dose (preferably a unit dose) of lidagliptin is about 2.5 mg or about 5 mg.
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • the dose preferably a unit dose
  • HMS5552 or its isotope marker or pharmaceutically acceptable salt
  • saxagliptin in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose compound preparation) as follows:
  • HMS5552 exists in the form of a solid dispersion.
  • the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose compound preparation) is preferably in the form of a tablet.
  • the aforementioned tablet is a fixed-dose compound tablet of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) and ligagliptin.
  • HMS5552 glucokinase activator
  • ligagliptin ligagliptin
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is 25 mg of a glucokinase activator (HMS5552 or its isotope marker or a pharmaceutically acceptable salt) / 5 mg of a tablet of Ligliptin), by weight, containing the following components: about 25 mg of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 5 mg of Ligrate Liptin; about 0 to 90% of optional filler; about 2 to 8% of binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of A glidant and a coating agent of about 0 to 5%; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains About 1: 1 glucokina
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is a 50 mg glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 5 mg of a tablet of Ligliptin), by weight, containing the following components: about 50 mg of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 5 mg of Ligrate Liptin; about 0 to 90% of optional filler; about 2 to 8% of binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of A glidant and a coating agent of about 0 to 5%; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains About 1: 1 glucokina
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is a 75 mg glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 5 mg of a tablet of Ligliptin), comprising, by weight, each component in the following amount: about 75 mg of a glucokinase activator (HMS5552 or its isotope marker or a pharmaceutically acceptable salt); about 5 mg of Ligrate Liptin; about 0 to 90% of optional filler; about 2 to 8% of binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of A glidant and a coating agent of about 0 to 5%; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains About
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is a 100 mg glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 5 mg of a tablet of Ligliptin), by weight, containing the following components: about 100 mg of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 5 mg of Ligrate Liptin; about 0 to 90% of optional filler; about 2 to 8% of binder; about 1 to 5% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of A glidant and a coating agent of about 0 to 5%; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains About 1: 1 glucokina
  • the second active ingredient is vitagliptin.
  • the above-mentioned glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) and the pharmaceutical combination, pharmaceutical composition, or pharmaceutical preparation (preferably a fixed-dose combination preparation) of vitagliptin include, by weight, About 1 to 80% glucokinase activator (preferably HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 1 to 50% vildagliptin; about 0 to 55% of a bulking agent; about 1 to 25 % Binder; about 0-15% disintegrant; about 0.1-10% lubricant; about 0-3% glidant; about 0-5% coating agent.
  • the pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation) is prepared by a wet granulation method or a dry granulation method, and is preferably prepared by
  • glucokinase activator HMS5552 or its isotope marker or pharmaceutically acceptable salt
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed-dose combination preparation of vitagliptin
  • the dosage (preferably a unit dose) of a glucokinase activator is about 1 mg to 200 mg.
  • the preferred dose (preferably a unit dose) of a glucokinase activator is about 5 mg to 100 mg.
  • the dose (preferably a unit dose) of the glucokinase activator is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg , About 80 mg, about 90 mg, about 100 mg, or any range therebetween.
  • a more preferred dose (preferably a unit dose) of a glucokinase activator is about 25 mg, about 50 mg, about 75 mg, about 100 mg.
  • pharmaceutical composition or pharmaceutical preparation preferably a fixed dose compound preparation
  • HMS5552 exists in the form of a solid dispersion.
  • glucokinase activator HMS5552 or its isotope marker or pharmaceutically acceptable salt
  • a pharmaceutical composition or pharmaceutical preparation preferably a fixed-dose combination preparation
  • the dose (preferably a unit dose) of vitagliptin is about 10 mg to about 150 mg, preferably about 50 mg and about 100 mg, and the most preferred dose (preferred unit dose) of vitagliptin is about 50 mg.
  • composition or pharmaceutical preparation preferably a fixed-dose combination preparation
  • dose of HMS5552 or its isotope marker or pharmaceutically acceptable salt
  • dose of vitagliptin preferably Specific embodiments of the unit dose
  • HMS5552 exists in the form of a solid dispersion.
  • the pharmaceutical composition, the pharmaceutical composition or the pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention is preferably a tablet.
  • the above-mentioned fixed-dose compound tablet is a tablet of glucokinase activator (preferably HMS5552 or its isotope marker or pharmaceutically acceptable salt) and vitagliptin.
  • glucokinase activator preferably HMS5552 or its isotope marker or pharmaceutically acceptable salt
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed-dose compound tablet, which is 25 mg of a glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 50 mg Vitagliptin tablets), by weight, containing the following components: about 25 mg of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 50 mg of vigor Ting; about 0 to 80% of filler; about 2 to 8% of binder; about 1 to 8% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant and about 0 to 5% coating agent; preferably, the glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains about 1: 1 Glucokinase activator and Eudragit L100
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation preferably a fixed-dose compound tablet, which is 50 mg of a glucokinase activator (HMS5552 or its isotope marker or a pharmaceutically acceptable salt) / 50 mg Vitagliptin tablets), by weight, each component in the following amount: about 50 mg of a glucokinase activator (HMS5552 or its isotope marker or a pharmaceutically acceptable salt); about 50 mg of vitagliptin Ting; about 0 to 80% of filler; about 2 to 8% of binder; about 1 to 8% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant and about 0 to 5% coating agent; preferably, the glucokinase activator is in the form of the solid dispersion described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains about 1: 1 Glucokina
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is a 75 mg glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 50 mg of a tablet of Vitagliptin), by weight, containing the following components: about 75 mg of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 50 mg of Vigor Litin; about 0 to 80% of filler; about 2 to 8% of binder; about 1 to 8% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant And about 0 to 5% of the coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains about 1: 1 glucokinase activator
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound tablet, which is a 100 mg glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt) / 50 mg of a tablet of Vitagliptin), by weight, containing the following components: about 100 mg of glucokinase activator (HMS5552 or its isotope marker or pharmaceutically acceptable salt); about 50 mg of Vigor Litin; about 0 to 80% of filler; about 2 to 8% of binder; about 1 to 8% of disintegrant; about 0.5 to 3% of lubricant; about 0 to 0.5% of glidant And about 0 to 5% of the coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion contains a glucokinase activator and a polymer carrier, and preferably contains about 1: 1 glucokinase activator
  • the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose compound preparation) further comprises an excipient, wherein the excipient includes, but is not limited to, a diluent, a binder, a filler, a disintegrating agent Mixtures of one or more of an antidote, a lubricant, a glidant, a flavoring agent (flavor), a sweetener and a colorant, a coating agent.
  • the excipient includes, but is not limited to, a diluent, a binder, a filler, a disintegrating agent Mixtures of one or more of an antidote, a lubricant, a glidant, a flavoring agent (flavor), a sweetener and a colorant, a coating agent.
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention contains optional one or more fillers (diluents).
  • fillers include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or lignocellulose (including microcrystalline cellulose and silicified microcrystalline cellulose), lactose, lactose, anhydrous or monohydrate, sucrose, starch, pregelatin Starch, dextrose, mannitol (including Pearlitol SD 200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate , Dextrin / glucose binding agents, maltodextrin, compressible sugars and other known compatibilizers or fillers and / or mixtures of two or more of them.
  • cellulose derivatives such as microcrystalline cellulose or lignocellulose (including microcrystalline cellulose and
  • fillers examples include microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose, mannitol, sorbitol, calcium dihydrogen phosphate (dihydrate), corn starch, Gelatinized starch and powdered cellulose. More preferred fillers (diluents) are microcrystalline cellulose and silicified microcrystalline cellulose. Microcrystalline cellulose can be obtained from several suppliers, including Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105, and Avicel PH 200 manufactured by FMC Corporation.
  • the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed-dose combination preparation) of the present invention contains one or more optional binders.
  • optional binders 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 methyl cellulose (HPMC) (including hydroxypropyl methyl cellulose 2208), lactose, sucrose, gum arabic, ethyl cellulose, cellulose acetate and wax binders such as Brazil Carnauba wax, paraffin wax, whale wax, polyethylene or microcrystalline wax and other conventional binders and / or mixtures of two or more of them.
  • the binders suitable for the present invention include but are not limited to alginic acid, microcrystalline cellulose, dextrin, gelatin, amylopectin, liquid glucose, guar gum, methyl cellulose , Polyethylene oxide, povidone, and syrup, and combinations thereof.
  • Preferred embodiments of the binder include hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HMPC), polyvinylpyrrolidone (povidone), hydroxyethyl cellulose, starch 1500, and co-prenpyrone . More preferred binders are hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
  • the aforementioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation contains optional one or more disintegrants.
  • 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.
  • 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, polaklin potassium and calcium carboxymethyl cellulose (CMC Calcium).
  • the disintegrant is crospovidone.
  • the disintegrant is sodium starch glycolate.
  • the disintegrant is croscarmellose sodium. Croscarmellose sodium NF type A is commercially available under the trade name "Ac-di-sol".
  • the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation contains one or more lubricants.
  • 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, laurel Sodium sulfate, glyceryl palmitate stearate, 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.
  • embodiments of the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil, and mixtures thereof. More preferred lubricants are magnesium stearate, or sodium fumarate, or a mixture thereof.
  • the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation contains one or more glidants and / or anti-adhesive agents.
  • 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 dioxide Silicon such as aggregated silicates and hydrated silica gel.
  • embodiments of the glidant include colloidal silicon dioxide, calcium phosphate, magnesium silicate and talc, or a mixture thereof.
  • a preferred glidant is colloidal silica.
  • the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation may optionally further contain one or more surfactants or wetting agents.
  • the surfactant can be anionic, cationic or neutral surfactant.
  • Anionic surfactants include sodium lauryl sulfate, sodium lauryl sulfonate, sodium oleyl sulfate, and sodium laurate mixed with stearates and talc.
  • Cationic surfactants include benzalkonium chloride and alkyltrimethylammonium bromide.
  • Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, and sorbitan esters.
  • wetting agents include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene stearate.
  • the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation may further contain an optional antioxidant to give it chemical stability.
  • antioxidants suitable for use in the present invention include, but are not limited to, tocopherol, ascorbic acid, gallic acid ester, ascorbyl palmitate, butanilol, butylated toluene, thioglycerol, potassium pyrosulfite, propionic acid, gallic acid Propyl ester, sodium ascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite and combinations thereof.
  • the antioxidant is selected from the group consisting of ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, extracts of natural sources enriched with tocopherol, L-ascorbic acid and its sodium or calcium salt, ascorbyl palmitate Esters, propyl gallic acid, octyl gallic acid, dodecyl gallic acid, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
  • the antioxidant is BHT or BHA.
  • the preferred formulation of the above-mentioned fixed-dose combination formulation is a tablet prepared by a compression method.
  • the tablet may be coated, and preferred examples of the coating substrate include a sugar coating substrate, a water-soluble film coating substrate, an enteric film coating substrate, and the like.
  • sucrose was used as the sugar coating substrate.
  • one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, acacia, amylopectin, carnauba wax, and the like may be used in combination.
  • water-soluble film coating substrate examples include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, and the like; synthetic polymers such as Polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, and the like.
  • enteric film coating substrates examples include cellulose polymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, acetic acid 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.
  • cellulose polymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, acetic acid Cellulose phthalate, etc .
  • acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name
  • Preferred examples of the coating additive include a plasticizer such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), propylene glycol, triethyl citrate, castor oil, polysorbate, etc. or two or more thereof Sunscreen agents such as titanium dioxide; colorants, dyes, and lakes such as iron oxide red (ferric oxide), yellow oxide, and the like; glidants such as talc and the like.
  • a plasticizer such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), propylene glycol, triethyl citrate, castor oil, polysorbate, etc. or two or more thereof
  • Sunscreen agents such as titanium dioxide; colorants, dyes, and lakes such as iron oxide red (ferric oxide), yellow oxide, and the like; glidants such as talc and the like.
  • the tablets may be coated with, for example, a mixture of hydroxypropyl cellulose and hydroxypropyl methyl cellulose, the mixture containing titanium dioxide and / or other colorants such as iron oxide, dyes, and lakes; Mixtures of polyvinyl alcohol (PVA) and polyethylene glycol (PEG); or any other suitable immediate release coating agent.
  • PVA polyvinyl alcohol
  • PEG polyethylene glycol
  • the coating provides taste masking and additional stability to the final tablet.
  • a commercially available coating material is Opadry, a pre-formulated powder mix supplied by Colorcon. ), Such as Opadry 03K12429.
  • the above-mentioned pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation may also be added with a sweetener and / or a flavoring agent as needed.
  • the binder is polyvinylpyrrolidone or hydroxypropyl cellulose or hydroxypropyl methyl cellulose
  • the filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose or calcium dihydrogen phosphate.
  • the disintegrant is croscarmellose sodium or crospovidone or sodium starch glycolate
  • the lubricant is magnesium stearate or stearic acid-rich Sodium maleate
  • the glidant is colloidal silica.
  • the binder is hydroxypropyl cellulose
  • the filler is microcrystalline cellulose or siliconized microcrystalline cellulose, or lactose
  • the disintegrant is croscarmellose sodium or crosslinked.
  • Povidone or sodium starch glycolate and the lubricant is magnesium stearate or sodium stearyl fumarate, and the glidant is colloidal silicon dioxide.
  • the binder is polyvinylpyrrolidone
  • the filler is microcrystalline cellulose or silicified microcrystalline cellulose
  • the disintegrant is croscarmellose sodium or crospovidone
  • the lubricant is magnesium stearate or sodium stearyl fumarate
  • the glidant is colloidal silica.
  • the binder is hydroxypropyl methylcellulose
  • the filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose
  • the disintegrant is croscarmellose sodium or Cross-linked povidone or sodium starch glycolate
  • the lubricant is magnesium stearate or sodium stearyl fumarate
  • the glidant is colloidal silicon dioxide.
  • the binder is hydroxypropyl cellulose
  • the filler is microcrystalline cellulose or silicified microcrystalline cellulose or lactose
  • the disintegrant is croscarmellose sodium
  • the above The lubricant is magnesium stearate or sodium fumarate.
  • the binder is polyvinylpyrrolidone
  • the lubricant is magnesium stearate
  • the glidant is colloidal silica
  • the pharmaceutical composition or fixed dose compound formulation of the invention is prepared by wet granulation (high shear and / or fluidized bed).
  • Granulation is a method of adding a binder to a solvent to prepare a binder solution, and then adding or directly adding the binder to a granulator to make wet granules.
  • the steps involved in the wet granulation method include the following:
  • glucokinase activator preferably HMS5552
  • a combination drug preferably sitagliptin, saxagliptin, vitagliptin and lidagliptin
  • step (2) adding an optional filler (such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to the mixture obtained in step (1);
  • an optional filler such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose
  • step (3) adding an optional disintegrant (such as croscarmellose sodium, crospovidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);
  • an optional disintegrant such as croscarmellose sodium, crospovidone, sodium starch glycolate
  • a binder such as hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • a binder solution is sprayed in by compressed air.
  • the binder solution is an aqueous solution composed of a binder and pure water.
  • a suitable mixer add optional fillers (diluents, such as microcrystalline cellulose) and optional disintegrants (such as croscarmellose sodium) to mix with the dried granules;
  • optional fillers such as microcrystalline cellulose
  • optional disintegrants such as croscarmellose sodium
  • step (9) adding a lubricant (such as magnesium stearate and sodium stearyl fumarate) to the mixture of step (8);
  • a lubricant such as magnesium stearate and sodium stearyl fumarate
  • step (10) adding an optional glidant (such as colloidal silica) to the mixture of step (9);
  • an optional glidant such as colloidal silica
  • step (1) filling the lubricated granule mixture of step (9) or (10) into a vial, sachet or capsule or compressing it into a desired tablet shape;
  • the obtained tablet is film-coated.
  • the pharmaceutical composition of the present invention is prepared by wet granulation (high shear and / or fluidized bed).
  • Granulation is a method in which a binder solution and a second active ingredient are added to a solvent to prepare a binder solution (or suspension), and then added to a granulator to make wet granules.
  • the steps involved in the wet granulation method include the following:
  • glucokinase activator preferably HMS5552
  • step (1) (2) adding optional fillers (such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to the mixture in step (1);
  • optional fillers such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose
  • step (3) adding an optional disintegrant (such as croscarmellose sodium, crospovidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);
  • an optional disintegrant such as croscarmellose sodium, crospovidone, sodium starch glycolate
  • a binder such as hydroxypropylcellulose or polyvinylpyrrolidone or hydroxypropylmethylcellulose
  • active ingredients preferably sitagliptin, saxagliptin, vitagliptin, and lidagliptin
  • This system was added to a granulator and stirred for granulation.
  • an active pharmaceutical ingredient such as HMS5552 is added to the fluidized bed, and a binder system is sprayed in by compressed air, the binder solution is composed of a binder and pure water or organic A solution or suspension in a solvent (such as ethanol);
  • a suitable mixer add optional fillers (diluents, such as microcrystalline cellulose) and optional disintegrants (such as croscarmellose sodium) to mix with the dried granules;
  • optional fillers such as microcrystalline cellulose
  • optional disintegrants such as croscarmellose sodium
  • step (9) adding a lubricant (such as magnesium stearate and sodium stearyl fumarate) to the mixture of step (8);
  • a lubricant such as magnesium stearate and sodium stearyl fumarate
  • a glidant such as colloidal silica is added to the mixture of step (9);
  • the obtained tablet is film-coated.
  • the steps involved in dry processing include:
  • glucokinase activator preferably HMS5552
  • a combination drug preferably sitagliptin, saxagliptin, vitagliptin, and lidagliptin
  • step (1) (2) adding optional fillers (such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to step (1);
  • optional fillers such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose
  • step (3) adding an optional binder (such as hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methyl cellulose) to the mixture obtained in step (1) or (2);
  • an optional binder such as hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • step (3) (4) adding lubricant or glidant to step (3) and mixing;
  • step (4) can be filled into a vial, sachet or capsule or compressed into a desired tablet shape, or processed by a roller compressor;
  • step (3) If processing is performed by a roller compressor, the mixture in step (3) is mixed in advance, and then roller-rolled; if necessary, the particles can be granulated on a suitable grinder to obtain particles of a desired size;
  • an optional diluent may be added to the granules obtained in step (6), thereby improving the compression performance
  • step (7) adding an optional disintegrant (such as croscarmellose sodium, crospovidone, sodium starch glycolate) to step (7);
  • an optional disintegrant such as croscarmellose sodium, crospovidone, sodium starch glycolate
  • step (9) adding an optional lubricant or glidant to the mixture of step (8);
  • the tablets obtained in step (5) or step (10) may be film-coated.
  • the glucokinase activator in the pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of the present invention is in the form of a solid dispersion, which can be selected from a spray drying method, a fluid bed drying method, and a solvent method , Melt extrusion method and other methods.
  • One embodiment of the present invention is a method for preparing a solid dispersion of a glucokinase activator by a spray drying method, which comprises the steps of:
  • preparing a spray-dried solution comprising dissolving a polymer carrier and a glucokinase activator (preferably HMS5552) in a solvent;
  • the solvent used in the preparation of the solid dispersion of the glucokinase activator includes, but is not limited to, alkanol, ester, nitrile, cycloalkane, aromatic hydrocarbon, ketone and the like.
  • the solvent is selected from the following solvents: absolute ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene, and toluene. It can be a single solvent, a mixed solvent, or a mixture of an organic solvent and water.
  • Yet another embodiment of the present invention relates to the use of the glucokinase activator-containing composition or preparation of the present invention (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose combination preparation) to treat and / or prevent the following diseases and medical conditions, especially one Or more methods or uses of a disease selected from type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, and hyperglycemia, comprising administering to a subject a therapeutically effective amount of a composition or formulation of the invention Fixed-dose combination pharmaceutical composition or fixed-dose combination preparation):
  • a metabolic disorder selected from, slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight , Obesity and metabolic syndrome; or
  • a condition or disorder selected from, slowing the progression of the condition or disorder, delaying or treating the condition or disorder: diabetic complications such as cataracts and microvascular and macrovascular diseases such as nephropathy, retinopathy, neuropathy, learning and memory Damage, neurodegeneration or cognitive impairment, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, Stable angina, stroke, peripheral arterial obstructive disease, cardiomyopathy, heart failure, arrhythmia, and restenosis; or
  • pancreatic ⁇ -cell degradation and / or decreased pancreatic ⁇ -cell function and / or improving and / or restoring or protecting pancreatic ⁇ -cell function and / or restoring pancreatic insulin secretion;
  • NODAT new onset of diabetes
  • PTMS metabolic syndrome
  • the present invention also provides a therapeutically effective amount of a pharmaceutical composition or preparation containing a glucokinase activator and a combination drug of the present invention (preferably a fixed-dose combination drug composition or fixed Dose compound preparation) method for treating type II diabetes.
  • a pharmaceutical composition or preparation containing a glucokinase activator and a combination drug of the present invention preferably a fixed-dose combination drug composition or fixed Dose compound preparation
  • the subject in need of said treatment is a human.
  • the pharmaceutical composition is in the form of a tablet.
  • the glucokinase activator-containing composition or preparation of the present invention (preferably a fixed-dose combination pharmaceutical composition or a fixed-dose combination preparation) can be administered once daily (QD), twice daily (BID), or three times daily (TID). medicine.
  • the present invention relates to the following specific embodiments.
  • Embodiment I-glucokinase activator + DPP-IV inhibitor e.g. sitagliptin
  • Scheme 1 Pharmaceutical combination, pharmaceutical composition or fixed dose compound preparation, comprising:
  • a glucokinase activator which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form, a hydrate, a solvate, a diastereomer, or an enantiomer form,
  • the above drugs (a) and (b) are used simultaneously, separately or sequentially.
  • Embodiment 2 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of Embodiment 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 100: 1, preferably about 1 : 4 to 40: 1, more preferably about 1: 4, about 1: 2, about 1: 1, about 1.5: 1, about 1.5: 2, about 2: 1, about 5: 1, and about 10: 1 , About 15: 1, about 20: 1, or about 40: 1.
  • Embodiment 3 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 1 or 2, wherein the glucokinase activator is approximately 1 to 98% by weight; and the DPP-IV inhibitor is approximately 1 to 98% by weight. 0.2 to 80%.
  • Embodiment 4 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to any one of Embodiments 1-3, wherein the glucokinase activator is a compound represented by the following formula HMS5552 or a pharmaceutically acceptable salt thereof, or an isotope marker thereof , Crystalline form, hydrate, solvate, diastereomer or enantiomeric form,
  • Embodiment 5 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to any one of Embodiments 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.
  • Embodiment 6 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 5, wherein the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • Embodiment 7 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 6, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about 5: 6 or any range therebetween.
  • the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about
  • Embodiment 8 The pharmaceutical combination, the pharmaceutical composition or the fixed dose compound preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or saxagliptin monohydrate), Vilagliptin, Ligliptin, Alogliptin, Denagliptin, Megliptin, Goseliptin, Teligliptin, Degree Gliptin, and a pharmaceutically acceptable salt thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vitagliptin And Ligliptin, and their pharmaceutically acceptable salts.
  • the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or s
  • Embodiment 9 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of any one of Embodiments 1-8, wherein the glucokinase activator is at about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg.
  • Embodiment 10 The pharmaceutical combination, the pharmaceutical composition or the fixed dose compound preparation according to any one of Embodiments 1-9, wherein the DPP-IV inhibitor is in a range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 A range of doses (preferably unit doses) of milligrams exists, preferably wherein the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, or About 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg, or about 100 mg; preferably, the DPP-IV inhibitor is sitagliptin with a dose (preferably a unit dose) of about 25 mg ⁇ 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, more preferably about 25 mg, 50 mg Or about 100 mg; preferably, the DPP-IV inhibitor is lidagliptin, and its dosage (preferably a unit dose)
  • Embodiment 11 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-10, the one or more excipients are selected from the group consisting of a binder, a filler, a disintegrant, a lubricant, Glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.
  • Embodiment 12 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-11, which is a tablet.
  • Embodiment 13 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to Embodiment 12, which is a coated tablet.
  • Embodiment 14 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of Embodiment 13, wherein the coated tablet is a film-coated tablet, and the film-coated agent comprises:
  • Film-coated substrates such as hypromellose, hydroxypropylmethylcellulose, or mixtures thereof;
  • plasticizers such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or mixtures thereof;
  • Optional colorants such as iron oxide red, iron oxide yellow, or mixtures thereof;
  • An optional sunscreen such as titanium dioxide, and
  • Embodiment 15 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 14, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.
  • Embodiment 16 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-15, comprising by weight:
  • a glucokinase activator preferably HMS5552 or its isotope label or a pharmaceutically acceptable salt
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably Solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • sitagliptin or sitagliptin phosphate monohydrate About 1 to 80% of sitagliptin or sitagliptin phosphate monohydrate
  • Embodiment 17 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation according to Embodiment 16, comprising by weight,
  • a glucokinase activator preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably Solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • sitagliptin or sitagliptin phosphate monohydrate About 5 to 75% sitagliptin or sitagliptin phosphate monohydrate
  • Scheme 18 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 16, by weight, the dosage (preferably a unit dose) of the active ingredient is:
  • glucokinase activator preferably HMS5552;
  • Embodiment 19 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of the embodiment 18 (the fixed-dose combination is preferably a tablet of 50 mg HMS5552 / 50 mg sitagliptin or a corresponding amount of sitagliptin phosphate monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of the scheme 18 (the fixed-dose combination is preferably a tablet of 75 mg HMS5552 / 50 mg sitagliptin or a corresponding amount of sitagliptin phosphate monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination of the scheme 18 (the fixed-dose combination is preferably a tablet of 50 mg HMS5552 / 100 mg sitagliptin or a corresponding amount of sitagliptin phosphate monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of the scheme 18 (the fixed-dose combination is preferably a tablet of 75 mg HMS5552 / 100 mg sitagliptin or a corresponding amount of sitagliptin phosphate monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of the scheme 18 (the fixed-dose combination is preferably a 25 mg tablet of HMS5552 / 100 mg sitagliptin or a corresponding amount of sitagliptin phosphate monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of the scheme 18 (the fixed-dose combination is preferably a tablet of 100 mg HMS5552 / 50 mg sitagliptin or a corresponding amount of sitagliptin phosphate monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Embodiment 25 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 18, comprising about 100 mg of a solid dispersion, about 64.25 mg of sitagliptin phosphate monohydrate, about 40.30 mg of microcrystalline cellulose, and about 6.60 mg Hydroxypropyl cellulose, about 6.60 mg croscarmellose sodium, about 2.20 mg magnesium stearate, and about 6.60 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and Contains about 50mg HMS5552.
  • Scheme 26 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 18, comprising about 150 mg of a solid dispersion, about 64.25 mg of sitagliptin phosphate monohydrate, about 27.55 mg of microcrystalline cellulose, and about 7.80 mg Hydroxypropyl cellulose, about 7.80 mg croscarmellose sodium, about 2.60 mg magnesium stearate, and about 7.80 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and Contains about 75mg HMS5552.
  • Scheme 27 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 18, comprising about 100 mg of a solid dispersion, about 128.50 mg of sitagliptin phosphate monohydrate, about 41.20 mg of microcrystalline cellulose, and about 8.70 mg Hydroxypropyl cellulose, about 8.70 mg croscarmellose sodium, about 2.90 mg magnesium stearate, and about 8.70 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and Contains about 50mg HMS5552.
  • Scheme 28 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 18, comprising about 150 mg of a solid dispersion, about 128.50 mg of sitagliptin phosphate monohydrate, about 47.00 mg of microcrystalline cellulose, and about 10.50 mg Hydroxypropyl cellulose, about 10.50 mg croscarmellose sodium, about 3.50 mg magnesium stearate, and about 10.50 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and Contains about 75mg HMS5552.
  • Scheme 29 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 18, comprising about 50 mg of a solid dispersion, about 128.50 mg of sitagliptin phosphate monohydrate, about 100.50 mg of microcrystalline cellulose, and 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 contains about 1: 1 HMS5552 and Eudragit L100, and Contains about 25mg HMS5552.
  • Embodiment 30 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 18, comprising about 200 mg of a solid dispersion, about 64.25 mg of sitagliptin phosphate monohydrate, about 61.26 mg of microcrystalline cellulose, and about 10.50 mg Hydroxypropyl cellulose, about 10.50 mg croscarmellose sodium, about 3.50 mg magnesium stearate, and about 10.50 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and Contains about 100mg HMS5552.
  • Scheme 31 A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose compound preparation according to any one of Schemes 1-30, the method comprising granulating the active ingredient in one or more excipients, preferably The prepared granule mixture is further filled into a vial, sachet or capsule or compressed into a desired tablet shape; more preferably, the obtained tablet is further coated.
  • Embodiment 32 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to embodiment 31, wherein the preparation is performed by wet granulation (high-shear and / or fluidized bed), or by dry processing (direct compression or dry production) Granules).
  • Embodiment 33 The method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose combination preparation according to any one of Embodiments 31-32, wherein the glucokinase activator is prepared in the form of a solid dispersion.
  • Embodiment 34 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to any one of embodiments 31-33, wherein the glucokinase activator and the second or more active ingredients can also be prepared together into a compound In the form of a solid dispersion (i.e. a solid dispersion containing 2 or more active ingredients).
  • a solid dispersion i.e. a solid dispersion containing 2 or more active ingredients.
  • Embodiment 35 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to any one of Embodiments 1-30, which is used to treat or prevent one or more metabolic disorders selected from the group consisting of Progress, delay or treat the metabolic disorder: Type I diabetes, Type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetes awareness Dysfunction, memory impairment, dementia and / or metabolic syndrome; or improve glycemic control and / or decrease fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or prevent, slow, delay or reverse the complications of diabetes disease.
  • the metabolic disorder selected from the group consisting of Progress, delay or treat the metabolic disorder: Type I diabetes, Type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetes awareness Dysfunction, memory impairment, dementia and /
  • Scheme 36 A method of treating or preventing one or more metabolic disorders selected from the group consisting of: slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, Hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory impairment, dementia and / or metabolic syndrome; or improve blood glucose control and / or lower fasting plasma Glucose, postprandial plasma glucose, and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or reversing diabetic complications, including administering to a subject a therapeutically effective amount of a pharmaceutical combination according to any one of Schemes 1-30 , Pharmaceutical composition or fixed dose compound preparation.
  • Embodiment 37 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-30 is prepared for the treatment or prevention of one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorder.
  • Embodiment II-glucokinase activator + DPP-IV inhibitor e.g., vitagliptin
  • Scheme 1 Pharmaceutical combination, pharmaceutical composition or fixed dose compound preparation, comprising:
  • a glucokinase activator which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form, a hydrate, a solvate, a diastereomer, or an enantiomer form,
  • the above drugs (a) and (b) are used simultaneously, separately or sequentially.
  • Embodiment 2 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation according to Embodiment 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 50: 1, preferably about 1 : 4 to 40: 1, more preferably about 1: 4, about 1: 2, about 1: 1, about 1.5: 1, about 1.5: 2, about 2: 1, about 5: 1, and about 10: 1 , About 15: 1, about 20: 1, or about 40: 1.
  • Embodiment 3 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 1 or 2, wherein the glucokinase activator is approximately 1 to 80% by weight; and the DPP-IV inhibitor is approximately 1 to 80% by weight. 1 to 50%.
  • Embodiment 4 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to any one of Embodiments 1-3, wherein the glucokinase activator is a compound represented by the following formula HMS5552 or a pharmaceutically acceptable salt thereof, or an isotope marker thereof , Crystalline form, hydrate, solvate, diastereomer or enantiomeric form,
  • Embodiment 5 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to any one of Embodiments 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.
  • Embodiment 6 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 5, wherein the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • Embodiment 7 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 6, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about 5: 6 or any range therebetween.
  • the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about
  • Embodiment 8 The pharmaceutical combination, the pharmaceutical composition or the fixed dose compound preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or saxagliptin monohydrate), Vilagliptin, Ligliptin, Alogliptin, Denagliptin, Megliptin, Goseliptin, Teligliptin, Degree Gliptin, and a pharmaceutically acceptable salt thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vitagliptin And Ligliptin, and their pharmaceutically acceptable salts.
  • the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or s
  • Embodiment 9 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of any one of Embodiments 1-8, wherein the glucokinase activator is a dose of about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg A range of (preferably a unit dose) exists, preferably wherein the dose (preferably a unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg, or about 100 mg.
  • Embodiment 10 The pharmaceutical combination, the pharmaceutical composition or the fixed dose compound preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is in a range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg
  • a range of doses (preferably unit doses) exists, preferably, wherein the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, or about 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg, or about 100 mg;
  • the DPP-IV inhibitor is sitagliptin, and its dose (preferably a unit dose) is about 25 mg to About 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, more preferably about 25 mg, 50 mg, or About 100 mg; preferably, the DPP-IV inhibitor is lidagliptin, and its dose (preferably a unit dose) is
  • Embodiment 11 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-10, the one or more excipients are selected from the group consisting of a binder, a filler, a disintegrant, a lubricant, Glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.
  • Embodiment 12 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-11, which is a tablet.
  • Embodiment 13 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to Embodiment 12, which is a coated tablet.
  • Embodiment 14 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of Embodiment 13, wherein the coated tablet is a film-coated tablet, and the film-coated agent comprises:
  • Film-coated substrates such as hypromellose, hydroxypropylmethylcellulose, or mixtures thereof;
  • plasticizers such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or mixtures thereof;
  • Optional colorants such as iron oxide red, iron oxide yellow, or mixtures thereof;
  • An optional sunscreen such as titanium dioxide, and
  • Embodiment 15 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 14, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.
  • Embodiment 16 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-15, comprising by weight:
  • a glucokinase activator preferably HMS5552 or its isotope label or a pharmaceutically acceptable salt
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably Solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Scheme 17 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 16, the dosage (preferably a unit dosage) of the active ingredient by weight is:
  • glucokinase activator preferably HMS5552;
  • Embodiment 18 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation of Embodiment 17 (the fixed-dose combination preparation is preferably a 25 mg tablet of HMS5552 / 50 mg of vitagliptin), and comprises, by weight, each group of the following content Minute:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Embodiment 19 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation of the item 17 (the fixed-dose combination preparation is preferably a 50 mg tablet of HMS5552 / 50 mg of vitagliptin), and comprises, by weight, each group of the following content Minute:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of the scheme 17 (the fixed-dose compound preparation is preferably a tablet of 75 mg HMS5552 / 50 mg of vitagliptin), comprising, by weight, each group of the following content Minute:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Scheme 21 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 17, comprising about 50 mg of a solid dispersion, about 50.00 mg of vitagliptin, about 464.00 mg of microcrystalline cellulose, and about 24.00 mg of croscarmellose Sodium cellulose, about 6.00 mg of micronized silica gel, about 6.00 mg of magnesium stearate, and about 18.00 mg of Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100 and about 25 mg of HMS5552.
  • Embodiment 22 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 17, which comprises about 100 mg of a solid dispersion, about 50.00 mg of vitagliptin, about 414.00 mg of microcrystalline cellulose, and about 24.00 mg of croscarmellose.
  • a solid dispersion about 50.00 mg of vitagliptin, about 414.00 mg of microcrystalline cellulose, and about 24.00 mg of croscarmellose.
  • Embodiment 23 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 17, comprising about 150 mg of a solid dispersion, about 50.00 mg of vitagliptin, about 512.50 mg of silicified microcrystalline cellulose, and about 30.00 mg of croscarmellose.
  • a solid dispersion about 50.00 mg of vitagliptin, about 512.50 mg of silicified microcrystalline cellulose, and about 30.00 mg of croscarmellose.
  • Scheme 24 A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose compound formulation according to any one of Schemes 1-23, the method comprising granulating the active ingredient in one or more excipients, preferably The prepared granule mixture is further filled into a vial, sachet or capsule or compressed into a desired tablet shape; more preferably, the obtained tablet is further coated.
  • Embodiment 25 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to embodiment 24, wherein the preparation is performed by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry production) Granules).
  • Embodiment 26 The pharmaceutical combination, the pharmaceutical composition, or the method for preparing a fixed-dose combination preparation according to any one of Embodiments 24-25, wherein the glucokinase activator is prepared in the form of a solid dispersion.
  • Embodiment 27 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to any one of embodiments 24-26, wherein the glucokinase activator and the second or more active ingredients can also be prepared together into a compound In the form of a solid dispersion (i.e. a solid dispersion containing 2 or more active ingredients).
  • a solid dispersion i.e. a solid dispersion containing 2 or more active ingredients.
  • Embodiment 28 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-23, for preventing one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorders, Delay or treat this metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction , Memory disorders, dementia and / or metabolic syndrome; or improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or prevent, slow, delay or reverse complications of diabetes.
  • type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction , Memory disorders, dementia and / or metabolic syndrome or improve glycemic control and / or reduce fast
  • Scheme 29 A method of preventing one or more metabolic disorders selected from the group consisting of: slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia Disease, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory impairment, dementia and / or metabolic syndrome; or to improve blood glucose control and / or reduce fasting plasma glucose, Postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or reversing diabetic complications, including administering to a subject a therapeutically effective amount of the drug combination or drug according to any one of Schemes 1-23 Composition or fixed dose compound preparation.
  • Embodiment 30 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-23 is prepared for treating or preventing one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorders.
  • Embodiment III-glucokinase activator + DPP-IV inhibitor e.g. saxagliptin
  • Scheme 1 Pharmaceutical combination, pharmaceutical composition or fixed dose compound preparation, comprising:
  • a glucokinase activator which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form, a hydrate, a solvate, a diastereomer, or an enantiomer form,
  • the above drugs (a) and (b) are used simultaneously, separately or sequentially.
  • Embodiment 2 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of Embodiment 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 100: 1, preferably about 1 : 4 to 40: 1, more preferably about 1: 4, about 1: 2, about 1: 1, about 1.5: 1, about 1.5: 2, about 2: 1, about 5: 1, and about 10: 1 , About 15: 1, about 20: 1, or about 40: 1.
  • Embodiment 3 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 1 or 2, wherein the glucokinase activator is approximately 1 to 80% by weight; and the DPP-IV inhibitor is approximately 1% by weight. 1 to 20%.
  • Embodiment 4 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to any one of Embodiments 1-3, wherein the glucokinase activator is a compound represented by the following formula HMS5552 or a pharmaceutically acceptable salt thereof, or an isotope marker thereof , Crystalline form, hydrate, solvate, diastereomer or enantiomeric form,
  • Embodiment 5 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to any one of Embodiments 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.
  • Embodiment 6 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 5, wherein the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • Embodiment 7 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 6, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about 5: 6 or any range therebetween.
  • the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about
  • Embodiment 8 The pharmaceutical combination, the pharmaceutical composition or the fixed dose compound preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or saxagliptin monohydrate), Vilagliptin, Ligliptin, Alogliptin, Denagliptin, Megliptin, Goseliptin, Teligliptin, Degree Gliptin, and a pharmaceutically acceptable salt thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vitagliptin And Ligliptin, and their pharmaceutically acceptable salts.
  • the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or s
  • Embodiment 9 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of any one of Embodiments 1-8, wherein the glucokinase activator is at about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg.
  • Embodiment 10 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation according to any one of Embodiments 1-9, wherein the DPP-IV inhibitor is in a range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg
  • a range of doses (preferably unit doses) exists, preferably, wherein the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, or about 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg, or about 100 mg;
  • the DPP-IV inhibitor is sitagliptin, and its dose (preferably a unit dose) is about 25 mg to About 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, more preferably about 25 mg, 50 mg, or About 100 mg; preferably, the DPP-IV inhibitor is lidagliptin, and its dose (preferably a unit dose
  • Embodiment 11 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-10, the one or more excipients are selected from the group consisting of a binder, a filler, a disintegrant, a lubricant, Glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.
  • Embodiment 12 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-11, which is a tablet.
  • Embodiment 13 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to Embodiment 12, which is a coated tablet.
  • Embodiment 14 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of Embodiment 13, wherein the coated tablet is a film-coated tablet, and the film-coated agent comprises:
  • Film-coated substrates such as hypromellose, hydroxypropylmethylcellulose, or mixtures thereof;
  • plasticizers such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or mixtures thereof;
  • Optional colorants such as iron oxide red, iron oxide yellow, or mixtures thereof;
  • An optional sunscreen such as titanium dioxide, and
  • Embodiment 15 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 14, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.
  • Embodiment 16 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-15, comprising by weight:
  • a glucokinase activator preferably HMS5552 or its isotope label or a pharmaceutically acceptable salt
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably Solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Scheme 17 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 16, the dosage (preferably a unit dosage) of the active ingredient by weight is:
  • glucokinase activator preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof
  • Embodiment 18 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation of Embodiment 17 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 5 mg saxagliptin or a corresponding amount of saxagliptin monohydrate), It contains the following components by weight:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation of the scheme 17 (the fixed-dose compound preparation is preferably a tablet of 50 mg HMS5552 / 2.5 mg saxagliptin or a corresponding amount of saxagliptin monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation of Scheme 17 (the fixed-dose combination preparation is preferably a tablet of 75 mg HMS5552 / 5 mg saxagliptin or a corresponding amount of saxagliptin monohydrate), It contains the following components by weight:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Scheme 21.
  • the fixed-dose compound preparation is preferably a tablet of 100 mg HMS5552 / 2.5 mg saxagliptin or a corresponding amount of saxagliptin monohydrate) , By weight, it contains the following components:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Scheme 22 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Scheme 17, comprising about 150 mg of a solid dispersion, about 5.29 mg of saglitinin monohydrate, about 7.50 mg of hydroxypropyl cellulose, and about 79.71 mg of micro Crystalline cellulose, about 2.50 mg magnesium stearate, about 5.00 mg croscarmellose sodium, and about 7.50 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and contains about 75mg HMS5552.
  • Scheme 23 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Scheme 17, comprising about 100 mg of a solid dispersion, about 2.64 mg of saxagliptin monohydrate, about 7.50 mg of hydroxypropyl cellulose, and about 132.36 mg of micro Crystalline cellulose, about 2.50 mg magnesium stearate, about 5.00 mg croscarmellose sodium, and about 7.50 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and contains about 50mg HMS5552.
  • Scheme 24 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Scheme 17, comprising about 200 mg of a solid dispersion, about 2.64 mg of saxagliptin monohydrate, about 9.00 mg of povidone, and about 79.36 mg of microcrystalline fiber Glucoside, about 3.00 mg magnesium stearate, about 6.00 mg croscarmellose sodium and about 9.00 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100 and about 100 mg HMS5552 .
  • Embodiment 25 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 17, which comprises about 50 mg of a solid dispersion, about 5.29 mg of saxagliptin monohydrate, about 7.50 mg of povidone, and about 179.71 mg of microcrystalline fiber Glucotin, about 2.50 mg magnesium stearate, about 5.00 mg croscarmellose sodium, and about 7.50 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and about 25 mg HMS5552 .
  • Scheme 26 A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose compound formulation according to any one of Schemes 1-25, the method comprising granulating the active ingredient by incorporating it into one or more excipients, preferably The prepared granule mixture is further filled into a vial, sachet or capsule or compressed into a desired tablet shape; more preferably, the obtained tablet is further coated.
  • Embodiment 27 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to embodiment 26, wherein the preparation is performed by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry production) Granules).
  • Embodiment 28 A method of preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose combination formulation according to any one of embodiments 26-27, wherein the glucokinase activator is prepared in the form of a solid dispersion.
  • Embodiment 29 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to any one of embodiments 26-28, wherein the glucokinase activator and the second or more active ingredients can also be prepared together into a compound In the form of a solid dispersion (i.e. a solid dispersion containing 2 or more active ingredients).
  • a solid dispersion i.e. a solid dispersion containing 2 or more active ingredients.
  • Embodiment 30 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to any one of Embodiments 1-25, for preventing one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorders, Delay or treat this metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction , Memory disorders, dementia and / or metabolic syndrome; or improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or prevent, slow, delay or reverse complications of diabetes.
  • type I diabetes, type II diabetes impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction , Memory disorders, dementia and / or metabolic syndrome; or improve glycemic control and / or reduce fast
  • Scheme 31 A method for preventing one or more metabolic disorders selected from the group consisting of: slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia Disease, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory impairment, dementia and / or metabolic syndrome; or to improve blood glucose control and / or reduce fasting plasma glucose, Postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or reversing diabetic complications, including administering to a subject a therapeutically effective amount of the drug combination or drug according to any one of Schemes 1-25 Composition or fixed dose compound preparation.
  • Embodiment 32 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-25 is prepared for preventing one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorder, delaying Or use in medicine for treating the metabolic disorder or preventing, slowing, delaying or reversing the complications of diabetes: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, Obesity, hypertension, insulin resistance, diabetic cognitive impairment, memory impairment, dementia and / or metabolic syndrome; or improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylation Hemoglobin HbA1c.
  • one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorder, delaying Or use in medicine for treating the metabolic disorder or preventing, slowing, delaying or reversing the complications of diabetes: type I diabetes, type II diabetes, impaired
  • Embodiment IV-glucokinase activator + DPP-IV inhibitor e.g., Ligliptin
  • Scheme 1 Pharmaceutical combination, pharmaceutical composition or fixed dose compound preparation, comprising:
  • a glucokinase activator which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form, a hydrate, a solvate, a diastereomer, or an enantiomer form,
  • the above drugs (a) and (b) are used simultaneously, separately or sequentially.
  • Embodiment 2 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation according to Embodiment 1, wherein the weight ratio of the glucokinase activator to the DPP-IV inhibitor is about 1:10 to 50: 1, preferably about 1 : 4 to 40: 1, more preferably about 1: 4, about 1: 2, about 1: 1, about 1.5: 1, about 1.5: 2, about 2: 1, about 5: 1, and about 10: 1 , About 15: 1, about 20: 1, or about 40: 1.
  • Embodiment 3 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 1 or 2, wherein the glucokinase activator is approximately 1 to 90% by weight; and the DPP-IV inhibitor is approximately 1% by weight. 1 to 20%.
  • Embodiment 4 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to any one of Embodiments 1-3, wherein the glucokinase activator is a compound represented by the following formula HMS5552 or a pharmaceutically acceptable salt thereof, or an isotope marker thereof , Crystalline form, hydrate, solvate, diastereomer or enantiomeric form,
  • Embodiment 5 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to any one of Embodiments 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.
  • Embodiment 6 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 5, wherein the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • the glucokinase activator is in the form of a solid dispersion including a polymer carrier, and the polymer carrier is a methacrylic acid copolymer type A (Anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)) is preferably Eudragit, and more preferably Eudragit L100.
  • Embodiment 7 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to Embodiment 6, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about 5: 6 or any range therebetween.
  • the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10: 1, preferably about 1: 9 to 9: 1, about 1: 4 to 4: 1, about 3: 7 to 7: 3, about 2: 3 to 3: 2, about 3: 4 to 4: 3, about 4: 5 to 5: 4, or about 5: 6 to 6: 5, more preferably about 1: 1, about 2: 3, about 3: 4, about 4: 5, or about
  • Embodiment 8 The pharmaceutical combination, the pharmaceutical composition or the fixed dose compound preparation according to any one of Embodiments 1-7, wherein the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or saxagliptin monohydrate), Vilagliptin, Ligliptin, Alogliptin, Denagliptin, Megliptin, Goseliptin, Teligliptin, Degree Gliptin, and a pharmaceutically acceptable salt thereof, preferably selected from sitagliptin (or sitagliptin phosphate monohydrate), saxagliptin (or saxagliptin monohydrate), vitagliptin And Ligliptin, and their pharmaceutically acceptable salts.
  • the DPP-IV inhibitor is selected from the group consisting of sitagliptin (or sitagliptin phosphate monohydrate), Saxagliptin (or s
  • Embodiment 9 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination of any one of Embodiments 1-8, wherein the glucokinase activator is at about 1 mg to about 200 mg, preferably about 25 mg to about 100 mg.
  • Embodiment 10 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation according to any one of Embodiments 1-9, wherein the DPP-IV inhibitor is in a range of about 1 mg to 200 mg, preferably about 2.5 mg to about 100 mg
  • a range of doses (preferably unit doses) exists, preferably, wherein the dose (preferably unit dose) of the DPP-IV inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, or about 100 mg, most preferably about 2.5 mg, about 5 mg, about 50 mg, or about 100 mg;
  • the DPP-IV inhibitor is sitagliptin, and its dose (preferably a unit dose) is about 25 mg to About 200 mg, preferably about 50 mg to about 100 mg, preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, more preferably about 25 mg, 50 mg, or About 100 mg; preferably, the DPP-IV inhibitor is lidagliptin, and its dose (preferably a unit dose
  • Embodiment 11 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-10, the one or more excipients are selected from the group consisting of a binder, a filler, a disintegrant, a lubricant, Glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.
  • Embodiment 12 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-11, which is a tablet.
  • Embodiment 13 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to Embodiment 12, which is a coated tablet.
  • Embodiment 14 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation of Embodiment 13, wherein the coated tablet is a film-coated tablet, and the film-coated agent comprises:
  • Film-coated substrates such as hypromellose, hydroxypropylmethylcellulose, or mixtures thereof;
  • plasticizers such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or mixtures thereof;
  • Optional colorants such as iron oxide red, iron oxide yellow, or mixtures thereof;
  • An optional sunscreen such as titanium dioxide, and
  • Embodiment 15 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 14, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.
  • Embodiment 16 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to any one of Embodiments 1-15, comprising by weight:
  • a glucokinase activator preferably HMS5552 or its isotope label or a pharmaceutically acceptable salt
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably Solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Scheme 17 The pharmaceutical combination, pharmaceutical composition, or fixed-dose compound formulation of Scheme 16, the dosage (preferably a unit dosage) of the active ingredient by weight is:
  • glucokinase activator preferably HMS5552 or an isotope marker or a pharmaceutically acceptable salt thereof
  • lidagliptin About 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of lidagliptin;
  • Embodiment 18 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation of the item 17 (the fixed-dose combination preparation is preferably a tablet of 25 mg HMS5552 / 5 mg Ligliptin), comprising, by weight, each group of the following content Minute:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Embodiment 19 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation of the item 17 (the fixed-dose combination preparation is preferably a tablet of 50 mg HMS5552 / 5 mg Ligliptin), comprising, by weight, each group of the following content Minute:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • the pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation of the scheme 17 (the fixed-dose compound preparation is preferably a tablet of 100 mg HMS5552 / 5 mg Ligliptin), and comprises, by weight, each group of the following content Minute:
  • HMS5552 preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, preferably a solid dispersion containing about 1: 1 HMS5552 and Eudragit L100;
  • Embodiment 22 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation according to Embodiment 17, which comprises about 50 mg of a solid dispersion, about 5.00 mg of lidagliptin, about 151.80 mg of microcrystalline cellulose, and about 6.60 mg of hydroxypropyl cellulose , About 4.40 mg croscarmellose sodium, about 2.20 mg magnesium stearate, and about 6.60 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100 and about 25 mg HMS5552.
  • Embodiment 23 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination preparation according to Embodiment 17, which comprises about 100 mg of a solid dispersion, about 5.00 mg of lidagliptin, about 120.60 mg of microcrystalline cellulose, and about 7.20 mg of hydroxypropyl cellulose , About 4.80 mg of croscarmellose sodium, about 2.40 mg of magnesium stearate, and about 7.20 mg of Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100 and about 50 mg of HMS5552.
  • Scheme 24 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose combination formulation of Scheme 17, comprising about 150 mg of a solid dispersion, about 5.00 mg of Ligliptin, about 27.50 mg of microcrystalline cellulose, about 50.00 mg of mannitol, and about 7.50 mg hydroxypropyl cellulose, about 7.50 mg croscarmellose sodium, about 2.50 mg magnesium stearate, and about 7.50 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, And contains about 75mg HMS5552.
  • the pharmaceutical combination, pharmaceutical composition, or fixed-dose compound preparation according to Scheme 25, comprising about 50 mg of a solid dispersion, about 5.00 mg of lidagliptin, about 137.00 mg of microcrystalline cellulose, and about 4.00 mg of croscarmellose Sodium solid, about 2.00 mg magnesium stearate, about 2.00 mg micronized silica gel, and about 6.00 mg Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100 and about 25 mg HMS5552.
  • Embodiment 26 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose compound preparation according to Embodiment 17, which comprises about 200 mg of a solid dispersion, about 5.00 mg of lidagliptin, about 77.0 mg of microcrystalline cellulose, and about 9.00 mg of hydroxypropyl cellulose , About 6.00 mg of croscarmellose sodium, about 3.00 mg of magnesium stearate, and about 9.00 mg of Opadry, wherein the solid dispersion contains about 1: 1 HMS5552 and Eudragit L100, and about 100 mg of HMS5552.
  • Scheme 27 A method for preparing a pharmaceutical combination, a pharmaceutical composition or a fixed-dose compound formulation according to any one of Schemes 1-26, the method comprising granulating the active ingredient by incorporating it into one or more excipients, preferably The prepared granule mixture is further filled into a vial, sachet or capsule or compressed into a desired tablet shape; more preferably, the obtained tablet is further coated.
  • Embodiment 28 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to embodiment 27, wherein the preparation is performed by wet granulation (high shear and / or fluidized bed), or by dry processing (direct compression or dry production) Granules).
  • Embodiment 29 A method of preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose combination formulation according to any one of embodiments 27-28, wherein the glucokinase activator is prepared in the form of a solid dispersion.
  • Embodiment 30 A method for preparing a pharmaceutical combination, a pharmaceutical composition, or a fixed-dose compound preparation according to any one of embodiments 27-29, wherein the glucokinase activator and the second or more active ingredients can also be prepared together into a compound In the form of a solid dispersion (i.e. a solid dispersion containing 2 or more active ingredients).
  • a solid dispersion i.e. a solid dispersion containing 2 or more active ingredients.
  • Embodiment 31 The pharmaceutical combination, the pharmaceutical composition or the fixed-dose combination preparation according to any one of Embodiments 1-26, for preventing one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorders, Delay or treat this metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction , Memory disorders, dementia and / or metabolic syndrome; or improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or prevent, slow, delay or reverse complications of diabetes.
  • type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction , Memory disorders, dementia and / or metabolic syndrome or improve glycemic control and / or reduce fast
  • Scheme 32 A method for preventing one or more metabolic disorders selected from the group consisting of: slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia Disease, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic cognitive dysfunction, memory impairment, dementia and / or metabolic syndrome; or to improve blood glucose control and / or reduce fasting plasma glucose, Postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or reversing diabetic complications, including administering to a subject a therapeutically effective amount of the drug combination or drug according to any one of Schemes 1-26 Composition or fixed dose compound preparation.
  • Embodiment 33 The pharmaceutical combination, the pharmaceutical composition, or the fixed-dose compound preparation according to any one of Embodiments 1-26 is prepared for preventing one or more metabolic disorders selected from the group consisting of slowing the progress of the metabolic disorder, delaying Or use in medicine for treating the metabolic disorder or preventing, slowing, delaying or reversing the complications of diabetes: type I diabetes, type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, Obesity, hypertension, insulin resistance, diabetic cognitive impairment, memory impairment, dementia and / or metabolic syndrome; or improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylation Hemoglobin HbA1c.
  • Chemicals used in the present invention can be purchased from companies such as Shin-Etsu Japan, Evonik Germany, J.T. Baker US, SCR China, Ashland US, FMC US, JRS Germany, Colorcon US, Capsugel, BASF, revitalization reagents, and the like.
  • Production equipment and analytical testing instruments can be purchased from such companies as Sartorius, Nikon, Sympatec, Bruker, Gea Niro, Korsch, Erweka, Agilent, Quadro Engineering, Canada; Warters, US; TA, US; SOTAX, Switzerland; Mettler Toledo Instrument Newark, DE.
  • Example 1A (weight ratio of active ingredient to polymer is 1: 9)
  • Example 2A (weight ratio of active ingredient to polymer is 3: 7)
  • Example 3A (weight ratio of active ingredient to polymer is 5: 5)
  • Example 4A (weight ratio of active ingredient to polymer is 7: 3)
  • Example 5A weight ratio of active ingredient to polymer is 8: 2
  • Example 6A weight ratio of active ingredient to polymer is 9: 1)
  • Example 7A (weight ratio of active ingredient to polymer is 6: 4)
  • Example 8A (weight ratio of active ingredient to polymer is 4: 6)
  • Example 9A (weight ratio of active ingredient to polymer is 5: 5)
  • Spray drying equipment suitable for the present invention includes, but is not limited to, spray drying equipment made by Niro GEA Process Engineering Inc., Buchi Labortechnik AG, ProCept and SPX ANHYDROUS.
  • the spray drying can be performed by selecting a suitable drying gas inlet air temperature, air inlet volume, liquid inlet speed, and atomizing pressure, so that the droplets are fully dried when they reach the device wall. This helps to ensure that the dried droplets are essentially solid, can form a fine powder, do not stick to the wall, and are not difficult to collect in a cyclone.
  • the resulting powder is dried twice to ensure that the product meets quality requirements.
  • the solution prepared in the above Examples 1A-8A was spray-dried to prepare a solid dispersion.
  • the inlet temperature of the spray dryer was set to 90-150 ° C, and the inlet air flow rate was set to 0.3-0.5 m 3 / min.
  • the flow rate is 15-30 L / min, the spraying speed of the above solution is 5-7 mL / min, and the spray drying is performed to obtain a solid dispersion 1-8.
  • the solution prepared in the above Example 9A was spray-dried to prepare a solid dispersion, wherein the inlet air temperature of the spray dryer was set to 90-150 ° C, the inlet air flow rate was set to 20-30 kg / h, and the air flow rate was 3- 30 kg / h, spray speed of the above solution is 5-200 mL / min, and spray-dried to obtain solid dispersion 9.
  • the mass fraction of compound HMS5552 in solid dispersion 1 is 10%; the mass fraction of compound HMS5552 in solid dispersion 2 is 30%; the mass fraction of compound HMS5552 in solid dispersion 3 is 50%; the mass of compound HMS5552 in solid dispersion 4
  • the mass fraction is 70%; the mass fraction of compound HMS5552 in solid dispersion 5 is 80%; the mass fraction of compound HMS5552 in solid dispersion 6 is 90%; the mass fraction of compound HMS5552 in solid dispersion 7 is 60%; solid dispersion
  • the mass fraction of the compound HMS5552 in the body 8 is 40%; the mass fraction of the compound HMS5552 in the solid dispersion 9 is 50%.
  • the HMS5552 solid dispersion and the combined drug prepared according to the above-mentioned solid dispersion preparation of a glucokinase activator are added to a high-shear wet granulator, and a filler (such as microcrystalline cellulose, or siliconized microcrystalline fiber) is added.
  • a filler such as microcrystalline cellulose, or siliconized microcrystalline fiber
  • disintegrants such as croscarmellose sodium, or crospovidone, or sodium starch glycolate
  • the wet granules were granulated on a Comil granulator to obtain wet granules of a suitable size.
  • the wet granules are dried in a tray oven at about 60 ° C or in a fluid bed dryer (inlet air temperature 40-60 ° C) for 20-40 minutes. Then, the dried material is ground with a grinder to obtain particles of a proper size. After milling, microcrystalline cellulose or silicified microcrystalline cellulose (for fillers with an additional portion) and disintegrants (such as croscarmellose sodium, or crospovidone, or starch glycolate) Sodium) is added to the granules and mixed in a barrel mixer.
  • disintegrants such as croscarmellose sodium, or crospovidone, or starch glycolate
  • a lubricant magnesium stearate or sodium stearyl fumarate
  • an optional glidant micronized silica gel
  • the lubricated mixture is compressed using a rotary tablet press to obtain tablets (plain tablets, uncoated cores) of different tablet weights and tablet types corresponding to different specifications.
  • the resulting tablets are optionally used A film coating weight increase of about 3% was performed to obtain a film-coated tablet.
  • sitagliptin phosphate monohydrate is equivalent to 50.0 mg of sitagliptin free anhydrate.
  • Prescription composition Unit prescription amount / mg % (W / w) Sitagliptin phosphate monohydrate ** 128.50 44.31 HMS5552 solid dispersion * 100.00 34.48 Microcrystalline cellulose 41.20 14.21 Hydroxypropyl cellulose 8.70 3.00 Croscarmellose sodium 8.70 3.00 Magnesium stearate 2.90 1.00
  • sitagliptin phosphate monohydrate is equivalent to 100.0 mg of sitagliptin free anhydrate.
  • Prescription composition Unit prescription amount / mg % (W / w) Sitagliptin phosphate monohydrate ** 128.50 36.71 HMS5552 solid dispersion * 150.00 42.86 Microcrystalline cellulose 47.00 13.43 Hydroxypropyl cellulose 10.50 3.00 Croscarmellose sodium 10.50 3.00 Magnesium stearate 3.50 1.00 Total core weight 350.00 100.00 Opadry 10.50 3.00 Total weight of coated tablets 360.50 -
  • sitagliptin phosphate monohydrate is equivalent to 100.0 mg of sitagliptin free anhydrate.
  • Prescription composition Unit prescription amount / mg % (W / w) Sitagliptin phosphate monohydrate ** 128.50 42.83 HMS5552 solid dispersion * 50.00 16.67 Microcrystalline cellulose 100.50 33.50 Hydroxypropyl cellulose 9.00 3.00 Croscarmellose sodium 9.00 3.00 Magnesium stearate 3.00 1.00 Total core weight 300.00 100.00 Opadry 9.00 3.00 Total weight of coated tablets 309.00 Zh
  • sitagliptin phosphate monohydrate is equivalent to 100.0 mg of sitagliptin free anhydrate.
  • sitagliptin phosphate monohydrate is equivalent to 50.0 mg of sitagliptin free anhydrate.
  • Example 10B HMS5552 + Ligliptin Compound Tablets (Dose Specification 100mg / 5mg)
  • Example 12B HMS5552 + saxagliptin compound tablet (dose specification 50mg / 2.5mg)
  • Prescription composition Unit prescription amount / mg % (W / w) HMS5552 solid dispersion * 100.00 40.00 Saxagliptin monohydrate ** 2.64 1.06 Hydroxypropyl cellulose 7.50 3.00 Microcrystalline cellulose 132.36 52.94 Magnesium stearate 2.50 1.00 Croscarmellose sodium 5.00 2.00 Total core weight 250.00 100.00 Opadry 7.50 3.00 Total weight of coated tablets 257.50 -
  • Prescription composition Unit prescription amount / mg % (W / w) HMS5552 solid dispersion * 200.00 66.67 Saxagliptin monohydrate ** 2.64 0.88 Povidone 9.00 3.00 Microcrystalline cellulose 79.36 26.45 Magnesium stearate 3.00 1.00 Croscarmellose sodium 6.00 2.00
  • the HMS5552 solid dispersion and the combined drug prepared according to the above-mentioned solid dispersion preparation of a glucokinase activator are added to a fluidized bed granulator, and an optional filler (for example, microcrystalline cellulose) is added.
  • the prepared binder such as polyvinylpyrrolidone
  • the prepared binder solution is sprayed into the mixture in a fluidized bed for granulation within 20-60 minutes, and then granulated in a fluidized bed dryer (inlet air temperature 40-60 ° C) Continue to dry. Then, the dried material is ground with a grinder to obtain particles of a proper size.
  • microcrystalline cellulose or silicified microcrystalline cellulose (prescribed for fillers with an added portion) is added to the granules and mixed in a barrel mixer. Then, a lubricant (magnesium stearate) and / or an optional glidant (micronized silica gel) are added thereto and further mixed uniformly.
  • the lubricated mixture is compressed using a rotary tablet press to obtain tablets (plain tablets, uncoated cores) of different tablet weights and tablet types corresponding to different specifications.
  • the obtained tablet is optionally subjected to a film coating weight increase of about 3%, which is prepared by the method for preparing a solid dispersion of a glucokinase activator, to obtain a film-coated tablet.
  • saxagliptin monohydrate is equivalent to 5.0 mg of saxagliptin free anhydrate.
  • HMS5552 solid dispersion and combination drug prepared according to the preparation example of the solid dispersion of the glucokinase activator to the mixing tank, add the filler (such as microcrystalline cellulose) and the binder (such as hydroxypropyl fiber (Vein), mix well. Then, it is rolled by a roller compaction granulator to obtain a bar, which is crushed and granulated by a pulverizer, so as to obtain granules of an appropriate size. After milling, add optional microcrystalline cellulose or silicified microcrystalline cellulose (for fillers with an added portion) and disintegrants (such as croscarmellose sodium) to the granules and in a barrel Mix them in a mixer.
  • the filler such as microcrystalline cellulose
  • the binder such as hydroxypropyl fiber (Vein)
  • Vein hydroxypropyl fiber
  • a lubricant magnesium stearate or sodium stearyl fumarate
  • an optional glidant micronized silica gel
  • the lubricated mixture is compressed using a rotary tablet press to obtain tablets (plain tablets, uncoated cores) of different tablet weights and tablet types corresponding to different specifications.
  • the resulting tablets are optionally used A film coating weight increase of about 3% was performed to obtain a film-coated tablet.
  • Prescription composition Unit prescription amount / mg % (W / w) HMS5552 solid dispersion * 100.00 16.67 Vigliptin 50.00 8.33 Microcrystalline cellulose 414.00 69.00 Croscarmellose sodium 24.00 4.00 Micro powder silica gel 6.00 1.00 Magnesium stearate 6.00 1.00 Total core weight 600.00 100.00 Opadry 18.00 3.00 Total weight of coated tablets 618.00 -
  • the HMS5552 solid dispersion and the combined drug prepared according to the above-mentioned preparation example of the solid dispersion of glucokinase activator are pre-mixed uniformly according to the principle of geometric increment, and then added to the mixing barrel, and a filler (such as microcrystalline cellulose) is added to disintegrate
  • a dissolving agent such as croscarmellose sodium
  • an optional glidant micronized silica gel
  • the lubricated mixture is compressed using a rotary tablet press to obtain tablets (plain tablets, uncoated cores) of different tablet weights and tablet types corresponding to different specifications.
  • the resulting tablets are optionally used
  • a film coating weight increase of about 3% was performed to obtain a film-coated tablet.
  • composition of the compound tablet described according to the above preparation process is:
  • the dissolution rate of the tablets was measured by the paddle method of the Chinese Pharmacopoeia (2015 edition), and the dissolution of HMS5552 and another combination drug in a medium of pH 6.8 were measured at 5 minutes, 15 minutes, 30 minutes, 45 At 5 minutes and 60 minutes, 5 ml were taken for HPLC analysis.
  • SD obese rats were induced by STZ to form a type 2 diabetes model rat, which were orally administered with lysozyme, 10mg / kg HMS5552, 30mg / kg HMS5552, 10mg / kg sitagliptin, 30mg / kg sitagliptin, 10 mg / kg HMS5552 combined with 10 mg / kg sitagliptin, or 10 mg / kg HMS5552 combined with 30 mg / kg sitagliptin.
  • Sitagliptin a dipeptidyl peptidase-4 (DPP-IV) inhibitor, improves blood glucose control and lowers postprandial blood glucose by inhibiting the degradation of insulinotropic GLP-1 and increasing the level of active insulinotropic insulinotropic insulin.
  • DPP-IV dipeptidyl peptidase-4
  • HMS5552 a new type of glucokinase activator, can improve islet function, promote intestinal insulin secretion, reduce insulin resistance in type 2 diabetic patients, and has the dual therapeutic effect of reducing fasting and postprandial blood glucose.
  • DPP-IV inhibitor combined with HMS5552, For patients with DPP-IV inhibitors failing to control blood glucose, obese and diabetic patients with cardiovascular disease, it has better blood glucose control efficacy and reduces the risk of diabetes complications.

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Abstract

一种药物组合，所述药物组合包含葡萄糖激酶激活剂或其可药用盐、其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式和DPP-IV抑制剂。一种药物组合物、固定剂量复方制剂，以及所述药物组合物和所述固定剂量复方制剂的制备方法及其用途。

Description

含有葡萄糖激酶激活剂和DPP-IV抑制剂的药物组合、组合物和复方制剂及其制备方法和用途
优先权要求
本申请要求申请日为2018年5月31日的中国发明专利申请号201810556685.6的优先权，其全部公开内容通过引用并入本文。
技术领域
本发明涉及包含葡萄糖激酶激活剂(Glucokinase Activator,GKA)药物与组合药物(partner drug)的药物组合、组合物和固定剂量复方(fixed dose combination,FDC)制剂，其制备方法及其用于治疗某些疾病的用途。
在更详细方面中，本发明涉及包含葡萄糖激酶激活剂药物与组合药物的药物组合、药物组合物或固定剂量复方的口服固体制剂，及其制备方法。本发明还涉及包含葡萄糖激酶激活剂的药物组合、药物组合物或固定剂量复方制剂的用途，其用于治疗和/或预防一种或多种疾病及医学病症，包括但不限于I型糖尿病、II型糖尿病、糖尿病认知功能障碍，记忆力功能障碍，老年痴呆、葡萄糖耐量降低、空腹血糖异常、肥胖症以及高血压症。此外，本发明还涉及治疗和/或预防一种或多种疾病及医学病症的方法，其中包括向有需要的受试者给予治疗有效量的本发明的药物组合、药物组合物或固定剂量复方制剂。
背景技术
糖尿病已成为世界范围的普遍性疾病，其全球患者数量现为4.25亿，而中国患者人数高达1.2亿(International Diabetes Federation,Diabetes Atlas,2015)。II型糖尿病即非胰岛素依赖型糖尿病(non-insulin dependent diabetes mellitus，NIDDM)，占糖尿病患者的90％以上。II型糖尿病，是一种由于胰岛素分泌障碍和胰岛素抵抗引起的人体血糖稳态平衡失调而导致的高血糖慢性代谢功能紊乱性疾病。人体血糖平衡主要是由胰岛素、胰高糖素两个控糖激素协调完成。
葡萄糖传感器葡萄糖激酶(Glucokinase,GK)感应血糖变化，调控信使控糖激素、胰岛素和胰高糖素以及GLP-1(胰高血糖素样肽-1)的分泌，构成人体血糖稳态调控的传感系统。控糖激素控制的葡萄糖摄取时葡萄糖储备和空腹时葡萄糖供给，构成人体血糖稳态调控。参与葡萄糖储备的器官主要有肝脏、肌肉和脂肪，在血糖和胰岛素的作用下摄取葡萄糖并转化为肝糖原、肌糖原和甘油三酯。参与葡萄糖供给的主要器官为肝脏，在血糖和胰高糖素的作用下，通过肝糖合成和肝糖输出为人体供糖。胰岛素还可有效调节钠-葡萄糖协同转运蛋白SGLT-2的活性，在血糖升高时，把肾脏排泄的葡萄糖重新吸收，为人体葡萄糖储备所用。葡萄糖摄取和肝糖输出，以及各器官对葡萄糖的使用构成人体血糖稳态平衡的操作运营系统。葡萄糖的传感系统和操作运营系统的协同运作，构成对人体血糖稳态的随机调控。
在糖尿病患者中，由于葡萄糖激酶功能和表达受损，传感器功能失调，造成控糖激素早相分泌失调，影响葡萄糖的摄取和输出，造成餐后高血糖、餐前低血糖。控糖激素信号指令异常，造成葡萄糖 摄取和输出操作执行系统中关键蛋白的功能和表达异常，形成异常状态运行，形成II型糖尿病。
现有糖尿病口服降糖药，通常作用于单一控糖器官，不能有效治疗血糖稳态平衡系统失调的问题。葡萄糖激酶激活剂代表一类开发用于治疗或者改进患有II型糖尿病患者疾病状态的新药。例如，((S)-2-[4-((2-氯-苯氧基)-2-氧代-2,5-二氢-吡咯-1-基]-4-甲基-戊酸[1-((R)-2,3-二羟基-丙基)-1H-吡唑-3-基]-酰胺(下文中称作HMS5552)能有效改善糖尿病患者的葡萄糖传感器功能，是目前最有希望解决以上临床需求的糖尿病治疗药物。
发明内容
糖尿病患者在治疗中经常碰到这样的情况：仅使用DPP-IV抑制剂疗效不佳，无法将血糖控制在理想水平，尤其在使用一段时间之后。对此，本发明人发现，将DPP-IV抑制剂和葡萄糖激酶激活剂联合，能够显著提高DPP-IV抑制剂的降糖效果并降低安全风险，因而得到了本发明的含有葡萄糖激酶激活剂和DPP-IV抑制剂的药物组合、组合物和复方制剂。
更具体而言，作用不同的糖尿病口服药物联合使用，提高中晚期患者多器官功能，更有效地治疗糖尿病以及伴随疾病和并发症。能够减少患者的服药粒数，提高患者的顺应性；减少了达到相同疗效的药物总剂量，使用最小的剂量达到了最大的药效，对治疗或预防一种或多种Ⅰ型糖尿病、II型糖尿病、高血糖症、葡萄糖耐量降低、肥胖症等症状有良好的效果和实际的意义。
另一方面，本发明的含有葡萄糖激酶激活剂和组合药物(第二种或更多种活性药物成分)的固定剂量复方制剂，不仅其治疗效果优于这两种或多种药物的单独使用，还解决了复方制剂中通常存在的技术挑战。本发明的固定剂量复方制剂能够解决两种或者多种活性成分释放同步且含量均匀的问题，并可优化制剂中含有的活性成分的溶出速率，尤其是使得制剂中含有的活性成分在小肠pH环境中快速释放，这有益于药物及时或同时到达在肠道，胰岛和肝脏靶点器官，实现一靶多点、协同降糖的临床优势，起到发挥更好的疗效和降低毒副作用的效果。其次，本发明的含有葡萄糖激酶激活剂和组合药物(第二种或更多种活性药物成分)的固定剂量复方制剂还具有较短的崩解时限，并具有良好溶出特性和/或使得葡萄糖激酶激活剂能够在患者中具有高生物利用度。
本发明提供了包含葡萄糖激酶激活剂，例如，结构如下所示的HMS5552，或其同位素标记物，或其可药用盐，与其他口服降糖药物的药物组合、药物组合物、固定剂量复方制剂，尤其固体制剂，例如口服固体制剂，例如片剂，
Figure PCTCN2019088864-appb-000001
具体的，本发明还提供了包含葡萄糖激酶激活剂药物例如HMS5552或其可药用盐与DPP-IV抑制剂的药物组合、药物组合物或固定剂量复方制剂。进一步的，所述DPP-Ⅳ抑制剂的实例包括但不限于：西格列汀、沙格列汀、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特 力列汀、度格列汀，及其可药用盐。其中，优选西格列汀、沙格列汀、维格列汀和利格列汀。
更具体而言，本发明还提供了包含葡萄糖激酶激活剂药物例如HMS5552或其可药用盐及组合药物例如西格列汀的固定剂量复方的固体制剂。所述固体制剂优选为片剂，并且更优选是包衣片剂。在一个实施方案中，所述葡萄糖激酶激活剂例如HMS5552为固体分散体形式。
更具体而言，本发明还提供了包含葡萄糖激酶激活剂药物例如HMS5552或其可药用盐及组合药物例如维格列汀的固定剂量复方的固体制剂。所述固体制剂优选为片剂，并且更优选是包衣片剂。在一个实施方案中，所述葡萄糖激酶激活剂例如HMS5552为固体分散体形式。
更具体而言，本发明还提供了包含葡萄糖激酶激活剂药物例如HMS5552或其可药用盐及组合药物例如沙格列汀的固定剂量复方的固体制剂。所述固体制剂优选为片剂，并且更优选是包衣片剂。在一个实施方案中，所述葡萄糖激酶激活剂例如HMS5552为固体分散体形式。
更具体而言，本发明还提供了包含葡萄糖激酶激活剂药物HMS5552或其可药用盐及组合药物例如利格列汀的固定剂量复方的固体制剂。所述固体制剂优选为片剂，并且更优选是包衣片剂。在一个实施方案中，所述葡萄糖激酶激活剂例如HMS5552为固体分散体形式。
本发明还提供了通过干法或者湿法处理方法制备的葡萄糖激酶激活剂药物和组合药物(第二种或更多种活性药物成分)的药物组合、药物组合物或固定剂量复方制剂。本发明的药物组合、药物组合物或固定剂量复方制剂的释放方式为所述两种或多种活性药物成分的快速释放。
本发明还提供了包含葡萄糖激酶激活剂药物及组合药物(第二种或更多种活性药物成分)的药物制剂，其具有短的崩解时限，其具有良好溶出特性和/或使得葡萄糖激酶激活剂能够在患者中具有高生物利用度。本发明还提供了通过干法或者湿法处理方法制备葡萄糖激酶激活剂药物和组合药物(第二种或更多种活性药物成分，例如西格列汀、沙格列汀、维格列汀和利格列汀)的固定剂量组合的药物组合物或药物制剂的方法。干法处理方法包括干法压缩(压片)和干法制粒；湿法处理方法包括湿法制粒。
本发明还提供了包含葡萄糖激酶激活剂药物及组合药物(第二种或更多种活性药物成分)的药物组合、药物组合物或药物制剂，以及用于预防代谢病症(尤其为II型糖尿病)、减缓其进展、延迟或治疗该代谢病症的方法。
本发明还提供了包含葡萄糖激酶激活剂药物及组合药物(第二种或更多种活性药物成分)的药物组合、药物组合物或药物制剂，以及用于在有需要的患者(尤其为患有II型糖尿病的患者)中改善血糖控制的方法。
本发明还提供了包含葡萄糖激酶激活剂药物及组合药物的药物组合、药物组合物或药物制剂，以及在血糖控制不充分的患者中改善血糖控制的方法。
本发明还提供了包含葡萄糖激酶激活剂药物及组合药物的药物组合、药物组合物或药物制剂，以及用于预防、减缓或延迟糖尿病认知功能障碍、记忆力功能障碍、老年痴呆、葡萄糖耐量降低(IGT)、空腹血糖异常(IFG)、高血压症、胰岛素抵抗和/或代谢综合征进展成II型糖尿病的方法。
本发明还提供了包含葡萄糖激酶激活剂药物及组合药物的药物组合、药物组合物及药物制剂，以及用于预防包括糖尿病并发症在内的疾病或病症、减缓其进展、延迟或治疗该疾病或病症的方法。
本领域技术人员通过上下文说明以及通过实施例可明了本发明的其他目的。
发明概述
本发明的第一个方面提供包含以下组分的药物组合、药物组合物或药物制剂，及其制备方法和治疗糖尿病及其相关疾病的用途：
(a)葡萄糖激酶激活剂，其为选自下列的化合物，或其可药用盐、其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式；优选的，所述葡萄糖激酶激活剂为HMS5552；更优选的，HMS5552的存在方式是固体分散体形式，
Figure PCTCN2019088864-appb-000002
(b)DPP-IV抑制剂；和
(c)一种或多种赋形剂。
本发明的另一个方面提供包含以下组分的药物组合、药物组合物或药物制剂，及其制备方法和治疗糖尿病及其相关疾病的用途：
(a)葡萄糖激酶激活剂，其为选自HMS5552化合物，或其可药用盐、其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式；优选的，所述葡萄糖激酶激活剂为HMS5552；更优选的，HMS5552的存在方式是固体分散体形式；
(b)西格列汀、维格列汀、沙格列汀、利格列汀，或其可药用盐、其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式；和
(c)一种或多种赋形剂。
特别是，本发明的一个方面还涉及含有HMS5552固体分散体和组合药物(例如，西格列汀、维格列汀、沙格列汀、利格列汀)的固定剂量组合的药物组合、药物组合物或药物制剂，及其制备方法和用途。
定义
除非另有说明，本文使用的所有技术和科学术语具有与本发明所属领域的技术人员通常理解相同的含义，但如有冲突，则以本说明书中的定义为准。
如说明书和权利要求书中所用，单数形式“一”、“一个”和“该(所述)”包括复数形式，除非上下文另有明确说明。
如无特殊说明，本说明书中的百分比(％)均为重量百分比(重量％)。
在说明书和权利要求书中使用的涉及组分量、工艺条件等的所有数值或表述在所有情形中均应理解被“约”修饰。术语“约”当指数量或数值范围时，意思是所指数量或者数值范围是试验变异性内(或统 计学实验误差内)的近似值，因此该数量或者数值范围可以在所述数量或数值范围的例如+5之间变化。
涉及相同组分或性质的所有范围均包括端点，该端点可独立地组合。由于这些范围是连续的，因此它们包括在最小值与最大值之间的每一数值。还应理解的是，本申请引用的任何数值范围预期包括该范围内的所有子范围。
当本发明针对物理性质例如分子量或者针对化学性质以范围定义时，应包括范围的所有组合和亚组合以及其内的具体实施方式。术语“包含”(以及相关术语例如“含有”或“含”或“具有”或“包括”)包括这样一些实施方式，该实施方式为例如，物质、组合物、方法或过程等的任何组合，其“由所描述的特征组成”或者“基本上由所描述的特征组成”。
本说明书和权利要求中使用的“和/或”，应当理解为相关联的组分“二者择一或二者”，即组分在一些情况中联合存在而在另一些情况中分开存在。多个用“和/或”列出的组分应当以同样的方式理解，即“一种或多种”相关联的组分。除了“和/或”从句具体确定的组分，其它组分可任选地存在，无论与那些具体确定的组分相关还是不相关。因此，作为非限制性实例，提及“A和/或B”，当用于连接开放式结尾的文字如“包括”，在一个实施方案中，可仅指A(任选地包括除B外的组分)；在另一实施方案，可仅指B(任选地包括除A外的组分)；在再一实施方案中，指A和B(任选的包括其它组分)等。
应当理解，除非明确地相反指示，否则在本文要求保护的包括多于一步或一个行为的任何方法中，该方法的步骤和行为的顺序不必限制于所叙及的方法的步骤和行为的顺序。
本发明使用的缩写具有在化学、生物学和制剂领域的通常含义。
除非另有说明，否则在本发明上下文中的术语“DPP-IV抑制剂”或其任何种类(如“西格列汀、维格列汀、沙格列汀、利格列汀”)还意欲包括其任一药学上可接受的盐、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体。
HMS5552，其曾用名为RO5305552，英文名为Dorzagliatin，化学名为(S)-2-[4-(2-氯-苯氧基)-2-氧代-2,5-二氢-吡咯-1-基]-4-甲基-戊酸[1-((R)-2,3-二羟基-丙基)-1H-吡唑-3-基]-酰胺。
除非另有说明，重量％(wt％)表示为占药物组合、药物组合物或药物制剂的总重量的百分比。
固体分散体(solid dispersion,SD)是指将一种或多种药物活性成分高度分散到无活性的辅料或载体所形成的固体分散体系。
EUDRAGIT(尤特奇)是合成药用辅料的商品名，它包括甲基丙烯酸共聚物和甲基丙烯酸酯共聚物，通称为聚丙烯酸树脂。聚丙烯酸树脂类辅料按其构成、比例及聚合度不同而分为不同的型号。其中，Eudragit E为甲基丙烯酸二甲胺基乙酯与甲基丙烯酸酯的聚合物；Eudragit L为甲基丙烯酸与甲基丙烯酸甲酯的聚合物，游离羧基:酯＝1:1，Eudragit S为甲基丙烯酸与甲基丙烯酸甲酯的聚合物，游离羧基:酯＝1:2。
在此使用的术语“片剂”意图包括所有形状和大小的经压缩的药物制剂，无论包衣与否。
术语“有效量”或“治疗有效量”是指足以提供希望的生物结果的试剂的量。该结果可为疾病的征兆、症状或原因的减少和/或减轻，或任何其它希望的生物系统的变化。例如，治疗用途的“有效量”是指包含作为本发明活性成分的化合物的临床上显著减少疾病所需要的组合物的量。在任何个案中，适当的“有效”量可由本领域普通技术人员使用常规实验来测定。因此，表达方式“有效量”通常是指活 性物质具有治疗效果时的量。
本申请使用的术语“治疗(treat)”或“处置(treatment)”与术语“预防(prevent)”同义，意在表示推迟疾病发展、防止疾病发展和/或降低将会发展或预期会发展的所述症状的严重性。因此，这些术语包括改善已有的疾病症状、预防另外的症状、改善或预防症状的潜在的代谢原因、抑制障碍或疾病，例如，阻止障碍或疾病的发展、减轻障碍或疾病、使障碍或疾病退行、减轻由疾病或障碍导致的病症，或使疾病或障碍的症状停止。
“药用的”或“药理上可接受的”是指并非在生物学上或其它方面实质上不希望的物质，即，可将所述物质给药于个体，而不会导致任何不希望的生物作用或不会以有害的方式与包含这种物质的组合物的任何其它组分相互作用。
本申请使用的术语“受试者”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人、非人灵长类如黑猩猩及其它猿类和猴类；农场动物如牛、马、绵羊、山羊、猪；家养动物如兔、狗和猫；实验室动物，包括啮齿类动物如大鼠、小鼠和豚鼠等。非哺乳动物的实例包括但不限于鸟、鱼等。在本发明一个实施方案中，哺乳动物为人。
作为本发明的含有葡萄糖激酶激活剂的药物组合、药物组合物或药物制剂(例如，固定剂量组合制剂)中的活性成分的化合物可以形成盐。除非另有说明，当提及本申请中具有所述化合物时，应理解为其包括对其盐的提及。本申请使用的术语“盐(一种或多种)”是指与无机和/或有机酸形成的酸式盐及与无机和/或有机碱形成的碱式盐。另外，当所述化合物含有碱性部分(例如但不限于，吡啶或咪唑)和酸性部分(例如但不限于，羧酸)时，可形成两性离子(“内盐”)且所述两性离子(“内盐”)包含在本申请使用的术语“盐(一种或多种)”中。优选为药用(即，无毒的，生理学上可接受的)盐，但其它盐也是有用的。所述化合物的盐可例如通过以下方法形成：在介质中使所述化合物与一定量的(例如等量的)酸或碱反应，所述介质为例如盐在其中析出的介质或为含水介质(反应后冻干)。
不同化合物及其盐、溶剂化物、酯和前药的多晶型形式意在包括在本发明中。
应当理解本文采用的术语用于描述具体实施方案的目的，而不意在进行限制。此外，尽管在本发明的实践或试验中可以使用与本文描述的那些类似或等价的任何方法、装置和材料，但是下文描述了优选的方法、装置和材料。
附图说明
图1为实施例4B和同剂量单方片剂的溶出结果；
图2为2型糖尿病模型大鼠参与的HMS5552联合西格列汀的药效学动物研究结果。
发明详述
本发明的一方面涉及葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)和组合药物(例如，西格列汀、维格列汀、沙格列汀、利格列汀)的药物组合、药物组合物或者药物制剂如固定剂量复方制剂。所述制剂可以为粉剂、颗粒剂、片剂、胶囊、小袋或者其他固体形式等。具体而言，本发明的一个方面涉及含有葡萄糖激酶激活剂和组合药物(例如，西格列汀、维格列汀、 沙格列汀、利格列汀)的固定剂量组合的片剂。
在本发明的一个具体方面中，药物组合、药物组合物或药物制剂包含：
(1)葡萄糖激酶激活剂或其可药用盐、或其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式；优选的，所述葡萄糖激酶激活剂优选为HMS5552；更优选的，HMS5552的存在形式是固体分散体形式，例如包含聚合物载体的固体分散体形式(例如，喷雾干燥粉末)；
(2)DPP-IV抑制剂；优选的，其选自：西格列汀、维格列汀、沙格列汀、利格列汀，或其可药用盐、其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式；和/或
(3)填充剂；和/或
(4)粘合剂；和/或
(5)崩解剂；和/或
(6)润滑剂或者助流剂；和/或
(7)包衣剂。
在本发明的一个实施方案中，药物组合、药物组合物或者药物制剂还可以含有一种或者多种赋形剂，所述赋形剂选自一种或者多种粘合剂；一种或者多种稀释剂(填充剂)；一种或者多种崩解剂；一种或者多种润滑剂；一种或者多种助流剂；一种或者多种表面活性剂或者润湿剂；和一种或者多种抗氧化剂；和一种或多种包衣剂。
药物组合、药物组合物或药物制剂
葡萄糖激酶激活剂+DPP-IV抑制剂类药物
在一个实施方案中，本发明涉及一种药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)，其包含：
(a)葡萄糖激酶激活剂，其为下式表示的化合物，或其可药用盐、其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式
Figure PCTCN2019088864-appb-000003
Figure PCTCN2019088864-appb-000004
(b)DPP-Ⅳ抑制剂；
优选的，其选自西格列汀、沙格列汀、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特力列汀、度格列汀，及其可药用盐。其中，优选西格列汀、沙格列汀、维格列汀和利格列汀；
(c)一种或多种赋形剂；
其中上述药物(a)和(b)同时、分别或相继使用。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，所述葡萄糖激酶激活剂与DPP-IV抑制剂的重量比为约1:10至100:1，优选地为约1:4至40:1，更优选地为约1:4、约1:2、约1:1、约1.5:1、约1.5:2、约2:1、约5:1、约10:1、约15:1、约20:1或约40:1。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，所述葡萄糖激酶激活剂以约1毫克至约200毫克，优选地约25毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述葡萄糖激酶激活剂的剂量(优选单位剂量)为约25毫克、约50毫克、约75毫克或约100毫克。
在一个实施方案中，上述药物组合、药物组合物或药物制剂中，所述DPP-IV抑制剂以约1毫克至200毫克，优选地约2.5毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述DPP-IV抑制剂的剂量(优选单位剂量)为约2.5毫克、约5毫克、约10毫克、约20毫克、约50毫克或约100毫克，最优选为约2.5毫克、约5毫克、约50毫克或约100毫克；优选地，所述DPP-IV抑制剂为西格列汀，其剂量(优选单位剂量)为约25毫克～约200毫克，优选地为约50毫克～约100毫克，优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克，更优选为约25mg、50mg或约100mg；优选地，所述DPP-IV抑制剂为利格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约5毫克或约10毫克，更优选为约5mg；优选地，所述DPP-IV抑制剂为沙格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约2.5毫克、约5毫克或约10毫克，更优选为约2.5mg或约5mg；优选地，所述DPP-IV抑制剂为维格列汀，其剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选为约50毫克。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，上述的葡萄糖激酶激活剂为化合物HMS5552，或其同位素标记物，或其可药用盐。
Figure PCTCN2019088864-appb-000005
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，葡萄糖激酶激活剂以固体分散体的形式存在。
在一个实施方案中，所述固体分散体通过葡萄糖激酶激活剂，或其同位素标记物，或其药学上可接受的盐与聚合物载体一起通过喷雾干燥、热熔或冷冻干燥等方式得到。
在一个实施方案中，固体分散体中葡萄糖激酶激活剂的含量，以固体分散体的总重量计，可以在约1重量％至约99重量％之间变化，优选为10重量％～90重量％。在一个实施方案中，葡萄糖激酶激活剂的含量范围为约1重量％，约2重量％，约3重量％，约4重量％，约5重量％，约6重量％，约7重量％，约8重量％，约9重量％，约10重量％，约11重量％，约12重量％，约13重量％，约14重量％，约15重量％，约16重量％，约17重量％，约18重量％，约19重量％，约20重量％，约21重量％，约22重量％，约23重量％，约24重量％，约25重量％，约26重量％，约27重量％，约28重量％，约29重量％，约30重量％，约31重量％，约32重量％，约33重量％，约34重量％，约35重量％，约36重量％，约37重量％，约38重量％，约39重量％，约40重量％，约41重量％，约42重量％，约43重量％，约44重量％，约45重量％，约46重量％，约47重量％，约48重量％，约49重量％，约50重量％，约51重量％，约52重量％，约53重量％，约54重量％，约55重量％，约56重量％，约57重量％，约58重量％，约59重量％，约60重量％，约61重量％，约62重量％，约63重量％，约64重量％，约65重量％，约66重量％，约67重量％，约68重量％，约69重量％，约70重量％，约71重量％，约72重量％，约73重量％，约74重量％，约75重量％，约76重量％，约77重量％，约78重量％，约79重量％，约80重量％，约81重量％，约82重量％，约83重量％，约84重量％，约85重量％，约86重量％，约87重量％，约88重量％，约89重量％，约90重量％，约91重量％，约92重量％，约93重量％，约94重量％，约95重量％，约96重量％，约97重量％，约98重量％，或约99重量％，或其间的任意范围。
在一个实施方案中，固体分散体中葡萄糖激酶激活剂的含量，以固体分散体的总重量计，为约1重量％至约20重量％、约2重量％至约40重量％、约30重量％至约60重量％、约60重量％至约80重量％、约70重量％至约90重量％，或者约80重量％至约100重量％。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，所述葡萄糖激酶激活剂以固体分散体的形式存在，所述固体分散体中，所述葡萄糖激酶激活剂与聚合物载体的重量比为约1:10至10:1，优选地为约1:9至9:1、约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5，更优选地为约1:1、约2:3、约3:4、约4:5或约5:6或其间的任意范围。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，葡 萄糖激酶激活剂为化合物HMS5552、其同位素标记物或其药学上可接受的盐，其与聚合物载体一起通过喷雾干燥、热熔或冷冻干燥等方式得到固体分散体。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，上述固体分散体中的聚合物载体选自聚丙烯树脂类聚合物，其是由丙烯酸(或甲基丙烯酸及它们的酯如：甲酯、乙酯等)以本体(一种单体)聚合，或者与甲基丙烯酸(或它的酯如：甲酯、乙酯、二甲胺基乙酯等)以二种单体(二元)或以三种单体(三元)按一定比例共聚而形成的高分子化合物。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中的固体分散体中使用的所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸和丙烯酸乙酯的共聚物，甲基丙烯酸和甲基丙烯酸甲酯的共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯的共聚物，丙烯酸乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸与丙烯酸丁酯的共聚物。
在一个实施方案中，上述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物，甲基丙烯酸和丙烯酸乙酯(1:1)共聚物，甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，丙烯酸乙酯和甲基丙烯酸甲酯(2:1)共聚物，甲基丙烯酸与丙烯酸丁酯(35:65)共聚物，甲基丙烯酸与甲基丙烯酸甲酯(1:1)共聚物，甲基丙烯酸与甲基丙烯酸甲酯(35:65)共聚物。
在一个实施方案中，上述聚合物载体为Eudragit(尤特奇)，包括Eudragit E、Eudragit L、Eudragit S、Eudragit RL和Eudragit RS，其中Eudragit E是以二甲胺基甲基丙烯酸酯和其他中性甲基丙烯酸酯类共聚而成，包括甲基丙烯酸二甲胺基乙酯与甲基丙烯酸酯的聚合物；Eudragit L和Eudragit S是以甲基丙烯酸与不同比例甲基丙烯酸酯类共聚而成，包括甲基丙烯酸与甲基丙烯酸甲酯，游离羧基：酯＝1:1或甲基丙烯酸与甲基丙烯酸甲酯，游离羧基：酯＝1:2；Eudragit RL和Eudragit RS型为含有某些季胺基因的丙烯酸和甲基丙烯酸酯的共聚物，包括含有10％季胺基团的丙烯酸与甲基丙烯酸酯的共聚物和含有5％季胺基团的丙烯酸与甲基丙烯酸酯的共聚物。
在一个实施方案中，上述聚合物载体选自：
Eudragit E100(尤特奇E 100)，其为甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物，包括尤特奇E PO；
Eudragit L100(尤特奇L100)，是甲基丙烯酸共聚物A型，其为甲基丙烯酸和甲基丙烯酸甲酯(1:1)阴离子共聚物；
Eudragit S100(尤特奇S 100)，其为甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物；
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552固体分散体中的聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙烯酸甲酯(1:1)的阴离子共聚物)，优选为Eudragit，更优选为EudragitL100。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552固体分散体中HMS5552与Eudragit L100的重量比为约1:10至10:1、约1:9至9:1、约2:3 至9:1、约3:4至9:1、约4:5至9:1、约5:6至9:1或约1:1至9:1；约2:3至4:1、约3:4至4:1、约4:5至4:1、约5:6至4:1或约1:1至4:1；约2:3至7:3、约3:4至7:3、约4:5至7:3、约5:6至7:3或约1:1至7:3；约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5；约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5或其间的任意范围。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552固体分散体中HMS5552与Eudragit L100的重量比为约1:1、约2:3、约3:2、约1:4、约4:1、约3:4、约4:3、约4:5、约5:4、约5:6、约6:5、约7:3、约3:7、约1:9、约9:1，或其间的任意范围。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为西格列汀或磷酸西格列汀一水合物，按重量计，包含：约1～80％葡萄糖激酶激活剂(优选HMS5552或其同位素标记物或其可药用盐)；约1～80％的西格列汀(或磷酸西格列汀一水合物)；约0～55％的填充剂；约1～25％的粘合剂；约0～15％的崩解剂；约0.1～10％的润滑剂，约0～3％的助流剂和0～5％的包衣剂。
在一个实施方案中，上述葡萄糖激酶激活剂(优选HMS5552或其同位素标记物或其可药用盐)和西格列汀(或磷酸西格列汀一水合物)的药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，按重量计，包含：约5～45％葡萄糖激酶激活剂(优选HMS5552或其同位素标记物或其可药用盐)；约5～75％西格列汀或磷酸西格列汀一水合物；约0～50％的填充剂；约1～10％的粘合剂；约1～10％的崩解剂；约0.1～5％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂。所述药物组合物或药物制剂(优选为固定剂量复方制剂)通过湿法制粒方法或干法制粒方法制备，优选通过湿法制粒方法制备。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约1毫克～200毫克。优选的葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克～100毫克。优选的，葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克、约10毫克、约20毫克、约25毫克、约30毫克、约40毫克、约50毫克、约60毫克、约75毫克、约80毫克、约90毫克、约100毫克，或其间任意范围。更优选的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约25毫克、约50毫克、约75毫克、约100毫克。优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为西格列汀(或磷酸西格列汀一水合物)，以西格列汀的含量计算，其剂量(优选单位剂量)为约25毫克～约200毫克,优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克,更优选地为约25mg、50mg或约100mg。优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552(或其同位素标记物或药学上可接受的盐)和西格列汀(或磷酸西格列汀一水合物)的剂量(优选单位剂量)的具体实施方案如下：
(1)约25毫克HMS5552和约50毫克西格列汀(或约64.25毫克磷酸西格列汀一水合物)；
(2)约50毫克HMS5552和约50毫克西格列汀(或约64.25毫克磷酸西格列汀一水合物)；
(3)约75毫克HMS5552和约50毫克西格列汀(或约64.25毫克磷酸西格列汀一水合物)；
(4)约100毫克HMS5552和约50毫克西格列汀(或约64.25毫克磷酸西格列汀一水合物)；
(5)约25毫克HMS5552和约100毫克西格列汀(或约128.5毫克磷酸西格列汀一水合物)；
(6)约50毫克HMS5552和约100毫克西格列汀(或约128.5毫克磷酸西格列汀一水合物)；
(7)约75毫克HMS5552和约100毫克西格列汀(或约128.5毫克磷酸西格列汀一水合物)；
(8)约100毫克HMS5552和约100毫克西格列汀(或约128.5毫克磷酸西格列汀一水合物)；
优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。在一个实施方案中，上述药物组合、药物组合物或药物制剂优选剂型为片剂。
在一个实施方案中，上述片剂为葡萄糖激酶激活剂(HMS5552及其同位素标记物或药学上可接受的盐)和西格列汀或磷酸西格列汀一水合物的固定剂量复方片剂。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为25mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/50mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约25mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为50mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/50mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约50mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为75mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/50mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约75mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为100mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/50mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约100mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为25mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/100mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约25mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约100mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为50mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/100mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约50mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约100mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为75mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/100mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约75mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约100mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为100mg葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)/100mg西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约100mg 的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约100mg的西格列汀(或可获得该剂量的量的磷酸西格列汀一水合物)；约0～50％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为沙格列汀或沙格列汀一水合物，按重量计包含：约1～80％葡萄糖激酶激活剂(或其同位素标记物或药学上可接受的盐)；约0.5～20％沙格列汀(或沙格列汀一水合物)；约0～90％的填充剂；约1～25％的粘合剂；约0～15％的崩解剂；约0.1～10％的润滑剂，约0～3％的助流剂和约0～5％的包衣剂。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为沙格列汀(或沙格列汀一水合物)，按重量计包含：约1～80％葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约0.5～20％沙格列汀(或沙格列汀一水合物)；约0～90％的填充剂；约1～25％的粘合剂；约0～15％的崩解剂；约0.1～10％的润滑剂，约0～3％的助流剂和约0～5％的包衣剂。所述药物组合物或药物制剂(优选为固定剂量复方制剂)通过湿法制粒方法或干法制粒方法制备，优选通过湿法制粒方法制备。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约1毫克～200毫克。优选的葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克～100毫克。优选的，葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克、约10毫克、约20毫克、约25毫克、约30毫克、约40毫克、约50毫克、约60毫克、约75毫克、约80毫克、约90毫克、约100毫克，或其间任意范围。更优选的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约25毫克、约50毫克、约75毫克、约100毫克。优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为沙格列汀(或沙格列汀一水合物)，以沙格列汀的含量计算，其剂量(优选单位剂量)为约1毫克～约50毫克，优选为约2.5毫克、约5毫克、约7.5毫克和约10毫克，最优选为约2.5毫克和约5毫克。优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在本发明的药物组合物或者固定剂量复方制剂中，HMS5552(或其同位素标记物或药学上可接受的盐)和沙格列汀(或沙格列汀一水合物)的剂量(优选单位剂量)的具体实施方案如下：
(1)约25毫克HMS5552和约2.5毫克沙格列汀(或约2.64mg沙格列汀一水合物)；
(2)约50毫克HMS5552和约2.5毫克沙格列汀(或约2.64mg沙格列汀一水合物)；
(3)约75毫克HMS5552和约2.5毫克沙格列汀(或约2.64mg沙格列汀一水合物)；
(4)约100毫克HMS5552和约2.5毫克沙格列汀(或约2.64mg沙格列汀一水合物)；
(5)约25毫克HMS5552和约5毫克沙格列汀(或约5.29mg沙格列汀一水合物)；
(6)约50毫克HMS5552和约5毫克沙格列汀(或约5.29mg沙格列汀一水合物)；
(7)约75毫克HMS5552和约5毫克沙格列汀(或约5.29mg沙格列汀一水合物)；
(8)约100毫克HMS5552和约5毫克沙格列汀(或约5.29mg沙格列汀一水合物)；
优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)优选剂型为片剂。
在一个实施方案中，上述片剂为葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)和沙格列汀(或沙格列汀一水合物)的固定剂量复方片剂。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为25mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/2.5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约25mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约2.5mg的沙格列汀(或可获得该剂量的量的沙格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为50mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/2.5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约50mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约2.5mg的沙格列汀(或可获得该剂量的量的沙格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为75mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/2.5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约75mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约2.5mg的沙格列汀(或可获得该剂量的量的沙格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为100mg 葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/2.5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约100mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约2.5mg的沙格列汀(或可获得该剂量的量的沙格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为25mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约25mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约5mg的沙格列汀(或可获得该剂量的量的沙格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为50mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约50mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约5mg的沙格列汀(或可获得该剂量的量的沙格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为75mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约75mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约5mg的沙格列汀(或可获得该剂量的量的沙格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为100mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg沙格列汀(或可获得该剂量的量的沙格列汀一水合物)的片剂)，按重量计，包含以下含量的各组分：约100mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约5mg的沙格列汀(或可获得该剂量的量的沙 格列汀一水合物)；约0～80％的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为利格列汀，上述的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)和利格列汀的药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，按重量计，包含一种或多种以下量的物质，约1～90％葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约1～20％利格列汀；约0～90％的填充剂；约1～25％的粘合剂；约0～15％的崩解剂；约0.1～10％的润滑剂，约0～3％的助流剂和约0～5％的包衣剂。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为利格列汀，上述的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)和利格列汀的药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，按重量计，包含一种或多种以下量的物质，约1～80％葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约1～20％利格列汀；约0～90％的填充剂；约1～25％的粘合剂；约0～15％的崩解剂；约0.1～10％的润滑剂，约0～3％的助流剂和约0～5％的包衣剂。所述药物组合物或药物制剂(优选为固定剂量复方制剂)通过湿法制粒方法或干法制粒方法制备，优选通过湿法制粒方法制备。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约1毫克～200毫克。优选的葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克～100毫克。优选的，葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克、约10毫克、约20毫克、约25毫克、约30毫克、约40毫克、约50毫克、约60毫克、约75毫克、约80毫克、约90毫克、约100毫克，或其间任意范围。更优选的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约25毫克、约50毫克、约75毫克、约100毫克。优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为利格列汀，利格列汀的剂量(优选单位剂量)为约1毫克～约50毫克，优选为约2.5毫克、约5毫克、约7.5毫克或约10毫克，最优选的利格列汀的剂量(优选单位剂量)为约2.5毫克或约5毫克。优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552(或其同位素标记物或药学上可接受的盐)和沙格列汀的剂量(优选单位剂量)的具体实施方案如下：
(1)约25毫克HMS5552和约2.5毫克利格列汀；
(2)约25毫克HMS5552和约5毫克利格列汀；
(3)约50毫克HMS5552和约2.5毫克利格列汀；
(4)约50毫克HMS5552和约5毫克利格列汀；
(5)约75毫克HMS5552和约2.5毫克利格列汀；
(6)约75毫克HMS5552和约5毫克利格列汀；
(7)约100毫克HMS5552和约2.5毫克利格列汀；和
(8)约100毫克HMS5552和约5毫克利格列汀；
优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)优选剂型为片剂。
在一个实施方案中，上述片剂为葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)和利格列汀的固定剂量复方片剂。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为为25mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg利格列汀的片剂)，按重量计，包含以下含量的各组分：约25mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约5mg的利格列汀；约0～90％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为为50mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg利格列汀的片剂)，按重量计，包含以下含量的各组分：约50mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约5mg的利格列汀；约0～90％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为为75mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg利格列汀的片剂)，按重量计，包含以下含量的各组分：约75mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约5mg的利格列汀；约0～90％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为为100mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/5mg利格列汀的片剂)，按重量计，包含以下含量的各组分：约100mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药 学上可接受的盐)；约5mg的利格列汀；约0～90％的任选的填充剂；约2～8％的粘合剂；约1～5％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，第二种活性成分为维格列汀。上述葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)和维格列汀的药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，按重量计，包含约1～80％葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；约1～50％维格列汀；约0～55％的填充剂；约1～25％的粘合剂；约0～15％的崩解剂；约0.1～10％的润滑剂，约0～3％的助流剂约0～5％的包衣剂。所述药物组合物或药物制剂(优选为固定剂量复方制剂)通过湿法制粒方法或干法制粒方法制备，优选通过干法制粒方法制备。
在一个实施方案中，上述葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)和维格列汀的药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约1毫克～200毫克。优选的葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克～100毫克。优选的，葡萄糖激酶激活剂的剂量(优选单位剂量)为约5毫克、约10毫克、约20毫克、约25毫克、约30毫克、约40毫克、约50毫克、约60毫克、约75毫克、约80毫克、约90毫克、约100毫克，或其间任意范围。更优选的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)的剂量(优选单位剂量)为约25毫克、约50毫克、约75毫克、约100毫克。优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，上述葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)和维格列汀的药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，维格列汀的剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选的维格列汀的剂量(优选单位剂量)为约50毫克。
在一个实施方案中，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552(或其同位素标记物或药学上可接受的盐)和维格列汀的剂量(优选单位剂量)的具体实施方案如下：
(1)约25毫克HMS5552和约50毫克维格列汀；
(2)约50毫克HMS5552和约50毫克维格列汀；
(3)约75毫克HMS5552和约50毫克维格列汀；和
(4)约100毫克HMS5552和约50毫克维格列汀；
优选的，上述药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)中，HMS5552以固体分散体的形式存在。
在一个实施方案中，本发明的药物组合、药物组合物或药物制剂(优选为固定剂量复方制剂)优选剂型为片剂。
在一个实施方案中，上述固定剂量复方片剂为葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)和维格列汀的片剂。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为25mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/50mg维格列汀的片剂)，按重量计，包含以下含量的各组分：约25mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的维格列汀；约0～80％的填充剂；约2～8％的粘合剂；约1～8％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为50mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/50mg维格列汀的片剂)，按重量计，包含以下含量的各组分：约50mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的维格列汀；约0～80％的填充剂；约2～8％的粘合剂；约1～8％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为为75mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/50mg维格列汀的片剂)，按重量计，包含以下含量的各组分：约75mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的维格列汀；约0～80％的填充剂；约2～8％的粘合剂；约1～8％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，所述药物组合、药物组合物或药物制剂(优选为固定剂量复方片剂，其为为100mg葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)/50mg维格列汀的片剂)，按重量计，包含以下含量的各组分：约100mg的葡萄糖激酶激活剂(HMS5552或其同位素标记物或药学上可接受的盐)；约50mg的维格列汀；约0～80％的填充剂；约2～8％的粘合剂；约1～8％的崩解剂；约0.5～3％的润滑剂；约0～0.5％的助流剂和约0～5％的包衣剂；优选地，上述葡萄糖激酶激活剂为上文所述的固体分散体形式，优选所述固体分散体含葡萄糖激酶激活剂和聚合物载体，优选含约1:1的葡萄糖激酶激活剂和Eudragit L100。
在一个实施方案中，上述药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)还包含赋形剂，其中所述赋形剂包括但不限于稀释剂、粘合剂、填充剂、崩解剂、润滑剂、助流剂、增香剂(香精)、甜味剂和着色剂、包衣剂的一种或多种的混合物。
在一个实施方案中，本发明的药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)中，含有任选的一种或者多种填充剂(稀释剂)。填充剂的实例包括但不限于纤维素衍生物诸如微晶纤维素 或木纤维素(包括微晶纤维素和硅化微晶纤维素)、乳糖、无水或一水乳糖、蔗糖、淀粉、预胶化淀粉、右旋糖、甘露醇(包括甘露醇Pearlitol SD 200)、果糖、木糖醇、山梨醇、玉米淀粉、改性玉米淀粉、无机盐诸如碳酸钙、磷酸钙、磷酸二钙、硫酸钙、糊精/葡萄糖结合剂、麦芽糊精、可压缩糖及其它已知的增容剂或填充剂和/或它们中两种或更多种的混合物。
优选的填充剂(稀释剂)的实例包括微晶纤维素(MCC)、硅化微晶纤维素(SMCC)、乳糖、甘露醇、山梨醇、磷酸二氢钙(二水合物)、玉米淀粉、预胶化淀粉和粉化纤维素。更优选的填充剂(稀释剂)是微晶纤维素、硅化微晶纤维素。微晶纤维素可以得自于数个供应商，包括FMC Corporation制造的Avicel PH 101、Avicel PH 102,Avicel PH 103,Avicel PH 105和Avicel PH 200。
在一个实施方案中，本发明的药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)中，含有任选的一种或者多种粘合剂。实例包括但不限于羧甲基纤维素(包括羧甲基纤维素钠)、羟丙基纤维素(包括羟丙基纤维素EXF)、玉米淀粉、预胶化淀粉、改性玉米淀粉、聚乙烯基吡咯烷酮(PVP)、羟丙基甲基纤维素(HPMC)(包括羟丙基甲基纤维素2208)、乳糖、蔗糖、阿拉伯胶、乙基纤维素、乙酸纤维素及蜡粘合剂诸如巴西棕榈蜡、石蜡、鲸蜡、聚乙烯类或微晶蜡及其它常规粘合剂和/或它们中两种或更多种的混合物。进一步，除了上述粘合剂外，适用于本发明的粘合剂还包括但不限于海藻酸、微晶纤维素、糊精、明胶、支链淀粉、液体葡萄糖、瓜尔胶、甲基纤维素、聚氧化乙烯、聚维酮和糖浆以及它们的组合。
粘合剂的优选实施方案包括羟丙基纤维素(HPC)、羟丙基甲基纤维素(HMPC)、聚乙烯吡咯烷酮(聚维酮)、羟乙基纤维素、淀粉1500和共聚烯吡酮。更优选的粘合剂是羟丙基纤维素、羟丙基甲基纤维素和聚乙烯吡咯烷酮。
在一个实施方案中，上述药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)中，含有任选的一种或者多种崩解剂。适用于本发明的崩解剂的实例包括但不限于交联羧甲基纤维素钠、交聚维酮、乳糖、蔗糖、淀粉、马铃薯淀粉、预胶化淀粉、玉米淀粉、羧甲基淀粉钠、羟基乙酸淀粉钠、微晶纤维素、轻质硅酸酐、低取代的羟丙基纤维素及其它已知的崩解剂。
优选的，崩解剂选自改性淀粉、改性纤维素聚合物或者聚羧酸中的一种或多种，具体为选自交联羧甲基纤维素钠、交联聚维酮、羟基乙酸淀粉钠、波拉克林钾和羧甲基纤维素钙(CMC Calcium)。在一个实施方案中，崩解剂是交联聚维酮。在另一种实施方案中，崩解剂是羟基乙酸淀粉钠。在另一个实施方案中，崩解剂是交联羧甲基纤维素钠。交联羧甲基纤维素钠NF类型A在市场上以商品名“Ac-di-sol”获得。
在一个实施方案中，上述药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)含有一种或者多种润滑剂。适用于本发明的润滑剂的实例包括但不限于硬脂酸镁、硬脂酸锌、硬脂酸钙、滑石、巴西棕榈蜡、硬脂酸、棕榈酸、硬脂基富马酸钠、月桂基硫酸钠、棕榈酸硬脂酸甘油酯、棕榈酸、豆蔻酸及氢化植物油(包括氢化蓖麻油)和脂肪及其它已知的润滑剂和/或它们中两种或更多种的混合物。
优选的，润滑剂的实施方案包括硬脂酸镁、硬脂酸钙、硬脂酸、硬脂酰富马酸钠、氢化蓖麻油及其混合物。更优选的润滑剂是硬脂酸镁，或者硬脂富马酸钠，或者其混合物。
在一个实施方案中，上述药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)含有一种 或者多种助流剂和/或抗粘附剂。适用于本发明的助流剂和/或抗粘附剂的实例包括但不限于二氧化硅、胶态二氧化硅、硅酸镁、磷酸钙、三硅酸镁、滑石及其它形式的二氧化硅诸如聚集的硅酸盐和水化硅胶。
优选的，助流剂的实施方案包括胶体二氧化硅、磷酸钙、硅酸镁和滑石，或及其混合物。优选的助流剂是胶体二氧化硅。
在一个实施方案中，上述药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)还可以任选的含有一种或者多种表面活性剂或者润湿剂。表面活性剂可以为阴离子、阳离子或者中性表面活性剂。阴离子表面活性剂包括月桂基硫酸钠、十二烷基磺酸钠、油烯基硫酸钠和与硬脂酸酯和滑石混合的月桂酸钠。阳离子表面活性剂包括苯扎氯铵和烷基三甲基溴化铵。中性表面活性剂包括甘油单油酸酯、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚乙烯醇和脱水山梨糖醇酯。润湿剂的实施方案包括泊洛沙姆、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物和聚氧乙烯硬脂酸酯。
在一个实施方案中，上述药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)中还可以含有任选的抗氧化剂从而给予其化学稳定性。适用于本发明的抗氧化剂的实例包括但不限于生育酚、抗坏血酸、五倍子酸酯、抗坏血酸棕榈酸酯、丁羟茴醚、丁羟甲苯、硫代甘油、焦亚硫酸钾、丙酸、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、偏亚硫酸氢钠和亚硫酸钠以及它们的组合。
优选的，抗氧化剂选自α-生育酚、γ-生育酚、δ-生育酚、富集生育酚的天然来源的提取物，L-抗坏血酸和它的钠或者钙盐、抗坏血酰棕榈酸酯、五倍子酸丙酯、五倍子酸辛酯、五倍子酸十二烷基酯、丁羟甲苯(BHT)和丁羟茴醚(BHA)。在一种实施方案中，抗氧化剂为BHT或者BHA。
在一个实施方案中，上述固定剂量复方制剂的优选制剂是通过压制方法制备的片剂。所述片剂可以进行包衣，包衣基材的优选例包括糖包衣基材、水溶性膜包衣基材、肠溶膜包衣基材等。
糖包衣基材使用蔗糖。另外，还可组合使用选自滑石粉、沉淀碳酸钙、明胶、阿拉伯胶、支链淀粉、巴西棕榈蜡等中的一种或多种。
水溶性膜包衣基材的例子包括纤维素聚合物，例如羟丙基纤维素、羟丙基甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素等；合成的聚合物例如聚乙烯醇缩醛二乙基氨基乙酸酯、甲基丙烯酸氨基烷基酯共聚物E[Eudragit E(商品名称)]、聚乙烯吡咯烷酮等。
肠溶膜包衣基材的例子包括纤维素聚合物，例如羟丙基甲基纤维素邻苯二甲酸酯、乙酸琥珀酸羟丙基甲基纤维素、羧甲基乙基纤维素、乙酸邻苯二甲酸纤维素等；丙烯酸聚合物，例如甲基丙烯酸共聚物L[Eudragit L(商品名称)]、甲基丙烯酸共聚物LD[Eudragit L-30D55(商品名称)]、甲基丙烯酸共聚物S[Eudragit S(商品名称)]等。
包衣添加剂的优选例包括：增塑剂例如聚乙烯醇(PVA)、聚乙二醇(PEG)、丙二醇、柠檬酸三乙酯、蓖麻油、聚山梨酯等或其中两种或更多种的混合物；遮光剂例如二氧化钛等；着色剂、染料和色淀例如氧化铁红(三氧化二铁)，氧化铁黄等；助流剂例如滑石等。
优选的，所述片剂可以用例如羟丙基纤维素和羟丙基甲基纤维素的混合物进行包衣，该混合物中含有二氧化钛和/或其它着色剂，例如氧化铁、染料和色淀；聚乙烯醇(PVA)和聚乙二醇(PEG)的混合物；或者任何其它适宜的即时释放包衣剂。包衣对最终的片剂提供味道掩蔽和另外的稳定性。市售的 包衣材料为Colorcon提供的为预配制粉末混合物的欧巴代(Opadry
Figure PCTCN2019088864-appb-000006
)，例如欧巴代03K12429。
在一个实施方案中，上述的药物组合、药物组合物或者药物制剂(优选固定剂量复方制剂)，也可以根据需要加入甜味剂和/或增香剂。
在一个实施方案中，上述粘合剂为聚乙烯吡咯烷酮或者羟丙基纤维素或者羟丙基甲基纤维素，上述填充剂为微晶纤维素或硅化微晶纤维素或乳糖或磷酸二氢钙或甘露醇或玉米淀粉及预胶化淀粉，上述崩解剂为交联羧甲基纤维素钠或交联聚维酮或羟基乙酸淀粉钠，和上述润滑剂为硬脂酸镁或者硬脂富马酸钠，上述助流剂为胶体二氧化硅。
在一个实施方案中，上述粘合剂为羟丙基纤维素，上述填充剂为微晶纤维素或硅化微晶纤维素或乳糖，上述崩解剂为交联羧甲基纤维素钠或交联聚维酮或羟基乙酸淀粉钠，和上述润滑剂为硬脂酸镁或者硬脂富马酸钠，上述助流剂为胶体二氧化硅。
在一个实施方案中，上述粘合剂为聚乙烯吡咯烷酮，上述填充剂为微晶纤维素或硅化微晶纤维素，上述崩解剂为交联羧甲基纤维素钠或交联聚维酮，和上述润滑剂为硬脂酸镁或者硬脂富马酸钠，上述助流剂为胶体二氧化硅。
在一个实施方案中，上述粘合剂为羟丙基甲基纤维素，上述填充剂为微晶纤维素或硅化微晶纤维素或乳糖，上述崩解剂为交联羧甲基纤维素钠或交联聚维酮或羟基乙酸淀粉钠，和上述润滑剂为硬脂酸镁或者硬脂富马酸钠，上述助流剂为胶体二氧化硅。
在一个实施方案中，上述粘合剂为羟丙基纤维素，上述填充剂为微晶纤维素或硅化微晶纤维素或乳糖，上述崩解剂为交联羧甲基纤维素钠，和上述润滑剂为硬脂酸镁或者硬脂富马酸钠。
在一个实施方案中，上述粘合剂为聚乙烯吡咯烷酮，上述润滑剂为硬脂酸镁，上述助流剂为胶体二氧化硅。
制备方法
在一个实施方案中，通过湿法制粒(高剪切和/或流化床)制备本发明的药物组合物或者固定剂量复方制剂。制粒是将粘合剂加入到溶剂中配制成粘合剂溶液，然后加入或者直接加入到制粒机中制成湿颗粒的方法。在湿法粒化方法中涉及的步骤包括以下：
(1)将活性药物成分葡萄糖激酶激活剂(优选为HMS5552)和组合药物(优选为西格列汀、沙格列汀、维格列汀和利格列汀)加入到制粒机中；
(2)将任选的填充剂(例如微晶纤维素，硅化微晶纤维素，乳糖)加入到步骤(1)得到的混合物中；
(3)将任选的崩解剂(例如交联羧甲基纤维素钠，交联聚维酮，羟基乙酸淀粉钠)加入到步骤(1)或(2)得到的混合物中；
(4)对于高剪切制粒，将粘合剂(例如羟丙基纤维素或聚乙烯吡咯烷酮或者羟丙基甲基纤维素)加入到纯水中配成粘合剂溶液，然后将其加入到制粒机中进行搅拌制粒。对于流化床制粒，将两种活性药物成分加入到流化床中，并通过压缩空气将粘合剂溶液喷入，所述粘合剂溶液为由粘合剂和纯水配成的水溶液；
(5)得到的湿颗粒通过在适宜的整粒机整粒，得到适宜尺寸的湿颗粒；
(6)通过高剪切制粒制备的颗粒在烘箱中进行托架干燥或者在流化床干燥器中进行干燥。对于通过流化床制粒得到的颗粒，颗粒然后在流化床中进行干燥；
(7)在适宜的研磨机上整粒，得到适宜尺寸的干燥颗粒；
(8)在适宜的混合机中，加入任选的填充剂(稀释剂，例如微晶纤维素)和任选的崩解剂(例如交联羧甲基纤维素钠)与干燥的颗粒混合；
(9)将润滑剂(例如硬脂酸镁和硬脂富马酸钠)加入到步骤(8)的混合物中；
(10)将任选的助流剂(例如胶态二氧化硅)加入到步骤(9)的混合物中；
(11)将步骤(9)或(10)的经润滑颗粒混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状；和
(12)任选地，将所得的片剂进行薄膜包衣。
在另一种实施方案中，本发明的药物组合物通过湿法制粒(高剪切和/或流化床)进行制备。制粒是其中将粘合剂和第二种活性成分加入到溶剂中配制成粘合剂溶液(或混悬液)，然后加入到制粒机中制成湿颗粒的方法。在湿法粒化方法中涉及的步骤包括以下：
(1)将活性药物成分葡萄糖激酶激活剂(优选为HMS5552)加入到制粒机中；
(2)将任选的填充剂(例如微晶纤维素，硅化微晶纤维素，乳糖)加入到步骤(1)混合物中；
(3)将任选的崩解剂(例如交联羧甲基纤维素钠，交联聚维酮，羟基乙酸淀粉钠)加入到步骤(1)或(2)得到的混合物中；
(4)对于高剪切制粒，将粘合剂(例如羟丙基纤维素或聚乙烯吡咯烷酮或者羟丙基甲基纤维素)加入到溶剂中均匀分散或溶解，然后加入处方量的第二种活性成分(优选为西格列汀、沙格列汀、维格列汀和利格列汀)进行分散或溶解，配成均匀的粘合剂体系。将该体系加入到制粒机中进行搅拌制粒。对于流化床制粒，将一种活性药物成分例如HMS5552加入到流化床中，并通过压缩空气将粘合剂体系喷入，所述粘合剂溶液为由粘合剂和纯水或有机溶剂(例如乙醇)配成的溶液或混悬液；
(5)得到的湿颗粒通过在适宜的整粒机中整粒，得到适宜尺寸的湿颗粒；
(6)通过高剪切制粒制备的颗粒在烘箱中进行托架干燥或者在流化床干燥器中进行干燥。对于通过流化床制粒得到的颗粒，颗粒然后在流化床中进行干燥；
(7)在适宜的研磨机上整粒，得到适宜尺寸的干燥颗粒；
(8)在适宜的混合机中，加入任选的填充剂(稀释剂，例如微晶纤维素)和任选的崩解剂(例如交联羧甲基纤维素钠)与干燥的颗粒混合；
(9)将润滑剂(例如硬脂酸镁和硬脂富马酸钠)加入到步骤(8)的混合物中；
(10)任选地，将助流剂(例如胶态二氧化硅)加入到步骤(9)的混合物中；
(11)将(9)或(10)的经润滑颗粒混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状；和
(12)任选地，将所得的片剂进行薄膜包衣。
在干法处理(直接压制或者干法制粒)方法中涉及的步骤包括：
(1)将活性药物成分葡萄糖激酶激活剂(优选为HMS5552)和组合药物(优选为西格列汀、沙格列汀、维格列汀和利格列汀)加入到混合桶中；
(2)将任选的填充剂(例如微晶纤维素，硅化微晶纤维素，乳糖)加入到步骤(1)中；
(3)将任选的粘合剂(例如羟丙基纤维素或聚乙烯吡咯烷酮或者羟丙基甲基纤维素)加入到步骤(1)或(2)得到的混合物中；
(4)将润滑剂或者助流剂加入到步骤(3)中，进行混合；
(5)可以将步骤(4)的混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状，或者通过滚轴压缩机进行处理；
(6)如果通过滚轴压缩机进行处理，将步骤(3)中的混合物事先进行混合，再进行滚轴碾压；如有必要，可以在适宜的研磨机上整粒得到所需尺寸的颗粒；
(7)在适宜的混合器中，可以将任选的稀释剂加入到步骤(6)所得的颗粒中，从而改良压缩性能；
(8)将任选的崩解剂(例如交联羧甲基纤维素钠，交联聚维酮，羟基乙酸淀粉钠)加入到步骤(7)中；
(9)将任选的润滑剂或者助流剂加入到步骤(8)的混合物中；
(10)将(9)或(10)的经润滑的颗粒混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状；和
(11)任选地，将步骤(5)或者步骤(10)所得的片剂可以进行薄膜包衣。
本发明一个实施方案中，本发明的药物组合、药物组合物或者固定剂量复方制剂中的葡萄糖激酶激活剂为固体分散体形式，其可通过选自喷雾干燥法，流化床干燥法，溶剂法，熔融挤出法等的方法制备。
本发明一个实施方案为通过喷雾干燥法制备葡萄糖激酶激活剂的固体分散体的方法，其包括的步骤为：
(1)配制喷雾干燥溶液，包括将聚合物载体和葡萄糖激酶激活剂(优选为HMS5552)溶于溶剂中；
(2)喷雾干燥，控制进风温度，进风量，雾化气流的流速和压力，和溶液的喷液速度等。
本发明实施方案中，葡萄糖激酶激活剂的固体分散体的制备中所使用的溶剂包括但不限于链烷醇、酯、腈、环烷烃、芳烃、酮等。具体地，所述溶剂选自以下溶剂：无水乙醇，甲醇，异丙醇，乙酸乙酯，丙酮，乙腈，异丁醇，正己烷，苯和甲苯。可以是单一溶剂，也可以是混合溶剂，或者是有机溶剂和水的混合物。
治疗和/或预防疾病的方法和用途
本发明又一个实施方案涉及使用本发明的含有葡萄糖激酶激活剂的组合物或者制剂(优选固定剂量组合药物组合物或者固定剂量复方制剂)治疗和/或预防下列疾病及医学病症，尤其是一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的方法或用途，包括向受试者给予治疗有效量的本发明的组合物或者制剂(优选固定剂量组合药物组合物或者固定剂 量复方制剂)：
-预防选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症和代谢综合征；或
-改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或
-预防、减缓、延迟或逆转葡萄糖耐量降低、胰岛素抵抗和/或代谢综合征进展成II型糖尿病；或
-预防选自以下的病症或障碍、减缓该病症或障碍进展、延迟或治疗该病症或障碍：糖尿病并发症，例如白内障及微血管及大血管疾病，例如肾病、视网膜病变、神经病变、学习和记忆受损、神经变性或认知障碍、心血管或脑血管疾病、组织缺血、糖尿病足或溃疡、动脉硬化、高血压、内皮功能障碍、心肌梗塞、急性冠状动脉综合征、不稳定型心绞痛、稳定型心绞痛、中风、外周动脉阻塞性疾病、心肌病、心力衰竭、心律失常及血管再狭窄；或
-降低体重和/或身体脂肪、或预防体重和/或身体脂肪增加、或促进体重和/或身体脂肪的降低；或
-预防、减缓、延迟或治疗胰腺β细胞退化和/或胰腺β细胞功能降低，和/或改善和/或恢复或保护胰腺β细胞功能和/或恢复胰腺胰岛素分泌功能；或
-预防、减缓、延迟或治疗由肝脏或异位脂肪异常蓄积引起的疾病或病症；或
-保持和/或改善胰岛素敏感性和/或治疗或预防高胰岛素血症和/或胰岛素抵抗；或
-预防移植后新发作的糖尿病(NODAT)和/或移植后的代谢综合征(PTMS)、减缓其进展、延迟或治疗这些病症；或-预防、延迟或减少NODAT和/或PTMS相关并发症，包括微血管及大血管疾病及事件、移植排斥、感染及死亡；或
-治疗高尿酸血症及高尿酸血症相关病症；或
-糖尿病认知功能障碍，记忆力功能障碍，老年痴呆。
本发明还提供了通过口服给药需要所述治疗的受试者治疗有效量的一种本发明的含有葡萄糖激酶激活剂和组合药物的药物组合物或者制剂(优选固定剂量组合药物组合物或者固定剂量复方制剂)治疗II型糖尿病的方法。在一种实施方案中，需要所述治疗的受试者是人类。在另一实施方案中，药物组合物为片剂的形式。本发明的含有葡萄糖激酶激活剂的组合物或者制剂(优选固定剂量组合药物组合物或者固定剂量复方制剂)可以每日一次(QD)、每日两次(BID)或者每日三次(TID)给药。
具体地，本发明涉及以下具体实施方案。
实施方案I-葡萄糖激酶激活剂+DPP-IV抑制剂(例如西格列汀)
方案1.药物组合、药物组合物或固定剂量复方制剂，其包含：
(a)葡萄糖激酶激活剂，其为下式表示的化合物，或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000007
(b)DPP-IV抑制剂；
(c)一种或多种赋形剂；
其中上述药物(a)和(b)同时、分别或相继使用。
方案2.方案1的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂与DPP-IV抑制剂的重量比为约1:10至100:1，优选地为约1:4至40:1，更优选地为约1:4、约1:2、约1:1、约1.5:1、约1.5:2、约2:1、约5:1、约10:1、约15:1、约20:1或约40:1。
方案3.方案1或2的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂按重量计约为1～98％；所述DPP-IV抑制剂按重量计约为0.2～80％。
方案4.方案1-3中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为下式表示的化合物HMS5552或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000008
方案5.方案1-4中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂为固体分散体形式。
方案6.方案5的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为包含聚合物载体的固体分散体形式，所述聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙烯酸甲酯(1:1)的阴离子共聚物)，优选为Eudragit，更优选为Eudragit L100。
方案7.方案6的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为约1:10至10:1，优选地为约1:9至9:1、约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5，更优选地为约1:1、约2:3、约3:4、约4:5或约5:6或其间的任意范围。
方案8.方案1-7中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述DPP-IV抑制剂选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特力列汀、度格列汀，及其可药用盐，优选地选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀和利格列汀，及它们的可药用盐。
方案9.方案1-8中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂以约1毫克至约200毫克，优选地约25毫克至约100毫克的剂量(优选为单位剂量)范围存在，优选地，其中所述葡萄糖激酶激活剂的剂量(优选为单位剂量)为约25毫克、约50毫克、约75毫克或约100毫克。
方案10.方案1-9中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，其中所述DPP-IV抑制剂以约1毫克至200毫克，优选地约2.5毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述DPP-IV抑制剂的剂量(优选单位剂量)为约2.5毫克、约5毫克、约10毫克、约20毫克、约50毫克或约100毫克，最优选为约2.5毫克、约5毫克、约50毫克或约100毫克；优选地，所述DPP-IV抑制剂为西格列汀，其剂量(优选单位剂量)为约25毫克～约200毫克，优选地为约50毫克～约100毫克，优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克，更优选为约25mg、50mg或约100mg；优选地，所述DPP-IV抑制剂为利格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约5毫克或约10毫克，更优选为约5mg；优选地，所述DPP-IV抑制剂为沙格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约2.5毫克、约5毫克或约10毫克，更优选为约2.5mg或约5mg；优选地，所述DPP-IV抑制剂为维格列汀，其剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选为约50毫克。
方案11.方案1-10中任一项的药物组合、药物组合物或固定剂量复方制剂，所述一种或者多种赋形剂选自粘合剂、填充剂、崩解剂、润滑剂、助流剂、表面活性剂、润湿剂、抗氧化剂、增香剂、甜味剂、着色剂或者包衣剂。
方案12.方案1-11中任一项的药物组合、药物组合物或固定剂量复方制剂，其为片剂。
方案13.方案12的药物组合、药物组合物或固定剂量复方制剂，其为包衣片剂。
方案14.方案13的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂包含：
膜包衣基材，例如羟丙甲纤维素、羟丙基甲基纤维素或其混合物；
任选的增塑剂，例如聚乙烯醇、聚乙二醇、丙二醇、聚山梨酯或它们的混合物；
任选的着色剂，例如氧化铁红、氧化铁黄或其混合物；
任选的遮光剂，如二氧化钛，和
任选的助流剂。
方案15.方案14的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂为欧巴代。
方案16.方案1-15中任一项的药物组合、药物组合物或固定剂量复方制剂，按重量计，其包含：
约1～80％葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)，优选HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
约1～80％西格列汀或磷酸西格列汀一水合物；
约0～55％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案17.方案方案16的药物组合、药物组合物或固定剂量复方制剂，按重量计，其包含
约5～70％葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)，优选HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
约5～75％西格列汀或磷酸西格列汀一水合物；
约0～50％的填充剂(稀释剂)；
约1～10％的粘合剂；
约1～10％的崩解剂；
约0.1～5％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案18.方案16的药物组合、药物组合物或固定剂量复方制剂，按重量计，活性成分的剂量(优选为单位剂量)为：
约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂，优选HMS5552；
约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克的西格列汀或可获 得该剂量的量的磷酸西格列汀一水合物；
约0～55％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案19.方案18的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为50mg HMS5552/50mg西格列汀或相应量的磷酸西格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约50mg的西格列汀或相应量的磷酸西格列汀一水合物；
-约0～50％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案20.方案18的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为75mg HMS5552/50mg西格列汀或相应量的磷酸西格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约50mg的西格列汀或相应量的磷酸西格列汀一水合物；
-约0～50％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；和
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案21.方案18的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为50mg HMS5552/100mg西格列汀或相应量的磷酸西格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分 散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约100mg的西格列汀或相应量的磷酸西格列汀一水合物；
-约0～50％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案22.方案18的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为75mg HMS5552/100mg西格列汀或相应量的磷酸西格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约100mg的西格列汀或相应量的磷酸西格列汀一水合物；
-约0～50％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案23.方案18的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为25mg HMS5552/100mg西格列汀或相应量的磷酸西格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约100mg的西格列汀或相应量的磷酸西格列汀一水合物；
-约0～50％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案24.方案18的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为100mg HMS5552/50mg西格列汀或相应量的磷酸西格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约100mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约50mg的西格列汀或相应量的磷酸西格列汀一水合物；
-约0～50％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案25.方案18的药物组合、药物组合物或固定剂量复方制剂，其中包含约100mg固体分散体、约64.25mg的磷酸西格列汀一水合物、约40.30mg微晶纤维素、约6.60mg羟丙基纤维素、约6.60mg交联羧甲基纤维素钠、约2.20mg硬脂酸镁和约6.60mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
方案26.方案18的药物组合、药物组合物或固定剂量复方制剂，其中包含约150mg固体分散体、约64.25mg的磷酸西格列汀一水合物、约27.55mg微晶纤维素、约7.80mg羟丙基纤维素、约7.80mg交联羧甲基纤维素钠、约2.60mg硬脂酸镁和约7.80mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
方案27.方案18的药物组合、药物组合物或固定剂量复方制剂，其中包含约100mg固体分散体、约128.50mg的磷酸西格列汀一水合物、约41.20mg微晶纤维素、约8.70mg羟丙基纤维素、约8.70mg交联羧甲基纤维素钠、约2.90mg硬脂酸镁和约8.70mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
方案28.方案18的药物组合、药物组合物或固定剂量复方制剂，其中包含约150mg固体分散体、约128.50mg的磷酸西格列汀一水合物、约47.00mg微晶纤维素、约10.50mg羟丙基纤维素、约10.50mg交联羧甲基纤维素钠、约3.50mg硬脂酸镁和约10.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
方案29.方案18的药物组合、药物组合物或固定剂量复方制剂，其中包含约50mg固体分散体、约128.50mg的磷酸西格列汀一水合物、约100.50mg微晶纤维素、约9.00mg羟丙基纤维素、约9.00mg交联羧甲基纤维素钠、约3.00mg硬脂酸镁和约9.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
方案30.方案18的药物组合、药物组合物或固定剂量复方制剂，其中包含约200mg固体分散体、约64.25mg的磷酸西格列汀一水合物、约61.26mg微晶纤维素、约10.50mg羟丙基纤维素、约10.50mg交联羧甲基纤维素钠、约3.50mg硬脂酸镁和约10.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约100mg HMS5552。
方案31.一种制备方案1-30中任一项的药物组合、药物组合物或固定剂量复方制剂的方法，该方法包括将活性成份掺入一种或多种赋形剂进行制粒，优选进一步地将制得的颗粒混合物填装入小 瓶、小袋或者胶囊中或者压缩成期望的片剂形状；更优选更进一步的将所得的片剂进行包衣。
方案32.方案31的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中通过湿法制粒(高剪切和/或流化床)制备，或者通过干法处理(直接压制或者干法制粒)制备。
方案33.方案31-32中任一项的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂制备成固体分散体形式。
方案34.方案31-33中任一项的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂和第二种或更多种活性成分也可以一起制备成复方固体分散体形式(即含有2种或多种活性成分的固体分散体)。
方案35.如方案1-30中任意一项所述的药物组合、药物组合物或固定剂量复方制剂，其用于治疗或预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症。
方案36.治疗或预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍的方法：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症，包括向受试者给予治疗有效量的方案1-30中任意一项所述的药物组合、药物组合物或固定剂量复方制剂。
方案37.方案1-30中任意一项所述的药物组合、药物组合物或固定剂量复方制剂在制备用于治疗或预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍或预防、减缓、延迟或逆转糖尿病并发症的药物中的用途：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c。
实施方案II-葡萄糖激酶激活剂+DPP-IV抑制剂(例如维格列汀)
方案1.药物组合、药物组合物或固定剂量复方制剂，其包含：
(a)葡萄糖激酶激活剂，其为下式表示的化合物，或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000009
(b)DPP-IV抑制剂；
(c)一种或多种赋形剂；
其中上述药物(a)和(b)同时、分别或相继使用。
方案2.方案1的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂与DPP-IV抑制剂的重量比为约1:10至50:1，优选地为约1:4至40:1，更优选地为约1:4、约1:2、约1:1、约1.5:1、约1.5:2、约2:1、约5:1、约10:1、约15:1、约20:1或约40:1。
方案3.方案1或2的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂按重量计约为1～80％；所述DPP-IV抑制剂按重量计约为1～50％。
方案4.方案1-3中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为下式表示的化合物HMS5552或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000010
方案5.方案1-4中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂为固体分散体形式。
方案6.方案5的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为包含聚合物载体的固体分散体形式，所述聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙烯酸甲酯(1:1)的阴离子共聚物)，优选为Eudragit，更优选为Eudragit L100。
方案7.方案6的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为约1:10至10:1，优选地为约1:9至9:1、约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5，更优选地为约1:1、约2:3、约3:4、约4:5或约5:6或其间的任意范围。
方案8.方案1-7中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述DPP-IV抑制剂选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特力列汀、度格列汀，及其可药用盐，优选地选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀和利格列汀，及它们的可药用盐。
方案9.方案1-8中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂约1毫克至约200毫克，优选地约25毫克至约100毫克的剂量(优选为单位剂量)范围存在，优选地，其中所述葡萄糖激酶激活剂的剂量(优选为单位剂量)为约25毫克、约50毫克、约75毫克或约100毫克。
方案10.方案1-7中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，所述DPP-IV抑制剂以约1毫克至200毫克，优选地约2.5毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述DPP-IV抑制剂的剂量(优选单位剂量)为约2.5毫克、约5毫克、约10毫克、约20毫克、约50毫克或约100毫克，最优选为约2.5毫克、约5毫克、约50毫克或约100毫克；优选地，所述DPP-IV抑制剂为西格列汀，其剂量(优选单位剂量)为约25毫克～约200毫克，优选地为约50毫克～约100毫克，优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克，更优选为约25mg、50mg或约100mg；优选地，所述DPP-IV抑制剂为利格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约5毫克或约10毫克，更优选为约5mg；优选地，所述DPP-IV抑制剂为沙格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约2.5毫克、约5毫克或约10毫克，更优选为约2.5mg或约5mg；优选地，所述DPP-IV抑制剂为维格列汀，其剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选为约50毫克。
方案11.方案1-10中任一项的药物组合、药物组合物或固定剂量复方制剂，所述一种或者多种赋形剂选自粘合剂、填充剂、崩解剂、润滑剂、助流剂、表面活性剂、润湿剂、抗氧化剂、增香剂、甜味剂、着色剂或者包衣剂。
方案12.方案1-11中任一项的药物组合、药物组合物或固定剂量复方制剂，其为片剂。
方案13.方案12的药物组合、药物组合物或固定剂量复方制剂，其为包衣片剂。
方案14.方案13的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂包含：
膜包衣基材，例如羟丙甲纤维素、羟丙基甲基纤维素或其混合物；
任选的增塑剂，例如聚乙烯醇、聚乙二醇、丙二醇、聚山梨酯或它们的混合物；
任选的着色剂，例如氧化铁红、氧化铁黄或其混合物；
任选的遮光剂，如二氧化钛，和
任选的助流剂。
方案15.方案14的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂为欧巴代。
方案16.方案1-15中任一项的药物组合、药物组合物或固定剂量复方制剂，按重量计，其包含：
约1～80％葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)，优选HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
约1～50％维格列汀；
约0～55％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案17.方案16的药物组合、药物组合物或固定剂量复方制剂，按重量计，活性成分的剂量(优选为单位剂量)为：
约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂，优选HMS5552；
约50毫克或约100毫克的维格列汀；
约0～55％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案18.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为25mg HMS5552/50mg维格列汀的片剂)，按重量计，其包含以下含量的各组分：
-约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约50mg的维格列汀；
-约0～80％的填充剂；
-约2～8％的粘合剂；
-约1～8％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案19.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为50mg HMS5552/50mg维格列汀的片剂)，按重量计，其包含以下含量的各组分：
-约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约50mg的维格列汀；
-约0～80％的填充剂；
-约2～8％的粘合剂；
-约1～8％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案20.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为75mg HMS5552/50mg维格列汀的片剂)，按重量计，其包含以下含量的各组分：
-约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约50mg的维格列汀；
-约0～80％的填充剂；
-约2～8％的粘合剂；
-约1～8％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案21.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约50mg固体分散体、约50.00mg维格列汀、约464.00mg微晶纤维素、约24.00mg交联羧甲基纤维素钠、约6.00mg微粉硅胶、约6.00mg硬脂酸镁和约18.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
方案22.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约100mg固体分散体、约50.00mg维格列汀、约414.00mg微晶纤维素、约24.00mg交联羧甲基纤维素钠、约6.00mg微粉硅胶、约6.00mg硬脂酸镁和约18.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit  L100，并且含约50mg HMS5552。
方案23.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约150mg固体分散体、约50.00mg维格列汀、约512.50mg硅化微晶纤维素、约30.00mg交联羧甲基纤维素钠、约7.50mg硬脂酸镁和约21.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
方案24.一种制备方案1-23中任一项的药物组合、药物组合物或固定剂量复方制剂的方法，该方法包括将活性成份掺入一种或多种赋形剂进行制粒，优选进一步地将制得的颗粒混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状；更优选更进一步的将所得的片剂进行包衣。
方案25.方案24的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中通过湿法制粒(高剪切和/或流化床)制备，或者通过干法处理(直接压制或者干法制粒)制备。
方案26.方案24-25中任一项的药物组合、药物组合物或制备固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂制备成固体分散体形式。
方案27.方案24-26中任一项的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂和第二种或更多种活性成分也可以一起制备成复方固体分散体形式(即含有2种或多种活性成分的固体分散体)。
方案28.如方案1-23中任意一项所述的药物组合、药物组合物或固定剂量复方制剂，其用于预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症。
方案29.预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍的方法：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症，包括向受试者给予治疗有效量的方案1-23中任意一项所述的药物组合、药物组合物或固定剂量复方制剂。
方案30.方案1-23中任意一项所述的药物组合、药物组合物或固定剂量复方制剂在制备用于治疗或预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍或预防、减缓、延迟或逆转糖尿病并发症的药物中的用途：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c。
实施方案III-葡萄糖激酶激活剂+DPP-IV抑制剂(例如沙格列汀)
方案1.药物组合、药物组合物或固定剂量复方制剂，其包含：
(a)葡萄糖激酶激活剂，其为下式表示的化合物，或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000011
(b)DPP-IV抑制剂；
(c)一种或多种赋形剂；
其中上述药物(a)和(b)同时、分别或相继使用。
方案2.方案1的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂与DPP-IV抑制剂的重量比为约1:10至100:1，优选地为约1:4至40:1，更优选地为约1:4、约1:2、约1:1、约1.5:1、约1.5:2、约2:1、约5:1、约10:1、约15:1、约20:1或约40:1。
方案3.方案1或2的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂按重量计约为1～80％；所述DPP-IV抑制剂按重量计为约1～20％。
方案4.方案1-3中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为下式表示的化合物HMS5552或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000012
方案5.方案1-4中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂为固体分散体形式。
方案6.方案5的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为包含聚合物载体的固体分散体形式，所述聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙烯酸甲酯(1:1)的阴离子共聚物)，优选为Eudragit，更优选为Eudragit L100。
方案7.方案6的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为约1:10至10:1，优选地为约1:9至9:1、约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5，更优选地为约1:1、约2:3、约3:4、约4:5或约5:6或其间的任意范围。
方案8.方案1-7中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述DPP-IV抑制剂选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特力列汀、度格列汀，及其可药用盐，优选地选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀和利格列汀，及它们的可药用盐。
方案9.方案1-8中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂以约1毫克至约200毫克，优选地约25毫克至约100毫克的剂量(优选为单位剂量)范围存在，优选地，其中所述葡萄糖激酶激活剂的剂量(优选为单位剂量)为约25毫克、约50毫克、约75毫克或约100毫克。
方案10.方案1-9中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，所述DPP-IV抑制剂以约1毫克至200毫克，优选地约2.5毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述DPP-IV抑制剂的剂量(优选单位剂量)为约2.5毫克、约5毫克、约10毫克、约20毫克、约50毫克或约100毫克，最优选为约2.5毫克、约5毫克、约50毫克或约100毫克；优选地，所述DPP-IV抑制剂为西格列汀，其剂量(优选单位剂量)为约25毫克～约200毫克，优选地为约50毫克～约100毫克，优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克，更优选为约25mg、50mg或约100mg；优选地，所述DPP-IV抑制剂为利格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约5毫克或约10毫克，更优选为约5mg；优选地，所述DPP-IV抑制剂为沙格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约2.5毫克、约5毫克或约10毫克，更优选为约2.5mg或约5mg；优选地，所述DPP-IV抑制剂为维格列汀，其剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选为约50毫克。
方案11.方案1-10中任一项的药物组合、药物组合物或固定剂量复方制剂，所述一种或者多种赋形剂选自粘合剂、填充剂、崩解剂、润滑剂、助流剂、表面活性剂、润湿剂、抗氧化剂、增香剂、甜味剂、着色剂或者包衣剂。
方案12.方案1-11中任一项的药物组合、药物组合物或固定剂量复方制剂，其为片剂。
方案13.方案12的药物组合、药物组合物或固定剂量复方制剂，其为包衣片剂。
方案14.方案13的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂包含：
膜包衣基材，例如羟丙甲纤维素、羟丙基甲基纤维素或其混合物；
任选的增塑剂，例如聚乙烯醇、聚乙二醇、丙二醇、聚山梨酯或它们的混合物；
任选的着色剂，例如氧化铁红、氧化铁黄或其混合物；
任选的遮光剂，如二氧化钛，和
任选的助流剂。
方案15.方案14的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂为欧巴代。
方案16.方案1-15中任一项的药物组合、药物组合物或固定剂量复方制剂，按重量计，其包含：
约1～80％葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)，优选HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
约1～20％沙格列汀或沙格列汀一水合物；
约0～90％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案17.方案16的药物组合、药物组合物或固定剂量复方制剂，按重量计，活性成分的剂量(优选为单位剂量)为：
约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；
约2.5毫克、约5毫克、约7.5毫克和约10毫克的沙格列汀或可获得该剂量的量的沙格列汀一水合物；
约0～90％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案18.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为25mg HMS5552/5mg沙格列汀或相应量的沙格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约5mg的沙格列汀或相应量的沙格列汀一水合物；
-约0～80％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案19.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为50mg HMS5552/2.5mg沙格列汀或相应量的沙格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约2.5mg的沙格列汀或相应量的沙格列汀一水合物；
-约0～80％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案20.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为75mg HMS5552/5mg沙格列汀或相应量的沙格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约5mg的沙格列汀或相应量的沙格列汀一水合物；
-约0～80％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案21.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为100mg HMS5552/2.5mg沙格列汀或相应量的沙格列汀一水合物的片剂)，按重量计，其包含以下含量的各组分：
-约100mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约2.5mg的沙格列汀或相应量的沙格列汀一水合物；
-约0～80％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案22.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约150mg固体分散体、约5.29mg沙格列汀一水合物、约7.50mg羟丙基纤维素、约79.71mg微晶纤维素、约2.50mg硬脂酸镁、约5.00mg交联羧甲基纤维素钠和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
方案23.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约100mg固体分散体、约2.64mg沙格列汀一水合物、约7.50mg羟丙基纤维素、约132.36mg微晶纤维素、约2.50mg硬脂酸镁、约5.00mg交联羧甲基纤维素钠和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
方案24.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约200mg固体分散体、约2.64mg沙格列汀一水合物、约9.00mg聚维酮、约79.36mg微晶纤维素、约3.00mg硬脂酸镁、约6.00mg交联羧甲基纤维素钠和约9.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约100mg HMS5552。
方案25.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约50mg固体分散体、约5.29mg沙格列汀一水合物、约7.50mg聚维酮、约179.71mg微晶纤维素、约2.50mg硬脂酸镁、约5.00mg交联羧甲基纤维素钠和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
方案26.一种制备方案1-25中任一项的药物组合、药物组合物或固定剂量复方制剂的方法，该方法包括将活性成份掺入一种或多种赋形剂进行制粒，优选进一步地将制得的颗粒混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状；更优选更进一步的将所得的片剂进行包衣。
方案27.方案26的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中通过湿法制粒 (高剪切和/或流化床)制备，或者通过干法处理(直接压制或者干法制粒)制备。
方案28.方案26-27中任一项的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂制备成固体分散体形式。
方案29.方案26-28中任一项的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂和第二种或更多种活性成分也可以一起制备成复方固体分散体形式(即含有2种或多种活性成分的固体分散体)。
方案30.如方案1-25中任意一项所述的药物组合、药物组合物或固定剂量复方制剂，其用于预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症。
方案31.预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍的方法：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症，包括向受试者给予治疗有效量的方案1-25中任意一项所述的药物组合、药物组合物或固定剂量复方制剂。
方案32.方案1-25中任意一项所述的药物组合、药物组合物或固定剂量复方制剂在制备用于预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍或预防、减缓、延迟或逆转糖尿病并发症的药物中的用途：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c。
实施方案IV-葡萄糖激酶激活剂+DPP-IV抑制剂(例如利格列汀)
方案1.药物组合、药物组合物或固定剂量复方制剂，其包含：
(a)葡萄糖激酶激活剂，其为下式表示的化合物，或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000013
Figure PCTCN2019088864-appb-000014
(b)DPP-IV抑制剂；
(c)一种或多种赋形剂；
其中上述药物(a)和(b)同时、分别或相继使用。
方案2.方案1的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂与DPP-IV抑制剂的重量比为约1:10至50:1，优选地为约1:4至40:1，更优选地为约1:4、约1:2、约1:1、约1.5:1、约1.5:2、约2:1、约5:1、约10:1、约15:1、约20:1或约40:1。
方案3.方案1或2的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂按重量计约为1～90％；所述DPP-IV抑制剂按重量计为约1～20％。
方案4.方案1-3中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为下式表示的化合物HMS5552或其可药用盐、其同位素标记物、结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式，
Figure PCTCN2019088864-appb-000015
方案5.方案1-4中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂为固体分散体形式。
方案6.方案5的药物组合、药物组合物或固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为包含聚合物载体的固体分散体形式，所述聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙 烯酸甲酯(1:1)的阴离子共聚物)，优选为Eudragit，更优选为Eudragit L100。
方案7.方案6的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为约1:10至10:1，优选地为约1:9至9:1、约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5，更优选地为约1:1、约2:3、约3:4、约4:5或约5:6或其间的任意范围。
方案8.方案1-7中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述DPP-IV抑制剂选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特力列汀、度格列汀，及其可药用盐，优选地选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀和利格列汀，及它们的可药用盐。
方案9.方案1-8中任一项的药物组合、药物组合物或固定剂量复方制剂，其中所述葡萄糖激酶激活剂以约1毫克至约200毫克，优选地约25毫克至约100毫克的剂量(优选为单位剂量)范围存在，优选地，其中所述葡萄糖激酶激活剂的剂量(优选为单位剂量)为约25毫克、约50毫克、约75毫克或约100毫克。
方案10.方案1-9中任一项的药物组合、药物组合物或固定剂量复方制剂，其中，所述DPP-IV抑制剂以约1毫克至200毫克，优选地约2.5毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述DPP-IV抑制剂的剂量(优选单位剂量)为约2.5毫克、约5毫克、约10毫克、约20毫克、约50毫克或约100毫克，最优选为约2.5毫克、约5毫克、约50毫克或约100毫克；优选地，所述DPP-IV抑制剂为西格列汀，其剂量(优选单位剂量)为约25毫克～约200毫克，优选地为约50毫克～约100毫克，优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克，更优选为约25mg、50mg或约100mg；优选地，所述DPP-IV抑制剂为利格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约5毫克或约10毫克，更优选为约5mg；优选地，所述DPP-IV抑制剂为沙格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约2.5毫克、约5毫克或约10毫克，更优选为约2.5mg或约5mg；优选地，所述DPP-IV抑制剂为维格列汀，其剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选为约50毫克。
方案11.方案1-10中任一项的药物组合、药物组合物或固定剂量复方制剂，所述一种或者多种赋形剂选自粘合剂、填充剂、崩解剂、润滑剂、助流剂、表面活性剂、润湿剂、抗氧化剂、增香剂、甜味剂、着色剂或者包衣剂。
方案12.方案1-11中任一项的药物组合、药物组合物或固定剂量复方制剂，其为片剂。
方案13.方案12的药物组合、药物组合物或固定剂量复方制剂，其为包衣片剂。
方案14.方案13的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂包含：
膜包衣基材，例如羟丙甲纤维素、羟丙基甲基纤维素或其混合物；
任选的增塑剂，例如聚乙烯醇、聚乙二醇、丙二醇、聚山梨酯或它们的混合物；
任选的着色剂，例如氧化铁红、氧化铁黄或其混合物；
任选的遮光剂，如二氧化钛，和
任选的助流剂。
方案15.方案14的药物组合、药物组合物或固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂为欧巴代。
方案16.方案1-15中任一项的药物组合、药物组合物或固定剂量复方制剂，按重量计，其包含：
约1～80％葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)，优选HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
约1～20％利格列汀；
约0～90％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案17.方案16的药物组合、药物组合物或固定剂量复方制剂，按重量计，活性成分的剂量(优选为单位剂量)为：
约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂(优选为HMS5552或其同位素标记物或药学上可接受的盐)；
约2.5毫克、约5毫克、约7.5毫克或约10毫克的利格列汀；
约0～90％的填充剂；
约1～25％的粘合剂；
约0～15％的崩解剂；
约0.1～10％的润滑剂；
约0～3％的助流剂；和
约0～5％的包衣剂。
方案18.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为25mg HMS5552/5mg利格列汀的片剂)，按重量计，其包含以下含量的各组分：
-约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约5mg的利格列汀；
-约0～90％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案19.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为50mg HMS5552/5mg利格列汀的片剂)，按重量计，其包含以下含量的各组分：
-约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约5mg的利格列汀；
-约0～90％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案20.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为75mg HMS5552/5mg利格列汀的片剂)，按重量计，其包含以下含量的各组分：
-约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约5mg的利格列汀；
-约0～90％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案21.方案17的药物组合、药物组合物或固定剂量复方制剂(所述固定剂量复方制剂优选为100mg HMS5552/5mg利格列汀的片剂)，按重量计，其包含以下含量的各组分：
-约100mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
-约5mg的利格列汀；
-约0～90％的填充剂；
-约2～8％的粘合剂；
-约1～5％的崩解剂；
-约0.5～3％的润滑剂；
-约0～0.5％的助流剂；和
-约0～5％的包衣剂。
方案22.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约50mg固体分散体、约5.00mg利格列汀、约151.80mg微晶纤维素、约6.60mg羟丙基纤维素、约4.40mg交联羧甲基纤维素钠、约2.20mg硬脂酸镁和约6.60mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
方案23.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约100mg固体分散体、约5.00mg利格列汀、约120.60mg微晶纤维素、约7.20mg羟丙基纤维素、约4.80mg交联羧甲基纤维素钠、约2.40mg硬脂酸镁和约7.20mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
方案24.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约150mg固体分散体、约5.00mg利格列汀、约27.50mg微晶纤维素、约50.00mg甘露醇、约7.50mg羟丙基纤维素、约7.50mg交联羧甲基纤维素钠、约2.50mg硬脂酸镁和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
方案25方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约50mg固体分散体、约5.00mg利格列汀、约137.00mg微晶纤维素、约4.00mg交联羧甲基纤维素钠、约2.00mg硬脂酸镁、约2.00mg微粉硅胶和约6.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
方案26.方案17的药物组合、药物组合物或固定剂量复方制剂，其中包含约200mg固体分散体、约5.00mg利格列汀、约77.0mg微晶纤维素、约9.00mg羟丙基纤维素、约6.00mg交联羧甲基纤维素钠、约3.00mg硬脂酸镁和约9.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约100mg HMS5552。
方案27.一种制备方案1-26中任一项的药物组合、药物组合物或固定剂量复方制剂的方法，该方法包括将活性成份掺入一种或多种赋形剂进行制粒，优选进一步地将制得的颗粒混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状；更优选更进一步的将所得的片剂进行包衣。
方案28.方案27的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中通过湿法制粒(高剪切和/或流化床)制备，或者通过干法处理(直接压制或者干法制粒)制备。
方案29.方案27-28中任一项的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂制备成固体分散体形式。
方案30.方案27-29中任一项的制备药物组合、药物组合物或固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂和第二种或更多种活性成分也可以一起制备成复方固体分散体形式(即含有2种或多种活性成分的固体分散体)。
方案31.如方案1-26中任意一项所述的药物组合、药物组合物或固定剂量复方制剂，其用于预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降 低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症。
方案32.预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍的方法：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症，包括向受试者给予治疗有效量的方案1-26中任意一项所述的药物组合、药物组合物或固定剂量复方制剂。
方案33.方案1-26中任意一项所述的药物组合、药物组合物或固定剂量复方制剂在制备用于预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍或预防、减缓、延迟或逆转糖尿病并发症的药物中的用途：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c。
以下实施例进一步描述和说明了在本发明范围内的实施方案。但本发明并不局限于实施例，在本发明的技术基础上做出的若干修改和替换均属于本发明的保护范围。
实施例
葡萄糖激酶激活剂的复方片剂的制备
本发明使用的化学品可以购自公司如Shin-Etsu Japan，Evonik Germany,J.T.Baker US,SCR China,Ashland US,FMC US,JRS Germany,Colorcon US,Capsugel,BASF，振兴试剂等。生产设备和分析测试仪器等可以购自这样的公司如Sartorius，Nikon，Sympatec，Bruker，Gea Niro，Korsch，Erweka，Agilent，Quadro Engineering,Canada；Warters,US；TA,US；SOTAX,Switzerland；Mettler Toledo Instrument Newark，DE。
I.葡萄糖激酶激活剂的固体分散体的制备
1.1固体分散体喷雾干燥前溶液的制备
实施例1A(活性成分与聚合物的重量比为1:9)
称取Eudragit L100(优特奇L100，Evonik Germany)6.75克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入0.75克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml溶液。
实施例2A(活性成分与聚合物的重量比为3:7)
称取Eudragit L100(优特奇L100，Evonik Germany)5.25克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入2.25克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml 溶液。
实施例3A(活性成分与聚合物的重量比为5:5)
称取Eudragit L100(优特奇L100，Evonik Germany)3.75克，在搅拌条件下加入无水乙醇(J.T.Baker/)中，至完全溶解后加入3.75克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml溶液。
实施例4A(活性成分与聚合物的重量比为7:3)
称取Eudragit L100(优特奇L100，Evonik Germany)2.25克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入5.25克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml溶液。
实施例5A(活性成分与聚合物的重量比为8:2)
称取Eudragit L100(优特奇L100，Evonik Germany)1.5克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入6克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml溶液。
实施例6A(活性成分与聚合物的重量比为9:1)
称取Eudragit L100(优特奇L100，Evonik Germany)0.75克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入6.75克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml溶液。
实施例7A(活性成分与聚合物的重量比为6:4)
称取Eudragit L100(优特奇L100，Evonik Germany)3.0克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入4.5克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml溶液。
实施例8A(活性成分与聚合物的重量比为4:6)
称取Eudragit L100(优特奇L100，Evonik Germany)4.5克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入3.0克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml溶液。
实施例9A(活性成分与聚合物的重量比为5:5)
称取Eudragit L100(优特奇L100，Evonik Germany)187.5克，在搅拌条件下加入无水乙醇(振兴试剂)中，至完全溶解后加入187.5克化合物HMS5552，继续搅拌得到2500ml溶液。
1.2葡萄糖激酶激活剂的固体分散体的制备
针对上述制备的溶液进行喷雾干燥，来制备葡萄糖激酶激活剂固体分散体。所得固体分散体的编号与上面实施例的编号对应。适用于本发明喷雾干燥设备包括但不限于Niro GEA Process Engineering  Inc.,Buchi Labortechnik AG，ProCept和SPX ANHYDROUS公司制作的喷雾干燥设备。可以通过选择合适的干燥气体进风温度、进风量、进液速度和雾化压力进行喷雾干燥，以便液滴在其到达装置壁时被充分干燥。这有助于确保干燥的液滴基本上是固体，可以形成细粉末，并且不会粘壁，也不至于难以在旋风器中收集。所得粉末进行二次干燥，确保产品符合质量要求。
喷雾干燥法制备葡萄糖激酶激活剂固体分散体生产工艺流程描述
对上述实施例1A-8A中制备的溶液通过喷雾干燥来制备固体分散体，其中喷雾干燥机设置的进风温度为90-150℃，进风流速设置为0.3-0.5m 3/min，气流的流速为15-30L/min，上述溶液的喷液速度为5-7mL/min，喷雾干燥得到固体分散体1-8。
对上述实施例9A中制备的溶液通过喷雾干燥来制备固体分散体，其中喷雾干燥机设置的进风温度为90-150℃，进风流速设置为20-30kg/h，气流的流速为3-30kg/h，上述溶液的喷液速度为5-200mL/min，喷雾干燥得到固体分散体9。
按照上述方式，分别制备了固体分散体1-9，其中：
固体分散体1中化合物HMS5552的质量分数为10％；固体分散体2中化合物HMS5552的质量分数为30％；固体分散体3中化合物HMS5552的质量分数为50％；固体分散体4中化合物HMS5552的质量分数为70％；固体分散体5中化合物HMS5552的质量分数为80％；固体分散体6中化合物HMS5552的质量分数为90％；固体分散体7中化合物HMS5552的质量分数为60％；固体分散体8中化合物HMS5552的质量分数为40％；固体分散体9中化合物HMS5552的质量分数为50％。
II.制备复方片剂
2.1高剪切湿法制粒制备复方片剂
将按照上述葡萄糖激酶激活剂的固体分散体的制备实施例制备的HMS5552固体分散体和组合药物加入到高剪切湿法制粒机中，加入填充剂(例如微晶纤维素，或硅化微晶纤维素，或乳糖)和崩解剂(例如交联羧甲基纤维素钠，或交联聚维酮，或羟基乙酸淀粉钠)，加入部分粘合剂粉末，高剪切搅拌混合5min。在1-6分钟时间内将配好的粘合剂(例如羟丙基纤维素或聚乙烯吡咯烷酮或者羟丙基甲基纤维素)溶液，高剪切搅拌下加入到上述干混物中进行制粒。湿颗粒在Comil整粒机上进行整粒得到适宜尺寸的湿颗粒。将湿颗粒在约60℃托盘烘箱或者在流化床干燥机中(进风温度40-60℃)干燥20-40分钟。然后，利用研磨机对干燥的物料进行研磨，从而获得合适大小的颗粒。在研磨之后，将微晶纤维素或硅化微晶纤维素(针对有外加部分的填充剂)和崩解剂(例如交联羧甲基纤维素钠，或交联聚维酮，或羟基乙酸淀粉钠)加入到颗粒中和在桶式混合器中将其混合。然后，将润滑剂(硬脂酸镁或硬脂富马酸钠)和/或任选的助流剂(微粉硅胶)加入其中并且另外混合均匀。润滑的混合物利用旋转压片机进行压片，得到对应不同规格的不同片重和片型的片剂(素片，未包衣的片芯)。所得片剂任选用
Figure PCTCN2019088864-appb-000016
进行薄膜包衣重量增加大约3％，从而得到薄膜包衣片。
实施例1B HMS5552+西格列汀复方片剂(剂量规格50mg/50mg)
处方组成 单位处方量/mg ％(w/w)
磷酸西格列汀一水合物* 64.25 29.20
HMS5552固体分散体 100.00 45.46
微晶纤维素 40.35 18.34
羟丙基纤维素 6.60 3.00
交联羧甲基纤维素钠 6.60 3.00
硬脂酸镁 2.20 1.00
片芯总重 220.00 100.00
欧巴代 6.60 3.00
包衣片总重 226.60 --
*100.00mg HMS5552固体分散体相当于50mg HMS5552；
**64.25mg磷酸西格列汀一水合物相当于50.0mg西格列汀游离无水化物
实施例2B HMS5552+西格列汀复方片剂(剂量规格75mg/50mg)
处方组成 单位处方量/mg ％(w/w)
磷酸西格列汀一水合物** 64.25 24.71
HMS5552固体分散体* 150.00 57.69
微晶纤维素 27.55 10.60
羟丙基纤维素 7.80 3.00
交联羧甲基纤维素钠 7.80 3.00
硬脂酸镁 2.60 1.00
片芯总重 260.00 100.00
欧巴代 7.80 3.00
包衣片总重 267.80 --
*150.00mg HMS5552固体分散体相当于75mg HMS5552；
**64.25mg磷酸西格列汀一水合物相当于50.0mg西格列汀游离无水化物。
实施例3B HMS5552+西格列汀复方片剂(剂量规格50mg/100mg)
处方组成 单位处方量/mg ％(w/w)
磷酸西格列汀一水合物** 128.50 44.31
HMS5552固体分散体* 100.00 34.48
微晶纤维素 41.20 14.21
羟丙基纤维素 8.70 3.00
交联羧甲基纤维素钠 8.70 3.00
硬脂酸镁 2.90 1.00
片芯总重 290.0 100.00
欧巴代 8.70 3.00
包衣片总重 298.70 --
*100.00mg HMS5552固体分散体相当于50mg HMS5552；
**128.5mg磷酸西格列汀一水合物相当于100.0mg西格列汀游离无水化物。
实施例4B HMS5552+西格列汀复方片剂(剂量规格75mg/100mg)
处方组成 单位处方量/mg ％(w/w)
磷酸西格列汀一水合物** 128.50 36.71
HMS5552固体分散体* 150.00 42.86
微晶纤维素 47.00 13.43
羟丙基纤维素 10.50 3.00
交联羧甲基纤维素钠 10.50 3.00
硬脂酸镁 3.50 1.00
片芯总重 350.00 100.00
欧巴代 10.50 3.00
包衣片总重 360.50 --
*150.00mg HMS5552固体分散体相当于75mg HMS5552；
**128.50mg磷酸西格列汀一水合物相当于100.0mg西格列汀游离无水化物。
实施例5B HMS5552+西格列汀复方片剂(剂量规格25mg/100mg)
处方组成 单位处方量/mg ％(w/w)
磷酸西格列汀一水合物** 128.50 42.83
HMS5552固体分散体* 50.00 16.67
微晶纤维素 100.50 33.50
羟丙基纤维素 9.00 3.00
交联羧甲基纤维素钠 9.00 3.00
硬脂酸镁 3.00 1.00
片芯总重 300.00 100.00
欧巴代 9.00 3.00
包衣片总重 309.00  
*50.00mg HMS5552固体分散体相当于25mg HMS5552；
**128.50mg磷酸西格列汀一水合物相当于100.0mg西格列汀游离无水化物。
实施例6B HMS5552+西格列汀复方片剂(剂量规格100mg/50mg)
处方组成 单位处方量/mg ％(w/w)
磷酸西格列汀一水合物* 64.25 18.36
HMS5552固体分散体 200.00 57.14
微晶纤维素 61.26 17.50
羟丙基纤维素 10.50 3.00
交联羧甲基纤维素钠 10.50 3.00
硬脂酸镁 3.50 1.00
片芯总重 350.00 100.00
欧巴代 10.50 3.00
包衣片总重 360.50  
*200.00mg HMS5552固体分散体相当于100mg HMS5552；
**64.25mg磷酸西格列汀一水合物相当于50.0mg西格列汀游离无水化物。
实施例7B HMS5552+利格列汀复方片剂(剂量规格25mg/5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 50.00 22.73
利格列汀 5.00 2.27
微晶纤维素 151.80 69.00
羟丙基纤维素 6.60 3.00
交联羧甲基纤维素钠 4.40 2.00
硬脂酸镁 2.20 1.00
片芯总重 220.00 100.00
欧巴代 6.60 3.00
包衣片总重 226.60 --
*50.00mg HMS5552固体分散体相当于25mg HMS5552。
实施例8B HMS5552+利格列汀复方片剂(剂量规格50mg/5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 100.00 41.67
利格列汀 5.00 2.08
微晶纤维素 120.60 50.25
羟丙基纤维素 7.20 3.00
交联羧甲基纤维素钠 4.80 2.00
硬脂酸镁 2.40 1.00
片芯总重 240.00 100.0
欧巴代 7.20 3.00
包衣片总重 247.20 --
*100.00mg HMS5552固体分散体相当于50mg HMS5552。
实施例9B HMS5552+利格列汀复方片剂(剂量规格75mg/5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 150.00 60.00
利格列汀 5.00 2.00
微晶纤维素 27.50 11.00
甘露醇 50.00 20.00
羟丙基纤维素 7.50 3.00
交联羧甲基纤维素钠 7.50 3.00
硬脂酸镁 2.50 1.00
片芯总重 250.00 100.00
欧巴代 7.50 3.00
包衣片总重 257.50 --
*150.00mg HMS5552固体分散体相当于75mg HMS5552。
实施例10B HMS5552+利格列汀复方片剂(剂量规格100mg/5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 200.0 66.67
利格列汀 5.0 1.67
微晶纤维素 77.0 25.67
羟丙基纤维素 9.00 3.00
交联羧甲基纤维素钠 6.00 2.00
硬脂酸镁 3.00 1.00
片芯总重 300.00 100.0
欧巴代 9.00 3.00
包衣片总重 309.00 --
*200.00mg HMS5552固体分散体相当于100mg HMS5552。
实施例11B HMS5552+沙格列汀复方片剂(剂量规格75mg/5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 150.00 60.00
沙格列汀一水合物** 5.29 2.12
羟丙基纤维素 7.50 3.00
微晶纤维素 79.71 31.88
硬脂酸镁 2.50 1.00
交联羧甲基纤维素钠 5.00 2.00
片芯总重 250.00 100.00
欧巴代 7.50 3.00
包衣片总重 257.50 --
*150.00mg HMS5552固体分散体相当于75mg HMS5552；
**5.29mg沙格列汀一水合物相当于5.0mg沙格列汀游离无水化物。
实施例12B HMS5552+沙格列汀复方片剂(剂量规格50mg/2.5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 100.00 40.00
沙格列汀一水合物** 2.64 1.06
羟丙基纤维素 7.50 3.00
微晶纤维素 132.36 52.94
硬脂酸镁 2.50 1.00
交联羧甲基纤维素钠 5.00 2.00
片芯总重 250.00 100.00
欧巴代 7.50 3.00
包衣片总重 257.50 --
*100.00mg HMS5552固体分散体相当于50mg HMS5552；
**2.64mg沙格列汀一水合物相当于2.5mg沙格列汀游离无水化物。
实施例13B HMS5552+沙格列汀复方片剂(剂量规格100mg/2.5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 200.00 66.67
沙格列汀一水合物** 2.64 0.88
聚维酮 9.00 3.00
微晶纤维素 79.36 26.45
硬脂酸镁 3.00 1.00
交联羧甲基纤维素钠 6.00 2.00
片芯总重 300.00 100.00
欧巴代 9.00 3.00
包衣片总重 309.00 --
*200.00mg HMS5552固体分散体相当于100mg HMS5552；
**2.64mg沙格列汀一水合物相当于2.5mg沙格列汀游离无水化物。
2.2流化床湿法制粒制备复方片剂
将按照上述葡萄糖激酶激活剂的固体分散体的制备实施例制备的HMS5552固体分散体和组合药物加入到流化床制粒机中，加入可选的填充剂(例如微晶纤维素)。在20-60分钟时间内将配好的粘合剂(例如聚乙烯吡咯烷酮)溶液喷入流化床中混合物中进行制粒，然后在流化床干燥机中(进风温度40-60℃)继续干燥。然后，利用研磨机对干燥的物料进行研磨，从而获得合适大小的颗粒。在研磨之后，将微晶纤维素或硅化微晶纤维素(针对有外加部分的填充剂的处方)加入到颗粒中和在桶式混合器中将其混合。然后，将润滑剂(硬脂酸镁)和/或任选的助流剂(微粉硅胶)加入其中并且另外混合均匀。润滑的混合物利用旋转压片机进行压片，得到对应不同规格的不同片重和片型的片剂(素片，未包衣的片芯)。所得片剂任选用将按照上述葡萄糖激酶激活剂的固体分散体的制备方法制备的进行薄膜包衣重量增加大约3％，从而得到薄膜包衣片。
实施例14B HMS5552+沙格列汀复方片剂(剂量规格25mg/5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 50.0 20.0
沙格列汀一水合物** 5.29 2.12
聚维酮 7.50 3.00
微晶纤维素 179.71 71.88
硬脂酸镁 2.50 1.00
交联羧甲基纤维素钠 5.00 2.00
片芯总重 250.0 100.0
欧巴代 7.50 3.00
包衣片总重 257.50 --
*50.00mg HMS5552固体分散体相当于25mg HMS5552；
**5.29mg沙格列汀一水合物相当于5.0mg沙格列汀游离无水化物。
2.3干法碾压制粒制备复方片剂
将按照上述葡萄糖激酶激活剂的固体分散体的制备实施例制备的HMS5552固体分散体和组合药物加入到混合桶中，加入填充剂(例如微晶纤维素)和粘合剂(例如羟丙基纤维素)混合均匀。然后通过滚轴碾压制粒机进行碾压，得到条状物通过粉碎机进行粉碎整粒，从而获得合适大小的颗粒。在 研磨之后，将可选的微晶纤维素或硅化微晶纤维素(针对有外加部分的填充剂)和崩解剂(例如交联羧甲基纤维素钠)加入到颗粒中和在桶式混合器中将其混合。然后，将润滑剂(硬脂酸镁或硬脂富马酸钠)和/或任选的助流剂(微粉硅胶)加入其中并且另外混合均匀。润滑的混合物利用旋转压片机进行压片，得到对应不同规格的不同片重和片型的片剂(素片，未包衣的片芯)。所得片剂任选用
Figure PCTCN2019088864-appb-000017
进行薄膜包衣重量增加大约3％，从而得到薄膜包衣片。
实施例15B HMS5552+维格列汀复方片剂(剂量规格25mg/50mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 50.00 8.33
维格列汀 50.00 8.33
微晶纤维素 464.00 77.33
交联羧甲基纤维素钠 24.00 4.00
微粉硅胶 6.00 1.00
硬脂酸镁 6.00 1.00
片芯总重 600 100.00
欧巴代 18.00 3.00
包衣片总重 618.00 --
*100.00mg HMS5552固体分散体相当于50mg HMS5552。
实施例16B HMS5552+维格列汀复方片剂(剂量规格50mg/50mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 100.00 16.67
维格列汀 50.00 8.33
微晶纤维素 414.00 69.00
交联羧甲基纤维素钠 24.00 4.00
微粉硅胶 6.00 1.00
硬脂酸镁 6.00 1.00
片芯总重 600.00 100.00
欧巴代 18.00 3.00
包衣片总重 618.00 --
*100.00mg HMS5552固体分散体相当于50mg HMS5552。
实施例17B HMS5552+维格列汀复方片剂(剂量规格75mg/50mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 150.00 20.00
维格列汀 50.00 6.67
硅化微晶纤维素 512.50 68.33
交联羧甲基纤维素钠 30.00 4.00
硬脂酸镁 7.50 1.00
片芯总重 750.00 100.00
欧巴代 21.50 3.00
包衣片总重 771.50 --
*150.00mg HMS5552固体分散体相当于75mg HMS5552。
2.4粉末混合直接压片制备复方片剂
将按照上述葡萄糖激酶激活剂的固体分散体的制备实施例制备的HMS5552固体分散体和组合药物按照几何递增原则预混均匀后加入到混合桶中，加入填充剂(例如微晶纤维素)，崩解剂(例如交联羧甲基纤维素钠)和任选的助流剂(微粉硅胶)加入到颗粒中和在桶式混合器中将其混合。然后，将润滑剂(硬脂酸镁或硬脂富马酸钠)加入其中并且另外混合均匀。润滑的混合物利用旋转压片机进行压片，得到对应不同规格的不同片重和片型的片剂(素片，未包衣的片芯)。所得片剂任选用
Figure PCTCN2019088864-appb-000018
进行薄膜包衣重量增加大约3％，从而得到薄膜包衣片。
按上述制备工艺描述的复方片剂的配方组成为：
实施例18B HMS5552+利格列汀复方片剂(剂量规格25mg/5mg)
处方组成 单位处方量/mg ％(w/w)
HMS5552固体分散体* 50.00 25.00
利格列汀 5.00 2.50
微晶纤维素 137.00 68.50
交联羧甲基纤维素钠 4.00 2.00
硬脂酸镁 2.00 1.00
微粉硅胶 2.00 1.00
片芯总重 200.00 100.00
欧巴代 6.00 3.00
包衣片总重 206.00 --
*50.00mg HMS5552固体分散体相当于25mg HMS5552
III.含有葡萄糖激酶激活剂的复方制剂的体外溶出度测试
片剂的溶出度是采用《中国药典》(2015年版)的桨法，分别测试在pH6.8的介质中的HMS5552和另一种组合药物的溶出，在5分钟，15分钟，30分钟，45分钟和60分钟时，分别取样5ml，进 行HPLC分析。
按照上述测试方法，测量上述几种固定剂量规格的片剂和其相应的单方片剂，其溶出度结果如下。
表1实施例1B制备的固定剂量复方片剂的溶出结果
Figure PCTCN2019088864-appb-000019
表2实施例4B制备的固定剂量复方片剂的溶出结果
Figure PCTCN2019088864-appb-000020
表3实施例7B制备的固定剂量复方片剂的溶出结果
Figure PCTCN2019088864-appb-000021
表4实施例9B制备的固定剂量复方片剂的溶出结果
Figure PCTCN2019088864-appb-000022
表5实施例11B制备的固定剂量复方片剂的溶出结果
Figure PCTCN2019088864-appb-000023
表6实施例14B制备的固定剂量复方片剂的溶出结果
Figure PCTCN2019088864-appb-000024
表7实施例17B制备的固定剂量复方片剂的溶出结果
Figure PCTCN2019088864-appb-000025
Figure PCTCN2019088864-appb-000026
从上述固定剂量复方制剂的溶出结果可以看出，本发明的固定复方制剂的溶出达到快速释放制剂的要求。
IV.含有葡萄糖激酶激活剂的复方制剂物理属性
按照药典相关的仪器和方法，对上述几种固定剂量规格的片剂的物理属性进行测试，结果描述如下。
表8不同实施例制备的固定剂量复方片剂的物理属性
Figure PCTCN2019088864-appb-000027
表9不同实施例制备的固定剂量复方片芯的物理属性
Figure PCTCN2019088864-appb-000028
表10不同实施例制备的固定剂量复方片芯的物理属性
Figure PCTCN2019088864-appb-000029
表11不同实施例制备的固定剂量复方片芯的物理属性
Figure PCTCN2019088864-appb-000030
V.含有葡萄糖激酶激活剂的复方制剂的药效学研究
实施例1C
2型糖尿病模型大鼠参与的HMS5552联合西格列汀的药效学动物研究
SD肥胖大鼠经STZ诱导后形成2型糖尿病模型大鼠，每天一次分别口服给予溶酶、10mg/kg HMS5552、30mg/kg HMS5552、10mg/kg西格列汀、30mg/kg西格列汀、10mg/kg HMS5552联合10mg/kg西格列汀、或10mg/kg HMS5552联合30mg/kg西格列汀，治疗30天后，经口服糖耐量试验(OGTT)，分析0-4小时血糖曲线下面积(AUEC0-4hr,hr*mg/dL)对比用药前基线变化(AUEC)，结果显示10mg/kg HMS5552联合30mg/kg西格列汀降糖效果最佳，优于HMS5552和西格列汀高剂量单药治疗(30mg/kg)，具有统计学显著性差异。
西格列汀，一种二肽基肽酶-4(DPP-IV)抑制剂，通过抑制肠促胰岛素GLP-1的降解，增加活性肠促胰岛素的水平而改善血糖控制，降低餐后血糖，用于治疗2型糖尿病。HMS5552，一种新型葡萄糖激酶激活剂，能够改善2型糖尿病患者胰岛功能、促进肠促胰岛素的分泌、降低胰岛素抵抗，具有减低空腹和餐后血糖的双重治疗效果，DPP-IV抑制剂联合HMS5552，针对DPP-IV抑制剂控制血糖失效的患者、肥胖和具有心血管疾病的糖尿病患者，具有更好的血糖控制疗效和降低糖尿病并发症的风险。
上述关于HMS5552联合现有口服糖尿病药进行的有效性研究表明，联合使用能够提高HMS5552或现有降糖药的功效，降低安全风险，提高医疗效果。将HMS5552和现有口服糖尿病药开发成口服固定剂量复方制剂，是目前最有希望解决以上临床需求的复方糖尿病治疗药物。

Claims (77)

  1. 药物组合，其包含：
    (a)葡萄糖激酶激活剂，其中所述葡萄糖激酶激活剂为下式表示的化合物，或其可药用盐、其同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式：
    Figure PCTCN2019088864-appb-100001
    (b)DPP-IV抑制剂；
    其中上述药物(a)和(b)同时、分别或相继使用。
  2. 权利要求1的药物组合，其中所述葡萄糖激酶激活剂与DPP-IV抑制剂的重量比为约1:10至100:1，优选地为约1:4至40:1，更优选地为约1:4、约1:2、约1:1、约1.5:1、约1.5:2、约2:1、约5:1、约10:1、约15:1、约20:1或约40:1。
  3. 权利要求1或2的药物组合，其中，所述葡萄糖激酶激活剂为下式表示的化合物HMS5552，或其同位素标记物或其可药用盐，
    Figure PCTCN2019088864-appb-100002
  4. 权利要求1-3中任一项的药物组合，其中所述葡萄糖激酶激活剂为固体分散体形式；优选地，所述葡萄糖激酶激活剂为包含聚合物载体的固体分散体形式，其中所述聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙烯酸甲酯(1:1)的阴离子共聚物)，优选为Eudragit，更优选为Eudragit L100。
  5. 权利要求4的药物组合，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为约1:10至10:1，优选地为约1:9至9:1、约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5，更优选地为约1:1、约2:3、约3:4、约4:5或约5:6。
  6. 权利要求1-5中任一项所述的药物组合，其中所述DPP-IV抑制剂选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特力列汀、度格列汀，及其可药用盐，优选地选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀和利格列汀，及它们的可药用盐。
  7. 权利要求1-6中任一项所述的药物组合，其中所述葡萄糖激酶激活剂以约1毫克至约200毫克，优选地约25毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述葡萄糖激酶激活剂的剂量(优选单位剂量)为约25毫克、约50毫克、约75毫克或约100毫克。
  8. 权利要求1-7中任一项所述的药物组合，其中所述DPP-IV抑制剂以约1毫克至200毫克，优选地约2.5毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述DPP-IV抑制剂的剂量(优选单位剂量)为约2.5毫克、约5毫克、约10毫克、约20毫克、约50毫克或约100毫克，最优选为约2.5毫克、约5毫克、约50毫克或约100毫克；优选地，所述DPP-IV抑制剂为西格列汀，其剂量(优选单位剂量)为约25毫克～约200毫克，优选地为约50毫克～约100毫克，优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克，更优选为约25mg、50mg或约100mg；优选地，所述DPP-IV抑制剂为利格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约5毫克或约10毫克，更优选为约5mg；优选地，所述DPP-IV抑制剂为沙格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约2.5毫克、约5毫克或约10毫克，更优选为约2.5mg或约5mg；优选地，所述DPP-IV抑制剂为维格列汀，其剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选为约50毫克。
  9. 权利要求1-8中任一项所述的药物组合，其为药物组合物的形式。
  10. 权利要求9所述的药物组合物，其包含葡萄糖激酶激活剂的固体分散体和DPP-IV抑制剂，优选地，其中葡萄糖激酶激活剂的固体分散体与DPP-IV抑制剂的重量比为约1:5至100:1，优选地为约1:2至80:1，更优选地为约1:2、约1:1、约2:1、约3:1、约3:2、约4:1、约10:1、约20:1、约30:1、约40:1或约80:1。
  11. 权利要求9或10的药物组合物，其中所述葡萄糖激酶激活剂的固体分散体按重量计约为1～98％；所述DPP-IV抑制剂按重量计约为0.2～80％。
  12. 权利要求9-11中任一项所述的药物组合物，其中还包含一种或者多种赋形剂，优选地，所述赋形剂选自粘合剂、填充剂、崩解剂、润滑剂、助流剂、表面活性剂、润湿剂、抗氧化剂、增香剂、甜味剂、着色剂或者包衣剂。
  13. 权利要求9-12中任一项所述的药物组合物，其为选自片剂、胶囊、丸剂和锭剂的形式，优 选为片剂，更优选为包衣片剂。
  14. 一种固定剂量复方制剂，其包含：
    (a)葡萄糖激酶激活剂，其为下式表示的化合物，或其可药用盐、其
    同位素标记物、其结晶形式、水合物、溶剂合物、非对映异构体或对映异构体形式：
    Figure PCTCN2019088864-appb-100003
    (b)DPP-IV抑制剂；
    (c)一种或多种赋形剂。
  15. 权利要求14的固定剂量复方制剂，其中葡萄糖激酶激活剂与DPP-IV抑制剂的重量比为约1:10至100:1，优选地为约1:4至40:1，更优选地为约1:4、约1:2、约1:1、约1.5:1、约1.5:2、约2:1、约5:1、约10:1、约15:1、约20:1或约40:1。
  16. 权利要求14或15的固定剂量复方制剂，其中，所述葡萄糖激酶激活剂按重量计约为1～98％；所述DPP-IV抑制剂按重量计约为0.2～80％。
  17. 权利要求14-16中任一项的固定剂量复方制剂，其中，所述葡萄糖激酶激活剂为下式表示的化合物HMS5552，或其同位素标记物或其可药用盐，
    Figure PCTCN2019088864-appb-100004
  18. 权利要求14-17中任一项的固定剂量复方制剂，其中所述葡萄糖激酶激活剂为固体分散体形式，优选地，其中，所述葡萄糖激酶激活剂为包含聚合物载体的固体分散体形式，所述聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙烯酸甲酯(1:1)的阴离子共聚物)，优选为Eudragit，更优选为Eudragit L100。
  19. 权利要求14-18中任一项的固定剂量复方制剂，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为约1:10至10:1，优选地为约1:9至9:1、约1:4至4:1、约3:7至7:3、约2:3至3:2、约3:4至4:3、约4:5至5:4或约5:6至6:5，更优选地为约1:1、约2:3、约3:4、约4:5或约5:6。
  20. 权利要求14-19中任一项的固定剂量复方制剂，其中所述DPP-IV抑制剂选自西格列汀(或磷酸西格列汀一水合物)、沙格列汀(或沙格列汀一水合物)、维格列汀、利格列汀、阿洛列汀、地那列汀、美格列汀、戈塞列汀、特力列汀、度格列汀，及其可药用盐，优选地选自西格列汀(或)、沙格列汀(或沙格列汀一水合物)、维格列汀和利格列汀，及它们的可药用盐。
  21. 权利要求14-20中任一项所述的固定剂量复方制剂，其中所述葡萄糖激酶激活剂以约1毫克至约200毫克，优选地约25毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述葡萄糖激酶激活剂的剂量(优选单位剂量)为约25毫克、约50毫克、约75毫克或约100毫克。
  22. 权利要求14-21中任一项所述的固定剂量复方制剂，其中所述DPP-IV抑制剂以约1毫克至200毫克，优选地约2.5毫克至约100毫克的剂量(优选单位剂量)范围存在，优选地，其中所述DPP-IV抑制剂的剂量(优选单位剂量)为约2.5毫克、约5毫克、约10毫克、约20毫克、约50毫克或约100毫克，最优选为约2.5毫克、约5毫克、约50毫克或约100毫克；优选地，所述DPP-IV抑制剂为西格列汀，其剂量(优选单位剂量)为约25毫克～约200毫克，优选地为约50毫克～约100毫克，优选地为约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克，更优选为约25mg、50mg或约100mg；优选地，所述DPP-IV抑制剂为利格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约5毫克或约10毫克，更优选为约5mg；优选地，所述DPP-IV抑制剂为沙格列汀，其剂量(优选单位剂量)为约1毫克～约20毫克，优选地为约1毫克、约2.5毫克、约5毫克或约10毫克，更优选为约2.5mg或约5mg；优选地，所述DPP-IV抑制剂为维格列汀，其剂量(优选单位剂量)为约10毫克～约150毫克，优选为约50毫克和约100毫克，最优选为约50毫克。
  23. 权利要求14-22中任一项的固定剂量复方制剂，其中葡萄糖激酶激活剂的固体分散体与DPP-IV抑制剂的重量比为约约1:5至100:1，优选地为约1:2至80:1，更优选地为约1:2、约1:1、约2:1、约3:1、约3:2、约4:1、约10:1、约20:1、约30:1、约40:1或约80:1。
  24. 权利要求23的固定剂量复方制剂，其中所述葡萄糖激酶激活剂的固体分散体按重量计约为1～98％；所述DPP-IV抑制剂按重量计约为0.2～80％。
  25. 权利要求14-24中任一项的固定剂量复方制剂，所述一种或者多种赋形剂选自粘合剂、填充剂、崩解剂、润滑剂、助流剂、表面活性剂、润湿剂、抗氧化剂、增香剂、甜味剂、着色剂或者包衣剂。
  26. 权利要求25的固定剂量复方制剂，所述粘合剂选自聚乙烯吡咯烷酮、羟丙基纤维素或者羟丙基甲基纤维素；填充剂选自微晶纤维素、硅化微晶纤维素、乳糖、磷酸二氢钙、甘露醇、玉米淀粉或预胶化淀粉；崩解剂选自交联羧甲基纤维素钠、交联聚维酮或羟基乙酸淀粉钠；润滑剂选自硬脂酸镁或者硬脂酰富马酸钠；助流剂选自胶体二氧化硅或者滑石。
  27. 权利要求14-26中任一项的固定剂量复方制剂，其为片剂。
  28. 权利要求27的固定剂量复方制剂，其为包衣片剂。
  29. 权利要求28的固定剂量复方制剂，所述包衣片剂为膜包衣片剂，其中膜包衣剂包含：
    膜包衣基材，例如羟丙甲纤维素、羟丙基甲基纤维素或其混合物；
    任选的增塑剂，例如聚乙烯醇、聚乙二醇、丙二醇、聚山梨酯或它们的混合物；
    任选的着色剂，例如氧化铁红、氧化铁黄或其混合物；
    任选的遮光剂，如二氧化钛，和
    任选的助流剂。
  30. 权利要求29的固定剂量复方制剂，所述包衣片剂为膜包衣片剂，所述膜包衣剂为欧巴代。
  31. 权利要求14-30中任一项的固定剂量复方制剂，按重量计，其包含：
    -约1～80％，优选地约5～75％葡萄糖激酶激活剂，优选HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约0.2～80％，优选地约0.5～75％DPP-IV抑制剂；
    -约0～55％的填充剂；
    -约1～25％的粘合剂；
    -约0～15％的崩解剂；
    -约0.1～10％的润滑剂；
    -约0～3％的助流剂；和
    -约0～5％的包衣剂。
  32. 权利要求31的固定剂量复方制剂，按重量计，活性成分的剂量(优选单位剂量)为：
    约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂，优选HMS5552；
    约25毫克、约50毫克、约75毫克、约100毫克、约150毫克或约200毫克的西格列汀或相应量的磷酸西格列汀一水合物。
  33. 权利要求32的固定剂量复方制剂，所述固定剂量复方制剂为50mg HMS5552/50mg西格列汀或相应量的磷酸西格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约50mg的西格列汀或相应量的磷酸西格列汀一水合物；
    -约0～50％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  34. 权利要求32的固定剂量复方制剂，所述固定剂量复方制剂为75mg HMS5552/50mg西格列汀或相应量的磷酸西格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约50mg的西格列汀或相应量的磷酸西格列汀一水合物；
    -约0～50％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；和
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  35. 权利要求32的固定剂量复方制剂，所述固定剂量复方制剂为50mg HMS5552/100mg西格列汀或相应量的磷酸西格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约100mg的西格列汀或相应量的磷酸西格列汀一水合物；
    -约0～50％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  36. 权利要求32的固定剂量复方制剂，所述固定剂量复方制剂为75mg HMS5552/100mg西格列汀或相应量的磷酸西格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约100mg的西格列汀或相应量的磷酸西格列汀一水合物；
    -约0～50％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  37. 权利要求32的固定剂量复方制剂，所述固定剂量复方制剂为25mg HMS5552/100mg西格列汀或相应量的磷酸西格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约100mg的西格列汀或相应量的磷酸西格列汀一水合物；
    -约0～50％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  38. 权利要求32的固定剂量复方制剂，所述固定剂量复方制剂为100mg HMS5552/50mg西格列汀或相应量的磷酸西格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约100mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约50mg的西格列汀或相应量的磷酸西格列汀一水合物；
    -约0～50％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  39. 权利要求32的固定剂量复方制剂，其中包含约100mg固体分散体、约64.25mg的磷酸西格列汀一水合物、约40.35mg微晶纤维素、约6.60mg羟丙基纤维素、约6.60mg交联羧甲基纤维素钠、约2.20mg硬脂酸镁和约6.60mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
  40. 权利要求32的固定剂量复方制剂，其中包含约150mg固体分散体、约64.25mg的磷酸西格列汀一水合物、约27.55mg微晶纤维素、约7.80mg羟丙基纤维素、约7.80mg交联羧甲基纤维素钠、约2.60mg硬脂酸镁和约7.80mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
  41. 权利要求32的固定剂量复方制剂，其中包含约100mg固体分散体、约128.50mg的磷酸西格列汀一水合物、约41.20mg微晶纤维素、约8.70mg羟丙基纤维素、约8.70mg交联羧甲基纤维素钠、约2.90mg硬脂酸镁和约8.70mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
  42. 权利要求32的固定剂量复方制剂，其中包含约150mg固体分散体、约128.50mg的磷酸西格列汀一水合物、约47.00mg微晶纤维素、约10.50mg羟丙基纤维素、约10.50mg交联羧甲基纤维素钠、约3.50mg硬脂酸镁和约10.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
  43. 权利要求32的固定剂量复方制剂，其中包含约50mg固体分散体、约128.50mg的磷酸西格列汀一水合物、约100.50mg微晶纤维素、约9.00mg羟丙基纤维素、约9.00mg交联羧甲基纤维素钠、约3.00mg硬脂酸镁和约9.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
  44. 权利要求32的固定剂量复方制剂，其中包含约200mg固体分散体、约64.25mg的磷酸西格列汀一水合物、约61.26mg微晶纤维素、约10.50mg羟丙基纤维素、约10.50mg交联羧甲基纤维素钠、约3.50mg硬脂酸镁和约10.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约100mg HMS5552。
  45. 权利要求31的固定剂量复方制剂，按重量计，活性成分的剂量(优选单位剂量)为：
    约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂，优选HMS5552；
    约50毫克或约100毫克的维格列汀。
  46. 权利要求45的固定剂量复方制剂，所述固定剂量复方制剂为25mg HMS5552/50mg维格列汀的片剂，按重量计，其包含以下含量的各组分：
    -约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约50mg的维格列汀；
    -约0～80％的填充剂；
    -约2～8％的粘合剂；
    -约1～8％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  47. 权利要求45的固定剂量复方制剂，所述固定剂量复方制剂为50mg HMS5552/50mg维格列汀的片剂，按重量计，其包含以下含量的各组分：
    -约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约50mg的维格列汀；
    -约0～80％的填充剂；
    -约2～8％的粘合剂；
    -约1～8％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  48. 权利要求45的固定剂量复方制剂，所述固定剂量复方制剂为75mg HMS5552/50mg维格列汀的片剂，按重量计，其包含以下含量的各组分：
    -约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约50mg的维格列汀；
    -约0～80％的填充剂；
    -约2～8％的粘合剂；
    -约1～8％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  49. 权利要求45的固定剂量复方制剂，其中包含约50mg固体分散体、约50.00mg维格列汀、约464.00mg微晶纤维素、约24.00mg交联羧甲基纤维素钠、约6.00mg微粉硅胶、约6.00mg硬脂酸镁和约18.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
  50. 权利要求45的固定剂量复方制剂，其中包含约100mg固体分散体、约50.00mg维格列汀、约414.00mg微晶纤维素、约24.00mg交联羧甲基纤维素钠、约6.00mg微粉硅胶、约6.00mg硬脂酸镁和约18.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
  51. 权利要求45的固定剂量复方制剂，其中包含约150mg固体分散体、约50.00mg维格列汀、约512.50mg硅化微晶纤维素、约30.00mg交联羧甲基纤维素钠、约7.50mg硬脂酸镁和约21.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
  52. 权利要求31的固定剂量复方制剂，按重量计，活性成分的剂量(优选单位剂量)为：
    约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂，优选HMS5552；
    约2.5毫克、约5毫克、约7.5毫克和约10毫克的沙格列汀或相应量的沙格列汀一水合物。
  53. 权利要求52的固定剂量复方制剂，所述固定剂量复方制剂为25mg HMS5552/5mg沙格列汀或相应量的沙格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约5mg的沙格列汀或相应量的沙格列汀一水合物；
    -约0～80％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  54. 权利要求52的固定剂量复方制剂，所述固定剂量复方制剂为50mg HMS5552/2.5mg沙格列汀或相应量的沙格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约2.5mg的沙格列汀或相应量的沙格列汀一水合物；
    -约0～80％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  55. 权利要求52的固定剂量复方制剂，所述固定剂量复方制剂为75mg HMS5552/5mg沙格列汀或相应量的沙格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约5mg的沙格列汀或相应量的沙格列汀一水合物；
    -约0～80％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  56. 权利要求52的固定剂量复方制剂，所述固定剂量复方制剂为100mg HMS5552/2.5mg沙格列汀或相应量的沙格列汀一水合物的片剂，按重量计，其包含以下含量的各组分：
    -约100mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约2.5mg的沙格列汀或相应量的沙格列汀一水合物；
    -约0～80％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  57. 权利要求52的固定剂量复方制剂，其中包含约150mg固体分散体、约5.29mg沙格列汀一水合物、约7.50mg羟丙基纤维素、约79.71mg微晶纤维素、约2.50mg硬脂酸镁、约5.00mg交联羧甲基纤维素钠和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
  58. 权利要求52的固定剂量复方制剂，其中包含约100mg固体分散体、约2.64mg沙格列汀一水合物、约7.50mg羟丙基纤维素、约132.36mg微晶纤维素、约2.50mg硬脂酸镁、约5.00mg交联羧甲基纤维素钠和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
  59. 权利要求52的固定剂量复方制剂，其中包含约200mg固体分散体、约2.64mg沙格列汀一水合物、约9.00mg聚维酮、约79.36mg微晶纤维素、约3.00mg硬脂酸镁、约6.00mg交联羧甲基纤维素钠和约9.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约100mg HMS5552。
  60. 权利要求52的固定剂量复方制剂，其中包含约50mg固体分散体、约5.29mg沙格列汀一水合物、约7.50mg聚维酮、约179.71mg微晶纤维素、约2.50mg硬脂酸镁、约5.00mg交联羧甲基纤维素钠和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
  61. 权利要求31的固定剂量复方制剂，按重量计，活性成分的剂量(优选单位剂量)为：
    约25mg，约50mg，约75mg或约100mg的葡萄糖激酶激活剂，优选HMS5552；
    约2.5毫克、约5毫克、约7.5毫克或约10毫克的利格列汀。
  62. 权利要求61的固定剂量复方制剂，所述固定剂量复方制剂为25mg HMS5552/5mg利格列汀的片剂，按重量计，其包含以下含量的各组分：
    -约25mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约5mg的利格列汀；
    -约0～90％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  63. 权利要求61的固定剂量复方制剂，所述固定剂量复方制剂为50mg HMS5552/5mg利格列汀的片剂，按重量计，其包含以下含量的各组分：
    -约50mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约5mg的利格列汀；
    -约0～90％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  64. 权利要求61的固定剂量复方制剂，所述固定剂量复方制剂为75mg HMS5552/5mg利格列汀的片剂，按重量计，其包含以下含量的各组分：
    -约75mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约5mg的利格列汀；
    -约0～90％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  65. 权利要求61的固定剂量复方制剂，所述固定剂量复方制剂为100mg HMS5552/5mg利格列汀的片剂，按重量计，其包含以下含量的各组分：
    -约100mg的HMS5552，优选HMS5552的固体分散体，优选含HMS5552和聚合物载体的固体分散体，优选含约1:1的HMS5552和Eudragit L100的固体分散体；
    -约5mg的利格列汀；
    -约0～90％的填充剂；
    -约2～8％的粘合剂；
    -约1～5％的崩解剂；
    -约0.5～3％的润滑剂；
    -约0～0.5％的助流剂；和
    -约0～5％的包衣剂。
  66. 权利要求61的固定剂量复方制剂，其中包含约50mg固体分散体、约5.00mg利格列汀、约151.80mg微晶纤维素、约6.60mg羟丙基纤维素、约4.40mg交联羧甲基纤维素钠、约2.20mg硬脂酸 镁和约6.60mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
  67. 权利要求61的固定剂量复方制剂，其中包含约100mg固体分散体、约5.00mg利格列汀、约120.60mg微晶纤维素、约7.20mg羟丙基纤维素、约4.80mg交联羧甲基纤维素钠、约2.40mg硬脂酸镁和约7.20mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约50mg HMS5552。
  68. 权利要求61的固定剂量复方制剂，其中包含约150mg固体分散体、约5.00mg利格列汀、约27.50mg微晶纤维素、约50.00mg甘露醇、约7.50mg羟丙基纤维素、约7.50mg交联羧甲基纤维素钠、约2.50mg硬脂酸镁和约7.50mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约75mg HMS5552。
  69. 权利要求61的固定剂量复方制剂，其中包含约50mg固体分散体、约5.00mg利格列汀、约137.00mg微晶纤维素、约4.00mg交联羧甲基纤维素钠、约2.00mg硬脂酸镁、约2.00mg微粉硅胶和约6.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约25mg HMS5552。
  70. 权利要求61的固定剂量复方制剂，其中包含约200mg固体分散体、约5.00mg利格列汀、约77.0mg微晶纤维素、约9.00mg羟丙基纤维素、约6.00mg交联羧甲基纤维素钠、约3.00mg硬脂酸镁和约9.00mg欧巴代，其中所述固体分散体含约1:1的HMS5552和Eudragit L100，并且含约100mg HMS5552。
  71. 一种制备前述任一项权利要求的固定剂量复方制剂的方法，该方法包括将活性成份掺入一种或多种赋形剂进行制粒，优选进一步地将制得的颗粒混合物填装入小瓶、小袋或者胶囊中或者压缩成期望的片剂形状；更优选更进一步的将所得的片剂进行包衣。
  72. 权利要求71的制备固定剂量复方制剂的方法，其中通过湿法制粒(高剪切和/或流化床)制备，或者通过干法处理(直接压制或者干法制粒)制备。
  73. 权利要求71-72任一项的制备固定剂量复方制剂的方法，其中将所述葡萄糖激酶激活剂制备成固体分散体形式。
  74. 权利要求71-73任一项的制备固定剂量复方制剂的方法，其中所述葡萄糖激酶激活剂和第二种或更多种活性成分一起制备成复方固体分散体形式。
  75. 如权利要求1-13中任一项所述的药物组合或药物组合物或权利要求14-70中任一项所述的固定剂量复方制剂，其用于预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症。
  76. 预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍的方法：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、 肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c；或预防、减缓、延迟或逆转糖尿病并发症，包括向受试者给予治疗有效量的权利要求1-13中任一项所述的药物组合或药物组合物或权利要求14-70中任一项所述的固定剂量复方制剂。
  77. 权利要求1-13中任一项所述的药物组合或药物组合物或权利要求14-70中任意一项所述的固定剂量复方制剂在制备用于预防一种或多种选自以下的代谢障碍、减缓该代谢障碍的进展、延迟或治疗该代谢障碍或预防、减缓、延迟或逆转糖尿病并发症的药物中的用途：I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常、高血糖症、餐后高血糖症、超重、肥胖症、高血压症、胰岛素抵抗、糖尿病认知功能障碍、记忆障碍、老年痴呆和/或代谢综合征；或改善血糖控制和/或降低空腹血浆葡萄糖、餐后血浆葡萄糖和/或糖基化血红蛋白HbA1c。
PCT/CN2019/088864 2018-05-31 2019-05-28 含有葡萄糖激酶激活剂和dpp-iv抑制剂的药物组合、组合物和复方制剂及其制备方法和用途 Ceased WO2019228365A1 (zh)

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ES19811377T ES3015131T3 (en) 2018-05-31 2019-05-28 Pharmaceutical combination, composition and compound preparation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof
AU2019278016A AU2019278016B2 (en) 2018-05-31 2019-05-28 Pharmaceutical combination, composition and combination formulation comprising glucokinase activator and DPP‐IV inhibitor, and preparation method and use thereof
HRP20250258TT HRP20250258T1 (hr) 2018-05-31 2019-05-28 Farmaceutska kombinacija, pripravak, i kombinirana priprema koja sadrži aktivator glukokinaze i inhibitor dpp-iv te metode pripreme, i njihova uporaba
MX2020012965A MX2020012965A (es) 2018-05-31 2019-05-28 Combinacion, composicion y preparacion de compuesto farmaceutico que comprende activador de glucocinasa e inhibidor de dpp-iv, metodo de preparacion y uso del mismo.
LTEPPCT/CN2019/088864T LT3804715T (lt) 2018-05-31 2019-05-28 Farmacinis derinys, kompozicija ir junginio preparatas, apimantys gliukokinazės aktyvatorių ir dpp-iv inhibitorių, bei jų gamybos ir panaudojimo būdas
IL279039A IL279039B2 (en) 2018-05-31 2019-05-28 Pharmaceutical combination, composition and combination formulation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof
FIEP19811377.1T FI3804715T3 (fi) 2018-05-31 2019-05-28 Farmaseuttinen yhdistelmä, koostumus ja yhdistelmävalmiste, joka käsittää glukokinaasin aktivaattorin ja dpp-iv:n estäjän ja niiden valmistusmenetelmä ja käyttö
SM20250104T SMT202500104T1 (it) 2018-05-31 2019-05-28 Preparazione di combinazione, composizione e composto farmaceutici comprendenti attivatore di glucochinasi e inibitore di dpp-iv, e relativi metodo di preparazione e uso
JP2020566718A JP7565589B2 (ja) 2018-05-31 2019-05-28 グルコキナーゼ活性化剤およびｄｐｐ－ｉｖ阻害薬を含む医薬品の組合せ、組成物、配合剤、ならびにその調製方法および使用
US17/058,903 US11963947B2 (en) 2018-05-31 2019-05-28 Pharmaceutical combination, composition and compound preparation comprising glucokinase activator and DPP-IV inhibitor, and preparation method and use thereof
KR1020207037560A KR102695135B1 (ko) 2018-05-31 2019-05-28 글루코키나제 활성화제 및 dpp-iv 억제제를 포함하는 약제학적 병용물, 조성물 및 병용 제제, 및 이의 제조 방법 및 용도
RU2020143045A RU2770775C1 (ru) 2018-05-31 2019-05-28 Фармацевтическая комбинация, композиция и комбинированный состав, содержащий активатор глюкокиназы и ингибитор dpp-iv, и способ его приготовления и применения
EP19811377.1A EP3804715B1 (en) 2018-05-31 2019-05-28 Pharmaceutical combination, composition and compound preparation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof
SG11202011881PA SG11202011881PA (en) 2018-05-31 2019-05-28 Pharmaceutical combination, composition and combination formulation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof
BR112020024125-3A BR112020024125A2 (pt) 2018-05-31 2019-05-28 combinação farmacêutica, composição e preparação de composto compreendendo ativador de glucoquinase e inibidor de dpp-iv, e método de preparação e uso dos mesmos
PL19811377.1T PL3804715T3 (pl) 2018-05-31 2019-05-28 Farmaceutyczna kombinacja, kompozycja i preparat związku zawierające aktywator glukokinazy i inhibitor dpp-iv oraz sposób ich wytwarzania i ich zastosowanie
SI201930906T SI3804715T1 (sl) 2018-05-31 2019-05-28 Farmacevtska kombinacija, sestava in priprava spojine, ki vsebuje aktivator glukokinaze in inhibitor dpp-iv, ter metode priprave in uporaba tega
DK19811377.1T DK3804715T3 (da) 2018-05-31 2019-05-28 Farmaceutisk kombination, sammensætning og forbindelsespræparat omfattende glucokinase-aktivator og dpp-iv-inhibitor, og fremgangsmåde til fremstilling og anvendelser deraf
CA3101831A CA3101831A1 (en) 2018-05-31 2019-05-28 Pharmaceutical combination, composition and combination formulation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof
RS20250230A RS66564B1 (sr) 2018-05-31 2019-05-28 Farmaceutska kombinacija, kompozicija i preparat jedinjenja koji sadrže aktivator glukokinaze i inhibitor dpp-iv, i postupak njihove pripreme i upotreba
ZA2020/07681A ZA202007681B (en) 2018-05-31 2020-12-09 Pharmaceutical combination, composition and combination formulation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof
JP2022178385A JP2022190170A (ja) 2018-05-31 2022-11-07 グルコキナーゼ活性化剤およびｄｐｐ－ｉｖ阻害薬を含む医薬品の組合せ、組成物、配合剤、ならびにその調製方法および使用
US18/610,100 US20240299357A1 (en) 2018-05-31 2024-03-19 Pharmaceutical combination, composition and compound preparation comprising glucokinase activator and dpp-iv inhibitor, and preparation method and use thereof

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