Pharmaceutical composition of GLP-1r agonist and empagliflozin and use

Abstract

A combined pharmaceutical composition and a formulated pharmaceutical composition comprising empagliflozin or a pharmaceutically acceptable salt thereof and a small molecule GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof, and use of the compositions in the treatment of metabolic diseases and / or kidney diseases.

Description

Pharmaceutical compositions and uses of GLP-1R agonists and empagliflozin TECHNICAL FIELD

[0001] The present application relates to the field of biopharmaceuticals, in particular to a pharmaceutical composition of a small molecule GLP-1 receptor agonist (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin, and uses thereof in the treatment or prevention of diabetes and kidney disease. BACKGROUND

[0002] Type II diabetes mellitus is a common chronic progressive disease caused by a complex pathophysiology involving both insulin resistance and impaired insulin secretion. Treatment of type II diabetes mellitus usually starts with diet and exercise, followed by monotherapy with oral hypoglycemic agents. With monotherapy, some subjects can achieve glycemic control initially, but there is a secondary failure, and thus multiple drugs are required for treatment. Especially in the case of long-term treatment, even some subjects who respond well in the initial period of conventional therapy can eventually require dose escalation or the use of insulin. Although existing combination therapies have the efficacy of enhancing glycemic control, there is still a lack of long-term effectiveness and a risk of long-term side effects (such as weight gain or hypoglycemia).

[0003] In addition, complications or chronic damage associated with long-term hyperglycemia, such as diabetic nephropathy, retinopathy, neuropathy, etc., can be seen in type II diabetes mellitus subjects. There is still a need in the art to provide effective, safe, and tolerable anti-diabetic drug therapy.

[0004] The pathogenesis of chronic kidney disease (CKD) is complex and diverse, and secondary CKD is common in patients with diabetes and hypertension. Diseases that cause chronic kidney disease include various primary and secondary glomerulonephritis, renal tubular damage, and renal vascular lesions. Early detection and early intervention can significantly reduce the complications of CKD patients and significantly improve survival.

[0005] WO2022268152A1 discloses small molecule compounds as glucagon-like peptide-1 (GLP-1) receptor agonists, including Compound 1 having the following structural formula, (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof:

[0006] WO2024 / 125446 discloses a hydrochloride salt, a methanesulfonic acid salt, a meglumine salt and a tris(hydroxymethyl)aminomethane salt of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and a method for preparing the same. SUMMARY

[0007] The present application provides a combination of a small molecule GLP-1 receptor (GLP-1R) agonist and empagliflozin, which can improve glycemic control in a subject in need thereof, and also can reduce the risk of kidney disease-related diseases in a subject in need thereof.

[0008] In some embodiments, the small molecule GLP-1R agonist is (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0009] In the present application, (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and "Compound 1" are used interchangeably.

[0010] Combination pharmaceutical composition

[0011] The present inventors have shown that Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin in combination therapy for diabetes and diabetic nephropathy produce a better therapeutic effect in reducing blood glucose levels and improving kidney function and kidney tissue lesions (e.g., glomerular injury and kidney inflammation) than when either of the two pharmaceutically active ingredients is administered alone, showing a synergistic effect.

[0012] In one aspect, the present application provides a combination pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin.

[0013] In another aspect, the present application provides a combination pharmaceutical composition for treating or preventing metabolic or kidney-related diseases, comprising a GLP-1R agonist Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin.

[0014] In another aspect, the present application provides a method for treating or preventing metabolic or kidney-related diseases, comprising administering the above combination pharmaceutical composition to a subject in need thereof.

[0015] In another aspect, the present application provides a method of administration, which comprises administering the above-mentioned combination pharmaceutical composition to a subject in need thereof.

[0016] The metabolic or renal diseases described in the present application include, but are not limited to, diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, hyperuricemia, chronic kidney disease, kidney injury, chronic renal failure, hypertensive nephropathy.

[0017] The chronic kidney disease (CKD) described in the present application refers to abnormality of kidney structure or function caused by various reasons for ≥3 months, including appearance of kidney injury markers such as albuminuria, abnormal urine sediment, tubular related lesions, abnormal histological examination and abnormal imaging examination, or history of kidney transplantation, with or without decrease of glomerular filtration rate (GFR), or decrease of GFR (<60 ml / min) for ≥3 months without known reason. Among them, the chronic kidney disease can be clinically divided into 5 stages according to glomerular filtration rate (GFR).

[0018] In some embodiments, the compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin in the combination pharmaceutical composition are present in the same pharmaceutical composition.

[0019] In some embodiments of the present application, the compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin in the combination pharmaceutical composition are packaged in the same kit, and the kit further comprises instructions for using the compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin in combination to treat or prevent metabolic or renal diseases.

[0020] In some embodiments of the present application, the compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin in the combination pharmaceutical composition are each in the form of a pharmaceutical composition, wherein the pharmaceutical composition of the compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin can be administered simultaneously, sequentially or at intervals.

[0021] In some embodiments of the present application, the combination pharmaceutical composition comprises a pharmaceutical composition of the compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of empagliflozin.

[0022] In some embodiments, the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin in the combination pharmaceutical composition are formulated as a single pharmaceutical composition. In some embodiments, the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are mixed uniformly together. In some embodiments, the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are formulated into a multi-layer structure (e.g., a bilayer or more, in particular, a bilayer tablet or a multi-layer tablet), wherein each layer in the multi-layer structure is prepared from one of the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin, and the adjacent layer prepared from the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin directly contact, or are separated by an intervening layer, wherein the intervening layer comprises a pharmaceutically acceptable excipient or adjuvant, and comprises or does not comprise an active ingredient selected from Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin.

[0023] In some embodiments of the present application, the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin in the combination pharmaceutical composition are packaged in the same kit, which further comprises instructions for using the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin in combination to treat or prevent metabolic or renal diseases.

[0024] In some embodiments of the present application, the pharmaceutically acceptable salt of Compound 1 is selected from the group consisting of a mesylate salt, a meglumine salt and a tromethamine salt. The mesylate salt, the meglumine salt and the tromethamine salt are described in, for example, WO2024 / 125446.

[0025] In some embodiments of the present application, the pharmaceutically acceptable salt of Compound 1 is a tromethamine salt. In the present application, (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid · tromethamine salt is used interchangeably with Compound 1 · tromethamine salt.

[0026] In some embodiments of the present application, the combination pharmaceutical composition contains 10-600 mg, 20-400 mg, 25-300 mg, 50-250 mg, 75-200 mg or 100-150 mg of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in terms of Compound 1.

[0027] In some embodiments, the combination pharmaceutical composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as Compound 1. In some embodiments of the application, the combination pharmaceutical composition contains 50 mg, 100 mg, 200 mg, 400 mg, or 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as Compound 1.

[0028] In some embodiments of the application, in the combination pharmaceutical composition, the Compound 1, or a pharmaceutically acceptable salt thereof, is in a single dose or multiple doses.

[0029] In some embodiments of the application, in the combination pharmaceutical composition, the Compound 1, or a pharmaceutically acceptable salt thereof, is in a single dose or multiple doses.

[0030] In some preferred embodiments of the application, the combination pharmaceutical composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as Compound 1.

[0031] In some preferred embodiments of the application, the combination pharmaceutical composition contains 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Alternatively, the combination pharmaceutical composition is in a single administration preparation, each dose being a single dose or multiple doses, the combination pharmaceutical composition containing 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as Compound 1.

[0032] In some embodiments of the application, the combination pharmaceutical composition contains 2.5-50 mg, 5-25 mg, 10-20 mg, or 12.5-15 mg of empagliflozin, or a pharmaceutical composition thereof. Alternatively, the combination pharmaceutical composition is in a single administration preparation, the combination pharmaceutical composition containing 2.5-50 mg, 5-25 mg, 10-20 mg, or 12.5-15 mg of empagliflozin, or a pharmaceutical composition thereof.

[0033] In some embodiments of the invention, the combination drug composition contains 5 mg, 10 mg, 12.5 mg, or 25 mg of empagliflozin, or a drug composition thereof. Alternatively, the combination drug composition is in the form of a single-dose formulation containing 5 mg, 10 mg, 12.5 mg, or 25 mg of empagliflozin, or a drug composition thereof.

[0034] In some embodiments of the present invention, the empagliflozin pharmaceutical composition is in a single-dose or multiple-dose form in the combined drug composition.

[0035] In some embodiments of the present invention, the empagliflozin drug composition is a daily dose, wherein the daily dose is selected from a once-daily dose or a twice-daily dose.

[0036] In some embodiments, the combination drug composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 600 mg of compound 1 or a pharmaceutically acceptable salt thereof; and 5 mg, 10 mg, 12.5 mg or 25 mg of empagliflozin.

[0037] In some embodiments of the invention, the combination drug composition contains 100 mg, 200 mg, 300 mg, 400 mg or 600 mg of compound 1 or a pharmaceutically acceptable salt thereof; and 5 mg, 10 mg, 12.5 mg or 25 mg of empagliflozin.

[0038] In some embodiments, the combination drug composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg or 400 mg of compound 1 or a pharmaceutically acceptable salt thereof; and 10 mg of empagliflozin.

[0039] In some embodiments, the combination drug composition contains 50 mg, 100 mg, 150 mg or 200 mg of compound 1 or a pharmaceutically acceptable salt thereof, and 10 mg of empagliflozin.

[0040] In some embodiments, the combination drug composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250, 300 mg or 400 mg of compound 1 or a pharmaceutically acceptable salt thereof; and 12.5 mg of empagliflozin.

[0041] In some embodiments, the pharmaceutical combination composition contains 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as Compound 1; and contains 12.5 mg of empagliflozin.

[0042] In some embodiments, the pharmaceutical combination composition contains 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as Compound 1; and contains 25 mg of empagliflozin.

[0043] In some embodiments, the pharmaceutical combination composition contains 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as Compound 1; and contains 25 mg of empagliflozin.

[0044] In some embodiments of the present application, in the pharmaceutical combination composition, the pharmaceutical combination composition contains Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and empagliflozin, or a pharmaceutical composition thereof, in a mass ratio of 1:1 to 100:1, 1.5:1 to 75:1, 2:1 to 60:1, 2.5:1 to 50:1, 3:1 to 40:1, 4:1 to 30:1, 5:1 to 25:1, 6:1 to 20:1, 8:1 to 15:1, 10:1 to 12:1, or any ratio within the above ranges, wherein the Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is calculated based on the mass of Compound 1, and the empagliflozin, or a pharmaceutical composition thereof, is calculated based on the mass of empagliflozin.

[0045] In some embodiments, in the pharmaceutical combination composition, the pharmaceutical combination composition contains Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and empagliflozin, or a pharmaceutical composition thereof, in a mass ratio of 4:1 to 30:1, 5:1 to 25:1, 6:1 to 20:1, 8:1 to 15:1, or 10:1 to 12:1, or any ratio within the above ranges, wherein the Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is calculated based on the mass of Compound 1, and the empagliflozin, or a pharmaceutical composition thereof, is calculated based on the mass of empagliflozin.

[0046] In some embodiments, in the combination pharmaceutical composition, the combination pharmaceutical composition contains Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and empagliflozin or a pharmaceutical composition thereof in a mass ratio of 4:1 to 20:1, 5:1 to 20:1, 6:1 to 20:1, 8:1 to 15:1, or 10:1 to 12:1, or any ratio within the above ranges, wherein the Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is based on the mass of Compound 1, and the empagliflozin or a pharmaceutical composition thereof is based on the mass of empagliflozin.

[0047] In some embodiments, in the combination pharmaceutical composition, the combination pharmaceutical composition contains Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and empagliflozin or a pharmaceutical composition thereof in a mass ratio of 3.3:1 to 16.6:1, 4.2:1 to 16.6:1, 5:1 to 16.6:1, 6.6:1 to 12.5:1, or 8.3:1 to 10:1, or any ratio within the above ranges, wherein the Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is based on the mass of Compound 1, and the empagliflozin or a pharmaceutical composition thereof is based on the mass of empagliflozin.

[0048] In some embodiments, in the combination pharmaceutical composition, the combination pharmaceutical composition contains Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and empagliflozin or a pharmaceutical composition thereof in a mass ratio of 5:1, 10:1, 20:1, 30:1, or 40:1, wherein the Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is based on the mass of Compound 1, and the empagliflozin or a pharmaceutical composition thereof is based on the mass of empagliflozin.

[0049] In some embodiments of the present application, in the combination pharmaceutical composition, the Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin can be in the form of a pharmaceutical composition, respectively, or together in the form of a pharmaceutical composition.

[0050] In some embodiments, in the combination pharmaceutical composition, the Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin are present in the same pharmaceutical composition.

[0051] In some embodiments, the present application provides the combination pharmaceutical composition described above for use in the treatment or prevention of metabolic or renal diseases.

[0052] In some embodiments, the present application provides the combination pharmaceutical composition described above for use in the treatment or prevention of diabetes.

[0053] In some embodiments, the present application provides the above-mentioned pharmaceutical combination composition for use in the treatment or prevention of chronic kidney disease and / or kidney injury.

[0054] In another aspect, the present application provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, and empagliflozin in the preparation of a pharmaceutical composition for the treatment or prevention of a metabolic or renal condition, preferably a pharmaceutical combination composition as described above.

[0055] In another aspect, the present application also provides a kit comprising (a) a first pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, as described herein; and (b) a second pharmaceutical composition comprising empagliflozin. Optionally, the kit further comprises instructions for using the first and second pharmaceutical compositions in combination to treat or prevent a metabolic or renal condition.

[0056] In some embodiments, the present application provides the above-mentioned kit for use in the treatment or prevention of a metabolic or renal condition.

[0057] In some embodiments, the present application provides the above-mentioned kit for use in the treatment or prevention of diabetes.

[0058] In some embodiments, the present application provides the above-mentioned kit for use in the treatment or prevention of chronic kidney disease and / or kidney injury.

[0059] In another aspect, the present application also provides a method of treating or preventing a metabolic or renal condition, comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and empagliflozin, for example, administering to a subject in need thereof a therapeutically effective amount of the above-mentioned pharmaceutical combination composition or kit, or administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, separately from administering to the subject a therapeutically effective amount of empagliflozin or a pharmaceutical composition thereof.

[0060] In another aspect, the present application also provides a method of administering, comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and empagliflozin, for example, administering to a subject in need thereof a therapeutically effective amount of the above-mentioned pharmaceutical combination composition or kit, or administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, separately from administering to the subject a therapeutically effective amount of empagliflozin or a pharmaceutical composition thereof.

[0061] In another aspect, the present application also provides a combination therapy for treating a subject having a metabolic or renal condition, which, in some embodiments, comprises administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and administering to the subject a therapeutically effective amount of empagliflozin or a pharmaceutical composition thereof, alone, and, in other embodiments, comprises administering to the subject a therapeutically effective amount of a combination pharmaceutical composition or kit described herein.

[0062] In another aspect, the present application also provides the use of Compound 1 or a pharmaceutically acceptable salt thereof in combination with empagliflozin for the manufacture of a medicament for treating or preventing a metabolic or renal condition.

[0063] In another aspect, the present application also provides the use of Compound 1 or a pharmaceutically acceptable salt thereof in combination with empagliflozin for the manufacture of a medicament for treating or preventing diabetes.

[0064] Diabetes described herein includes, but is not limited to, Type I diabetes (T1D) and / or Type II diabetes (T2DM), idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, juvenile onset non- insulin dependent diabetes, gestational diabetes, and other special types of diabetes.

[0065] In another aspect, the present application also provides the use of Compound 1 or a pharmaceutically acceptable salt thereof in combination with empagliflozin for the manufacture of a medicament for treating chronic kidney disease and / or kidney injury.

[0066] In another aspect, the present application also provides the use of Compound 1 or a pharmaceutically acceptable salt thereof in combination with empagliflozin for the manufacture of a medicament for treating or preventing diabetes.

[0067] In another aspect, the present application also provides the use of Compound 1 or a pharmaceutically acceptable salt thereof in combination with empagliflozin for the manufacture of a medicament for treating chronic kidney disease and / or kidney injury.

[0068] In some embodiments of the present application, in the kit, method, combination therapy or use, each of Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin is defined as described above in the combination pharmaceutical composition, such as the amount, dosage, form, etc.

[0069] In some embodiments of the present application, in the method, combination therapy or use, each of Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin is in the form of a pharmaceutical composition, wherein the pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin can be administered simultaneously, separately, concurrently, sequentially, or intermittently.

[0070] In some embodiments, the kidney disease is chronic kidney disease. In some embodiments, the kidney disease is chronic kidney disease.

[0071] In some embodiments, the kidney disease is kidney injury. In some embodiments, the kidney disease is kidney injury.

[0072] In some of the above embodiments, the kidney disease is diabetic nephropathy. In some of the above embodiments, the kidney disease is diabetic nephropathy.

[0073] In some embodiments of the application, in the method, the combination therapy or the use, Compound 1, or a pharmaceutically acceptable salt thereof, and empagliflozin have the same or different treatment cycles, respectively.

[0074] In some embodiments of the application, in the method, the combination therapy or the use, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a daily dose, which can be administered once daily or twice daily.

[0075] In some embodiments, in the method, the combination therapy or the use, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a daily dose of 50 mg; or 100 mg; or 150 mg; or 200 mg; or 250 mg; or 300 mg; or 400 mg; or 600 mg.

[0076] In some embodiments of the application, in the method, the combination therapy or the use, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a daily dose of 200 mg; or, in a daily dose of 100 mg; or, in a daily dose of 400 mg; or, in a daily dose of 600 mg; or, in a daily dose of 300 mg.

[0077] In some embodiments of the application, in the method, the combination therapy or the use, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a single dose or in multiple doses, the multiple doses consisting of single doses of 50 mg, 100 mg, 200 mg, 300 mg or 400 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments of the application, in the method, the combination therapy or the use, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a single dose or in multiple doses, the multiple doses consisting of single doses of 100 mg, 200 mg or 400 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments of the application, in the method, the combination therapy or the use, the amount of empagliflozin in the pharmaceutical composition for combination is a daily dose, which can be administered once daily or twice daily.

[0079] In some embodiments of the application, in the method, the combination therapy or the use, the amount of empagliflozin in the pharmaceutical composition for combination is a daily dose, wherein empagliflozin is administered in a single dose or in multiple doses.

[0080] In some embodiments of the application, in the method, the combination therapy or the use, the empagliflozin is administered at a daily dose of 5 mg; or at a daily dose of 10 mg; or at a daily dose of 25 mg.

[0081] In some embodiments of the application, in the method, the combination therapy or the use, the empagliflozin is administered in a single dose or in multiple doses, wherein the single dose is a pharmaceutical composition of empagliflozin at 10 mg or 25 mg.

[0082] In some embodiments, in the method, the combination therapy or the use, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 50 mg; or 100 mg; or 150 mg; or 200 mg; or 250 mg; or 300 mg; or 400 mg; and the daily dose of empagliflozin is 10 mg. In some embodiments, in the method, the combination therapy or the use, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 50 mg; or 100 mg; or 150 mg; or 200 mg; or 300 mg; or 400 mg; and the daily dose of empagliflozin is 10 mg.

[0083] In some embodiments, in the method, the combination therapy or the use, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 100 mg; or 150 mg; or 200 mg; or 250 mg; or 300 mg; or 400 mg; or 600 mg; and the daily dose of empagliflozin is 25 mg. In some embodiments, in the method, the combination therapy or the use, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 100 mg; or 150 mg; or 200 mg; or 250 mg; or 300 mg; or 400 mg; and the daily dose of empagliflozin is 25 mg.

[0084] Pharmaceutical composition

[0085] In one aspect, the present application provides a pharmaceutical composition comprising a GLP-1R agonist moiety and englitazone, which GLP-1R agonist can be (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can further comprise a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is, or is formulated as, a combination pharmaceutical composition as described above.

[0086] In one aspect, the present application provides a single product oral pharmaceutical composition comprising two fixed doses of a pharmaceutically active ingredient (API), wherein the pharmaceutical composition comprises: (a) an englitazone moiety; and (b) a GLP-1R agonist moiety.

[0087] In some embodiments, the present application provides a single product oral pharmaceutical composition comprising two fixed doses of a pharmaceutically active ingredient, wherein the pharmaceutically active ingredients are: (a) englitazone; and (b) a small molecule GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments of the present application, the small molecule GLP-1R agonist is selected from Compound 1 or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the single product oral formulation pharmaceutical composition is, or is formulated as, a combination pharmaceutical composition as described above, wherein in the combination pharmaceutical composition, the Compound 1 or a pharmaceutically acceptable salt thereof and the empagliflozin are present in the same pharmaceutical composition. In some embodiments, the combination pharmaceutical composition comprises a pharmaceutical composition of the Compound 1 or a pharmaceutically acceptable salt thereof (as the “GLP-1R agonist moiety”) and a pharmaceutical composition of empagliflozin (as the “empagliflozin moiety”), which are formulated as a single pharmaceutical composition. In some embodiments, the pharmaceutical composition of the Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are mixed together homogeneously. In some embodiments, the pharmaceutical composition of the Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are formulated as a multi-layer structure (e.g., a bilayer or more layers, in particular a bilayer tablet or a multi-layer tablet), wherein each layer in the multi-layer structure is made from one of the pharmaceutical composition of the Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin, and adjacent layers made from the pharmaceutical composition of the Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are in direct contact, or are separated by a spacer layer, wherein the spacer layer comprises a pharmaceutically acceptable excipient or adjuvant, and comprises or does not comprise an active ingredient selected from the Compound 1 or a pharmaceutically acceptable salt thereof and empagliflozin.

[0090] In some embodiments, the single product oral formulation pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, empagliflozin, and a pharmaceutically acceptable adjuvant.

[0091] In some embodiments of the present application, a pharmaceutical composition of a GLP-1R agonist and empagliflozin is provided, comprising Compound 1 or a pharmaceutically acceptable salt thereof, empagliflozin, and a pharmaceutically acceptable adjuvant. In some such embodiments, the pharmaceutical composition is, or is formulated as, a combination pharmaceutical composition as described above. In some embodiments, the Compound 1 or a pharmaceutically acceptable salt thereof and the empagliflozin are present in the same pharmaceutical composition. In some embodiments, the Compound 1 or a pharmaceutically acceptable salt thereof and the empagliflozin are packaged in the same kit, which further comprises instructions for using the Compound 1 or a pharmaceutically acceptable salt thereof and the empagliflozin in combination to treat or prevent a metabolic or renal disease. In some embodiments, the Compound 1 or a pharmaceutically acceptable salt thereof and the empagliflozin are each in the form of a pharmaceutical composition (as the “GLP-1R agonist moiety” and the “empagliflozin moiety”, respectively), wherein the pharmaceutical composition of the Compound 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin can be administered simultaneously, sequentially, or at intervals.

[0092] In some embodiments of the application, the excipient or adjuvant is selected from the group consisting of a filler, a disintegrant, a glidant, a lubricant, a solubilizer, and combinations of any two or more thereof.

[0093] In some embodiments, the Compound 1 or a pharmaceutically acceptable salt thereof is present in the form of a granule or a powder, wherein the granule or powder further comprises a filler and / or a disintegrant to form the GLP-1R agonist moiety.

[0094] In some embodiments, the Compound 1 or a pharmaceutically acceptable salt thereof is present in the form of a granule or a powder, wherein the granule or powder further comprises a glidant and / or a lubricant to form the GLP-1R agonist moiety. In some embodiments, the granule or powder optionally comprises a glidant.

[0095] In some embodiments according to the foregoing, the pharmaceutically acceptable salt of Compound 1 is selected from the group consisting of a mesylate salt, a meglumine salt, and a tromethamine salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is Compound 1 · tromethamine salt.

[0096] In some embodiments, in the GLP-1R agonist moiety, Compound 1 · tromethamine salt is present in the form of a granule or a powder, wherein the granule or powder further comprises a filler and / or a disintegrant.

[0097] In some embodiments, in the GLP-1R agonist moiety, Compound 1 · tromethamine salt is present in the form of a granule or a powder, wherein the granule or powder further comprises a glidant and / or a lubricant. In some embodiments, the GLP-1R agonist optionally comprises a glidant.

[0098] In some embodiments of the application, empagliflozin is present in the form of a granule or a powder, the granule or powder further comprising a filler and / or a disintegrant.

[0099] In some embodiments of the application, empagliflozin is present in the form of a granule or a powder, the granule or powder further comprising a glidant and / or a lubricant. In some embodiments, the granule or powder optionally comprises a glidant.

[0100] In some embodiments, in the empagliflozin moiety, empagliflozin is present in the form of a granule or a powder, wherein the granule or powder further comprises a filler and / or a disintegrant.

[0101] In some embodiments, in the said empagliflozin portion, empagliflozin is present in the form of granules or powder, wherein the said granules or powder further comprises a glidant and / or a lubricant. In some embodiments, the said empagliflozin portion optionally comprises a glidant.

[0102] In some embodiments, the said GLP-1R agonist portion comprises or consists of the following components in mass percentage:

[0103] 20% to 40% of the said Compound 1 or a pharmaceutically acceptable salt thereof, 50% to 66.5% of a filler, 2% to 6% of a glidant, 1% to 3% of a lubricant, and 3% to 6.5% of a disintegrant. In some embodiments, the said GLP-1R agonist portion comprises or consists of the following components in mass percentage: 20% to 30% or 30% to 40% of the said Compound 1 or a pharmaceutically acceptable salt thereof, 50% to 60% of a filler, 2% to 4% of a glidant, 1% to 3% of a lubricant, and 3% to 6% of a disintegrant.

[0104] In some embodiments of the present application, the said empagliflozin portion comprises or consists of the following components in mass percentage:

[0105] In some embodiments of the present application, the said empagliflozin portion comprises or consists of the following components in mass percentage:

[0106] In some embodiments of the present application, in the said empagliflozin portion, the mass ratio of empagliflozin to filler is 1:2.5 to 1:25, for example, 1:2.7 to 1:23, 1:2.9 to 1:21, 1:3 to 1:20, 1:3.2 to 1:19, 1:3.4 to 1:18.8, 1:3.6 to 1:18.6, 1:3.8 to 1:18.4, 1:4 to 1:18.2, 1:4.2 to 1:18, 1:4.4 to 1:16, 1:4.6 to 1:14, 1:4.8 to 1:12, or 1:5 to 1:10. In some embodiments of the present application, in the said empagliflozin portion, the mass ratio of empagliflozin to filler is 1:5 to 1:25.

[0107] In some embodiments of the present application, in the said empagliflozin portion, the mass ratio of empagliflozin to lubricant is 15:1 to 2:1. In some embodiments of the present application, in the said empagliflozin portion, the mass ratio of empagliflozin to lubricant is 5:1 to 3:1.

[0108] In some embodiments of the present application, in the said empagliflozin part, the mass ratio of empagliflozin to disintegrant is 20:1 to 5:1. In some embodiments of the present application, in the said empagliflozin part, the mass ratio of empagliflozin to disintegrant is 15:1 to 8:1, for example 12.5:1 to 10:1.

[0109] In some embodiments of the present application, the said GLP-1R agonist part comprises or consists of the following components in mass percentage:

[0110] In some embodiments of the present application, the said GLP-1R agonist part comprises or consists of the following components in mass percentage:

[0111] In some embodiments of the present application, in the said GLP-1R agonist part, the mass ratio of active ingredient to filler is 1:1 to 1:5. In some embodiments of the present application, in the said GLP-1R agonist part, the mass ratio of active ingredient to filler is 1:1.2 to 1:4, for example 1:1.3 to 1:3, 1:1.4 to 1:2.9, 1:1.5 to 1:2.8, 1:1.6 to 1:2.7, 1:1.9 to 1:2.6, or 1:2.0 to 1:2.4.

[0112] In some embodiments of the present application, the said pharmaceutical composition comprises or consists of the following components in mass percentage:

[0113] In some embodiments of the present application, the said pharmaceutical composition comprises or consists of the following components in mass percentage:

[0114] In some embodiments of the present application, the said pharmaceutical composition comprises or consists of the following components in mass percentage:

[0115] In some embodiments of the present application, the said filler is one or more selected from microcrystalline cellulose, silicified microcrystalline cellulose, glucose, lactose, sucrose, mannitol, pregelatinized starch, starch, calcium phosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, preferably one or more of microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate. In some embodiments, the said filler is a combination of microcrystalline cellulose and calcium hydrogen phosphate. In some embodiments, the said filler is a combination of microcrystalline cellulose and calcium phosphate. In some embodiments, the said filler is a combination of microcrystalline cellulose and anhydrous calcium hydrogen phosphate.

[0116] In some embodiments of the application, the microcrystalline cellulose is selected from the group consisting of Avicel® microcrystalline cellulose PH101, Avicel® microcrystalline cellulose PH102, Avicel® microcrystalline cellulose PH103, Avicel® microcrystalline cellulose PH105, Avicel® microcrystalline cellulose 112, Avicel® microcrystalline cellulose 113, Avicel® microcrystalline cellulose PH200, Avicel® microcrystalline cellulose 12, Avicel® microcrystalline cellulose PH301, Avicel® microcrystalline cellulose PH301, Avicel® microcrystalline cellulose PHF20JP, Asahigel® microcrystalline cellulose KG-802, Asahigel® microcrystalline cellulose KG-1000, Asahigel® microcrystalline cellulose UF-702, Asahigel® microcrystalline cellulose UF-711, Asahigel® microcrystalline cellulose M301, Asahigel® microcrystalline cellulose M302, Asahigel® microcrystalline cellulose M200, Asahigel® microcrystalline cellulose M105, and any combination thereof.

[0117] In some embodiments of the application, the glidant is selected from one or more of the group consisting of colloidal silicon dioxide, magnesium trisilicate, talc, tribasic calcium phosphate, stearate salt (e.g. magnesium stearate or calcium stearate), and colloidal silicon dioxide, preferably colloidal silicon dioxide.

[0118] In some embodiments of the application, the lubricant is selected from one or more of the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, hydrogenated vegetable oil, glyceryl behenate, and glyceryl monostearate, preferably one or more of magnesium stearate, sodium stearyl fumarate, more preferably sodium stearyl fumarate.

[0119] In some embodiments of the application, the disintegrant is selected from one or more of the group consisting of microcrystalline cellulose, crosscarmellose, low-substituted hydroxypropylcellulose, croscarmellose sodium, dry starch, corn starch, hydroxymethyl starch, sodium carboxymethyl starch, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, preferably one or more of crosscarmellose, low-substituted hydroxypropylcellulose, croscarmellose sodium, more preferably low-substituted hydroxypropylcellulose, croscarmellose sodium, and sodium carboxymethyl starch, or any combination thereof. Surprisingly, the inventors found that the choice of disintegrant can significantly influence the dissolution of the two active ingredients in the pharmaceutical composition. For example, in the case of a pharmaceutical composition in the form of a tablet (e.g. a common monolayer tablet or a bilayer tablet), when croscarmellose sodium is used as disintegrant, Compound 1 · Tromethamine salt exhibits significantly faster dissolution and higher dissolution rate and a longer and more stable plateau duration for the common monolayer tablet, and Englitazin also shows faster dissolution and a longer and more stable plateau duration; for the bilayer tablet, Compound 1 · Tromethamine salt achieves significantly faster dissolution and higher dissolution rate and a longer and more stable plateau duration, and Englitazin also achieves faster dissolution and higher dissolution rate. Thus, croscarmellose sodium is a particularly preferred disintegrant.

[0120] In some embodiments of the present application, the mass percentage content of Compound 1 · tromethamine salt in the preparation pharmaceutical composition is about 15-40%, preferably about 20-30%, based on the total weight of the pharmaceutical composition.

[0121] In some embodiments of the present application, the preparation pharmaceutical composition optionally comprises a solubilizer. In some embodiments, the solubilizer is selected from the group consisting of sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB), hydroxypropyl betadex, sulfobutyl betadex sodium, Tween 80, vitamin E succinate polyethylene glycol ester, and poloxamer. In some embodiments, the solubilizer is sodium dodecyl sulfate. It can be advantageous to include a solubilizer in the preparation pharmaceutical composition. As one of the advantageous aspects, the inventors have found that tablets of Compound 1 · tromethamine salt alone can have a raw material drug precipitation in pH 6.8 phosphate buffer, while a plurality of solubilizers can reduce this precipitation to varying degrees, among the solubilizers measured, SDS and CTAB show better effect, and SDS is the best.

[0122] In some embodiments of the present application, the mass percentage content of empagliflozin in the preparation pharmaceutical composition is about 1-20%, preferably about 1-10%, based on the total weight of the pharmaceutical composition.

[0123] In some embodiments of the present application, the mass percentage content of the filler in the preparation pharmaceutical composition is about 40%-90%, for example about 50%-85%, 60%-80%, 65-75%, 60%-70%, 62-68%, 64%-66%, based on the total weight of the pharmaceutical composition.

[0124] In some embodiments of the present application, the mass percentage content of the disintegrant in the preparation pharmaceutical composition is about 1-20%, for example about 1.5%-18%, 2%-16%, 2.5%-15%, 3%-12%, 3.5%-10%, 4%-8%, 4.5%-7%, 5%-6%, based on the total weight of the pharmaceutical composition.

[0125] In some embodiments of the present application, the mass percentage content of the lubricant in the preparation pharmaceutical composition is about 0.2%-6%, for example about 0.4%-5.5%, 0.6%-5%, 0.8%-4.5%, 1%-4%, 1.2%-3.5%, 1.5%-3%, 1.8%-2.7%, 2%-2.5%, 2.1%-2.4%, based on the total weight of the pharmaceutical composition.

[0126] In some embodiments of the application, the pharmaceutical formulation optionally comprises a glidant. In some embodiments of the application, the pharmaceutical formulation comprises a glidant in an amount of about 0.2% to 5%, for example about 0.4% to 4.5%, 0.6% to 4%, 0.8% to 3.5%, 1% to 3%, 1.2% to 2.5%, 1.4% to 2%, 1.6% to 1.8%, by weight of the total weight of the pharmaceutical formulation.

[0127] In some embodiments of the application, the pharmaceutical formulation comprises a solubilizing agent in an amount of about 0 to 5%, for example about 0.2% to 4.5%, 0.4% to 4%, 0.6% to 3.5%, 0.8% to 3%, 1% to 2.5%, 1.2% to 2%, or 1.5% to 1.8%, by weight of the total weight of the pharmaceutical formulation.

[0128] In some embodiments of the application, the pharmaceutical formulation comprises Compound 1 · tromethamine salt and empagliflozin in a mass ratio of 1 : 1 to 100: 1, 1.5: 1 to 75: 1, 2: 1 to 60: 1, 2.5: 1 to 50: 1, 3: 1 to 40: 1, 4: 1 to 30: 1, 5: 1 to 25: 1, 6: 1 to 20: 1, 8: 1 to 15: 1, 10: 1 to 12: 1, or any ratio within the above ranges.

[0129] In some embodiments of the application, the pharmaceutical formulation comprises Compound 1 · tromethamine salt and empagliflozin in a mass ratio of 40: 1 to 4: 1, for example 40: 1, 30: 1, 20: 1, 25: 1, 20: 1, 15: 1, 12: 1, 10: 1, 8: 1, 6: 1, 5: 1, 4: 1.

[0130] In some embodiments of the application, the pharmaceutical formulation comprises Compound 1 · tromethamine salt and empagliflozin in a mass ratio of 30: 1 to 4: 1, for example 30: 1, 20: 1, 25: 1, 20: 1, 15: 1, 12: 1, 10: 1, 8: 1, 6: 1, 5: 1, 4: 1.

[0131] In some embodiments of the application, the pharmaceutical formulation comprises Compound 1 · tromethamine salt and empagliflozin in a mass ratio of 20: 1 to 4: 1, for example 20: 1, 15: 1, 12: 1, 10: 1, 8: 1, 6: 1, 5: 1, 4: 1.

[0132] In some embodiments of the application, the pharmaceutical formulation comprises or consists of the following components, by weight percent:

[0133] In some embodiments of the present application, the pharmaceutical composition comprises or consists of the following components in percentage by mass:

[0134] In some embodiments of the present application, the pharmaceutical composition comprises or consists of the following components in percentage by mass:

[0135] In some embodiments of the present application, the pharmaceutical composition comprises or consists of the following components in percentage by mass:

[0136] In some embodiments of the present application, the pharmaceutical composition comprises or consists of the following components in percentage by mass:

[0137] In some embodiments of the present application, a method for preparing the formulation pharmaceutical composition is provided, which comprises the following steps:

[0138] (1) preparing a mixture of empagliflozin and optional glidant;

[0139] (2) mixing the mixture from step (1) with Compound 1 or a pharmaceutically acceptable salt thereof, filler, disintegrant, and optional solubilizer;

[0140] (3) mixing the mixture from step (2) with lubricant.

[0141] Optionally, the mixture from step (3) is tabletted to prepare the formulation pharmaceutical composition in the form of tablet.

[0142] In some embodiments of the present application, a method for preparing the formulation pharmaceutical composition is provided, which comprises the following steps:

[0143] The prescribed amount of empagliflozin and glidant are mixed and sieved; transferred to a mixer, the prescribed amount of Compound 1 or a pharmaceutically acceptable salt thereof, filler, and disintegrant are weighed and mixed; the lubricant is added, and after mixing, tabletted.

[0144] In some embodiments of the present application, a method for preparing the formulation pharmaceutical composition is provided, which comprises the following steps:

[0145] (1) mixing the prescribed amount of GLP-1R agonist and optional glidant, then mixing with the prescribed amount of filler, disintegrant, and optional solubilizer, and further mixing with the prescribed amount of lubricant to prepare the GLP-1R agonist part;

[0146] (2) the empagliflozin part: mixing the prescribed amount of empagliflozin, a filler, a disintegrant, a lubricant and an optional glidant to prepare the empagliflozin part; and

[0147] (3) mixing the granules prepared in steps (1) and (2) with additional pharmaceutical excipients and tableting, or bilayer tabletting.

[0148] In some embodiments of the present application, a method for preparing the pharmaceutical composition is provided, which comprises the following steps:

[0149] (1) the GLP-1R agonist part: weighing the prescribed amount of active ingredient, a glidant into a mixer, mixing, transferring into a mixer, weighing the prescribed amount of filler, disintegrant and optional solubilizer and mixing, adding a lubricant and mixing to obtain the GLP-1R agonist part;

[0150] (2) the empagliflozin part: weighing the prescribed amount of filler, active ingredient, glidant, disintegrant, lubricant and optional solubilizer into a mixer, mixing, sieving as needed, then transferring into a mixer, mixing to obtain the empagliflozin part;

[0151] (3) mixing the granules prepared in (1) and (2) with additional pharmaceutical excipients and tableting, or bilayer tabletting.

[0152] In some embodiments of the present application, a method for preparing the pharmaceutical composition is provided, which comprises the following steps: mixing the prescribed amount of empagliflozin and one or more excipients, sieving, then adding the prescribed amount of Compound 1· tromethamine salt and the remaining excipients into a mixer, mixing, granulating, sieving, then mixing with additional pharmaceutical excipients, and tableting.

[0153] In some embodiments of the present application, the pharmaceutical composition comprises:

[0154] In some embodiments of the present application, the pharmaceutical composition comprises:

[0155] In some embodiments of the present application, the pharmaceutical composition can be in the form of a microtablet, which comprises:

[0156] In some embodiments of the present application, the pharmaceutical composition can be a bilayer tablet or a common tablet, which comprises:

[0157] The percentage content described in the present application refers to the percentage of the total weight of the pharmaceutical composition. The total weight of the pharmaceutical composition does not include the weight of the coating (if present).

[0158] The pharmaceutical composition described in the present application is in a dosage form selected from the group consisting of a tablet, a pill, a capsule, a microtablet, or a granule, wherein the tablet, pill, granule can have or not have a coating.

[0159] The pharmaceutical composition described in the present application can optionally further comprise a coating layer, including the use of one or more selected from the group consisting of water-soluble polymers, water-insoluble polymers, gastric-soluble polymers, and enteric-soluble polymers as the coating layer.

[0160] The pharmaceutical composition described in the present application can be a tablet, preferably a tablet having a pharmaceutically acceptable size that can be completely swallowed by an adult.

[0161] The active ingredients in the combination pharmaceutical composition described in the present application can each be independently administered, or some or all of them together, by suitable various routes, including but not limited to, oral or parenteral (by intravenous, intramuscular, topical, or subcutaneous routes). In some embodiments of the present application, the active ingredients in the combination pharmaceutical composition can each be independently administered, or some or all of them together, orally.

[0162] Use of the pharmaceutical composition

[0163] In some embodiments, there is provided use of the pharmaceutical composition described in the present application in the manufacture of a medicament for the treatment or prevention of diabetes.

[0164] In some embodiments, there is provided use of the pharmaceutical composition described in the present application in the treatment or prevention of diabetes.

[0165] In some embodiments, there is provided use of the pharmaceutical composition described in the present application in the manufacture of a medicament for the treatment or prevention of chronic kidney disease and / or kidney injury.

[0166] In some embodiments, there is provided use of the pharmaceutical composition described in the present application in the treatment or prevention of chronic kidney disease and / or kidney injury.

[0167] The present application further provides a method of treating type 2 diabetes in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition of the present application. The present application further provides a method of treating chronic kidney disease and / or kidney injury in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition described in the present application.

[0168] In some embodiments, the pharmaceutical composition of the present application is administered to a subject once daily or twice daily.

[0169] Dosage can be individualized by clinicians based on the specific clinical condition of the subject being treated.

[0170] It should be understood that the specific dose level for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the specific disease being treated.

[0171] definition

[0172] As used herein, the term "combination drug composition" refers to a combination of two or more active ingredients administered simultaneously or sequentially (in the form of their respective active ingredients as they are, or in the form of their respective pharmaceutically acceptable salts or esters, prodrugs, or compositions). In this document, the terms "combination drug composition" and "drug combination" are used interchangeably.

[0173] The term "pharmaceutical excipient" broadly refers to any component other than the active therapeutic ingredient (also known in the art as the active pharmaceutical ingredient or active pharmaceutical ingredient).

[0174] The term "subject" refers to any mammal, such as, but not limited to, humans, horses, cattle, sheep, pigs, mice, rats, dogs, cats, and primates such as chimpanzees, gorillas, and rhesus monkeys. In some embodiments, "subject" is a human. In some such embodiments, "subject" is a human exhibiting one or more symptomatic characteristics of a disease, disorder, or symptom.

[0175] The terms “pharmaceutical acceptable” or “medicinal” refer to a carrier, excipient, or excipient used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and whose use in a human medicine is acceptable.

[0176] The term "about" means ±10%, and preferably, the term "about" means ±5%.

[0177] The word “comprise” or “comprise” and its English variants such as comprises or comprising, and their equivalents, should be understood in an open, non-exclusive sense, meaning “including but not limited to”, implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0178] The term "tablet" refers to oral dosage forms of medicine of all sizes and shapes.

[0179] The term "treatment" refers to therapeutic treatment of a patient diagnosed with a disorder. Therapeutic treatment can be symptomatic treatment in order to relieve the symptoms of the disorder or can slow down or halt progression of the disorder.

[0180] The term "therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to effect treatment for that disease.

[0181] The term "daily dose" refers to the dose administered to a patient per day.

[0182] The term "single dose" or "unit formulation" refers to the smallest unit of packaging of a pharmaceutical product containing a certain amount of active ingredient, for example, a box of medicine has seven capsules, each capsule is a single dose or unit formulation; for example, a box of medicine has seven pieces of medicine, each piece of medicine is a single dose or unit formulation.

[0183] The term "multiple dose" consists of multiple single doses.

[0184] As used herein, "in combination" or "in conjunction" means that two or more active substances can be administered to an individual each as a single formulation simultaneously, concurrently or sequentially in any order each as a single formulation.

[0185] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application or a pharmaceutical combination thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application or a pharmaceutical combination thereof to an individual.

[0186] The term "pharmaceutically acceptable size" refers to a size that is generally suitable for complete swallowing without breaking, crushing or crushing by an adult. Generally, the maximum size of a tablet should not exceed about 22 mm.

[0187] The terms "coating layer" and "coating" refer to a layer added to the outside of the composition. The coating layer can be added to enhance the appearance of the drug, taste masking, enhance stability, coloring, ease of swallowing, etc. Beneficial effects

[0188] Using the combination pharmaceutical composition and / or the formulation pharmaceutical composition described in the present application has the following advantages:

[0189] 1. Better therapeutic effect in reducing blood glucose levels and improving kidney function and kidney tissue lesions (such as glomerular injury and kidney inflammation) and the like in the treatment of diabetes, diabetic nephropathy, chronic kidney disease or kidney injury, showing synergistic effect compared to administration of any of the pharmaceutical active ingredients in the composition alone;

[0190] 2. Requires less amount of administration, provides treatment with less adverse reactions and / or complications in patients compared to administration of any of the pharmaceutical active ingredients in the composition alone;

[0191] 3. The preparation of the pharmaceutical composition effectively improves the stability and dissolution performance of the active ingredients. The prepared granules have stable content and uniform size; the prepared product has excellent dissolution performance, and the dissolution curve of the product is consistent with that of each single active ingredient composition in each dissolution medium. The product is safe and the quality is controllable. BRIEF DESCRIPTION OF DRAWINGS

[0192] Figure 1 shows the weight change rate of each group of mice in Example 1.

[0193] Figure 2 shows the reduction rate of random blood glucose of each group of mice in Example 1.

[0194] Figure 3 shows the blood glucose AUC of each group of mice in Example 1.

[0195] Figure 4 shows the blood glucose changes of each group of mice in Example 1 in the IPGTT experiment.

[0196] Figure 5 shows the IPGTT blood glucose AUC of each group of mice in Example 1 0～120min .

[0197] Figure 6 shows the glycated hemoglobin levels of each group of mice in Example 1.

[0198] Figure 7 shows the ALT blood indicators of each group of mice in Example 1.

[0199] Figure 8 shows the AST blood indicators of each group of mice in Example 1.

[0200] Figure 9 shows the effect of Compound 1·Tromethamine Salt combined with Empagliflozin on the area under the random blood glucose curve of DKD mice.

[0201] Figure 10 shows the effect of Compound 1·Tromethamine Salt combined with Empagliflozin on the 4h random urine UACR of DKD mice.

[0202] Figure 11 shows the effect of Compound 1·Tromethamine Salt combined with Empagliflozin on the SCR of DKD mice.

[0203] Figure 12 shows the effect of Compound 1·Tromethamine Salt combined with Empagliflozin on the glomerular injury score of DKD mice.

[0204] Figure 13 shows the effect of Compound 1·Tromethamine Salt combined with Empagliflozin on the kidney inflammation score of DKD mice.

[0205] Figure 14 shows the effect of Compound 1·Tromethamine Salt combined with Empagliflozin on the serum ALT of DKD mice.

[0206] Figure 15 shows the effect of Compound 1·Tromethamine Salt combined with Empagliflozin on the serum AST of DKD mice.

[0207] Figure 16 shows the effect of Compound 1·tromethamine salt combined with empagliflozin on serum ALP in DKD mice.

[0208] Figure 17: shows the dissolution profile of 10 mg / 400 mg empagliflozin / Compound 1·tromethamine salt double-layer tablets and respective single tablets in pH 6.8 phosphate buffer (0.1% SDS) (A and B), pH 4.5 phosphate buffer solution (0.1% SDS) (C and D) and water (E and F). DETAILED DESCRIPTION

[0209] The present application discloses pharmaceutical compositions, and those skilled in the art can improve the process parameters or prescription ratio according to the content of the present application combined with the principles of pharmacy. It is particularly important to note that all similar substitutions and changes are obvious to those skilled in the art, and they are considered to be within the scope of the present application. The application of the present application has been described by good examples, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present application, to realize and apply the present application technology.

[0210] The sources of the materials used in the examples of the present application are as follows:

[0211] Compound 1 or its pharmaceutically acceptable salt: prepared by Hangzhou Sino-United East China Pharmaceutical Co., Ltd. itself, and the preparation method can refer to WO2022268152A1.

[0212] Empagliflozin: from Hangzhou Huadong Pharmaceutical Group Zhejiang Huayi Pharmaceutical Co., Ltd., raw material drug.

[0213] Microcrystalline cellulose 102: 112, from JRS PHARMA, batch number 101122210010.

[0214] Microcrystalline cellulose pH 112: from Dupont.

[0215] Microcrystalline cellulose M302: from Mingtai Chemical Co., Ltd., batch number C2208027.

[0216] Microcrystalline cellulose-silica colloidal co-processing: model SMCC90, from JRS PHARMA, batch number P9S1667.

[0217] Silica colloidal: model 200, from Wincreate Chemical, batch number 113022014.

[0218] Croscarmellose sodium: model VIVASOL, from JRS PHARMA, batch number 32010211080.

[0219] Low-substituted hydroxypropyl cellulose: Type LH-21, from Shin-Etsu Chemical Co., Ltd., batch number 1074121.

[0220] Sodium stearyl fumarate: Type PRUV, from JRS PHARMA, batch number 3146.

[0221] Anhydrous dibasic calcium phosphate: Type DI-CAFOS-A60, from Chemische Fabrik Budenheim KG.

[0222] In order to further illustrate the present application, the fixed-dose oral pharmaceutical composition and the preparation method thereof provided by the present application are described in detail below in conjunction with examples, but they cannot be understood as limiting the scope of protection of the present application.

[0223] Example 1: Verification of synergistic effect of Compound 1·Tromethamine Salt and Empagliflozin

[0224] Example 1.1: Hypoglycemic effect of Compound 1·Tromethamine Salt combined with Empagliflozin on type 2 diabetic mice

[0225] Construction of type II diabetic mouse model: C57BL / 6J-GLP-1R mice (male, 104, 23w, body weight 30-35g) (Shanghai South Model Organism Technology Co., Ltd.) were induced by high-fat diet until the body weight reached about 40g. All mice were fasted overnight, and then intraperitoneally injected with streptozotocin (STZ) at a dose of 40mg / kg, once a day for 5 consecutive days. When the random blood glucose level (RBG) of the mice injected with STZ on the last day was greater than 16.7mmol / L for 2 consecutive days after one week, it was considered that the diabetic model was successfully established.

[0226] Preparation method of STZ used in this example: The required STZ was divided into 20 dry sterile bottles in a dry environment (humidity less than 30%), each bottle containing about 85mg of STZ powder, and stored in an ice box in the dark after preparation. The prepared STZ was used within 10 minutes.

[0227] Group administration: After the model was established, the animals were grouped according to the body weight and random blood glucose, n=6. The experimental grouping and administration scheme are shown in Table 1 below, and the administration period was 4 weeks.

[0228] Table 1 Note: The GLP-1 active ingredient described in this table refers to Compound 1·Tromethamine Salt.

[0229] The preparation method of Compound 1 ·Tromethamine salt used in this example: the solvent is DMSO:Solutol HS-15:saline = 5:10:85. An appropriate amount of Compound 1 ·Tromethamine salt is weighed and dissolved in an appropriate amount of DMSO, shaken and vortexed, and then Solutol HS-15 and saline are added in proportion to make the final concentration 400 mg / mL. Then it is diluted 100 times to 4.0 mg / mL and 200 times to 2.0 mg / mL, respectively.

[0230] The preparation method of Empagliflozin used in this example: an appropriate amount of Empagliflozin powder is weighed and added with an appropriate amount of 0.5% carboxymethylcellulose sodium (CMC-Na) solution to prepare a 0.5 mg / mL solution. Then it is diluted 5 times to prepare a 0.1 mg / mL solution. The solution is prepared and used immediately.

[0231] Experimental content:

[0232] 1. Body weight monitoring: During the administration period, the body weight of the animals was detected once every 3 days; at the end of the experiment, the body weight of the animals was detected.

[0233] 2. Random blood glucose: During the administration period, the random blood glucose was detected once every 3 days at a fixed time using a Roche blood glucose meter. The detection method is as follows: about 10 μL of blood is collected from the tip of the mouse tail, and the handheld blood glucose meter is used for measurement. Each animal is measured twice, and when the deviation is greater than 10%, the third measurement is performed. The two blood glucose values within 10% deviation are selected as the final result.

[0234] 3. Glycated hemoglobin: Four weeks after administration, the animals were fasted overnight, and 30 μL of blood was collected from the mouse retro-orbital plexus. The anti-coagulated whole blood sample was detected using a glycated hemoglobin analyzer (Siemens, DCA Vantage).

[0235] 4. IPGTT experiment (intraperitoneal glucose tolerance test): Four weeks after administration, the animals were fasted overnight, and each group of animals was intraperitoneally injected with 25% glucose solution at a dose of 2.5 g / kg and a volume of 10 mL / kg. The blood glucose monitoring time points were: before administration (-30 min), before administration (0 min), and 15, 30, 60, and 120 min after administration. When detecting blood glucose, blood glucose was detected twice at each point, and if the difference was greater than 10%, the third detection was required.

[0236] 5. Data analysis: All data will be recorded and expressed as Mean ± S.E.M, and the differences between groups will be compared using Graphpad Prism 7 software, using One-way analysis of variance (ANOVA) or Two-way analysis of variance (ANOVA) Dunnett’s method, and p value less than 0.05 will be considered as significant difference.

[0237] Results of the experiment:

[0238] Results of the glycosylated hemoglobin and IPGTT experiment on day 29 (Mean ± SEM) are shown in Table 2 below.

[0239] Table 2 *: compared with the vehicle group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; $ : compared with the compound 1 · tromethamine salt 40 mg / kg + empagliflozin 5 mg / kg group, $ p<0.05, $$ p<0.01, $$$ p<0.001, $$$$ p<0.0001; & : compared with the compound 1 · tromethamine salt 20 mg / kg + empagliflozin 5 mg / kg group, & p<0.05; One-way ANOVA.

[0240] The results of the experiment show that the combination of compound 1 · tromethamine salt and empagliflozin has a significant effect on reducing random blood glucose and glycosylated hemoglobin in T2DM mice, showing excellent hypoglycemic effect. During the experiment, no significant weight loss was observed in mice; and the results of ALT and AST showed that the combination of the two did not cause liver damage. Figure 1 shows the weight change rate of mice in each group during the experiment of Example 1; Figure 2 shows the random blood glucose reduction rate of mice in each group during the experiment of Example 1; Figure 3 shows the blood glucose AUC of mice in each group during the experiment of Example 1; Figure 4 shows the blood glucose changes of IPGTT experiment of mice in each group during the experiment of Example 1; Figure 6 shows the glycosylated hemoglobin level of mice in each group during the experiment of Example 1; Figure 7 shows the ALT blood index of mice in each group during the experiment of Example 1; and Figure 8 shows the AST blood index of mice in each group during the experiment of Example 1.

[0241] The results of glycosylated hemoglobin and IPGTT also show that the combination of Compound 1·Tromethamine salt and empagliflozin group exhibits significant synergistic hypoglycemic efficacy compared with the same dose of single drug group, especially the Compound 1·Tromethamine salt 40 mg / kg + empagliflozin 5 mg / kg group. Figure 5 shows the IPGTT blood glucose AUC of each group of mice during the experiment process of Example 1 0～120min .

[0242] In summary, the combination of Compound 1·Tromethamine salt and empagliflozin can significantly reduce random blood glucose levels, improve glucose tolerance, reduce glycosylated hemoglobin levels, and improve insulin resistance, and show significant synergistic blood glucose control effect compared with single drug treatment group.

[0243] Example 1.2: Hypoglycemic effect and kidney function improvement effect of Compound 1·Tromethamine salt combined with empagliflozin on diabetic nephropathy mice

[0244] Diabetic nephropathy mouse model construction: humanized GLP-1R (C57BL / 6Smoc-Glp1rem2(hGLP1R)Smoc) mice diabetic kidney disease (Diabetic Kidney Disease, DKD) model was constructed by feeding high-fat diet (High Fat Diet, HFD, source: Research Diets, item number: D12492) and combined with injection of streptozotocin (Streptozotocin, STZ, source: Sigma, item number: S0130). According to the changes of animal body weight, blood glucose, blood biochemical indicators, urine biochemical indicators, and renal histopathology diagnosis score, the therapeutic effect of Compound 1·Tromethamine salt combined with empagliflozin on diabetic nephropathy mice after 10 weeks of continuous administration was evaluated.

[0245] hGLP1R (C57BL / 6Smoc-Glp1rem2(hGLP1R)Smoc) is a CRISPR gene editing technology that replaces all or part of the Glp1r gene of C57BL / 6J mice with human hGLP1R, thereby expressing human or human-mouse chimeric hGLP1R protein instead of mouse endogenous Glp1r protein. Mouse source: Shanghai South Model Organisms Technology Co., Ltd., hGLP1R mice, SPF level; body weight at the first time of test grouping was 21-26 g.

[0246] Modeling method: humanized mice hGLP1R (C57BL / 6Smoc-Glp1rem2(hGLP1R)Smoc) were selected as experimental animals. After the adaptation period, all animals were fasted overnight except for 4 animals in the normal control group. The next morning, high-fat feed (D12492, containing 60kcal% HFD) was started, and the animals were continuously fed until the end of the experiment (26 weeks). At the 12th week of HFD induction, the animals were injected with STZ (40mg / kg, ip, fasted for more than 16h) for 5 consecutive days (fasted every day). At the 16th week of HFD induction, the success of the model was determined according to the results of the experimental animal's urinary albumin / creatinine ratio (UACR). The model reached the grouping standard: the random blood glucose value was greater than 16.7mmol / L, and the UACR of the model group mice was increased by 2-3 times compared with the normal control group, which was determined to have been induced into a diabetic nephropathy model in the early stage.

[0247] Preparation of Compound 1·Tromethamine salt: An appropriate amount of Compound 1·Tromethamine salt (source: Hangzhou Sino-United East Pharmaceutical Co., Ltd.) was dissolved in an appropriate amount of DMSO, vortexed and mixed, then Solutol HS-15 and saline were added in the ratio of DMSO:Solutol HS-15:Saline = 5:10:85 (v / v / v) and vortexed and mixed, respectively, to obtain 8, 4, and 2 mg / mL solutions. Each concentration of solution was divided into 7 parts and stored at -20°C. Each week, a new solution was prepared, and a small bottle was thawed for use before each administration.

[0248] Preparation of empagliflozin:

[0249] Days 1-32 (D1-D32): An appropriate amount of empagliflozin powder (source: Hangzhou Sino-United East Pharmaceutical Co., Ltd.) was added to an appropriate amount of 0.5% CMC-Na solution to obtain a 1 mg / mL suspension. An appropriate amount of 1 mg / mL empagliflozin suspension was mixed with an equal volume of 0.5% CMC-Na solution to dilute and obtain a 0.5 mg / mL empagliflozin suspension, which was prepared fresh each day.

[0250] Days 33-72 (D33-D72): An appropriate amount of empagliflozin powder was added to an appropriate amount of 0.5% CMC-Na solution to obtain a 2 mg / mL suspension. An appropriate amount of 2 mg / mL empagliflozin suspension was mixed with an equal volume of 0.5% CMC-Na solution to dilute and obtain a 1 mg / mL empagliflozin suspension, which was prepared fresh each day.

[0251] Preparation of Compound 1·Tromethamine salt + empagliflozin combination:

[0252] D1-D32: 4 mg / mL of Compound 1·triaminol salt solution and 1.0 mg / mL of empagliflozin suspension were mixed in equal volume to prepare Compound 1·triaminol salt low dose + empagliflozin combination preparation. 8 mg / mL of Compound 1·triaminol salt solution and 1.0 mg / mL of empagliflozin suspension were mixed in equal volume to prepare Compound 1·triaminol salt high dose + empagliflozin combination preparation. The combination preparation was prepared extemporaneously.

[0253] D33-D72: 4 mg / mL of Compound 1·triaminol salt solution and 2.0 mg / mL of empagliflozin suspension were mixed in equal volume to prepare Compound 1·triaminol salt low dose + empagliflozin combination preparation. 8 mg / mL of Compound 1·triaminol salt solution and 2.0 mg / mL of empagliflozin suspension were mixed in equal volume to prepare Compound 1·triaminol salt high dose + empagliflozin combination preparation. The combination preparation was prepared extemporaneously.

[0254] Group administration: Two random groups were used, and the number of animals in each test group was the same as the baseline; the number of animals in each test group was n = 6, and the number of animals in the normal control group (naive group) was n = 4. The experimental grouping and administration scheme are shown in Table 3 below, in which the administration date is D111 (HFD induction for 16 weeks, i.e., 4 weeks after STZ induction); the first day of the test was defined as day 0 (D0) on the day of the first grouping; the day of the start of administration was recorded as TD1, and the administration period was 10 weeks.

[0255] Table 3

[0256] “-” represents not applicable, “p.o.” represents oral administration, “QD” represents administration once a day; “W” represents week.

[0257] Main experimental content:

[0258] 1. Random blood glucose detection: All enrolled surviving animals were detected once before HFD induction, once before STZ injection, twice continuously 1 week after STZ injection, once before administration grouping, and once every 3 days during drug treatment. The mouse tail was cleaned with an alcohol cotton ball before administration on the same day, the tail vein was punctured with a 26G needle, the first drop of blood was discarded, and a handheld blood glucose meter was used for measurement. Each detection was measured twice, and when the deviation was greater than 10% and greater than 0.5 mmol / L, the third measurement was performed, and the average value was taken as the individual data for statistical analysis.

[0259] 2. Serum liver function detection: The levels of ALT, AST and ALP of all enrolled surviving animals were detected at weeks 4, 8 and 10 of administration to investigate the effect of the test substance on the liver function of DKD mice.

[0260] 3. Blood biochemical test: Blood biochemical test was performed on all the enrolled surviving animals before the first administration, at the 4th, 8th and 10th week of administration. After the animals were fasted overnight (without water restriction), 0.2 mL of blood was collected through the jugular vein, centrifuged at 4000 r / min and 4°C for 10 minutes in a separation glue-coagulation tube, and then the serum was separated and temporarily stored at 4°C; and a biochemical analyzer was used for detection. The detection indexes were: serum creatinine (SCR) and blood urea nitrogen (BUN) before the first administration; SCR, BUN, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at the 4th, 8th and 10th week of administration.

[0261] 4. Urine biochemical test: Random urine biochemical test was performed on all the enrolled surviving animals at the 2nd, 3rd, 5th, 6th and 7th week of administration. After the animals were fasted without water restriction on the day of administration, they were placed in a mouse metabolic cage, and 100-300 μL of 4 h urine was collected; and a biochemical analyzer was used for detection. The detection indexes included urine creatinine (U-Crea) and urine albumin (U-ALB), and UACR was calculated according to the following formula:

[0262] UACR (mg / mmol) = U-ALB (mg / L) / U-Crea (μmol / L) x 1000.

[0263] 5. Kidney histopathology test: At the end of the test (D77), gross anatomy, organ weighing and histopathology test were performed on all the enrolled surviving animals. For the kidney histopathology test, the left kidney tissue was fixed in 10% neutral formalin for 24 h, and then sampling, paraffin embedding, sectioning, PAS staining, H&E staining and Masson staining were performed, followed by histopathology test. A whole slide scanner was used for scanning, and kidney histopathology lesion characteristics were selected.

[0264] Experimental results:

[0265] 1. Random blood glucose

[0266] During the test period, the random blood glucose of the normal control group animals was at a normal level, and the random blood glucose of the model control group animals was in a hyperglycemic state (≥16.7 mmol / L) from the day of test grouping (TD1, 23.56±0.72 mmol / L) to TD70 (23.83±0.94 mmol / L), and was significantly higher than that of the normal control group at the same period (p<0.0001).

[0267] The random blood glucose results are shown in Table 4 below. Compound 1· tromethamine salt at 20 mg / kg or 40 mg / kg and empagliflozin at 10 mg / kg can improve the random blood glucose of mice alone and in a dose-dependent manner. The combination of Compound 1· tromethamine salt and empagliflozin showed improved hypoglycemic effect compared with the single drug group.

[0268] Table 4: Effect of Compound 1· tromethamine salt combined with empagliflozin on the random blood glucose level of DKD mice Note: TD1 is the random blood glucose on the first day of treatment, TD70 is the random blood glucose before administration on the 70th day of treatment, and all data are statistically analyzed using Mean ± SEM; **** p<0.0001 indicates comparison between the model control group and the normal control group; ## p<0.01 and #### p<0.0001 indicates comparison between the treatment group and the model control group; &&&& p<0.0001 indicates comparison between the 20 mg / kg Compound 1· tromethamine salt group, or the empagliflozin group, and the 20 mg / kg Compound 1· tromethamine salt + empagliflozin group; ^^^^ p<0.0001 indicates comparison between the 40 mg / kg Compound 1· tromethamine salt group, or the empagliflozin group, and the 40 mg / kg Compound 1· tromethamine salt + empagliflozin group.

[0269] The area under the curve of the random blood glucose results is shown in Figure 9. Compared with the equal-dose Compound 1· tromethamine salt or empagliflozin single drug group, the 20 / 40 mg / kg Compound 1· tromethamine salt combined with empagliflozin group showed a significant synergistic hypoglycemic effect &&&& p<0.0001, ^^^^ p<0.0001.

[0270] 2. Serum liver function indicators

[0271] The test results of ALT, AST and ALP are shown in Figures 14, 15 and 16, respectively.

[0272] The results showed that the 20 mg / kg or 40 mg / kg Compound 1 · tromethamine salt monotherapy group significantly improved the ALT and AST levels of the DKD mice at 4 weeks of treatment, dose-dependently improved the ALP level at 8 weeks of treatment, and maintained the improvement until the end of the test; the empagliflozin monotherapy group significantly improved the ALT level at 4 weeks of treatment, significantly improved the ALP level at 8 weeks of treatment, and significantly improved the AST level at 10 weeks of treatment in a time-dependent manner; the 20 / 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group stabilized and improved the ALT, AST and ALP of the DKD mice at 4 weeks of treatment. The ALT (T8W) and ALP (T4W) of the mice in the combination group showed a synergistic improvement trend compared with the equal-dose monotherapy. It is indicated that Compound 1 · tromethamine salt combined with empagliflozin can quickly and effectively improve the abnormal liver function of diabetic nephropathy mice, and shows a synergistic improvement trend compared with the equal-dose monotherapy.

[0273] 3. Blood biochemical test (serum renal function indicators):

[0274] The results of the treatment groups are shown in Table 5 and FIG. 11. The 20 mg / kg or 40 mg / kg Compound 1 · tromethamine salt monotherapy group, the empagliflozin monotherapy group and the 20 / 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group all reduced the expression level of SCR of the DKD mice at 8 weeks of treatment. At 10 weeks of treatment, each treatment group significantly reduced the SCR of the DKD mice to the expression level of the normal animals.

[0275] Table 5: Effect of Compound 1 · tromethamine salt combined with empagliflozin on the SCR of DKD mice Note: All data were statistically analyzed using Mean ± SEM; *** p < 0.001 and **** p < 0.0001 represent the comparison between the model control group and the normal control group. # p < 0.05, ## p < 0.01, ### p < 0.001 and #### p < 0.0001 represent the comparison between the treatment groups and the model control group.

[0276] The results of SCR showed that, compared with the model control group, at 10 weeks of treatment, each treatment group significantly reduced the SCR level of the DKD mice to the normal animal state.

[0277] 4. Urine biochemical test

[0278] The results of the treatment groups are shown in Table 6 and Figure 10. The 20 mg / kg or 40 mg / kg Compound 1 · tromethamine salt monotherapy significantly reduced the UACR level of mice at the second week of treatment and maintained the efficacy until the seventh week of detection; the empagliflozin monotherapy group showed a time-dependent reduction in UACR at the sixth week of treatment; the 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group steadily reduced the UACR level of mice to near normal mouse state from the fifth week of treatment and maintained the efficacy until the seventh week of detection. This suggests that Compound 1 · tromethamine salt combined with empagliflozin can quickly and effectively improve the UACR level of diabetic nephropathy mice, and show a synergistic improvement trend compared with the same dose of monotherapy.

[0279] Table 6: Effect of Compound 1 · tromethamine salt combined with empagliflozin on UACR of 4h random urine of DKD mice Note: All data were statistically analyzed using Mean ± SEM; ** p < 0.01 and *** p < 0.001 represent the comparison between the model control group and the normal control group; # p < 0.05, ## p < 0.01 and ### p < 0.001 represent the comparison between the treatment group and the model control group.

[0280] The UACR results showed that 20 mg / kg or 40 mg / kg Compound 1 · tromethamine salt monotherapy reduced the UACR level of DKD mice, and the 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group steadily reduced the UACR level of mice to near normal mouse state (0.07 ± 0.05 at 5 weeks, 0.04 ± 0.04 at 6 weeks, and 0.14 ± 0.07 at 7 weeks vs. 0.00 ± 0.00 mg / mmol) from the fifth week of treatment and maintained the efficacy until the seventh week of detection, and the UACR level of mice after 5 weeks of treatment was lower than that of the same dose of Compound 1 · tromethamine salt monotherapy group and the empagliflozin monotherapy group.

[0281] 5. Kidney histopathology detection:

[0282] As shown in Table 7 and FIG. 12, compared with the model control group of mice with slight thickening of the glomerular basement membrane and mild widening of the mesangium (1.67±0.33), the 20 mg / kg or 40 mg / kg Compound 1 · tromethamine salt monotherapy group dose-dependently improved the glomerular injury of DKD mice (1.17±0.31 and 0.67±0.33, p<0.01); the empagliflozin monotherapy group also significantly improved the glomerular injury of DKD mice (0.50±0.22, p<0.05); the 20 / 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group further dose-dependently improved the glomerular injury (0.33±0.21, p<0.01; 0.00±0.00 p<0.001), and the 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group of mice had a basically normal glomerular structure. It is suggested that Compound 1 · tromethamine salt combined with empagliflozin can effectively improve the glomerular injury of diabetic nephropathy mice, and show a synergistic improvement trend compared with the same dose of monotherapy.

[0283] As shown in Table 7 and FIG. 13, compared with the model control group of mice with multiple mild inflammatory reactions (2.50±0.22), the 20 mg / kg or 40 mg / kg Compound 1 · tromethamine salt monotherapy group, the empagliflozin monotherapy group and the 20 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group all improved the kidney inflammation of DKD mice (1.67±0.21, 1.83±0.17, 1.83±0.48, 1.67±0.42); while the 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group significantly improved the kidney inflammation of DKD mice (0.67±0.21, p<0.001), and had a synergistic improvement effect compared with the same dose of monotherapy group (p<0.05). It is suggested that Compound 1 · tromethamine salt combined with empagliflozin can effectively improve the kidney inflammation of diabetic nephropathy mice, and show a synergistic improvement effect compared with the same dose of monotherapy.

[0284] Table 7 Note: all data were statistically analyzed using Mean±SEM; # p<0.05 vs. model group (Model).

[0285] The results of kidney histopathology showed that the Compound 1 · tromethamine salt and empagliflozin monotherapy groups and the 20 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group slightly improved the glomerular injury and kidney inflammation of diabetic nephropathy mice; the 40 mg / kg Compound 1 · tromethamine salt combined with empagliflozin group effectively improved the glomerular injury to the state of normal mice, and effectively improved the kidney inflammation and showed a synergistic improvement effect compared with the same dose of monotherapy. The progression of renal interstitial fibrosis of DKD mice in each test group did not progress or worsen.

[0286] Experimental conclusion: Compound 1 ·Tromethamine salt combined with empagliflozin significantly improved the hyperglycemia, kidney filtration function, kidney tissue lesions and liver function abnormalities of the diabetic nephropathy model mice induced by high-fat diet combined with streptozotocin. The 40 mg / kg compound 1 ·Tromethamine salt combined with empagliflozin group had synergistic effect on improving the random blood glucose of the model mice and improving kidney inflammation, and the efficacy was better than that of the same dose of compound 1 ·Tromethamine salt or empagliflozin single drug (p<0.05); It had a synergistic trend in improving UACR, eGFR, glomerular injury and liver function abnormalities of the model mice, and the efficacy was slightly better than that of the same dose of compound 1 ·Tromethamine salt or empagliflozin single drug (p>0.05). In addition, the 40 mg / kg compound 1 ·Tromethamine salt combined with empagliflozin group made the blood glucose, glycosylated hemoglobin, UACR, serum creatinine value, glomerular injury, serum ALT and ALP of DKD mice return to the level of normal mice.

[0287] Example 2: GLP-1R agonist part of the formulation pharmaceutical composition

[0288] Compound 1 ·Tromethamine salt part formula:

[0289] According to the above prescription, the active substance, silicified microcrystalline cellulose, microcrystalline cellulose, colloidal silicon dioxide, disintegrant and sodium stearyl fumarate were manually mixed, sieved (60 mesh) for 3 times, and mixed again to obtain the GLP-1R agonist part. Experimental examples 2-1 to 2-7 were successfully produced, and the product quality was good. The granular or powdery properties are listed in the following table: Note: The content in the above table refers to the measured value / theoretical value of the mass percentage of the active ingredient in the composition; " / " indicates not detected.

[0290] Example 3: Empagliflozin part of the formulation pharmaceutical composition

[0291] Empagliflozin part formula:

[0292] According to the above prescription, the active ingredient empagliflozin, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and sodium stearyl fumarate were manually mixed, sieved (60 mesh) for 2 times, and mixed again to obtain the empagliflozin part. Examples 3-1 to 3-3 were successfully produced, and the product quality was good. The prescription had good compressibility and flowability, and the specific properties are listed in the following table:

[0293] Example 4: Formulation pharmaceutical composition

[0294] This example describes an exemplary formula and verification properties of the formulation form of the formulation pharmaceutical composition as a common tablet.

[0295] The prescribed amount of empagliflozin and colloidal silicon dioxide are mixed in a mixer, sieved as needed, and transferred to a mixer. The prescribed amount of Compound 1·tromethamine salt, microcrystalline cellulose, croscarmellose sodium, and / or low-substituted hydroxypropyl cellulose are weighed, sieved, mixed, and added to the sodium stearyl fumarate mixture. The resulting granules or powder are mixed and tableted.

[0296] The dissolution of the pharmaceutical composition of the preparation of the present application is determined using the dissolution and release determination method required by the Chinese Pharmacopoeia. Specifically, the determination is performed according to the first method (basket method) of dissolution and release determination method of Chinese Pharmacopoeia 2020 edition four, wherein the pH 6.8 phosphate solution is used as the dissolution medium, the rotation speed is 100 revolutions per minute, and the determination is performed according to the specified method operation.

[0297] The hardness of the product, tableting, and the like are determined using conventional preparation observation and detection methods.

[0298] The results show that when croscarmellose sodium is selected as the disintegrant in the Compound 1·tromethamine salt part, compared to the combination of croscarmellose sodium and low-substituted hydroxypropyl cellulose, Compound 1·tromethamine salt exhibits significantly faster dissolution and higher dissolution rate, and the plateau duration is longer and more stable, and empagliflozin also exhibits faster dissolution and longer and more stable plateau duration.

[0299] Example 5: Solubilizer screening

[0300] The inventors have found that the tablet of Compound 1·tromethamine salt alone can cause the precipitation of the drug substance in the pH 6.8 phosphate buffer (containing 0.1% HPC) medium. Therefore, the inventors investigated the effect of several solubilizers on the solubility of Compound 1·tromethamine salt in pH 6.8 phosphate buffer. Compound 1·tromethamine salt drug substance was prepared into a solution with a concentration of about 0.5 mg / ml using pH 6.8 phosphate buffer containing different solubilizers, respectively, and placed at room temperature. The precipitation of the drug substance was observed, and the concentration of Compound 1·tromethamine salt in the solution was detected at 33 h. The results are shown in the table below.

[0301] The results show that 0.1% to 0.5% concentration of SDS can effectively inhibit the precipitation of Compound 1·tromethamine salt drug substance in pH 6.8 phosphate buffer; 0.1% to 0.5% concentration of CTAB can also inhibit the precipitation of the drug substance, but its inhibitory effect is slightly worse than that of SDS; and 0.1% to 0.5% concentration of Tween 80 cannot completely inhibit the precipitation of the drug substance.

[0302] Example 6: Formulation pharmaceutical composition

[0303] This example describes an exemplary formulation of the formulation pharmaceutical composition in the form of a bilayer tablet and the verification of the properties.

[0304] The prescription amount of Compound 1 · TROMETHAMINE salt and colloidal silicon dioxide were taken into a mixer, mixed for 2 min, and sieved once through a 60-mesh sieve, and then transferred into a mixer. The prescription amount of microcrystalline cellulose, croscarmellose sodium, and / or low-substituted hydroxypropyl cellulose was weighed, mixed for 5 min, and sodium stearyl fumarate was added and mixed for 1 min to obtain a GLP-1R agonist part. The prescription amount of empagliflozin, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and / or low-substituted hydroxypropyl cellulose, and sodium stearyl fumarate was taken into a mixer, mixed for 2 min, and sieved three times through a 60-mesh sieve, and then transferred into a mixer and mixed for 5 min to obtain an empagliflozin part. The granules and / or powders obtained in the above two steps were mixed, and a bilayer tablet compression punch was selected, and the bilayer tablet was compressed.

[0305] The dissolution of the formulation pharmaceutical composition of the present application was determined according to the first method (basket method) of dissolution and release determination method in Chinese Pharmacopoeia 2020 edition volume IV 0931.

[0306] The results show that when croscarmellose sodium is selected as the disintegrant in the Compound 1 · TROMETHAMINE salt part, compared with low-substituted hydroxypropyl cellulose, Compound 1 · TROMETHAMINE salt achieves significantly faster dissolution and higher dissolution rate, and the platform period lasts longer and is more stable, and empagliflozin also achieves faster dissolution and higher dissolution rate.

[0307] Example 7: Formulation pharmaceutical composition

[0308] This example describes an exemplary formulation of the formulation pharmaceutical composition in the form of a bilayer tablet and the verification of the properties.

[0309] The preparation method of the microtablet of this example is similar to the aforementioned ordinary tablet and / or bilayer tablet. After the preparation of the formulation granules or powder, a microtablet punch is used to compress the microtablet.

[0310] Example 8: Formulation of the formulation pharmaceutical composition

[0311] This example describes an exemplary formulation of the formulation pharmaceutical composition in the form of an ordinary tablet.

[0312] The preparation method of the present embodiment is as follows: the prescription amount of empagliflozin and one or more excipients are mixed, sieved, and then the prescription amount of GLP-1R agonist and the remaining excipients are added into the mixer for mixing, and the mixed material is granulated, sized, mixed with additional pharmaceutical excipients, and then compressed into tablets.

[0313] Example 9: Preparation method of the pharmaceutical composition

[0314] The pharmaceutical composition described in the present application can be a fixed-dose combination formulation, including at least 5 specifications of 50 mg / 10 mg, 100 mg / 10 mg, 200 mg / 10 mg, 300 mg / 10 mg and 400 mg / 10 mg (based on free compound 1 / empagliflozin).

[0315] Example 9.1

[0316] Exemplarily, for the 50 mg / 10 mg and 100 mg / 10 mg specifications, the pharmaceutical composition has the prescription composition described in the following table: [1] : refers to a complete film coating system (gastroresistant) and purified water. As a specific embodiment, the complete film coating system is model 321A180025-CN, white; and the purified water is a dispersion medium for the film coating powder, which is removed in the production process.

[0317] Example 9.2

[0318] Exemplarily, for the 200 mg / 10 mg, 300 mg / 10 mg and 400 mg / 10 mg specifications, the pharmaceutical composition has the prescription composition described in the following table: [1] : refers to a complete film coating system (gastroresistant) and purified water. As a specific embodiment, the complete film coating system is model 321A180025-CN, white; and the purified water is a dispersion medium for the film coating powder, which is removed in the production process.

[0319] Example 10: Preparation method of the pharmaceutical composition

[0320] The pharmaceutical composition described in Example 9 can be prepared by the following exemplary preparation method.

[0321] Premix-1 and Sieving: Add empagliflozin and part of the intragranular microcrystalline cellulose to the hopper mixer and mix at 15 rpm for 5 minutes. The mixture is passed through a 1.0 mm screen once at a speed of 300 rpm - 600 rpm. After sieving, the mixture is transferred to the hopper mixer and mixed at 15 rpm for 5 minutes. The remaining intragranular microcrystalline cellulose is added and mixed at 15 rpm for 5 minutes. The mixture is then passed through a 1.0 mm screen once.

[0322] Add compound 1 · tromethamine salt, anhydrous dibasic calcium phosphate, intragranular croscarmellose sodium, sodium lauryl sulfate and intragranular sodium stearyl fumarate to the hopper mixer and mix at 15 rpm for 5 minutes. The mixture is then passed through a 1.0 mm screen once at a speed of 300 rpm - 600 rpm.

[0323] Premix-2: Pour all sieved materials into the hopper mixer and mix at 15 rpm for 10 minutes.

[0324] Transfer the above premix materials to the dry granulator for dry granulation. Dry granulation is performed according to the following table parameters.

[0325] According to the dry granulation yield, calculate the amount of extragranular microcrystalline cellulose, croscarmellose sodium and sodium stearyl fumarate, and weigh the extragranular excipients for use. Add the dry granulation granules and extragranular excipients to the hopper mixer and mix at 15 rpm for 10 minutes. After mixing, test the mixing uniformity. The final mixture is compressed into tablets.

[0326] Exemplarily, the tablet compression methods for different specifications can refer to:

[0327] Tablet compression for 50 mg / 10 mg specification tablets: Use a 7.0 mm round punch to produce tablets with a weight variation of 150 mg * (1 ± 7.5%). The hardness is controlled at 40 N - 120 N.

[0328] Tablet compression for 100 mg / 10 mg specification tablets: Use a 10.0 mm round punch to produce tablets with a weight variation of 300 mg * (1 ± 5.0%). The hardness is controlled at 40 N - 120 N.

[0329] Tablet compression for 200 mg / 10 mg specification tablets: Use a 15 mm * 8 mm oval punch to produce tablets with a weight variation of 600 mg * (1 ± 5.0%). The hardness is controlled at 100 N - 300 N.

[0330] Tablet compression for 300 mg / 10 mg specification tablets: Use a 17 mm * 8.5 mm oval punch to produce tablets with a weight variation of 900 mg * (1 ± 5.0%). The hardness is controlled at 100 N - 300 N.

[0331] Tabletting of 400 mg / 10 mg strength: Tablets with a weight variation of 1200 mg*(1 ± 5.0%) were produced using 19 mm*9.5 mm oblong punches. The hardness was controlled between 100 N-300 N.

[0332] Optionally, the pharmaceutical composition of the present application can be coated, coated, packaged, etc.

[0333] Illustratively, the coating can be a film coating of Opadry® film coating preblend (Gastroresistant) to coat the tablets with a weight gain ranging from 2.0% to 5.0% of the coating.

[0334] Illustratively, the tablets are packaged in HDPE bottles, 10 tablets per bottle, and contain a sachet of deoxidizing agent.

[0335] Example 11: Pharmaceutical composition of the formulation in a scale-up batch

[0336] This example is based on the pharmaceutical composition of the formulation described in Example 8, which is suitable for industrial scale-up production.

[0337] Illustratively, the batch prescription for 50 mg / 10 mg is shown in the following table:

[0338] Illustratively, the batch prescription for 100 mg / 10 mg is shown in the following table:

[0339] Illustratively, the batch prescription for 200 mg / 10 mg is shown in the following table:

[0340] Illustratively, the batch prescription for 300 mg / 10 mg is shown in the following table:

[0341] Illustratively, the batch prescription for 400 mg / 10 mg is shown in the following table: [1] : refers to the complete film coating system (Gastroresistant) with purified water. As a specific embodiment, the complete film coating system is of the type Opadry® 321 A180025-CN, white; and the purified water is the dispersion medium of the film coating powder, which is removed in the production process.

[0342] The dissolution of the above 400 mg / 10 mg tablets was also investigated in pH 6.8 phosphate buffer (0.1% SDS), pH 2.0 hydrochloric acid solution (0.1% HPC) according to the Chinese Pharmacopoeia 2020 Edition General Test 0931 Dissolution and Release Test Method 1 (Basket Method) as described above (n = 3 for each), the results of which are shown in the following table. Note: 90 min sampling point is after 60 min sampling, increase the rotation speed to 200 rpm and then sample.

[0343] Example 12: Pharmaceutical composition in the form of a bilayer tablet

[0344] This example provides another bilayer tablet exemplary formulation and its dissolution test.

[0345] Exemplarily, the batch formulation of 10 mg / 50 mg is shown in the following table:

[0346] Exemplarily, the batch formulation of 10 mg / 400 mg is shown in the following table: [1] : refers to The complete film coating system (gastroresistant) is with purified water. As a specific embodiment, the complete film coating system is Opadry®. The complete film coating system is Opadry® 321 A180025-CN, white; and the purified water is the dispersion medium of the film coating powder, which is removed in the production process.

[0347] Preparation method

[0348] Preparation of the empagliflozin layer:

[0349] - Premix: weigh the internal additives in a ziplock bag, mix for 5 min, pass through a 40 mesh sieve, and mix for another 10 min;

[0350] - Dry granulation: dry granulate the premixed material, pass through an 18 mesh sieve; and

[0351] - Total mix: add sodium stearyl fumarate, and mix for 5 min.

[0352] Preparation of the Compound 1·tromethamine salt layer:

[0353] - Premix: weigh the internal additives in a ziplock bag, mix for 5 min, pass through a 40 mesh sieve, and mix for another 10 min;

[0354] - Dry granulation: dry granulate the premixed material, pass through an 18 mesh sieve; and

[0355] - Total mix: mix the prepared granules with the external additives for 10 min.

[0356] Tablet compression:

[0357] The 10 mg / 50 mg tablets are compressed using an 11 mm punch; and the 10 mg / 400 mg tablets are compressed using a 21*9.6 mm punch. First fill the Compound 1·tromethamine salt layer, and then fill the empagliflozin layer.

[0358] Coat the 10 mg / 400 mg tablets.

[0359] The dissolution of 10 mg / 400 mg tablets was also investigated in pH 6.8 phosphate buffer (0.1% SDS), pH 4.5 phosphate buffer solution (0.1% SDS), and water (n = 3 for each) according to the Chinese Pharmacopoeia 2020 edition four general rules 0931 dissolution and release determination method first method (basket method) as described above. The results are shown in the table below.

[0360] It was also found that the dissolution profiles of both active ingredients, empagliflozin and Compound 1·tromethamine salt, of the bilayer tablet were similar to those of two tablets of the respective monotherapy formulation in the three dissolution media, pH 6.8 phosphate buffer (0.1% SDS), pH 4.5 phosphate buffer solution (0.1% SDS), and water, as shown in Figures 17, panels A-F.

[0361] The technical features of the above-mentioned embodiments can be combined in any manner. For the sake of brevity, not all possible combinations of the technical features in the above-mentioned embodiments are described, however, as long as the combination of the technical features does not result in a contradiction, it should be considered within the scope of the present disclosure.

[0362] The above-mentioned embodiments only express several implementation manners of the present application, and the description is more specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be noted that for ordinary skilled persons in the art, several modifications and controls can be made without departing from the concept of the present application, and these are within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the appended claims.

Claims

1. A combination pharmaceutical composition comprising (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin.

2. The combination pharmaceutical composition of claim 1, wherein: the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin are present in the same pharmaceutical composition; or the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin are each in the form of a pharmaceutical composition; or the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin are packaged in the same kit, the kit further comprising instructions for using the (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin in combination to treat or prevent a metabolic or renal class of diseases.

3. The combination pharmaceutical composition of claim 1 or 2, comprising a pharmaceutical composition of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of empagliflozin.

4. The combination pharmaceutical composition of claim 3, wherein: the pharmaceutical composition of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are formulated as a single pharmaceutical composition, the pharmaceutical composition of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are formulated as separate pharmaceutical compositions, or the pharmaceutical composition of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are packaged in the same kit, the kit further comprising instructions for using the (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin in combination to treat or prevent a metabolic or renal class of diseases. ​ ​ ​ ​ Preferably, the pharmaceutical composition of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are mixed uniformly together; or The pharmaceutical composition of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are formulated into a multi-layer structure (preferably a bilayer tablet or a multi-layer tablet), wherein each layer in the multi-layer structure is prepared from one of the pharmaceutical composition of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin, and the layer prepared from the pharmaceutical composition of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the layer prepared from the pharmaceutical composition of empagliflozin that are adjacent are in direct contact or are separated by an intervening layer, wherein the intervening layer comprises a pharmaceutically acceptable excipient or adjuvant, and comprises or does not comprise the active ingredients selected from (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin; or The pharmaceutical composition of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin are packaged in the same kit, which further comprises an instruction for using the pharmaceutical composition of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of empagliflozin in combination to treat or prevent metabolic or renal diseases.

5. The combined pharmaceutical composition of any one of claims 1-4, wherein: the pharmaceutically acceptable salt of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid is selected from the group consisting of a methanesulfonate salt, a meglumine salt, and a tromethamine salt, preferably (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid · tromethamine salt.

6. The combined pharmaceutical composition of any one of claims 1-5, which contains 10-600 mg, 20-400 mg, 25-300 mg, 50-250 mg, 75-200 mg, or 100-150 mg of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, based on (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; or which contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, based on (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; or which contains 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 600 mg of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

7. The combination pharmaceutical composition according to claim 6 or 6, wherein the pharmaceutical composition of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is in a single dose or multiple doses; and / or, the pharmaceutical composition of empagliflozin is in a single dose or multiple doses.

8. The combination pharmaceutical composition according to any one of claims 1 to 7, which contains 2.5 to 50 mg, 5 to 25 mg, 10 to 20 mg, or 12.5 to 15 mg of empagliflozin, or a pharmaceutical composition thereof; or, which contains 10 mg or 25 mg of empagliflozin, or a pharmaceutical composition thereof.

9. The combination pharmaceutical composition according to any one of claims 1 to 8, wherein: the combination pharmaceutical composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, based on the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; and contains 5 mg, 10 mg, 12.5 mg, or 25 mg of empagliflozin. Preferably, the combination pharmaceutical composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg, preferably 50 mg, 100 mg, 150 mg, or 200 mg, of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, calculated as the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; and contains 10 mg of empagliflozin; or The combination pharmaceutical composition contains 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg, preferably 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, calculated as the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; and contains 12.5 mg of empagliflozin; or The combination pharmaceutical composition contains 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 600 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg, of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, calculated as the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; and contains 25 mg of empagliflozin. 10.The combination pharmaceutical composition according to any one of claims 1-9, wherein the combination pharmaceutical composition contains the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and the empagliflozin or a pharmaceutical composition thereof in a mass ratio of 1:1 to 100:1, 1.5:1 to 75:1, 2:1 to 60:1, 2.5:1 to 50:1, 3:1 to 40:1, 4:1 to 30:1, 5:1 to 25:1, 6:1 to 20:1, 8:1 to 15:1, or 10:1 to 12:1, preferably 4:1 to 30:1, 5:1 to 25:1, 6:1 to 20:1, 8:1 to 15:1, or 10:1 to 12:1, more preferably 4:1 to 20:1, 5:1 to 20:1, 6:1 to 20:1, 8:1 to 15:1, or 10:1 to 12:1, or any ratio within the above ranges, wherein the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is based on the mass of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, and the empagliflozin or a pharmaceutical composition thereof is based on the mass of the empagliflozin. More preferably, wherein the mass ratio of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and the empagliflozin or a pharmaceutical composition thereof is 5:1, 10:1, 20:1, 30:1, or 40:1, wherein the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is based on the mass of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, and the empagliflozin or a pharmaceutical composition thereof is based on the mass of the empagliflozin.

11. A formulation pharmaceutical composition comprising a GLP-1R agonist moiety, an empagliflozin moiety, and a pharmaceutically acceptable excipient, wherein the GLP-1R agonist is (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, preferably wherein the pharmaceutically acceptable salt of (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid is selected from the group consisting of a mesylate salt, a meglumine salt, and a tromethamine salt, preferably (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid · tromethamine salt.

12. The formulation pharmaceutical composition of claim 11, wherein: the GLP-1R agonist moiety comprises the following components in mass percent: 20-40% of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, 50-66.5% of a filler, 2-6% of a glidant, 1-3% of a lubricant, and 3-6.5% of a disintegrant; or 20-30% or 30-40% of the (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, 50-60% of a filler, 2-4% of a glidant, 1-3% of a lubricant, and 3-6% of a disintegrant; and / or the empagliflozin moiety comprises the following components in mass percent: 5-25% empagliflozin, 66.5-93% of a filler, 0.1-1% of a glidant, 1.5-6% of a lubricant, and 0.5-2% of a disintegrant; or 5-25% empagliflozin, 66.5-92.5% of a filler, 0.25-1% of a glidant, 1.5-3% of a lubricant, and 0.5-2% of a disintegrant.

13. The formulation pharmaceutical composition of claim 11, wherein: the formulation pharmaceutical composition comprises the following components in total weight of the formulation pharmaceutical composition: about 10-50%, 12-30%, 15-32%, 18-35%, 20-38%, 22-40%, 24-42%, 26-45%, or 28-48% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; tromethamine; about 1-20% or 1-10% of empagliflozin; about 40-90%, 50-85%, 60-80%, 65-75%, 60-70%, 62-68%, or 64-66% of a filler; about 1-20%, 1.5-18%, 2-16%, 2.5-15%, 3-12%, 3.5-10%, 4-8%, 4.5-7%, or 5-6% of a disintegrant; about 0.2-6%, 0.4-5.5%, 0.6-5%, 0.8-4.5%, 1-4%, 1.2-3.5%, 1.5-3%, 1.8-2.7%, 2-2.5%, or 2.1-2.4% of a lubricant; about 0-5%, 0.2-5%, 0.4-4.5%, 0.6-4%, 0.8-3.5%, 1-3%, 1.2-2.5%, 1.4-2%, or 1.6-1.8% of a glidant; about 0-5%, 0.2-4.5%, 0.4-4%, 0.6-3.5%, 0.8-3%, 1-2.5%, 1.2-2%, or 1.5-1.8% of a solubilizer; and / or the mass ratio of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; tromethamine salt and empagliflozin in the formulation pharmaceutical composition is 1:1-100:1, 1.5:1-75:1, 2:1-60:1, 2.5:1-50:1, 3:1-40:1, 4:1-30:1, 5:1-25:1, 6:1-20:1, 8:1-15:1, 10:1-12:1, or any ratio within the above ranges; preferably 20:1-4:1, 20:1, 15:1, 12:1, 10:1, 8:1, 6:1, 5:1, or 4:

1.

14. The pharmaceutical formulation composition of claim 11, wherein, the formulation pharmaceutical composition comprises the following components in mass percentage: about 10-50%, 12-30%, 15-32%, 18-35%, 20-38%, 22-40%, 24-42%, 26-45%, or 28-48% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; tromethamine; about 1-20% or 1-10% of empagliflozin; about 40-90%, 50-85%, 60-80%, 65-75%, 60-70%, 62-68%, or 64-66% of a filler; about 1-20%, 1.5-18%, 2-16%, 2.5-15%, 3-12%, 3.5-10%, 4-8%, 4.5-7%, or 5-6% of a disintegrant; about 0.2-6%, 0.4-5.5%, 0.6-5%, 0.8-4.5%, 1-4%, 1.2-3.5%, 1.5-3%, 1.8-2.7%, 2-2.5%, or 2.1-2.4% of a lubricant; about 0-5%, 0.2-5%, 0.4-4.5%, 0.6-4%, 0.8-3.5%, 1-3%, 1.2-2.5%, 1.4-2%, or 1.6-1.8% of a glidant; about 0-5%, 0.2-4.5%, 0.4-4%, 0.6-3.5%, 0.8-3%, 1-2.5%, 1.2-2%, or 1.5-1.8% of a solubilizer; and / or the mass ratio of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid; tromethamine salt and empagliflozin in the formulation pharmaceutical composition is 1:1-100:1, 1.5:1-75:1, 2:1-60:1, 2.5:1-50:1, 3:1-40:1, 4:1-30:1, 5:1-25:1, 6:1-20:1, 8:1-15:1, 10:1-12:1, or any ratio within the above ranges; preferably 20:1-4:1, 20:1, 15:1, 12:1, 10:1, 8:1, 6:1, 5:1, or 4:

1. the formulation pharmaceutical composition comprises the following components in mass percentage: 10% to 50% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 0.5% to 10% of empagliflozin, 40% to 70% of a filler, 0 to 5% of a glidant, 0.5% to 5% of a lubricant, and 1% to 10% of a disintegrant; or 20% to 50% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 0.5% to 10% of empagliflozin, 40% to 80% of a filler, 0.5% to 5% of a glidant, 0.5% to 5% of a lubricant, and 1% to 10% of a disintegrant; or 10% to 50% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 0.5% to 10% of empagliflozin, 40% to 70% of a filler, 0 to 5% of a glidant, 0.5% to 5% of a lubricant, 1% to 10% of a disintegrant, and 0 to 5% of a solubilizer; or 15% to 30% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 1% to 10% of empagliflozin, 50% to 80% of a filler, 0.5 to 5% of a glidant, 0.5% to 5% of a lubricant, and 1% to 10% of a disintegrant; or 22.3% to 22.6% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 1.8% to 1.9% of empagliflozin, 65% to 68% of a filler, 1.2 to 1.4% of a glidant, 2.4% of a lubricant, and 4% of a disintegrant; or 22.3% to 22.6% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 1.8% to 1.9% of empagliflozin, 66% of a filler, 1.2 to 1.3% of a glidant, 2.4% of a lubricant, and 4% of a disintegrant; or 30% to 50% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 0.5% to 10% of empagliflozin, 40% to 60% of a filler, 0% to 1.5% of a glidant, 0.5% to 5% of a lubricant, 1% to 10% of a disintegrant, and 0 to 1.5% of a solubilizer; or 30% to 50% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 0.8% to 7% of empagliflozin, 40% to 60% of a filler, 0 to 1.5% of a glidant, 3% to 3.5% of a lubricant, 4% to 6.5% of a disintegrant, and 1% to 1.2% of a solubilizer; or 40% to 42.5% of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid · tris(hydroxymethyl)methylammonium salt, 0.8% to 6.7% of empagliflozin, 42% to 50% of a filler, 0 to 1.5% of a glidant, 3% to 3.2% of a lubricant, 4% to 6.5% of a disintegrant, and 1% to 1.2% of a solubilizer.

15. The pharmaceutical composition of any one of claims 12-14, wherein: the filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, dextrose, lactose, sucrose, mannitol, starch, pregelatinized starch, calcium phosphate, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate; the glidant is selected from one or more of colloidal silicon dioxide, magnesium trisilicate, talc, tribasic calcium phosphate, stearate, and colloidal silicon dioxide; the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, hydrogenated vegetable oil, glyceryl monostearate, and glyceryl monostearate, preferably one or more of magnesium stearate, sodium stearyl fumarate; the disintegrant is selected from one or more of microcrystalline cellulose, crosscarmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, dry starch, corn starch, hydroxymethyl starch, sodium carboxymethyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, preferably one or more of crosscarmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch, further more preferably croscarmellose sodium; the solubilizer is selected from one or more of sodium lauryl sulfate, hydroxypropyl betadex, sulfobutyl betadex sodium, Tween 80, vitamin E succinate polyethylene glycol ester, and poloxamer, preferably sodium lauryl sulfate.

16. A kit comprising: (a) a first pharmaceutical composition comprising (S)-2-((4-(6-((2-fluoro-4- (oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition comprising empagliflozin; The kit optionally further comprises instructions for using the first pharmaceutical composition and the second pharmaceutical composition in combination to treat or prevent a metabolic or renal condition.

17. Use of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2- yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin for the manufacture of a combined pharmaceutical composition for the prevention or treatment of a metabolic or renal condition, wherein the combined pharmaceutical composition is as defined in any one of claims 1-10.

18. A method of treating and / or preventing a metabolic or renal condition, comprising administering to a subject in need thereof a therapeutically effective amount of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof and empagliflozin, preferably administering a therapeutically effective amount of the combined pharmaceutical composition of any one of claims 1-10, or the formulation pharmaceutical composition of any one of claims 11-15, or the kit of claim 15, or administering a therapeutically effective amount of (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and administering a therapeutically effective amount of empagliflozin, or a pharmaceutical composition thereof, separately.

19. Use of the combined pharmaceutical composition of any one of claims 1-10 and the formulation pharmaceutical composition of any one of claims 11-15 for the manufacture of a medicament for the treatment and / or prevention of a metabolic or renal condition.

20. The combined pharmaceutical composition of claim 2 or 4, the kit of claim 16, the use of claim 17, the method of claim 18, or the use of claim 19, wherein: the metabolic or renal condition is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, hyperuricemia, chronic kidney disease, kidney injury, chronic renal failure, and hypertensive nephropathy; Preferably, said metabolic or renal-like disease is selected from the group consisting of diabetes, chronic kidney disease, kidney impairment, more preferably diabetes and chronic kidney disease.

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