阅读说明：本技术 含有葡萄糖激酶激活剂和ppar受体激活剂的药物组合及其制备方法和用途 (pharmaceutical composition containing glucokinase activator and PPAR receptor activator, and preparation method and application thereof ) 是由 陈力 李永国 王高森 高慧升 于 2019-05-28 设计创作，主要内容包括：本发明涉及一种药物组合,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PPAR受体激活剂。本发明进一步涉及药物组合物、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。(The present invention relates to a pharmaceutical combination comprising a glucokinase activator or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form thereof, a hydrate, a solvate, a diastereoisomeric or enantiomeric form thereof and a PPAR receptor activator. The invention further relates to a pharmaceutical composition, a fixed dose combination, and a preparation method and application of the pharmaceutical composition and the fixed dose combination.)

1. A pharmaceutical combination comprising:

(a) A glucokinase activator, wherein the glucokinase activator is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form thereof, a hydrate thereof, a solvate thereof, a diastereomer thereof, or an enantiomeric form thereof:

(b) A PPAR receptor activator;

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

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

3. The pharmaceutical combination according to claim 1 or 2, wherein the glucokinase activator is a compound represented by the formula HMS5552, or an isotopic label thereof or a pharmaceutically acceptable salt thereof,

4. The pharmaceutical combination of any one of claims 1-3, wherein the glucokinase activator is in the form of a solid dispersion; preferably, the glucokinase activator is in the form of a solid dispersion comprising a polymeric carrier, wherein the polymeric carrier is methacrylic acid copolymer type a (an anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)), preferably Eudragit, more preferably Eudragit L100.

5. The pharmaceutical combination of claim 4, wherein the weight ratio of glucokinase activator to polymeric 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.

6. The pharmaceutical combination of any one of claims 1 to 5, wherein the PPAR receptor activator is selected from rosiglitazone (or rosiglitazone maleate), pioglitazone (or pioglitazone hydrochloride), sitagliptin sodium and pharmaceutically acceptable salts thereof.

7. The pharmaceutical combination of any one of claims 1-6, wherein the glucokinase activator is present in a dosage (preferably unit dose) range of about 1 milligram to about 200 milligrams, preferably about 25 milligrams to about 100 milligrams, preferably wherein the dosage (preferably unit dose) of the glucokinase activator is about 25 milligrams, about 50 milligrams, about 75 milligrams, or about 100 milligrams.

8. the pharmaceutical combination of any one of claims 1-7, wherein the PPAR receptor activator is present in a dosage (preferably unit dose) range of about 1mg to about 50mg, preferably about 4mg to about 15mg, preferably wherein the dosage (preferably unit dose) of the PPAR receptor activator is about 1mg, about 2 mg, about 4mg, about 5mg, about 10mg, about 12 mg, about 14 mg or about 15mg, most preferably about 4mg or about 15 mg; preferably, the PPAR receptor activator is rosiglitazone or pioglitazone.

9. the pharmaceutical combination of any one of claims 1-8 in the form of a pharmaceutical composition.

10. The pharmaceutical composition of claim 9, comprising a solid dispersion of glucokinase activator and a PPAR receptor activator, preferably wherein the weight ratio of the solid dispersion of glucokinase activator to PPAR receptor activator is about 100:1 to 1:5, preferably about 50:1 to 2:5, more preferably about 1:5, about 2:5, about 1:1, about 3.33:1, about 6.67:1, about 10:1, about 12.5:1, about 13.3:1, about 25:1, about 37.5:1, or about 50: 1.

11. The pharmaceutical composition of claim 9 or 10, wherein the solid dispersion of glucokinase activator is about 1-98% by weight; the PPAR receptor activator is about 0.1-25% by weight.

12. The pharmaceutical composition according to any one of claims 9 to 11, further comprising one or more excipients, preferably selected from binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

13. The pharmaceutical composition according to any one of claims 9 to 12, which is in a form selected from the group consisting of tablets, capsules, pills and lozenges, preferably tablets, more preferably coated tablets.

14. A fixed-dose combination formulation comprising:

(a) A glucokinase activator which is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form thereof, a hydrate thereof, a solvate thereof, a diastereomer thereof, or an enantiomeric form thereof:

(b) A PPAR receptor activator;

(c) One or more excipients.

15. the fixed-dose combination formulation of claim 14, wherein the weight ratio of glucokinase activator to PPAR receptor activator is from about 50:1 to 1:10, preferably from about 25:1 to 1:5, more preferably about 1:10, about 1:5, about 1:2, about 1.67:1, about 3.33:1, about 5:1, about 6.25:1, about 6.67:1, about 12.5:1, about 18.75:1, or about 25: 1.

16. The fixed-dose combination formulation of claim 14 or 15, wherein the glucokinase activator is about 1-98% by weight; the PPAR receptor activator is about 0.1-25% by weight.

17. the fixed-dose combination formulation of any one of claims 14-16, wherein the glucokinase activator is a compound represented by the formula HMS5552, or an isotopic label thereof or a pharmaceutically acceptable salt thereof,

18. The fixed-dose combination formulation of any one of claims 14-17, wherein the glucokinase activator is in the form of a solid dispersion, preferably wherein the glucokinase activator is in the form of a solid dispersion comprising a polymeric carrier of methacrylic acid copolymer type a (anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)), preferably Eudragit, more preferably Eudragit L100.

19. The fixed-dose combination formulation of any one of claims 14-18, wherein the weight ratio of glucokinase activator to polymeric 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.

20. The fixed-dose combination formulation of any one of claims 14 to 19, wherein the PPAR receptor activator is selected from rosiglitazone (or rosiglitazone maleate), pioglitazone (or pioglitazone hydrochloride), sitagliptin sodium and pharmaceutically acceptable salts thereof.

21. the fixed-dose combination formulation of any one of claims 14-20, wherein the glucokinase activator is present in a dosage (preferably unit dose) range from about 1mg to about 200mg, preferably from about 25mg to about 100mg, preferably wherein the dosage (preferably unit dose) of the glucokinase activator is about 25mg, about 50mg, about 75mg, or about 100 mg.

22. The fixed-dose co-formulation of any one of claims 14-21, wherein the PPAR receptor activator is present in a dosage (preferably unit dose) range of about 1mg to about 50mg, preferably about 4mg to about 15mg, preferably wherein the dosage (preferably unit dose) of the PPAR receptor activator is about 1mg, about 2 mg, about 4mg, about 5mg, about 10mg, about 12 mg, about 14 mg, or about 15mg, most preferably about 4mg or about 15 mg; preferably, the PPAR receptor activator is rosiglitazone or pioglitazone.

23. The fixed-dose combination formulation of any one of claims 14-22, wherein the weight ratio of the solid dispersion of glucokinase activator to PPAR receptor activator is from about 100:1 to 1:5, preferably from about 50:1 to 2:5, more preferably about 1:5, about 2:5, about 1:1, about 3.33:1, about 6.67:1, about 10:1, about 12.5:1, about 13.3:1, about 25:1, about 37.5:1, or about 50: 1.

24. The fixed-dose combination of claim 23, wherein the glucokinase activator is about 1-98% by weight; the PPAR receptor activator is about 0.1-25% by weight.

25. The fixed-dose combination formulation of any one of claims 14-24, wherein the one or more excipients are selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants, and coatings.

26. The fixed-dose combination formulation of claim 25, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch or pregelatinized starch; the disintegrant is selected from croscarmellose sodium, crospovidone or sodium starch glycolate; the lubricant is selected from magnesium stearate or sodium stearyl fumarate; the glidant is selected from colloidal silicon dioxide or talc.

27. The fixed-dose combination formulation of any one of claims 11-26, which is a tablet.

28. the fixed-dose combination formulation of claim 27, which is a coated tablet.

29. The fixed-dose combination formulation of claim 28, wherein the coated tablet is a film-coated tablet, wherein the film-coated tablet comprises:

Film coating bases such as hypromellose, hydroxypropyl methylcellulose, or mixtures thereof;

optionally a plasticizer, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or mixtures thereof;

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

Optionally an opacifying agent, such as titanium dioxide, and

Optionally a glidant.

30. The fixed-dose combination formulation of claim 29, wherein the coated tablet is a film-coated tablet and the film-coated tablet is opadry.

31. The fixed-dose combination formulation of any one of claims 14-30, comprising by weight:

-about 1-98% glucokinase activator, preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion comprising HMS5552 and a polymeric carrier, preferably a solid dispersion comprising HMS5552 and Eudragit L100 at a ratio of about 1: 1;

-about 0.1-15% of a PPAR receptor activator;

-about 0-80% of a filler;

-about 1-25% binder;

-about 0-15% of a disintegrant;

-about 0.1-10% of a lubricant;

-about 0-3% of a glidant; and

-from about 0% to about 5% of a coating agent.

32. The fixed-dose combination formulation of claim 31, wherein the active ingredient is in a dosage (preferably a unit dose) by weight:

About 25mg, about 50mg, about 75mg or about 100mg of glucokinase activator, preferably HMS 5552;

about 2 mg, about 4mg and about 8 mg of rosiglitazone or a corresponding amount of rosiglitazone maleate.

33. The fixed-dose combination according to claim 32, which is a tablet of 25mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate, comprising the following amounts of the components by weight:

-about 25mg of HMS555, preferably a solid dispersion of HMS5552, preferably a solid dispersion comprising HMS5552 and a polymeric carrier, preferably a solid dispersion 2 comprising about 1:1 of HMS5552 and Eudragit L100;

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

34. The fixed-dose combination according to claim 32, which is a tablet of 50mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate, comprising the following amounts of the components by weight:

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

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

35. the fixed-dose combination according to claim 32, which is a tablet of 75mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate, comprising the following amounts of the components by weight:

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

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

36. the fixed-dose combination according to claim 32, which is a tablet of 100mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate, comprising the following amounts of the components by weight:

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

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

37. the fixed-dose combination formulation of claim 32, comprising about 50mg of the solid dispersion, about 5.30mg of rosiglitazone maleate, about 177.20mg of microcrystalline cellulose, about 7.50mg of hydroxypropyl cellulose, about 7.50mg of croscarmellose sodium, about 2.50mg of magnesium stearate, and about 7.50mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 25mg of HMS 5552.

38. the fixed-dose combination formulation of claim 32, comprising about 100mg of the solid dispersion, about 5.30mg of rosiglitazone maleate, about 77.20mg of microcrystalline cellulose, about 7.50mg of hydroxypropyl cellulose, about 7.50mg of croscarmellose sodium, about 2.50mg of magnesium stearate, and about 7.50mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 50mg of HMS 5552.

39. The fixed-dose combination formulation of claim 32, comprising about 150mg of the solid dispersion, about 5.30mg of rosiglitazone maleate, about 123.70mg of microcrystalline cellulose, about 9.00mg of hydroxypropyl cellulose, about 9.00mg of croscarmellose sodium, about 3.00mg of magnesium stearate, and about 9.00mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 75mg of HMS 5552.

40. The fixed-dose combination formulation of claim 32, comprising about 200mg of the solid dispersion, about 5.30mg of rosiglitazone maleate, about 73.7mg of microcrystalline cellulose, about 9.00mg of hydroxypropyl cellulose, about 9.00mg of croscarmellose sodium, about 3.00mg of magnesium stearate, and about 9.00mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 100mg of HMS 5552.

41. The fixed-dose combination formulation of claim 32, comprising about 50mg of the solid dispersion, about 5.30mg of rosiglitazone maleate, about 127.20mg of microcrystalline cellulose, about 7.50mg of polyvinylpyrrolidone, about 7.50mg of croscarmellose sodium, about 2.50mg of magnesium stearate, and about 7.50mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 25mg of HMS 5552.

42. The fixed-dose combination formulation of claim 31, wherein the active ingredient is in a dosage (preferably a unit dose) by weight:

About 25mg, about 50mg, about 75mg or about 100mg of glucokinase activator, preferably HMS 5552;

about 15mg, about 30mg and about 45 mg of pioglitazone or a corresponding amount of pioglitazone hydrochloride.

43. The fixed-dose combination formulation of claim 42, which is a tablet of 25mg HMS5552/15mg pioglitazone or a corresponding amount of pioglitazone hydrochloride, comprising the following amounts of the components by weight:

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

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

-about 0-90% of a filler;

-about 1-25% binder;

-about 1-8% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

44. the fixed-dose combination formulation of claim 42, which is a tablet of 50mg HMS5552/15mg pioglitazone or a corresponding amount of pioglitazone hydrochloride, comprising the following amounts of the components by weight:

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

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

-about 0-90% of a filler;

-about 1-25% binder;

-about 1-8% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

45. the fixed-dose combination formulation of claim 42, which is a tablet of 75mg HMS5552/15mg pioglitazone or a corresponding amount of pioglitazone hydrochloride, comprising the following amounts of the components by weight:

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

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

-about 0-90% of a filler;

-about 1-25% binder;

-about 1-8% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

46. The fixed-dose combination formulation of claim 42, which is a tablet of 100mg HMS5552/15mg pioglitazone or a corresponding amount of pioglitazone hydrochloride, comprising the following amounts of the components by weight:

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

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

-about 0-90% of a filler;

-about 1-25% binder;

-about 1-8% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

47. The fixed-dose combination formulation of claim 42, comprising about 150mg of the solid dispersion, about 15.91mg of the pioglitazone hydrochloride, about 113.09mg of the microcrystalline cellulose, about 9.00mg of the hydroxypropyl cellulose, about 9.00mg of the croscarmellose sodium, about 3.00mg of the magnesium stearate, and about 9.00mg of the opadry, wherein the solid dispersion comprises about 1:1 of the HMS5552 and Eudragit L100, and comprises about 75mg of the HMS 5552.

48. The fixed-dose combination formulation of claim 42, comprising about 200mg of the solid dispersion, about 15.91mg of the pioglitazone hydrochloride, about 63.09mg of the microcrystalline cellulose, about 9.00mg of the hydroxypropyl cellulose, about 9.00mg of the croscarmellose sodium, about 3.00mg of the magnesium stearate, and about 9.00mg of the opadry, wherein the solid dispersion comprises about 1:1 of the HMS5552 and the Eudragit L100, and comprises about 100mg of the HMS 5552.

49. The fixed-dose combination formulation of claim 42, comprising about 100mg of the solid dispersion, about 15.91mg of the pioglitazone hydrochloride, about 260.09mg of the microcrystalline cellulose, about 12.00mg of the hydroxypropyl cellulose, about 8.00mg of the croscarmellose sodium, about 4.00mg of the magnesium stearate, and about 12.00mg of the opadry, wherein the solid dispersion comprises about 1:1 of the HMS5552 and Eudragit L100, and comprises about 50mg of the HMS 5552.

50. The fixed-dose combination formulation of claim 42, comprising about 50mg of the solid dispersion, about 15.91mg of the pioglitazone hydrochloride, about 216.09mg of the microcrystalline cellulose, about 9.00mg of the hydroxypropyl cellulose, about 6.00mg of the croscarmellose sodium, about 3.00mg of the magnesium stearate, and about 9.00mg of the opadry, wherein the solid dispersion comprises about 1:1 of the HMS5552 and Eudragit L100, and comprises about 25mg of the HMS 5552.

51. A process for the preparation of a fixed dose combination according to any preceding claim, which process comprises granulating the active ingredient with one or more excipients, preferably further filling the resulting granulate mixture into vials, sachets or capsules or compressing into the desired tablet shape; more preferably, the resulting tablets are further coated.

52. The method of preparing a fixed-dose combination formulation of claim 51, wherein the formulation is prepared by wet granulation (high shear and/or fluidized bed) or by dry processing (direct compression or dry granulation).

53. the method of preparing a fixed dose combination according to any one of claims 51-52, wherein the glucokinase activator is prepared in the form of a solid dispersion.

54. the method of preparing a fixed dose combination according to any one of claims 51-53, wherein the glucokinase activator and the second or more active ingredients are prepared together in the form of a combination solid dispersion.

55. the pharmaceutical combination or composition of any one of claims 1-13 or the fixed dose combination of any one of claims 14-50 for use in preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1 c; or preventing, slowing, delaying or reversing diabetic complications.

56. A method of preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1 c; or preventing, slowing, delaying or reversing diabetic complications, comprising administering to a subject a therapeutically effective amount of a pharmaceutical combination or composition of any one of claims 1-13 or a fixed dose combination formulation of any one of claims 14-50.

57. Use of a pharmaceutical combination or composition according to any one of claims 1 to 13 or a fixed dose combination according to any one of claims 14 to 50 in the manufacture of a medicament for the prevention, slowing of the progression, delay of treatment or prevention, slowing of, delaying of or reversal of diabetic complications of one or more metabolic disorders selected from: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1 c.

Technical Field

The present invention relates to pharmaceutical combinations, compositions and Fixed Dose Combination (FDC) formulations comprising Glucokinase Activator (GKA) drugs and combination drugs, methods of preparation thereof and use thereof for the treatment of certain diseases.

in a more detailed aspect, the present invention relates to a pharmaceutical combination, a pharmaceutical composition or a fixed dose combination of a glucokinase activator drug and a combination drug, and a method for preparing the same. The present invention also relates to the use of a pharmaceutical combination, pharmaceutical composition or fixed dose combination 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, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, impaired glucose tolerance, impaired fasting glucose, obesity and hypertension. Furthermore, the present invention relates to a method for the treatment and/or prevention of one or more diseases and medical conditions, which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical combination, pharmaceutical composition or fixed dose combination according to the invention.

Background

Diabetes has become a worldwide common disease with a global population of 4.25 million patients, and chinese patients as high as 1.2 million (International Diabetes Federation, Diabetes Atlas, 2015). Type II diabetes, non-insulin dependent diabetes mellitus (NIDDM), accounts for over 90% of diabetics. Type II diabetes is a chronic metabolic dysfunction disease of hyperglycemia caused by imbalance of blood sugar homeostasis in a human body caused by insulin secretion disorder and insulin resistance. The blood sugar balance of human body is mainly coordinated by two sugar-controlling hormones of insulin and glucagon.

Glucose sensor Glucokinase (GK) senses blood sugar change, regulates and controls the secretion of messenger glucose control hormone, insulin, glucagon and GLP-1 (glucagon-like peptide-1), and forms a sensing system for regulating and controlling the blood sugar homeostasis of a human body. Glucose storage during glucose uptake and glucose supply during fasting controlled by glucose-controlling hormones constitute the regulation of the blood glucose homeostasis of the human body. The organs involved in glucose storage are mainly liver, muscle and fat, and glucose is taken up by blood glucose and insulin and converted into liver glycogen, muscle glycogen and triglyceride. The major organ involved in glucose supply is the liver, which supplies sugar to the body through hepatic glucose synthesis and hepatic glucose export under the action of blood glucose and glucagon. Insulin can also effectively regulate the activity of sodium-glucose cotransporter SGLT-2, and can reabsorb glucose excreted by the kidney when blood sugar rises, so that the insulin is used for storing human glucose. Glucose uptake and hepatic glucose output, as well as the use of glucose by various organs, constitute an operational system of homeostasis of blood glucose in the body. The glucose sensing system and the operation system cooperate to form random regulation and control of the blood sugar steady state of the human body.

In diabetic patients, glucose kinase function and expression are damaged, sensor dysfunction causes disorder of early phase secretion of glucose-controlling hormone, glucose uptake and output are affected, and postprandial hyperglycemia and preprandial hypoglycemia are caused. Abnormal signal instructions of the glucose-controlling hormone cause abnormal functions and expressions of key proteins in a glucose uptake and output operation execution system, and abnormal state operation is formed, so that type II diabetes is formed.

The existing oral hypoglycemic drugs for diabetes usually act on a single sugar control organ, and can not effectively treat the problem of imbalance of a blood sugar steady state balance system. Glucokinase activators represent a class of new drugs developed to treat or improve the disease state of patients with type II diabetes. For example, ((S) -2- [4- ((2-chloro-phenoxy) -2-oxo-2, 5-dihydro-pyrrol-1-yl ] -4-methyl-pentanoic acid [1- ((R) -2, 3-dihydroxy-propyl) -1H-pyrazol-3-yl ] -amide (hereinafter HMS5552) is an effective diabetes treatment drug that currently holds the greatest promise to address the above clinical needs.

disclosure of Invention

Diabetic patients often encounter such conditions in their treatment: the use of PPAR receptor activators alone is not therapeutically effective and does not control blood glucose to the desired level, especially after a period of use. In view of the above, the present inventors have found that the combination of a PPAR receptor activator and a glucokinase activator can significantly improve the hypoglycemic effect of the PPAR receptor activator and reduce the safety risk, thereby obtaining the pharmaceutical composition, composition and combination preparation containing the glucokinase activator and the PPAR receptor activator of the present invention.

more specifically, PPAR receptor activators and glucokinase activators in combination can improve the multi-organ function of patients in middle and late stages, and more effectively treat diabetes mellitus and accompanying diseases and complications; the number of the medicine taking grains of the patient can be reduced, and the compliance of the patient is improved; the total dosage of the medicine which achieves the same curative effect is reduced, the maximum drug effect is achieved by using the minimum dosage, and the medicine has good effect and practical significance for treating or preventing one or more symptoms of type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance, obesity and the like.

on the other hand, the fixed dose combination formulation of the present invention, which contains a glucokinase activator and a combination drug (second or more active pharmaceutical ingredients), not only has a better therapeutic effect than the single use of the two or more drugs, but also solves the technical challenges that are usually present in combination formulations. The fixed-dose compound preparation can solve the problems of synchronous release and uniform content of two or more active ingredients, can optimize the dissolution rate of the active ingredients contained in the preparation, particularly enables the active ingredients contained in the preparation to be quickly released in the pH environment of the small intestine, is beneficial to the fact that the medicine can reach target organs of intestinal tracts, pancreatic islets and livers in time or simultaneously, achieves the clinical advantages of one-target multi-point and cooperative blood sugar reduction, and plays the roles of better curative effect and toxic and side effect reduction. Secondly, the fixed-dose combination formulation of the present invention comprising a glucokinase activator and a combination drug (second or more active pharmaceutical ingredients) also has a shorter disintegration time and has good dissolution characteristics and/or enables a high bioavailability of the glucokinase activator in patients.

The invention provides a pharmaceutical combination, a pharmaceutical composition, a fixed dose combination, in particular a solid preparation, such as an oral solid preparation, such as a tablet,

In particular, the invention also provides a pharmaceutical combination, pharmaceutical composition or fixed dose combination comprising a glucokinase activator drug such as HMS5552 or a pharmaceutically acceptable salt thereof and a PPAR receptor activator. Examples of the PPAR receptor activator include rosiglitazone, pioglitazone, sitagliptar sodium (chiclitazar), and pharmaceutically acceptable salts thereof.

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

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

The invention also provides a pharmaceutical combination, pharmaceutical composition or fixed dose combination of a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients) prepared by a dry or wet processing method. The release profile of the pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of the invention is a rapid release of the two or more active pharmaceutical ingredients.

The invention also provides a pharmaceutical formulation comprising a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients) which has a short disintegration time, which has good dissolution characteristics and/or enables a high bioavailability of the glucokinase activator in a patient. The present invention also provides a process for the preparation of a pharmaceutical composition or pharmaceutical formulation of a fixed dose combination of a glucokinase activator drug and a combination drug (second active pharmaceutical ingredient or ingredients, such as rosiglitazone or pioglitazone) by a dry or wet processing method. The dry processing method comprises dry compression (tabletting) and dry granulation; the wet processing method includes wet granulation.

the invention also provides pharmaceutical combinations, pharmaceutical compositions or pharmaceutical formulations comprising a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients), as well as methods for preventing, slowing the progression of, delaying or treating a metabolic disorder, particularly type II diabetes.

The invention also provides a pharmaceutical combination, a pharmaceutical composition or a pharmaceutical formulation comprising a glucokinase activator drug and a combination drug (second or more active pharmaceutical ingredients), as well as a method for improving glycemic control in a patient in need thereof, especially a patient suffering from type II diabetes.

The invention also provides pharmaceutical combinations, pharmaceutical compositions or pharmaceutical formulations comprising glucokinase activator drugs and combinations, and methods of improving glycemic control in patients with inadequate glycemic control.

The invention also provides pharmaceutical combinations, pharmaceutical compositions or pharmaceutical formulations comprising a glucokinase activator drug and combinations, and methods for preventing, slowing or delaying the progression of Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), hypertension, insulin resistance and/or metabolic syndrome into type II diabetes.

The invention also provides pharmaceutical combinations, pharmaceutical compositions and pharmaceutical formulations comprising glucokinase activator drugs and combinations, and methods for preventing, slowing the progression of, delaying or treating diseases or conditions, including diabetic complications.

Other objects of the invention will become apparent to those skilled in the art from the context and examples.

drawings

FIG. 1 shows the effect of rosiglitazone alone and the combined administration of HMS5552 and rosiglitazone on blood glucose load in normal mice (II)n＝10)；

FIG. 2 is the AUC after glucose load in normal mice for rosiglitazone alone and for HMS5552 and rosiglitazone in combination_0-120minInfluence of (A), (B)n＝10；***，P<0.001)。

Detailed Description

One aspect of the invention relates to a pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation such as a fixed dose combination of a glucokinase activator, preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof, and a combination drug (e.g., rosiglitazone, pioglitazone). The formulation may be in the form of a powder, granule, tablet, capsule, sachet, or other solid form, and the like. In particular, one aspect of the invention relates to a tablet containing a fixed dose combination of a glucokinase activator and a combination drug (e.g., rosiglitazone, pioglitazone).

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

(1) a 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, the glucokinase activator is preferably HMS 5552; more preferably, the HMS5552 is present in the form of a solid dispersion, for example a solid dispersion comprising a polymeric carrier (e.g., a spray-dried powder);

(2) A PPAR receptor activator; preferably, it is selected from: rosiglitazone, pioglitazone, or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof; and/or

(3) A filler; and/or

(4) a binder; and/or

(5) A disintegrant; and/or

(6) a lubricant or glidant; and/or

(7) and (4) coating agent.

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

Pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation

glucokinase activator + PPAR receptor activator

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

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

(b) A PPAR receptor activator;

Preferably wherein the PPAR receptor activator is selected from rosiglitazone or rosiglitazone maleate, pioglitazone or pioglitazone hydrochloride and sitagliptin sodium;

(c) One or more excipients;

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

In one embodiment, the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation) has a weight ratio of glucokinase activator to PPAR receptor activator of about 50:1 to 1:10, preferably about 25:1 to 1:5, more preferably about 1:10, about 1:5, about 1:2, about 1.67:1, about 3.33:1, about 5:1, about 6.25:1, about 6.67:1, about 12.5:1, about 18.75:1 or about 25: 1.

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

In one embodiment, in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, the PPAR receptor activator is present in a dosage (preferably unit dosage) range of about 1mg to about 50mg, preferably about 4mg to about 15mg, preferably wherein the dosage (preferably unit dosage) of the PPAR receptor activator is about 1mg, about 2 mg, about 4mg, about 5mg, about 10mg, about 12 mg, about 14 mg or about 15mg, most preferably about 4mg or about 15 mg; preferably, the PPAR receptor activator is rosiglitazone or pioglitazone.

in one embodiment, in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the above glucokinase activator is compound HMS5552, or an isotopic label thereof, or a pharmaceutically acceptable salt thereof.

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

In one embodiment, the solid dispersion is obtained by spray drying, hot melt or freeze drying the glucokinase activator, or the isotopic label thereof, or the pharmaceutically acceptable salt thereof, together with a polymeric carrier.

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

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

In one embodiment, the above pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed dose combination formulation), the glucokinase activator is present as a solid dispersion, and the weight ratio of the solid dispersion of the glucokinase activator to the PPAR receptor activator is about 100:1 to 1:5, preferably about 50:1 to 2:5, more preferably about 1:5, about 2:5, about 1:1, about 3.33:1, about 6.67:1, about 10:1, about 12.5:1, about 13.3:1, about 25:1, about 37.5:1 or about 50: 1.

In one embodiment, in the above pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the glucokinase activator is compound HMS5552, an isotopic label thereof or a pharmaceutically acceptable salt thereof, which is mixed with a polymeric carrier to obtain a solid dispersion by spray drying, hot melting or freeze drying.

In one embodiment, in the pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination), the polymer carrier in the solid dispersion is selected from polypropylene resin polymers, which are high molecular compounds formed by polymerizing acrylic acid (or methacrylic acid and esters thereof such as methyl ester, ethyl ester and the like) in bulk (one monomer) or copolymerizing methacrylic acid (or esters thereof such as methyl ester, ethyl ester, dimethylaminoethyl ester and the like) with two monomers (binary) or three monomers (ternary) according to a certain ratio.

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

in one embodiment, the polymeric carrier is selected from the group consisting of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1) copolymers, methacrylic acid and ethyl acrylate (1:1) copolymers, methacrylic acid and methyl methacrylate (1:2) copolymers, ethyl acrylate, methyl methacrylate and chlorinated trimethyamino ethyl methacrylate (1:2:0.2) copolymers, ethyl acrylate, methyl methacrylate and chlorinated trimethyamino ethyl methacrylate (1:2:0.1) copolymers, ethyl acrylate and methyl methacrylate (2:1) copolymers, methacrylic acid and butyl acrylate (35:65) copolymers, methacrylic acid and methyl methacrylate (1:1) copolymers, methacrylic acid and methyl methacrylate (35:65) copolymers.

In one embodiment, the polymeric carrier is Eudragit (Eudragit), including Eudragit E, Eudragit L, Eudragit S, Eudragit RL and Eudragit RS, wherein Eudragit E is a copolymer of dimethylaminoethyl methacrylate and other neutral methacrylates, including polymers of dimethylaminoethyl methacrylate and methacrylates; eudragit L and Eudragit S are prepared by copolymerizing methacrylic acid and methacrylates with different proportions, and comprise methacrylic acid and methyl methacrylate copolymer, wherein the free carboxyl: 1:1, or methacrylic acid and methyl methacrylate copolymer, wherein the free carboxyl group: ester 1: 2; eudragit RL and Eudragit RS types are copolymers of acrylic acid and methacrylic acid esters containing certain quaternary amine genes, including copolymers of acrylic acid and methacrylic acid esters containing 10% quaternary amine groups and copolymers of acrylic acid and methacrylic acid esters containing 5% quaternary amine groups.

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

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

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

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

In one embodiment, in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the polymer carrier in the HMS5552 solid dispersion is methacrylic acid copolymer type a (an anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)), preferably Eudragit, more preferably Eudragit l 100.

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

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

in one embodiment, in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed dose combination formulation), the second active ingredient is rosiglitazone (or rosiglitazone maleate). In the pharmaceutical combination, pharmaceutical composition or fixed dose compound preparation of the glucokinase activator (HMS5552 or the isotopic label or the pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate), the glucokinase activator (preferably HMS5552 or the isotopic label or the pharmaceutically acceptable salt thereof) is contained by about 1-98% by weight; about 0.1-25% rosiglitazone or rosiglitazone maleate; about 0% to about 90% of a filler; about 1-25% binder; about 0-15% of a disintegrant; about 0.1-10% of a lubricant; about 0-3% of a glidant; and about 0-5% of a coating agent. The pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose combination, is prepared by a wet granulation method or a dry granulation method, preferably by a wet granulation method.

in one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination) of the glucokinase activator (HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate) described above, the dose (preferably the unit dose) of the glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof) is from about 1mg to about 200 mg. Preferred dosages (preferably unit dosages) of glucokinase activator are from about 5mg to 100 mg. Preferably, the dose (preferably unit dose) of glucokinase activator is about 5mg, about 10mg, about 20mg, about 25mg, about 30mg, about 40 mg, about 50mg, about 60 mg, about 75mg, about 80 mg, about 90 mg, about 100mg, or any range therebetween. More preferred doses (preferably unit doses) of glucokinase activator (preferably HMS5552 or an isotopic label or pharmaceutically acceptable salt thereof) are about 25mg, about 50mg, about 75mg, about 100 mg. Preferably, in the pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the HMS5552 is in the form of a solid dispersion.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination) of the glucokinase activator (HMS5552 or an isotopically labeled or pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate) described above has a dosage (preferably a unit dosage) of about 2 mg to about 8 mg, preferably a dosage (preferably a unit dosage) of about 2 mg, about 4mg and about 8 mg, calculated as the content of rosiglitazone. Preferably, in the pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the HMS5552 is in the form of a solid dispersion.

in the pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of the present invention, specific embodiments of the doses (preferably unit doses) of HMS5552 and rosiglitazone (or rosiglitazone maleate) are as follows:

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

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

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

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

Preferably, in the pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the HMS5552 is in the form of a solid dispersion.

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

in one embodiment, the above tablet is a fixed dose compound tablet of glucokinase activator (HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof) and rosiglitazone (or rosiglitazone maleate).

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 25mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/4 mg rosiglitazone (or rosiglitazone maleate in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 25mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 4mg rosiglitazone (or rosiglitazone maleate in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.5% to about 3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 50mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/4 mg rosiglitazone (or rosiglitazone maleate in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 50mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 4mg rosiglitazone (or rosiglitazone maleate in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.5% to about 3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

in one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 75mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/4 mg rosiglitazone (or rosiglitazone maleate in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 75mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 4mg rosiglitazone (or rosiglitazone maleate in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.5% to about 3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 100mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/4 mg rosiglitazone (or rosiglitazone maleate in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 100mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 4mg rosiglitazone (or rosiglitazone maleate in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.5% to about 3% of a lubricant; about 0-0.5% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

In one embodiment, in the above pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the second active ingredient is pioglitazone (or pioglitazone hydrochloride). The pharmaceutical composition, pharmaceutical composition or fixed dose compound preparation of the glucokinase activator (HMS5552 or the isotopic label or the pharmaceutically acceptable salt thereof) and the pioglitazone (or the pioglitazone hydrochloride) comprises about 1-85% by weight of the glucokinase activator (preferably HMS5552 or the isotopic label or the pharmaceutically acceptable salt thereof); about 0.1-25% pioglitazone (or pioglitazone hydrochloride); about 0% to about 90% of a filler; about 1-25% binder; about 0-15% of a disintegrant; about 0.1-10% of a lubricant; about 0-3% of a glidant; and about 0-5% of a coating agent. The pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose combination, is prepared by a wet granulation method or a dry granulation method, preferably by a wet granulation method.

In one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination) of the glucokinase activator (HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof) and pioglitazone (or pioglitazone hydrochloride) described above, the dose (preferably unit dose) of the glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof) is about 1mg to 200 mg. Preferred dosages (preferably unit dosages) of glucokinase activator are from about 5mg to 100 mg. Preferably, the dose (preferably unit dose) of glucokinase activator is about 5mg, about 10mg, about 20mg, about 25mg, about 30mg, about 40 mg, about 50mg, about 60 mg, about 75mg, about 80 mg, about 90 mg, about 100mg, or any range therebetween. More preferred doses (preferably unit doses) of glucokinase activator (preferably HMS5552 or an isotopic label or pharmaceutically acceptable salt thereof) are about 25mg, about 50mg, about 75mg, about 100 mg. Preferably, in the pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the HMS5552 is in the form of a solid dispersion.

in one embodiment, in the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination) of the glucokinase activator (HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof) and pioglitazone (or pioglitazone hydrochloride) described above, the dose (preferably unit dose) thereof is about 15mg to about 45 mg, and the dose (preferably unit dose) thereof is preferably about 15mg, about 30mg and about 45 mg, calculated on the content of pioglitazone. Preferably, in the pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the HMS5552 is in the form of a solid dispersion.

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

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

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

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

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

preferably, in the pharmaceutical composition, pharmaceutical composition or pharmaceutical preparation (preferably a fixed dose combination preparation), the HMS5552 is in the form of a solid dispersion

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

In one embodiment, the tablet is a fixed dose compound tablet of glucokinase activator (HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof) and pioglitazone (or pioglitazone hydrochloride).

in one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 25mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/15 mg pioglitazone (or pioglitazone hydrochloride in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 25mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 15mg of pioglitazone (or pioglitazone hydrochloride in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.1-10% of a lubricant; about 0-3% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 50mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/15 mg pioglitazone (or pioglitazone hydrochloride in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 50mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 15mg of pioglitazone (or pioglitazone hydrochloride in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.1-10% of a lubricant; about 0-3% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

in one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 75mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/15 mg pioglitazone (or pioglitazone hydrochloride in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 75mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 15mg of pioglitazone (or pioglitazone hydrochloride in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.1-10% of a lubricant; about 0-3% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation, preferably a fixed dose compound tablet, which is a tablet of 100mg glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof)/15 mg pioglitazone (or pioglitazone hydrochloride in an amount such that the dose is obtainable), comprises the following amounts of the respective components by weight: about 100mg of glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof); about 15mg of pioglitazone (or pioglitazone hydrochloride in an amount such that this dose is available); about 0% to about 75% of an optional filler; about 2-8% binder; about 1-15% of a disintegrant; about 0.1-10% of a lubricant; about 0-3% of a glidant and about 0-5% of a coating agent; preferably, the glucokinase activator is in the form of a solid dispersion as described above, preferably the solid dispersion comprises the glucokinase activator and a polymeric carrier, preferably about 1:1 glucokinase activator and Eudragit L100.

in one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed dose combination) as described above further comprises other excipients, wherein the other excipients include, but are not limited to, one or a mixture of diluents, flavoring agents (flavors), sweeteners and colorants.

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

examples of preferred fillers (diluents) include microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose, mannitol, sorbitol, monocalcium phosphate (dihydrate), corn starch, pregelatinized starch, and powdered cellulose. More preferred fillers (diluents) are microcrystalline cellulose, silicified microcrystalline cellulose. Microcrystalline cellulose is available from several suppliers, including Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH105, and Avicel PH 200 manufactured by FMC Corporation.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed dose combination formulation) of the invention comprises optionally one or more binders. Examples include, but are not limited to, carboxymethylcellulose (including sodium carboxymethylcellulose), hydroxypropylcellulose (including hydroxypropylcellulose EXF), corn starch, pregelatinized starch, modified corn starch, polyvinylpyrrolidone (PVP), Hydroxypropylmethylcellulose (HPMC) (including hydroxypropylmethylcellulose 2208), lactose, sucrose, acacia, ethylcellulose, cellulose acetate, and wax binders such as carnauba wax, paraffin wax, spermaceti, polyethylene or microcrystalline wax, and other conventional binders and/or mixtures of two or more thereof. Further, in addition to the above binders, binders suitable for use in the present invention include, but are not limited to, alginic acid, microcrystalline cellulose, dextrin, gelatin, pullulan, liquid glucose, guar gum, methyl cellulose, polyethylene oxide, povidone, and syrup, and combinations thereof.

preferred embodiments of the binder include hydroxypropyl cellulose (HPC), Hydroxypropyl Methylcellulose (HMPC), polyvinylpyrrolidone (povidone), hydroxyethyl cellulose, starch 1500, and copovidone. More preferred binders are hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed dose combination formulation) of the invention comprises optionally one or more disintegrants. Examples of disintegrants suitable for use in the 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.

In one embodiment, the disintegrant is selected from one or more of modified starch, modified cellulose polymer, or polycarboxylic acid, in particular from croscarmellose sodium, crospovidone, sodium starch glycolate, polacrilin potassium, and carboxymethylcellulose Calcium (CMC Calcium). In one embodiment, the disintegrant is crospovidone. In another embodiment, the disintegrant is sodium starch glycolate. In another embodiment, the disintegrant is croscarmellose sodium. Croscarmellose sodium NF type A is commercially available under the trade designation "Ac-di-sol".

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

In one embodiment, 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 stearyl fumarate, or mixtures thereof.

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

in one embodiment, an embodiment of a glidant includes colloidal silicon dioxide, calcium phosphate, magnesium silicate, and talc, or mixtures thereof. A preferred glidant is colloidal silicon dioxide.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation (preferably a fixed dose combination formulation) of the invention may also optionally contain one or more surfactants or wetting agents. The surfactant may be an anionic, cationic or neutral surfactant. Anionic surfactants include sodium lauryl sulfate, sodium dodecyl sulfate, sodium oleyl sulfate and sodium laurate mixed with stearate and talc. Cationic surfactants include benzalkonium chloride and alkyltrimethylammonium bromide. Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, and sorbitan esters. Embodiments of wetting agents include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene stearates.

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

In one embodiment, the antioxidant is selected from the group consisting of alpha-tocopherol, gamma-tocopherol, delta-tocopherol, a natural source extract enriched in tocopherols, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, Butylated Hydroxytoluene (BHT) and Butylated Hydroxyanisole (BHA). In one embodiment, the antioxidant is BHT or BHA.

In one embodiment, a preferred formulation of the fixed-dose combination of the present invention is a tablet prepared by a compression method. The tablet may be coated, and preferable examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base and the like.

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

examples of water-soluble film coating substrates include cellulosic polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, and the like; examples of the synthetic polymer include polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E [ eudragit E (trade name) ], polyvinylpyrrolidone, and the like.

Examples of enteric film coating substrates include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, and the like; examples of the acrylic acid polymer include 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) ], and the like.

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

In one embodiment, the tablets may be coated, for example, with a mixture of hydroxypropyl cellulose and hydroxypropyl methylcellulose containing titanium dioxide and/or other coloring agents, such as iron oxide, dyes, and lakes; a mixture of polyvinyl alcohol (PVA) and polyethylene glycol (PEG); or any other suitable immediate release coating. The coating provides taste masking and additional stability to the final tablet. A commercially available coating material is provided by Colorcon as an opadry of a pre-formulated powder mix Such as opadry 03K 12429.

In one embodiment, the pharmaceutical combination, pharmaceutical composition or pharmaceutical formulation of the invention (preferably a fixed dose combination formulation) may also contain sweetening and/or flavouring agents as required.

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

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

in one embodiment, the binder is polyvinylpyrrolidone, the filler is microcrystalline cellulose or silicified microcrystalline cellulose, the disintegrant is croscarmellose sodium or crospovidone, and the lubricant is magnesium stearate or sodium stearyl fumarate, and the glidant is colloidal silicon dioxide.

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

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

in one embodiment, the binder is polyvinylpyrrolidone, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

Preparation method

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

(1) adding the active pharmaceutical ingredients glucokinase activator (preferably HMS5552) and the combination drug (preferably rosiglitazone or pioglitazone) to a granulator;

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

(3) Adding an optional disintegrant (e.g., croscarmellose sodium, crospovidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);

(4) for high shear granulation, a binder (e.g., hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methylcellulose) is added to purified water to make a binder solution, which is then added to a granulator for granulation with stirring. For fluidized bed granulation, two active pharmaceutical ingredients are added into a fluidized bed, and a binder solution is sprayed by compressed air, wherein the binder solution is an aqueous solution prepared from a binder and pure water;

(5) Granulating the obtained wet granules by a proper granulator to obtain wet granules with proper size;

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

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

(8) mixing the dry granules with an optional filler (diluent, e.g. microcrystalline cellulose) and an optional disintegrant (e.g. croscarmellose sodium) in a suitable mixer;

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

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

(11) Filling the lubricated granular mixture of step (9) or (10) into a vial, sachet or capsule or compressing into a desired tablet shape; and

(12) Optionally, the resulting tablets are film coated.

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

(1) Adding an active pharmaceutical ingredient glucokinase activator (preferably HMS5552) to the granulator;

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

(3) Adding an optional disintegrant (e.g., croscarmellose sodium, crospovidone, sodium starch glycolate) to the mixture obtained in step (1) or (2);

(4) For high shear granulation, a binder (e.g., hydroxypropyl cellulose or polyvinylpyrrolidone or hydroxypropyl methylcellulose) is added to a solvent and uniformly dispersed or dissolved, followed by the addition of a prescribed amount of a second active ingredient (preferably rosiglitazone or pioglitazone) to disperse or dissolve and formulate a uniform binder system. The system is added into a granulator for stirring and granulation. For fluid bed granulation, an active pharmaceutical ingredient such as HMS5552 is added to the fluid bed and the binder system is sprayed by compressed air, the binder solution being a solution or suspension of the binder and pure water or an organic solvent (e.g. ethanol);

(5) Granulating the obtained wet granules in a proper granulator to obtain wet granules with proper size;

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

(7) Granulating on a suitable grinder to obtain dry granules with a suitable size;

(8) Mixing the dry granules with an optional filler (diluent, e.g. microcrystalline cellulose) and an optional disintegrant (e.g. croscarmellose sodium) in a suitable mixer;

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

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

(11) Filling the lubricated granular mixture of (9) or (10) into a vial, sachet, or capsule or compressing into a desired tablet shape; and

(12) optionally, the resulting tablets are film coated.

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

(1) Adding the active pharmaceutical ingredients glucokinase activator (preferably HMS5552) and the combination drug (preferably rosiglitazone or pioglitazone) to a mixing tank;

(2) Adding optional fillers (e.g. microcrystalline cellulose, silicified microcrystalline cellulose, lactose) to step (1);

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

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

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

(6) If the mixture is processed by a roller compressor, the mixture in the step (3) is mixed in advance, and then roller compaction is carried out; if necessary, the granules can be sized on a suitable mill to give granules of the desired size;

(7) Optional diluent may be added to the granules obtained in step (6) in a suitable mixer to improve compressibility;

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

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

(10) Filling the lubricated granule mixture of (9) or (10) into a vial, sachet or capsule or compressing into a desired tablet shape; and

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

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

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

(1) Preparing a spray-dried solution comprising dissolving a polymeric carrier and a glucokinase activator (preferably HMS5552) in a solvent;

(2) Spray drying, controlling the temperature of inlet air, the quantity of inlet air, the flow rate and pressure of atomized air flow, and the spraying speed of solution.

Solvents used in the preparation of the solid dispersion of glucokinase activator in the present embodiment include, but are not limited to, alkanols, esters, nitriles, cycloalkanes, aromatics, ketones, and the like. In particular, the solvent is selected from the following solvents: absolute ethyl alcohol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene and toluene. The solvent can be a single solvent, a mixed solvent or a mixture of an organic solvent and water.

Methods and uses for treating and/or preventing diseases

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

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

-improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1 c; or

-preventing, slowing, delaying or reversing impaired glucose tolerance, insulin resistance and/or the progression of the metabolic syndrome into type II diabetes; or

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

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

-preventing, slowing, delaying or treating degeneration of pancreatic beta cells and/or a reduction of pancreatic beta cell function, and/or improving and/or restoring or protecting pancreatic beta cell function and/or restoring pancreatic insulin secretion function; or

-preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of liver or ectopic fat; or

-maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance; or

-preventing, slowing the progression of, delaying or treating Newly Onset Diabetes After Transplantation (NODAT) and/or post-transplant metabolic syndrome (PTMS); or-preventing, delaying or reducing NODAT and/or PTMS-associated complications, including microvascular and macrovascular diseases and events, transplant rejection, infections and death; or

-treating hyperuricemia and hyperuricemia-related disorders; or

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

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

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

embodiment I Glucokinase activator + PPAR receptor activator (e.g., rosiglitazone)

Scheme 1. a pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation comprising:

(a) 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 enantiomeric form thereof,

(b) a PPAR receptor activator;

(c) One or more excipients;

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

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

scheme 3. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 1 or 2, wherein the glucokinase activator is about 1-98% by weight; the PPAR receptor activator is about 0.1-25% by weight.

Scheme 4. the pharmaceutical combination, pharmaceutical composition or fixed dose combination according to any of the schemes 1 to 3, wherein the glucokinase activator is the compound HMS5552 represented by the following formula or a pharmaceutically acceptable salt thereof, an isotopic label, a crystalline form, a hydrate, a solvate, a diastereomer or an enantiomeric form thereof,

scheme 5. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of any one of schemes 1 to 4, wherein the glucokinase activator is in the form of a solid dispersion.

Scheme 6. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 5, wherein the glucokinase activator is in the form of a solid dispersion comprising a polymeric carrier which is methacrylic acid copolymer type a (an anionic copolymer of methacrylic acid and methyl methacrylate (1: 1)), preferably Eudragit, more preferably Eudragit L100.

Scheme 7. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 6, wherein the weight ratio of glucokinase activator to polymeric carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6 or any range therebetween.

Scheme 8. the pharmaceutical combination, pharmaceutical composition or fixed dose combination according to any one of schemes 1 to 7, wherein the PPAR receptor activator is selected from rosiglitazone (or rosiglitazone maleate), pioglitazone (or pioglitazone hydrochloride), sitagliptin sodium and pharmaceutically acceptable salts thereof.

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

scheme 10. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of any one of schemes 1 to 9, wherein the PPAR receptor activator is present in a dosage (preferably unit dose) range of about 1mg to about 50mg, preferably about 4mg to about 15mg, preferably wherein the dosage (preferably unit dose) of the PPAR receptor activator is about 1mg, about 2 mg, about 4mg, about 5mg, about 10mg, about 12 mg, about 14 mg or about 15mg, most preferably about 4mg or about 15 mg; preferably, the PPAR receptor activator is rosiglitazone or pioglitazone.

Scheme 11. the pharmaceutical combination, pharmaceutical composition or fixed dose combination according to any of schemes 1 to 10, wherein the one or more excipients are selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweeteners, colorants or coating agents.

Scheme 12. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of any one of schemes 1 to 11, which is a tablet.

Scheme 13. the pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of scheme 12, which is a coated tablet.

Scheme 14. the pharmaceutical combination, pharmaceutical composition or fixed dose combination formulation of scheme 13, wherein the coated tablet is a film coated tablet comprising:

Film coating bases such as hypromellose, hydroxypropyl methylcellulose, or mixtures thereof;

Optionally a plasticizer, such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate or mixtures thereof;

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

optionally an opacifying agent, such as titanium dioxide, and

Optionally a glidant.

scheme 15. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 14, wherein the coated tablet is a film coated tablet and the film coated tablet is opadry.

Scheme 16. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of any one of schemes 1 to 15, comprising by weight:

About 1-98% glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion comprising HMS5552 and a polymeric carrier, preferably a solid dispersion comprising HMS5552 and eudragit l100 at a ratio of about 1: 1;

About 0.1% to about 25% rosiglitazone;

About 0% to about 90% of a filler;

About 1-25% binder;

About 0-15% of a disintegrant;

about 0.1-10% of a lubricant;

About 0-3% of a glidant; and

about 0% to about 5% of a coating agent.

Scheme 17. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 16, which comprises by weight

about 1-75% glucokinase activator (preferably HMS5552 or an isotopic label or a pharmaceutically acceptable salt thereof), preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion comprising HMS5552 and a polymeric carrier, preferably a solid dispersion comprising HMS5552 and Eudragit L100 at a ratio of about 1: 1;

About 0.1% to about 15% rosiglitazone;

about 0% to about 90% of a filler;

About 1-10% of a binder;

About 1-10% of a disintegrant;

About 0.1-5% of a lubricant;

About 0-3% of a glidant; and

About 0% to about 5% of a coating agent.

scheme 18. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 16, the dose (preferably unit dose) of the active ingredients is by weight:

about 25mg, about 50mg, about 75mg or about 100mg of glucokinase activator, preferably HMS 5552;

About 2 mg, about 4mg, and about 8 mg of rosiglitazone;

About 0% to about 90% of a filler;

about 1-25% binder;

about 0-15% of a disintegrant;

about 0.1-10% of a lubricant;

About 0-3% of a glidant; and

About 0% to about 5% of a coating agent.

scheme 19. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18 (preferably a tablet of 25mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate), comprising the following amounts of the components by weight:

-about 25mg of HMS555, preferably a solid dispersion of HMS5552, preferably a solid dispersion comprising HMS5552 and a polymeric carrier, preferably a solid dispersion 2 comprising about 1:1 of HMS5552 and Eudragit L100;

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

Scheme 20. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18 (preferably a tablet of 50mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate), comprising the following amounts of the components by weight:

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

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

scheme 21. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18 (preferably a tablet of 75mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate), comprising the following amounts of the components by weight:

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

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

scheme 22. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18 (preferably a tablet of 100mg HMS5552/4mg rosiglitazone or a corresponding amount of rosiglitazone maleate), comprising the following amounts of the components by weight:

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

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

-about 0-75% of a filler;

-about 2-8% binder;

-about 1-5% of a disintegrant;

-about 0.5-3% of a lubricant;

-about 0-0.5% of a glidant; and

-from about 0% to about 5% of a coating agent.

Scheme 23. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18, comprising about 50mg of a solid dispersion, about 5.30mg of rosiglitazone maleate, about 177.20mg of microcrystalline cellulose, about 7.50mg of hydroxypropyl cellulose, about 7.50mg of croscarmellose sodium, about 2.50mg of magnesium stearate and about 7.50mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 25mg of HMS 5552.

Scheme 24. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18, comprising about 100mg of a solid dispersion, about 5.30mg of rosiglitazone maleate, about 127.20mg of microcrystalline cellulose, about 7.50mg of hydroxypropyl cellulose, about 7.50mg of croscarmellose sodium, about 2.50mg of magnesium stearate and about 7.50mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 50mg of HMS 5552.

Scheme 25. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18, comprising about 150mg of a solid dispersion, about 5.30mg of rosiglitazone maleate, about 123.70mg of microcrystalline cellulose, about 9.00mg of hydroxypropyl cellulose, about 9.00mg of croscarmellose sodium, about 3.00mg of magnesium stearate and about 9.00mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 75mg of HMS 5552.

Scheme 26. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18, comprising about 200mg of a solid dispersion, about 5.30mg of rosiglitazone maleate, about 63.09mg of microcrystalline cellulose, about 9.00mg of hydroxypropyl cellulose, about 9.00mg of croscarmellose sodium, about 3.00mg of magnesium stearate and about 9.00mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 100mg of HMS 5552.

scheme 27. the pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 18, comprising about 50mg of a solid dispersion, about 5.30mg of rosiglitazone maleate, about 177.20mg of microcrystalline cellulose, about 7.50mg of polyvinylpyrrolidone, about 7.50mg of croscarmellose sodium, about 2.50mg of magnesium stearate and about 7.50mg of opadry, wherein the solid dispersion comprises about 1:1 of HMS5552 and Eudragit L100, and comprises about 25mg of HMS 5552.

scheme 28. a method of pharmaceutical combination, pharmaceutical composition or fixed dose combination of any of schemes 1-27, which method comprises granulating the active ingredient with one or more excipients, preferably further filling the resulting granulated mixture into vials, sachets or capsules or compressing into the desired tablet shape; more preferably, the resulting tablets are further coated.

scheme 29. the method of preparing a pharmaceutical combination, pharmaceutical composition or fixed dose combination of scheme 28, wherein the preparation is by wet granulation (high shear and/or fluidized bed) or by dry processing (direct compression or dry granulation).

scheme 30. the method of preparing a pharmaceutical combination, a pharmaceutical composition or a fixed dose combination of any of schemes 28-29, wherein the glucokinase activator is prepared in the form of a solid dispersion.

Scheme 31. the method of preparing a pharmaceutical combination, pharmaceutical composition or fixed dose combination of any of schemes 28-30, wherein the glucokinase activator and the second or more active ingredients can also be prepared together in the form of a combination solid dispersion (i.e., a solid dispersion containing 2 or more active ingredients).

Scheme 32. the pharmaceutical combination, pharmaceutical composition or fixed dose combination according to any of schemes 1 to 27 for use in preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1 c; or preventing, slowing, delaying or reversing diabetic complications.

scheme 33. a method of preventing, slowing the progression of, delaying or treating one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1 c; or preventing, slowing, delaying or reversing diabetic complications, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination, pharmaceutical composition or fixed dose combination according to any one of schemes 1-27.

scheme 34 use of a pharmaceutical combination, pharmaceutical composition or fixed dose combination according to any one of schemes 1 to 27 in the manufacture of a medicament for the prevention, slowing of progression, delaying or treatment of one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance and/or metabolic syndrome; or improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1 c.