Therapeutic use of pharmaceutical compositions containing insulin derivatives

Abstract

This relates to the use of a combination or composition of pharmaceuticals containing two active ingredients, an insulin derivative and a rapid-acting insulin, in the treatment of diabetes. A method is provided for treating or preventing metabolic syndrome and type II diabetes in a subject of need by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. A kit containing instructions for treatment according to said method is also provided.

Description

Therapeutic use of pharmaceutical compositions comprising insulin derivatives

[0001] This application claims priority to Chinese patent application 202311480982.4 with an application date of November 8, 2023, Chinese patent application 202410702342.1 with an application date of June 2, 2024, and Chinese patent application 202411090791.1 with an application date of August 9, 2024. The full text of the above three applications is incorporated into this application by reference. Technical Field

[0002] The present invention relates to the field of pharmaceutical applications of drugs, and in particular to the application of a drug containing two active ingredients, an insulin derivative and a fast-acting insulin, in the treatment of type II diabetes. Background Art

[0003] Diabetes is a metabolic disease characterized by hyperglycemia. Long-term high blood sugar levels can lead to chronic damage and dysfunction in various tissues, particularly the eyes, kidneys, heart, blood vessels, and nerves. Most diabetics suffer from type 2 diabetes. While oral antidiabetic medications and insulin are currently available, some patients still respond poorly to these medications. Therefore, there is an unmet need for medications to control blood sugar for these patients.

[0004] Summary of the Invention

[0005] In some embodiments, the present invention relates to a method for treating type 2 diabetes, comprising administering a therapeutically effective amount of a pharmaceutical composition to an adult patient with type 2 diabetes who is poorly controlled with oral hypoglycemic agents, or an adult patient with type 2 diabetes who is previously poorly controlled with basal / premixed insulin, wherein the method can achieve effective glycemic control within a certain dosage. The dosing regimen described herein provides benefits for the use of the compound of formula (I) in treating type 2 diabetes, maximizing its glucose-lowering efficacy and reducing or eliminating adverse side effects caused by its glucose-lowering properties.

[0006] The present invention provides a method for treating metabolic syndrome, comprising administering a combination of a compound having a structure of formula (I) and insulin aspart to a subject in need thereof, wherein the total dose of the compound having a structure of formula (I) and insulin aspart is about 5 U to 200 U, preferably about 5 U to 50 U, and preferably the total dose of each administration is independently the same or different; preferably, when administering the combination of the compound having a structure of formula (I) and insulin aspart, the compound having a structure of formula (I) and insulin aspart are administered together or separately; preferably, when administering the combination of the compound having a structure of formula (I) and insulin aspart, the compound having a structure of formula (I) and insulin aspart are administered simultaneously; preferably, the combination of the compound having a structure of formula (I) and insulin aspart is a pharmaceutical composition comprising the compound having a structure of formula (I) and insulin aspart;

[0007] In some embodiments, the metabolic syndrome is diabetes; preferably, the diabetes is type 2 diabetes.

[0008] In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of formula (I) and insulin aspart, wherein the total dose of the compound of formula (I) and insulin aspart is 5 U to 200 U, preferably about 5 U to 50 U; preferably, the total dose of each administration is independently the same or different;

[0009] Preferably, the metabolic syndrome is diabetes; preferably, the diabetes is type 2 diabetes.

[0010] In some embodiments, in the combination of the compound of formula (I) and insulin aspart, and in the pharmaceutical composition containing the compound of formula (I) and insulin aspart, the molar percentage of the compound of formula (I) in the combination or pharmaceutical composition is about 50%-99%; preferably, the molar percentage of the compound of formula (I) in the combination or pharmaceutical composition is about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95%; preferably, the molar percentage of the compound of formula (I) in the combination or pharmaceutical composition is about 50%, about 60%, about 70% or about 80%; preferably, the molar ratio of the compound of formula (I) to insulin aspart is 1:1 or 7:3.

[0011] In some embodiments, the total daily dose of the compound of formula (I) and insulin aspart is about 5U-200U, preferably about 5U-50U, preferably about 5U, about 6U, about 7U, about 8U, about 9U, about 10U, about 11U, about 12U, about 13U, about 14U, about 15U, about 16U, about 17U, about 18U, about 19U, about 20U, about 21U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U , about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 55U, about 60U, about 65U, about 70U, about 75U, about 80U, about 85U, about 90U, about 95U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U.

[0012] In some embodiments, the total dose administered each day is independently the same or different.

[0013] In some embodiments, the method comprises administering to a subject in need thereof a combination of a compound of formula (I) and insulin aspart, or administering a pharmaceutical composition containing a compound of formula (I) and insulin aspart, once a day or less, preferably with the total doses of each administration being independently the same or different.

[0014] In some embodiments, the method comprises administering to a subject in need thereof once a day or less frequently and with a total administration dose of about 5-200 U, preferably about 5-50 U, a compound of formula (I) and insulin aspart, preferably administering to a subject in need thereof once a day or less frequently and with a total administration dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 About 200U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, about 300U, about 310U, about 320U, about 330U, about 340U, about 350U, about 360U, about 370U, about 380U, about 390U, about 400U, about 410U, about 420U, about 430U, about 440U, about 450U, about 460U, about 470U, about 480U, about 490U, about 500U, about 550U, about 600U, about 650U, about 700U, about 750U, about 800U, about 850U, about 900U, about 950U, about 1000U, about 1100U, about 1200U, about 1300U, about 1400U, about 1500U, about 1600U, about 1700U, about 1800U, about 1900U, or about 2000U.

[0015] In some embodiments, for subjects who were previously taking once-daily basal or premixed insulin, when switching to a combination of a compound of formula (I) and insulin aspart, or a pharmaceutical composition containing a compound of formula (I) and insulin aspart, the total starting dose of the compound of formula (I) and insulin aspart is about 50%-90%, preferably about 60%-85%, preferably about 70%-80%, and preferably about 50%, about 60%, about 70%, about 75% or about 80% of the total daily dose of the previous basal or premixed insulin.

[0016] In some embodiments, the method further comprises administering the compound of formula (I) and insulin aspart to a subject in need thereof at the starting dose, and then administering the compound of formula (I) and insulin aspart once a day or less frequently. The total dose of each administration may be the same as or different from the starting dose. Preferably, the total dose of each administration is determined based on the individual condition of the subject.

[0017] In some embodiments, the method comprises administering the combination of the compound of formula (I) and insulin aspart, or administering a pharmaceutical composition containing the compound of formula (I) and insulin aspart, to a subject in need thereof once a day or less frequently and with a total administration dose of about 5-200 U, preferably about 5-50 U, as a starting dose. Preferably, the compound of formula (I) and insulin aspart are administered to a subject in need thereof once a day or less frequently and with a total administration dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 0U, about 21U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U , about 47U, about 48U, about 49U, about 50U, about 55U, about 60U, about 65U, about 70U, about 75U, about 80U, about 85U, about 90U, about 95U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U.

[0018] In some embodiments, after 1 day, 2 days, 3 days or 4 days of administration at the starting dose, or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks of administration, a total dose of M of the compound of formula (I) and insulin aspart is administered once a day, and the dose M administered each day is the same or different, and each is independently about 1U-200U, preferably about 1U-70U, preferably each is independently about 1U, about 2U, about 3U, about 4U, about 5U, about 6U, about 7U, about 8U, about 9U, about 10U, about 11U, about 12U, about 13U, about 14U, about 15U, about 16U, about 17U, about 18U, about 19U, about 20U, about 21U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about about 18U, about 19U, about 20U, about 21U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 55 U, about 60 U, about 65 U, about 70 U, about 75 U, about 80 U, about 85 U, about 90 U, about 95 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, or about 200 U.

[0019] In some embodiments, the method comprises administering to a subject in need thereof a compound of formula (I) and insulin aspart once a day or less frequently at a total dose of about 5-200 U as a starting dose, preferably administering to a subject in need thereof a compound of formula (I) and insulin aspart once a day or less frequently at a total dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 7 About 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 55U, about 60U, about 65U, about 70U, about 75U, about 80U, about 85U, about 90U, about 95U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U.

[0020] In some embodiments, the daily dose M administered is adjusted daily, weekly, or more frequently after 1, 2, 3, or 4 days of administration, or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks of administration at the starting dose.

[0021] In some embodiments, the dose M administered daily is adjusted daily, weekly, or more frequently according to the following rules:

[0022] a) when the subject's fasting blood glucose value before administration is 3.9-4.3 mmol / L, or when the average fasting peripheral blood glucose value before breakfast for three consecutive times 2 days or 3 days before administration is 3.9-4.3 mmol / L, the administered dose M needs to be adjusted to be reduced by about 1 U-6 U, preferably by about 1 U-4 U, preferably by about 1 U, about 2 U, about 3 U or about 4 U relative to the previous administered dose; or

[0023] b) when the subject's fasting blood glucose value before administration is 4.4-6.1 mmol / L, or when the average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days or 3 days before administration is 4.4-6.1 mmol / L, the administered dose M is the previous administered dose; or

[0024] c) when the subject's fasting blood glucose value before administration is 6.2-7.0 mmol / L, or when the subject's average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days or 3 days before administration is 6.2-7.0 mmol / L, the administered dose M needs to be adjusted to increase by about 1 U to 4 U, preferably by about 1 U, about 2 U, about 3 U or about 4 U relative to the previous administered dose; or

[0025] d) when the subject's fasting blood glucose value before administration is 7.1-8.0 mmol / L, or when the subject's average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days or 3 days before administration is 7.1-8.0 mmol / L, the administered dose M needs to be adjusted to increase by about 2 U to 6 U, preferably by about 3 U, about 4 U, about 5 U or about 6 U relative to the previous administered dose; or

[0026] e) when the subject's fasting blood glucose value before administration is 8.1-9.0 mmol / L, or when the subject's average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days or 3 days before administration is 8.1-9.0 mmol / L, the administered dose M needs to be adjusted to increase by about 4 U to 8 U, preferably by about 5 U, about 6 U, about 7 U or about 8 U relative to the previous administered dose; or

[0027] f) If the subject's fasting blood glucose value is > 9.0 mmol / L on the day before administration, or if the subject's average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days or 3 days before administration is > 9.0 mmol / L, the administered dose M needs to be adjusted to increase by about 6 U to 10 U, preferably by about 7 U, about 8 U, about 9 U or about 10 U relative to the previous administered dose; or

[0028] g) when the subject's fasting blood glucose value is ≤3.0 mmol / L before administration, or when the subject's lowest fasting peripheral blood glucose value before breakfast is ≤3.0 mmol / L for three consecutive times 2 days or 3 days before administration, the administered dose M needs to be adjusted to a dose reduced by about 1 U-8 U, preferably by about 2 U-6 U, preferably by about 3 U, about 4 U or about 5 U relative to the previous administered dose; or when the previous administered dose is >45 U, the administered dose M needs to be adjusted to a dose reduced by 5% to 15% relative to the previous administered dose, preferably by 10%; or

[0029] h) When the subject's fasting blood glucose value is 3.1-3.8 mmol / L before administration, or when the subject's lowest fasting peripheral blood glucose value before breakfast is 3.1-3.8 mmol / L for three consecutive times 2 days or 3 days before administration, the administered dose M needs to be adjusted to a dose reduced by about 1U-4U, preferably by about 1U-3U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose; or when the previous administered dose is greater than 45U, the administered dose M needs to be adjusted to a dose reduced by 2% to 10% relative to the previous administered dose, preferably by 5%.

[0030] In some embodiments, the subject is a patient with type 2 diabetes who is not well controlled by oral hypoglycemic drugs; or the subject is a patient with diabetes who was previously poorly controlled by basal insulin or premixed insulin; or the subject is a patient with type 2 diabetes who was previously poorly controlled by basal insulin or premixed insulin; or the subject is a patient with type 2 diabetes who was previously poorly controlled by once-a-day basal insulin or at least once-a-day premixed insulin, with or without pre-dinner insulin.

[0031] In some embodiments, the subject's BMI is between 10-50 kg / m 2 between 18.5-35kg / m 2 and / or

[0032] have an HbA1c of 7.5%-11.0%; and / or

[0033] Fasting venous blood glucose ≥7.0mmol / L; and / or

[0034] The patient has received one or more oral hypoglycemic drugs, preferably up to three oral hypoglycemic drugs, and the oral hypoglycemic drugs include metformin, and also include oral hypoglycemic drugs selected from DPP-4i, α-glucosidase inhibitors, SGLT2 inhibitors, and glucokinase activators in combination or not.

[0035] In some embodiments, the combination of the compound of formula (I) and insulin aspart, or the pharmaceutical composition containing the compound of formula (I) and insulin aspart, is administered at a fixed or irregular time before any meal, preferably before breakfast.

[0036] In some embodiments, the combination of the compound of formula (I) and insulin aspart, or the pharmaceutical composition containing the compound of formula (I) and insulin aspart, is administered by subcutaneous injection, preferably abdominal subcutaneous injection.

[0037] In some embodiments, the combination of a compound of formula (I) and insulin aspart, or a pharmaceutical composition comprising a compound of formula (I) and insulin aspart, is administered long-term, preferably for at least 4 weeks, preferably for at least 8 weeks, preferably for at least 16 weeks, preferably for at least 20 weeks, preferably for at least 25 weeks, and preferably for at least 32 weeks.

[0038] In some embodiments, when the subject is a diabetic patient who has previously been poorly controlled with basal and / or premixed insulin, the method further comprises administering insulin aspart alone to the subject, preferably administering insulin aspart alone before dinner every day.

[0039] In some embodiments, the method comprises administering to a subject in need thereof once a day or less frequently at a total dose of 50% to 100% of the total daily dose of previous basal and / or premixed insulin as a starting dose; and / or

[0040] Further, insulin aspart is administered once daily or twice daily at a total dose of 0% to 50% of the previous total daily dose of basal and / or premixed insulin as a starting dose;

[0041] Wherein, the compound of formula (I) and insulin aspart are administered at a first time point, the insulin aspart is administered at a second time point, and / or the insulin aspart is administered at a second time point and / or a third time point;

[0042] Preferably, the method comprises administering to a subject in need thereof once a day or less frequently at a first time point a total dose of 60%, 70%, 80%, 90% or 100% of the total daily dose of previous basal and / or premixed insulin as a starting dose; and / or

[0043] Furthermore, insulin aspart is administered once a day or twice a day at the second and / or third time points with a total dose of 5%, 10%, 15%, 20% or 40% of the total daily dose of previous basal and / or premixed insulin as a starting dose.

[0044] In some embodiments, the method comprises administering a compound having the structure of formula (I) and insulin aspart at a total dose of N once a day after administering the starting dose for one week and / or further administering insulin aspart at a dose of O once a day or twice a day, the dose N administered each day is the same or different, and / or the O administered each day is the same or different, wherein N and O are each independently 0%-100% of the total daily dose of previous basal and / or premixed insulin, preferably each independently 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the total daily dose of previous basal and / or premixed insulin.

[0045] In some embodiments, the method comprises administering the compound of formula (I) and insulin aspart once a day for a total dose of N after one week of administration at the starting dose, and / or further administering insulin aspart at a dose of O once a day or twice a day, the dose N administered each day is the same or different, and / or the O administered each day is the same or different, wherein N and O are each independently 0%-100% of the total daily dose of previous basal and / or premixed insulin, preferably each independently 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the total daily dose of previous basal and / or premixed insulin;

[0046] After 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks of administration at the initial dose, the daily doses of N and O are adjusted weekly or more frequently.

[0047] In some embodiments, the dose N administered daily is adjusted weekly or more frequently according to the following rules:

[0048] a) when the subject's fasting blood glucose value before administration is 3.9-4.3 mmol / L, or when the average of the subject's three consecutive pre-meal peripheral blood glucose values ​​before administration is 3.9-4.3 mmol / L, the administered dose N needs to be adjusted to be reduced by about 1 U-6 U, preferably by about 1 U-4 U, preferably by about 1 U, about 2 U, about 3 U or about 4 U relative to the previous administered dose; or

[0049] b) when the subject's fasting blood glucose value is 4.4-6.1 mmol / L before administration, or when the average value of the subject's three consecutive pre-meal blood glucose values ​​is 4.4-6.1 mmol / L before administration, the administered dose N is the previous administered dose; or

[0050] c) when the subject's fasting blood glucose value is 6.2-7.0 mmol / L before administration, or when the subject's average pre-meal blood glucose value for three consecutive times before administration is 6.2-7.0 mmol / L, the administered dose N needs to be adjusted to increase by about 1 U-4 U, preferably by about 1 U, about 2 U, about 3 U or about 4 U relative to the previous administered dose; or

[0051] d) when the subject's fasting blood glucose value before administration is 7.1-8.0 mmol / L, or when the average of the subject's three consecutive pre-meal peripheral blood glucose values ​​before administration is 7.1-8.0 mmol / L, the administered dose N needs to be adjusted to increase by about 2 U to 6 U, preferably by about 3 U, about 4 U, about 5 U or about 6 U relative to the previous administered dose; or

[0052] e) when the subject's fasting blood glucose value before administration is 8.1-9.0 mmol / L, or when the subject's average pre-meal blood glucose value for three consecutive times before administration is 8.1-9.0 mmol / L, the administered dose N needs to be adjusted to increase by about 4 U to 8 U, preferably by about 5 U, about 6 U, about 7 U or about 8 U relative to the previous administered dose; or

[0053] f) When the subject's fasting blood glucose value is >9.0 mmol / L before administration, or when the average of the subject's three consecutive pre-meal peripheral blood glucose values ​​is >9.0 mmol / L before administration, the administered dose N needs to be adjusted to increase by about 6 U to 10 U, preferably by about 7 U, about 8 U, about 9 U or about 10 U relative to the previous administered dose; or

[0054] g) when the subject's fasting blood glucose value is ≤3.0 mmol / L before administration, or when the subject's lowest peripheral blood glucose value before three consecutive meals is ≤3.0 mmol / L before administration, the administered dose N needs to be adjusted to a dose reduced by about 1 U-8 U, preferably by about 2 U-6 U, preferably by about 3 U, about 4 U or about 5 U relative to the previous administered dose; or when the previous administered dose is >45 U, the administered dose M needs to be adjusted to a dose reduced by 5% to 15% relative to the previous administered dose, preferably by 10%; or

[0055] h) When the subject's fasting blood glucose value is 3.1-3.8 mmol / L before administration, or when the subject's lowest peripheral blood glucose value before meals is 3.1-3.8 mmol / L for three consecutive times before administration, the administered dose N needs to be adjusted to a dose reduced by 1U-4U, preferably by 1U-3U, preferably by 1U, 2U or 3U relative to the previous dose; or when the previous administered dose is greater than 45U, N needs to be adjusted to a dose reduced by 2% to 10% relative to the previous dose, preferably by 5%.

[0056] In some embodiments, the daily dose administered is adjusted weekly or more frequently according to the following rules:

[0057] a) If the subject's lowest blood glucose level 2 hours after meals is less than 6.1 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to a decrease of about 1U-4U, preferably about 1U, about 2U or about 3U relative to the previous administered dose; or

[0058] b) If the subject's lowest blood glucose level 2 hours after meals for three consecutive times before administration is 6.1-6.9 mmol / L, the administered dose O is the previous administered dose; or

[0059] c) when the lowest blood glucose level of the subject 2 hours after meals for three consecutive times before administration is 7.0-7.8 mmol / L, the administered dose O needs to be adjusted to increase by about 0U-4U relative to the previous administered dose, preferably by about 0U, about 1U, about 2U or about 3U; or

[0060] d) when the subject's lowest blood glucose level 2 hours after meals for three consecutive times before administration is 7.9-10.0 mmol / L, the administered dose O needs to be adjusted to increase by about 0 U-4 U, preferably by about 0 U, about 1 U, about 2 U, or about 3 U relative to the previous administered dose; or

[0061] e) When the subject's lowest blood glucose value 2 hours after meals for three consecutive times before administration is ≥10.0 mmol / L, the administered dose O needs to be adjusted to increase by about 2 U to 5 U relative to the previous administered dose, preferably by about 2 U, about 3 U, about 4 U or about 5 U.

[0062] f) In some embodiments, the adjustment rule is further adjusted according to the previous dose of insulin aspart. When the dose of insulin aspart is less than 15U,

[0063] e) if the subject's lowest blood glucose level 2 hours after meals is less than 6.1 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to a decrease of about 1U-4U, preferably about 1U, about 2U or about 3U relative to the previous administered dose; or

[0064] f) If the subject's lowest blood glucose level 2 hours after meals for three consecutive times before administration is 6.1-7.8 mmol / L, the administered dose O is the previous administered dose; or

[0065] g) when the subject's 2-hour postprandial blood glucose nadir is 7.9-10.0 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to increase by about 1 U-4 U, preferably by about 1 U, about 2 U, or about 3 U relative to the previous administered dose; or

[0066] h) if the subject's lowest blood glucose level 2 hours after meals for three consecutive times before administration is ≥10.0 mmol / L, the administered dose O needs to be adjusted to increase the previous dose by about 2 U to 4 U, preferably by about 2 U, about 3 U, or about 4 U; or

[0067] When the dose of insulin aspart is ≥15U,

[0068] a) If the subject's lowest blood glucose level 2 hours after meals is less than 6.1 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to a decrease of about 1U-4U, preferably about 1U, about 2U or about 3U relative to the previous administered dose; or

[0069] b) If the subject's lowest blood glucose level 2 hours after meals for three consecutive times before administration is 6.1-6.9 mmol / L, the administered dose O is the previous administered dose; or

[0070] c) when the lowest blood glucose level of the subject 2 hours after meals for three consecutive times before administration is 7.0-7.8 mmol / L, the administered dose O is increased by about 1U-3U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose; or

[0071] d) when the subject's 2-hour postprandial blood glucose nadir is 7.9-10.0 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to increase by about 2 U to 4 U, preferably by about 2 U, about 3 U, or about 4 U relative to the previous administered dose; or

[0072] e) When the lowest blood glucose value of the subject 2 hours after meals for three consecutive times before administration is ≥10.0 mmol / L, the administered dose O needs to be adjusted to increase by about 3U-5U relative to the previous administered dose, preferably by about 3U, about 4U or about 5U.

[0073] In some embodiments, the first time point, the second time point and the third time point are arbitrarily selected from before breakfast, before lunch, and before dinner, respectively; preferably, the first time point is before breakfast, the second time point is before dinner, and the third time point is before lunch.

[0074] In some embodiments, the subject's BMI is between 10-50 kg / m 2 between 18.5-35kg / m 2 between; and / or

[0075] have an HbA1c of 7.5%-11.0%; and / or

[0076] Fasting venous blood glucose ≥7.0mmol / L; and / or

[0077] The patient has received one or more oral hypoglycemic drugs, preferably up to three oral hypoglycemic drugs in combination with one basal insulin or premixed insulin, wherein the basal insulin / premixed insulin is administered no more than twice a day, with a daily dose of about 10U-100U, and the basal insulin / premixed insulin is combined with a stable dose of oral hypoglycemic drugs for ≥3 months.

[0078] In some embodiments, the oral hypoglycemic drug includes metformin, which is further combined with or not combined with oral hypoglycemic drugs, and the oral hypoglycemic drugs include DPP4 inhibitors (DPP-4i), α-glucosidase inhibitors, SGLT2 inhibitors, glucokinase activators, sulfonylureas, and glinides.

[0079] In some embodiments, the pharmaceutical composition is administered by subcutaneous injection, preferably by subcutaneous injection into the abdomen.

[0080] In some embodiments, the pharmaceutical composition is administered in combination with insulin aspart for a long term, preferably for at least 4 weeks, preferably for at least 8 weeks, preferably for at least 16 weeks, preferably for at least 20 weeks, preferably for at least 25 weeks, and preferably for at least 32 weeks.

[0081] In some embodiments, the subject further takes metformin orally daily.

[0082] In some embodiments, in the pharmaceutical composition containing the compound of formula (I) and insulin aspart, the content of the compound of formula (I) is about 20-200 U / ml, preferably about 30-100 U / ml, preferably about 30 U / ml, about 40 U / ml, about 50 U / ml, about 60 U / ml, about 70 U / ml, about 80 U / ml, about 90 U / ml, about 100 U / ml, preferably about 30 U / ml, about 40 U / ml, about 50 U / ml, about 60 U / ml, or about 70 U / ml.

[0083] In some embodiments, the pharmaceutical composition comprising a compound of formula (I) and insulin aspart further comprises 10-25 mg / ml glycerol, 1.5-6 mg / ml phenol, 0.5-3 mg / ml m-cresol, 5-50 μg / ml zinc ion and 0.5-2.0 mg / ml sodium chloride, and the pH of the composition is 7.0-8.0;

[0084] Preferably, the pharmaceutical composition containing the compound of formula (I) and insulin aspart further contains 10-25 mg / ml glycerol, 1.5-3.5 mg / ml phenol, 0.5-2.0 mg / ml m-cresol, 5-50 μg / ml zinc ion and 0.5-2.0 mg / ml sodium chloride, and the pH of the composition is 7.0-8.0;

[0085] Preferably, the pharmaceutical composition comprising the compound of formula (I) and insulin aspart further comprises 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 15-40 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8;

[0086] Preferably, the pharmaceutical composition comprises 0.18 mM of the compound of formula (I), 0.18 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 18.75 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8;

[0087] Or the pharmaceutical composition comprises 0.42 mM of the compound of formula (I), 0.18 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 35.9 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8;

[0088] Or the pharmaceutical composition comprises 0.3 mM compound of formula (I), 0.3 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 31.25 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8.

[0089] Another aspect of the present invention provides a method for treating metabolic syndrome, comprising administering to a subject in need thereof a compound having the structure of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof.

[0090] In some embodiments, the metabolic syndrome is diabetes; preferably, the diabetes is type 1 diabetes or type 2 diabetes.

[0091] Preferably, the subject is a diabetic patient whose condition is poorly controlled by oral hypoglycemic drugs, preferably a type II diabetic patient;

[0092] Preferably, the subject is a diabetic patient whose diabetes was poorly controlled using basal and / or premixed insulin, preferably a type II diabetic patient.

[0093] In some embodiments, the single administration dose of the compound of formula (I) is calculated based on the subject's body weight, and the single administration dose is 0.2-30 nmol / kg, preferably 0.45 nmol / kg, 0.9 nmol / kg, 1.8 nmol / kg, 3.6 nmol / kg, 7.2 nmol / kg, 14.4 nmol / kg or 28.8 nmol / kg.

[0094] In some embodiments, the single administration dose of the compound of formula (I) is calculated based on the subject's body weight, and the single administration dose is about 0.03-5 U / kg, preferably, about 0.075 U / kg, about 0.15 U / kg, about 0.3 U / kg, about 0.6 U / kg, about 1.2 U / kg, about 2.4 U / kg or about 4.8 U / kg.

[0095] In some embodiments, after administering the combination or pharmaceutical composition of the compound of formula (I) and insulin aspart, the subject can achieve a reduction in glycated hemoglobin by more than 0.1%, preferably more than 0.2%, preferably more than 0.3%, preferably more than 0.4%, preferably more than 0.5%, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20% relative to before administration; preferably ... The combination or pharmaceutical composition of the compound containing the structure of formula (I) and insulin aspart can achieve a reduction of glycosylated hemoglobin by more than 0.1%, preferably more than 0.2%, preferably more than 0.3%, preferably more than 0.4%, preferably more than 0.5%, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20% after 16 weeks, after 20 weeks, after 25 weeks, after 30 weeks or after 35 weeks.

[0096] In some embodiments, the difference between the area under the glucose infusion rate (GIR) time curve within 0-24 hours and the area under the glucose infusion rate (GIR) time curve within 24-48 hours of administering the compound of the structure of formula (I) is less than 20hmg / kg / min, preferably, the difference is 2-15hmg / kg / min, more preferably, the difference is 2-10hmg / kg / min.

[0097] In some embodiments, the difference between the glucose infusion rate (GIR) GIRmax within 0-24 hours and the GIRmax within 24-48 hours after administration of the compound of formula (I) is less than 1.5 mg / kg / min, preferably, the difference is 0-1.2 hmg / kg / min, more preferably, the difference is 0-0.6 hmg / kg / min.

[0098] In some embodiments, after continuous administration of the compound of formula (I) for 2-10 days, the compound of formula (I) exhibits a stable PK characteristic, and the difference between Ctrough and Cmax of the compound of formula (I) at steady state is less than 8 ng / mL, preferably less than 7 ng / ml, and preferably less than 6 ng / ml.

[0099] In some embodiments, administration of a compound comprising the structure of formula (I) exhibits a prolonged, stable glucose-lowering effect compared to insulin degludec.

[0100] Another aspect of the present invention provides a kit comprising:

[0101] A compound of formula (I), or a pharmaceutically acceptable salt thereof,

[0102] packaging materials, and

[0103] A label or package insert contained within the packaging material indicates that the subject receiving the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be treated by the aforementioned method. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIG1 shows a graph of the change (Mean±SE) of fasting venous blood glucose from baseline over time in Example 1;

[0105] FIG2 shows a graph showing the change (Mean±SE) of fasting venous blood glucose compared with baseline in Example 1 over time. DETAILED DESCRIPTION

[0106] I. Definitions and Explanations

[0107] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0108] As used herein and unless otherwise specified, the terms "comprising", "including", and "having", including their grammatical equivalents, should generally be understood as open and non-limiting, e.g., not excluding other unrecited elements or steps.

[0109] As used herein, the term "about" when referring to a specifically recited value or range of values ​​generally means within 20%, preferably within 10%, and more preferably within 5% of the given value or range.

[0110] The term "basal insulin" means insulin that has a longer duration of action than normal or normal human insulin.

[0111] The term "insulin" includes naturally occurring insulin, such as human insulin, as well as insulin analogs and insulin derivatives thereof. The present invention also protects analogs and derivatives of acylated insulin that are equivalent to the compound represented by formula (I).

[0112] The term "insulin aspart" was created by recombinant DNA technology whereby amino acid B28 (i.e. amino acid number 28 in the B chain of human insulin), which is proline, was substituted with aspartic acid in human insulin.

[0113] The term "insulin analogue" comprises such polypeptide, which has a molecular structure that can be derived from the structure of naturally occurring insulin (e.g., human insulin) by formally disappearing and / or replacing one or more amino acid residues and / or adding one or more amino acid residues that exist in native insulin. The amino acid residue that adds and / or replaces can be a codable amino acid residue or other naturally occurring amino acid residue or a purely synthetic amino acid residue. Preferably, the amino acid residue that adds and / or replaces is a codable amino acid residue.

[0114] As used herein, the term "insulin derivative" refers to naturally occurring insulin or insulin analogs that have been chemically modified. Such modifications may include, for example, the introduction of side chains at one or more positions on the insulin backbone, oxidation or reduction of amino acid residues on the insulin, conversion of free carboxyl groups to ester groups, or acylation of free amino or hydroxyl groups. The acylated insulins of the present invention are insulin derivatives.

[0115] The term "insulin parent" refers to the insulin portion of an insulin derivative or acylated insulin (also referred to herein as parent insulin), for example, in the present invention, the portion of an insulin derivative or acylated insulin without a side chain attached or an acyl group attached. The insulin parent can be a naturally occurring insulin, such as human insulin or porcine insulin. Alternatively, the parent insulin can be an insulin analog.

[0116] Here, the term "amino acid residue" includes amino acids from which hydrogen atoms have been removed from amino groups and / or hydroxyl groups have been removed from carboxyl groups and / or hydrogen atoms have been removed from sulfhydryl groups. Inaccurately, amino acid residues may be referred to as amino acids.

[0117] Unless otherwise specified, all amino acids mentioned herein are L-amino acids.

[0118] The term "hypoglycemic event" is determined based on the lowest value of the subject's fasting peripheral blood glucose before breakfast for three consecutive times (including the day of the visit) from 2 days before administration. If the lowest value of the subject's fasting peripheral blood glucose before breakfast for three consecutive times (including the day of the visit) from 2 days before administration is ≥3.9mmol / L, the subject is judged as not having a hypoglycemic event. Conversely, if the lowest value of the subject's fasting peripheral blood glucose before breakfast for three consecutive times (including the day of the visit) from 2 days before administration is <3.9mmol / L, the subject is judged as having a hypoglycemic event.

[0119] The term "treatment" includes therapeutic treatment, prophylactic treatment, and use in reducing the risk of a subject developing a disease or other risk factors. Treatment includes, but is not limited to, complete cure of the disease, as well as alleviation of symptoms or mitigation of potential risks.

[0120] The term "metabolic syndrome" as used herein is a recognized clinical term used to describe a condition that includes a combination of type 2 diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperuricemia, hypercoagulability, and / or microalbuminuria.

[0121] The term "type II diabetes" (also known as "type 2 diabetes" and formerly "non-insulin-dependent diabetes" or "adult-onset diabetes") accounts for 90-95% of all diabetes and encompasses individuals who are insulin-resistant and usually relatively (rather than absolutely) insulin-deficient.

[0122] "Antidiabetic treatment" for type 2 diabetes includes:

[0123] Metformin: Metformin is often the first medication prescribed for type 2 diabetes. It works by increasing the sensitivity of body tissues to insulin, allowing the body to use it more efficiently. Metformin also reduces glucose production in the liver. Metformin itself may not lower blood sugar.

[0124] α-Glucosidase inhibitors: α-Glucosidase inhibitors inhibit α-glucosidase in the brush border of the small intestinal mucosa, thereby delaying carbohydrate absorption and reducing postprandial hyperglycemia. Key benefits include stable blood sugar reduction, a high safety profile, and reduced incidence of cardiovascular complications. They are one of the few oral hypoglycemic agents that can address impaired glucose tolerance. Commonly used α-glucosidase inhibitors include acarbose and voglibose.

[0125] Dipeptidyl peptidase-4 (DPP-4) inhibitors: These drugs also lower blood sugar levels. They do not cause weight gain. Examples of these drugs are sitagliptin, saxagliptin, vildagliptin, and linagliptin.

[0126] Sulfonylureas: These medications help the body produce more insulin. Examples of these medications include glyburide, glipizide, and glimepiride. Possible side effects include low blood sugar and weight gain.

[0127] Thiazolidinediones: Like metformin, these drugs make the body's tissues more sensitive to insulin. This class of drugs is associated with weight gain and other more serious side effects, such as an increased risk of heart failure and fractures. Because of these risks, these drugs are usually not the first choice of treatment. Pioglitazone is an example of a thiazolidinedione.

[0128] SGLT2 inhibitors: These are the newest diabetes medications on the market. They work by preventing the kidneys from reabsorbing sugar into the blood. Instead, the sugar is excreted in the urine. Examples include canagliflozin and dapagliflozin.

[0129] The term "compound" is used herein to refer to a molecular entity and, therefore, a "compound" may have different structural elements beyond the minimum elements defined for each compound or group of compounds. The term "compound" is intended to encompass pharmaceutically relevant forms thereof, i.e., the present invention relates to a compound as defined herein or a pharmaceutically acceptable salt, amide or ester thereof.

[0130] The term "pharmaceutically acceptable" refers to those compounds, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0131] The salt may be a basic salt, an acidic salt, or it may be neither (ie, a neutral salt). In water, basic salts produce hydroxide ions and acidic salts produce hydronium ions.

[0132] Salts of the derivatives of the invention may be formed by added cations or anions which react with anionic or cationic groups, respectively. These groups may be located in the peptide portion and / or in the side chains of the derivatives of the invention.

[0133] The limiting examples of the anionic group of derivatives of the present invention are included in the side chain (if any) and in the free carboxyl group in the peptide portion. The peptide portion usually comprises a free carboxyl group at the C-terminus, and it can also comprise a free carboxyl group at internal acidic amino acid residues such as Asp and Glu.

[0134] Non-limiting examples of cationic groups in the peptide portion include the free amino group at the N-terminus (if present), and any free amino groups of internal basic amino acid residues such as His, Arg, and Lys.

[0135] Esters of the derivatives according to the invention can be formed, for example, by reaction of a free carboxylic acid group with an alcohol or a phenol, which reaction results in the replacement of at least one hydroxyl group by an alkoxy or aryloxy group.

[0136] Ester formation may involve the free carboxyl group at the C-terminus of the peptide, and / or any free carboxyl group in the side chain.

[0137] Amides of the derivatives according to the invention can be formed, for example, by reaction of a free carboxylic acid group in activated form with an amine or substituted amine, or by reaction of a free or substituted amino group with a carboxylic acid in activated form.

[0138] Amide formation can involve the free carboxyl group at the C-terminus of the peptide, any free carboxyl group in a side chain, the free amino group at the N-terminus of the peptide, and / or any free or substituted amino group of the peptide in the peptide and / or side chains.

[0139] In a specific embodiment, the peptide or derivative is in the form of a pharmaceutically acceptable salt. In another specific embodiment, the derivative is in the form of a pharmaceutically acceptable amide, preferably with an amide group at the C-terminus of the peptide. In a further specific embodiment, the peptide or derivative is in the form of a pharmaceutically acceptable ester.

[0140] In this article, HbA1C refers to glycated hemoglobin. The glycated hemoglobin control target follows the patient-centered individualized principle. Currently, most diabetes guidelines recommend that the HbA1c target value for general adult T2DM patients be <7.0%.

[0141] II. Examples

[0142] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0143] Preparation Example

[0144] The injection formulation of the pharmaceutical composition 1 used in the following examples is as follows: 0.18 mM compound (I), 0.18 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 18.75 μg / ml zinc ion and 1.17 mg / ml sodium chloride. The pH of the composition is 7.2-7.8.

[0145] The injection formula of pharmaceutical composition 2 is as follows: 0.42 mM compound (I), 0.18 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 35.9 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8, wherein compound (I) can be prepared according to the preparation method described in, for example, WO2021136302.

[0146] Compound (I): B29K (N(ε)-docosandioyl-γGlu-6xOEG), desB30 human insulin (SEQ ID NO: 1 and SEQ ID NO: 2, representing the A chain and B chain, respectively)

[0147] SEQ ID NO.1:

[0148] DesB30 Human Insulin A Chain:

[0149] Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn

[0150] SEQ ID NO.2:

[0151] DesB30 Human Insulin B Chain:

[0152] Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys

[0153] Example 1: Clinical trial of pharmaceutical composition 1 containing compound (I) and insulin aspart in adult patients with type 2 diabetes poorly controlled by oral hypoglycemic drugs

[0154] Trial plan

[0155] This clinical trial was a randomized, double-blind, positive-controlled trial to evaluate the efficacy, safety, and tolerability of Pharmaceutical Composition 1 in adult patients with type 2 diabetes who were poorly controlled with oral hypoglycemic agents. The drugs used are shown in Table 1.

[0156] Table 1: Preparation name, specification and administration method of test drug and positive control drug

[0157] Note: Insulin injections must be equilibrated to room temperature before use (recommended about 30 minutes).

[0158] Research Methods

[0159] The trial enrolled adults with type 2 diabetes who were poorly controlled with oral hypoglycemic drugs. A multicenter, randomized, open-label, parallel-controlled trial design was used to compare the efficacy, safety, and tolerability of once-daily injection of the compound of formula (I) and degludec / insulin aspart injection in patients with type 2 diabetes who were poorly controlled with oral hypoglycemic drugs.

[0160] The study included a screening period of up to 17 days. Qualified participants were stratified based on glycated hemoglobin (HbA1c) levels (stratification factors: HbA1c ≥ 8.5% vs. HbA1c < 8.5%) and randomly assigned in a 1:1 ratio to receive either the injection of Pharmaceutical Composition 1 (Group A1) or the insulin degludec (Insulin Aspart) injection (Group A2). Administration was by subcutaneous injection in the abdomen.

[0161] During treatment, researchers adjusted the dose of Pharmaceutical Composition 1 injection or degludec insulin aspart injection weekly based on the subjects' pre-breakfast fasting blood glucose results until the fasting blood glucose control target was achieved [i.e., the average pre-breakfast fasting blood glucose value for three consecutive times was between 4.4 and 6.1 mmol / L (inclusive)]. A two-week safety follow-up period followed the end of the treatment period.

[0162] This study selected the marketed insulin degludec aspart injection (insulin degludec aspart injection) as the positive control drug, aiming to protect the subjects from ineffective placebo exposure, and at the same time explore the differences between the injection of drug composition 1 and insulin degludec aspart injection in lowering blood sugar in adult patients with type 2 diabetes.

[0163] Inclusion and exclusion criteria for subjects

[0164] The inclusion and exclusion criteria for the subjects are shown in Table 2 .

[0165] Table 2: Subject inclusion and exclusion criteria (eligible subjects should meet all inclusion criteria; for subjects to be excluded, they meet one or more exclusion criteria)

[0166] If the subject met the inclusion criteria and did not meet the exclusion criteria, they were randomly assigned to the respective groups and received 16 weeks of treatment. The insulin administration method is shown in Table 3. During the treatment period, the researchers adjusted the insulin dose weekly based on the subject's self-measured pre-breakfast fasting peripheral blood glucose (3 consecutive times starting 2 days before dosing, including the visit day). The dosage adjustment rules are shown in Tables 4 and 5. The adjustment target was an average of 3 consecutive pre-breakfast fasting peripheral blood glucose levels between 4.4 and 6.1 mmol / L (inclusive).

[0167] Table 3: Insulin administration during treatment

[0168] Table 4: Weekly Insulin Dose Adjustment Rules (No Hypoglycemic Events*)

[0169] Note: *The lowest pre-breakfast fasting blood glucose value must be ≥ 3.9 mmol / L for three consecutive times (including the visit day) starting from 2 days before dosing. If one or more pre-breakfast fasting blood glucose values ​​are missing, the dose should be adjusted based on the remaining SMBG values. If the subject's fasting blood glucose fails to reach the predetermined treatment target, the investigator may, after consultation with the sponsor, tailor the insulin dose adjustment rules based on the subject's condition.

[0170] Table 5: Weekly Insulin Dose Adjustment Rules (with Hypoglycemic Events*)

[0171] Note: * If any of the three consecutive pre-breakfast blood glucose levels (including the visit day) is <3.9 mmol / L starting from 2 days before dosing, the patient should be adjusted for doses according to Table 3 if their pre-breakfast blood glucose level is <3.9 mmol / L on days 1-4 after dosing, or if their random blood glucose level is <3.9 mmol / L after each dose, unless there is a clear explanation or cause for the lowest value, such as a missed meal.

[0172] If Group A1 forgets to take Pharmaceutical Composition 1 Injection at breakfast, it is recommended to make up for the missed dose at lunch. If the next main meal is dinner, it is recommended to make up for half of the missed dose. Resume the usual dosing schedule on the second day. If Group A2 forgets to take Degludec Insulin Aspart Injection, it is recommended to make up for the missed dose at the next main meal of the day and resume the usual dosing schedule on the second day.

[0173] In addition to the treatment according to Tables 3-5, the subjects also took metformin and / or other oral medications, where the frequency and dosage of metformin and / or other oral medications were the same as those taken by the subjects before this trial.

[0174] If the subject's fasting blood glucose fails to reach the predetermined treatment target or a hypoglycemic event occurs, the researcher can communicate with the sponsor to individualize the insulin dose adjustment rules based on the subject's condition.

[0175] Analytical methods

[0176] Intention-to-treat analysis (ITT): includes all randomized subjects.

[0177] Full analysis set (FAS): According to the basic principles of ITT, it includes all randomized subjects who have at least one record of study medication.

[0178] Per-protocol set (PPS): It is a subset of FAS, including all subjects who have good compliance during the study, complete data on the primary efficacy indicators and no major protocol deviations that affect the primary efficacy indicators, and the subjects must receive at least 12 weeks of insulin (study drug) treatment.

[0179] Study Results

[0180] Subject distribution

[0181] The 62 successfully screened subjects were randomly assigned in a 1:1 ratio to either the Pharmaceutical Composition 1 injection group (Group A1) or the degludec insulin aspart injection group (Group A2). All subjects received the study drug (31 subjects in Group A1 and 31 subjects in Group A2). One subject (Group A1) requested to withdraw from the trial early, while the remaining 61 subjects (98.4%) completed the trial as per the protocol.

[0182] All 62 subjects (100%) were enrolled in the ITT, FAS, PDAS, and SS. Because 3 subjects in group A1 were not enrolled in the PPS due to poor compliance, missing primary efficacy indicators, or other conditions that affected the primary efficacy assessment, the remaining 59 subjects (95.2%) were enrolled in the PPS. All 31 subjects in group A1 were enrolled in the PKAS and IS.

[0183] Demographic distribution and baseline characteristics

[0184] The baseline demographics and diabetes-related baseline characteristics of the subjects in groups A1 and A2 were basically balanced.

[0185] Effectiveness results

[0186] (1) Analysis of decreased glycated hemoglobin

[0187] Based on FAS, an ANCOVA model (MI imputed) was used to compare the changes in HbA1c compared to baseline after 16 weeks of treatment between the two groups. After 16 weeks of treatment, the mean (SD) HbA1c values ​​of group A1 and group A2 were 6.83 (0.701)% and 7.06 (0.728)%, respectively. The least squares mean (standard error) of the changes from baseline were -1.50 (0.127)% and -1.32 (0.125)%, respectively. The results showed that after 16 weeks of treatment, the HbA1c decrease in group A1 (drug composition 1 injection group) was greater than that in group A2 (deglucose aspart dual insulin injection group).

[0188] The HbA1c analysis of the subjects during treatment based on the FAS population is summarized in Table 6 below.

[0189] Table 6: HbA1c (%) analysis

[0190] Note: Baseline is defined as the last nonmissing measurement before the subject's first dose of trial medication.

[0191] The analysis of covariance (ANCOVA) model used the change in HbA1c from baseline after 16 weeks of treatment as the dependent variable, group (categorical variable) as the fixed factor, and stratification factors (baseline glycated hemoglobin included as a continuous variable) as the covariate.

[0192] The P value is the difference test of the least square means between the injection group of the compound of formula (I) and the control group.

[0193] (2) Venous fasting plasma glucose analysis

[0194] Based on the FAS, an ANCOVA model (MI imputed) was used to compare the changes in fasting plasma glucose from baseline between the two groups after 16 weeks of treatment. After 16 weeks of treatment, the least squares mean (standard error) of the changes in fasting plasma glucose from baseline in groups A1 and A2 were -3.515 (0.2560) mmol / L and -3.139 (0.2550) mmol / L, respectively. The decrease in fasting plasma glucose was greater in group A1 than in group A2. The changes in fasting plasma glucose from baseline at each visit were analyzed graphically using an ANCOVA model without imputation. The results are shown in Figure 1.

[0195] (3) Analysis of the proportion of subjects with decreased glycated hemoglobin

[0196] Logistic regression analysis (MI imputation) compared the proportions of subjects with HbA1c <7.0% and HbA1c ≤6.5% between groups after 16 weeks of treatment. After 16 weeks of treatment, the proportions of subjects with HbA1c <7.0% in Group A1 and Group A2 were 53.0% and 48.4%, respectively; and the proportions of subjects with HbA1c ≤6.5% were 32.8% and 29.0%, respectively. The proportions of subjects with HbA1c <7.0% and HbA1c ≤6.5% were significantly higher in the injection group than in the degludec dual insulin aspart injection group.

[0197] (4) Average decrease in 7-point peripheral blood glucose level

[0198] Based on the FAS, an ANCOVA model with MI was used to compare changes in SMBG levels from baseline between the two groups (before breakfast and 2 hours after breakfast, before lunch and 2 hours after lunch, before dinner and 2 hours after dinner, and before bedtime on the day before the visit). Both groups A1 and A2 showed decreases in SMBG levels from baseline before breakfast and 2 hours after breakfast, before lunch and 2 hours after lunch, before dinner and 2 hours after dinner, and before bedtime on the day before the visit. The decreases from baseline in SMBG 2 hours after breakfast and before lunch were greater in group A1 than in group A2, and the differences in changes from baseline were statistically significant.

[0199] Moreover, after 16 weeks of treatment, the 7-point peripheral blood glucose variability of the drug composition 1 injection group was lower than that of the degludec insulin aspart injection group, indicating that its blood glucose control was relatively stable.

[0200] Table 7: 7-point blood glucose levels (mmol / L) from self-monitoring of blood glucose (SMBG) after 16 weeks of treatment

[0201] Note: Baseline is defined as the last nonmissing measurement before the subject's first dose of trial medication.

[0202] The ANCOVA model used the change in peripheral blood glucose level at each SMBG time point after 16 weeks of treatment compared with the baseline as the dependent variable, and group (categorical variable), stratification factor (metformin + other oral hypoglycemic drugs vs. metformin), and baseline peripheral blood glucose level at each SMBG time point (continuous variable) as the explanatory variables.

[0203] The P value is the difference test of the least square means between the treatment group (drug composition 1 injection) and the degludec dual insulin aspart injection group.

[0204] (5) Daily dosage of Composition 1 injection and Insulin degludec injection in Week 16

[0205] Based on the FAS, an ANCOVA model was used to compare the dosages of Pharmaceutical Composition 1 Injection and Insulin Degludec Aspart Injection used by the subjects in the 16th week of treatment (i.e., the last week of treatment) between the two groups. The results of the covariance analysis of the daily dosages of Pharmaceutical Composition 1 Injection and Insulin Degludec Aspart Injection used by the subjects in the 16th week of treatment showed that at week 16, the adjusted geometric means (standard errors) of Pharmaceutical Composition 1 Injection in Group A1 and Insulin Degludec Aspart Injection in Group A2 were 28.17 (1.100) U and 30.75 (1.098) U, respectively. The insulin dosage in Group A1 was 8% less than that in Group A2.

[0206] That is, in the last week of treatment, the average daily insulin dose of the pharmaceutical composition 1 injection group was lower than that of the degludec and insulin aspart injection group.

[0207] (6) Changes in weight of subjects at each visit compared to baseline

[0208] Based on the FAS, an ANCOVA model was used to compare the change in weight from baseline between groups after 16 weeks of treatment. After 16 weeks of treatment, the least squares mean (standard error) of the change in weight from baseline in Groups A1 and A2 was 1.50 (0.371) kg and 1.75 (0.364) kg, respectively. The weight gain in Group A1 was smaller than that in Group A2. Analysis of the change in weight from baseline after 16 weeks of treatment showed that the least squares mean difference (95% CI) between Groups A1 and A2 was -0.25 (-1.29, 0.79) kg.

[0209] Safety analysis results

[0210] Safety analysis was based on SS. Throughout the study, no severe hypoglycemia events, TEAEs leading to medication suspension, TEAEs leading to premature withdrawal, or TEAEs resulting in death occurred in any group. According to the CTCAE classification, TEAEs were mostly grade 1-2 (98.4%). The most common TEAEs were hypoglycemia and weight gain, similar to those observed with other insulin analogs of the same type.

[0211] In general, the overall incidence of hypoglycemia in group A1 was lower than that in group A2, and the causes of hypoglycemia in the two groups were similar, with most cases being without any cause, followed by being caused by eating too little.

[0212] PK studies have shown that the long-acting component of Pharmaceutical Composition 1 Injection, the compound of formula (I), has a longer half-life, which helps to lower blood sugar more effectively, thereby supporting the effect of the long-acting product.

[0213] The immunogenicity risk of Pharmaceutical Composition 1 injection is low and has acceptable immunogenicity. Overall, Pharmaceutical Composition 1 injection has good safety.

[0214] Example 2: Clinical trial of a pharmaceutical composition containing a compound of formula (I) and insulin aspart in combination with insulin aspart in adult patients with type 2 diabetes who were previously poorly controlled with basal / premixed insulin

[0215] Trial plan

[0216] This clinical trial was a randomized, double-blind, positive-controlled study to evaluate the efficacy, safety, and tolerability of Pharmaceutical Composition 1 combined with insulin aspart in adult patients with type 2 diabetes who were previously poorly controlled with basal / premixed insulin. The drugs used are shown in Table 8.

[0217] Table 8: Preparation, strength and administration method of test drug and positive control drug

[0218] Note: Insulin injections must be equilibrated to room temperature before use (recommended about 30 minutes).

[0219] Research Methods

[0220] The study enrolled adults with type 2 diabetes who were previously poorly controlled with basal / premixed insulin. The study used a multicenter, randomized, open, parallel controlled trial design to compare the efficacy of drug composition 1 injection combined with Ruixiulin. Efficacy, safety, and tolerability of twice-daily degludec and insulin aspart injection in patients with type 2 diabetes who are inadequately controlled with oral hypoglycemic agents combined with basal / premixed insulin (premixed insulins in various ratios available on the market).

[0221] The study included a screening period of up to 17 days. After passing the screening, patients were stratified according to whether metformin was used in combination with other oral hypoglycemic drugs at the time of screening (stratification factors: metformin + other oral hypoglycemic drugs; metformin) and randomly assigned to receive the drug combination 1 injection combined with 1 dose of Ruixiulin in a 1:1:1 ratio. Group (B1), drug composition 1 injection combined with 2 doses of Ruixiulin Group B1 (Group B2) and Group B3 (Group B3) were planned to enroll 90 subjects, with 30 subjects in each of Group B1, Group B2, and Group B3. After randomization, all subjects entered a 16-week treatment period.

[0222] The researchers adjusted the dosage of drug composition 1 injection and Ruixiulin weekly based on the results of self-monitoring blood glucose (SMBG) of the subjects. Or the dose of degludec and insulin aspart injection until the fasting blood glucose control target is achieved [i.e., the average fasting peripheral blood glucose value before breakfast for three consecutive times is between 4.4 and 6.1 mmol / L (including the cut-off value)]. After the end of the treatment period, a 2-week safety follow-up period will begin.

[0223] Inclusion and exclusion criteria for subjects

[0224] The inclusion criteria for the subjects are shown in Table 9, and the exclusion criteria for the subjects are the same as those in Example 1.

[0225] Table 9. Subject inclusion criteria (eligible subjects should meet all inclusion criteria)

[0226] The basal insulin includes one or more of glargine insulin, detemir insulin, degludec insulin and intermediate-acting human insulin, and the premixed insulin includes all premixed insulins that are on the market.

[0227] If the subject met the inclusion criteria and did not meet the exclusion criteria, they were randomly assigned to each group and received 16 weeks of treatment. The insulin administration method is shown in Table 8. During the treatment period, the investigator adjusted the insulin dose weekly based on the subject's self-measured pre-breakfast fasting peripheral blood glucose results (three consecutive times starting from two days before dosing, including the visit day). The dosage adjustment rules are shown in Tables 4 and 5. The adjustment target was an average of three consecutive pre-breakfast fasting peripheral blood glucose levels between 4.4 and 6.1 mmol / L (inclusive).

[0228] Table 10: Insulin administration during treatment

[0229] Note: * Before randomization, patients should use basal / premixed insulin once daily. It is recommended that this amount be divided equally into two doses of degludec insulin aspart daily (the specific amount will be determined by the investigator based on the patient's blood sugar control needs), one before breakfast and one before dinner. Before randomization, patients should use basal / premixed insulin twice daily. The total daily amount should be divided equally into two doses of degludec insulin aspart daily (the specific amount will be determined by the investigator based on the patient's blood sugar control needs), one before breakfast and one before dinner.

[0230] The weekly dosage adjustment rules for the pharmaceutical composition containing the compound of formula (I) and insulin aspart, and degludec and insulin aspart are shown in Tables 11 and 12.

[0231] Table 11. Weekly Dosage Adjustment Rules for Degludec and Insulin Aspart Injection (No Hypoglycemic Events*)

[0232] Note: *The lowest value of pre-meal peripheral blood glucose for three consecutive times before administration is ≥3.9mmol / L. The pre-dinner injection of degludec aspart insulin is adjusted according to the average value of pre-breakfast fasting peripheral blood glucose for three consecutive times (including the day of visit) from 2 days before administration. The pre-breakfast injection of degludec aspart insulin is adjusted according to the average value of pre-dinner peripheral blood glucose for three consecutive times (excluding the day of visit) from 3 days before administration. The pre-breakfast injection of the pharmaceutical composition injection is adjusted according to the average value of pre-breakfast fasting peripheral blood glucose for three consecutive times (including the day of visit) from 2 days before administration. If one or more pre-meal peripheral blood glucose values ​​are missing, the dose should be adjusted based on the remaining SMBG values. If the subject's pre-meal peripheral blood glucose fails to reach the predetermined treatment target, the researcher can communicate with the sponsor to individualize the insulin dose adjustment rules based on the subject's situation.

[0233] Table 12: Weekly Dosage Adjustment Rules for Degludec / Insulin Aspart / Drug Combination Injection (with Hypoglycemic Events*)

[0234] Note: * If any of the three consecutive pre-meal peripheral blood glucose levels is <3.9 mmol / L before dosing. The dosage of the pharmaceutical composition injection before breakfast is adjusted based on the lowest fasting peripheral blood glucose level before breakfast for three consecutive times (including the visit day) from the 2nd day before dosing. If the subject's pre-meal peripheral blood glucose level is <3.9 mmol / L on days 1-4 after dosing on the weekly visit day, or if random blood glucose or nighttime blood glucose is <3.9 mmol / L from the time of each dose to the time before dinner in group B1, or if random blood glucose or nighttime blood glucose is <3.9 mmol / L from the time of each dose to the time before lunch in group B2, the dose should also be adjusted according to Table 10. The dosage of degludec aspart insulin before dinner is adjusted based on the lowest fasting peripheral blood glucose level before breakfast for three consecutive times (including the visit day) from the 2nd day before dosing. The dosage of degludec aspart insulin before breakfast is adjusted based on the lowest pre-dinner peripheral blood glucose level before dinner for three consecutive times (excluding the visit day) from the 3rd day before dosing. If a subject's pre-breakfast or pre-dinner blood glucose level is <3.9 mmol / L on days 1-4 after dosing on the day of the weekly visit, or if a random blood glucose level is <3.9 mmol / L at other times after each dose, dose adjustment should also be made according to Table 10. This is unless there is a clear explanation or cause for the lowest value, such as a missed meal. If a subject's pre-meal blood glucose level fails to reach the predetermined treatment target or a hypoglycemic event occurs, the investigator can communicate with the sponsor to individualize the insulin dose adjustment rules based on the subject's condition.

[0235] In addition, the weekly insulin aspart dose adjustment rules are shown in Table 13.

[0236] Table 13 Weekly insulin aspart dose adjustment rules

[0237] The pre-meal injection dose of insulin aspart is adjusted according to the average value of 2-hour post-meal peripheral blood glucose for 3 consecutive times (excluding the day of the visit) starting from 3 days before administration. If one or more 2-hour post-meal peripheral blood glucose values ​​are missing, the dose should be adjusted based on the remaining SMBG values. If the subject's blood glucose before bed is <4.4mmol / L, the researcher can reduce the dose of insulin aspart before dinner according to the subject's condition. If the subject's blood glucose before bed is ≥4.4mmol / L and the nighttime blood glucose is <3.9mmol / L, the dose of the drug composition needs to be reduced according to Table 11. If the subject's 2-hour post-meal peripheral blood glucose fails to reach the predetermined treatment target or a hypoglycemic event occurs, the researcher can communicate with the sponsor to individualize the insulin dose adjustment rules based on the subject's condition.

[0238] In addition to the treatment according to Tables 10-13, the subjects also took metformin and / or other oral medications, where the frequency and dosage of metformin and / or other oral medications were the same as those taken by the subjects before this trial.

[0239] Analytical methods

[0240] Intention-to-treat analysis (ITT): includes all randomized subjects.

[0241] Full analysis set (FAS): According to the basic principles of ITT, it includes all randomized subjects who have at least one record of study medication.

[0242] Per-protocol set (PPS): It is a subset of FAS, including all subjects who have good compliance during the study, complete data on the primary efficacy indicators and no major protocol deviations that affect the primary efficacy indicators, and the subjects must receive at least 12 weeks of insulin (study drug) treatment.

[0243] Safety data set (SS): refers to all subjects who have been randomized, taken the study drug at least once and have safety evaluation.

[0244] Pharmacokinetic Analysis Set (PKAS): includes all subjects who were randomized, received at least one dose of study drug, had at least one evaluable PK data set, and did not experience a protocol deviation that significantly affected the PK assessment.

[0245] Immunogenicity analysis set (IS): includes all subjects who were randomized, received at least one dose of study drug, and had at least one post-dose immunogenicity evaluation.

[0246] The FAS was used for the analysis of primary and secondary efficacy endpoints and hypoglycemia events, with the PPS used for supplementary analysis. The SS was used for the analysis of other safety endpoints.

[0247] Study Results

[0248] Subject distribution

[0249] A total of 149 subjects were screened in Part B of this study, and 91 successful subjects were randomly assigned to receive the drug composition 1 injection combined with Ruixiulin once daily. Group B1 (32 cases), drug composition 1 injection combined with Ruixiulin twice a day Group B1 (28 cases) and degludec insulin aspart injection group (31 cases) received study drugs. Except for 6 subjects (6.6%) (3 cases in group B1, 2 cases in group B2 and 1 case in group B3) who voluntarily requested to withdraw from the trial early, the remaining 85 subjects (93.4%) completed the trial as required by the protocol.

[0250] Demographic distribution and baseline characteristics

[0251] The baseline demographics and diabetes-related baseline characteristics of the subjects in groups B1, B2, and B3 were basically balanced.

[0252] Effectiveness results

[0253] (1) Analysis of decreased glycated hemoglobin

[0254] Based on the FAS, the analysis of covariance (ANCOVA) model [multiple imputation (MI) imputation] was used to compare the changes in HbA1c compared with baseline between the groups after 16 weeks of treatment (see Table 14).

[0255] After 16 weeks of treatment, the mean (SD) HbA1c values ​​of group B1, group B2 and group B3 were 6.78 (0.501)%, 6.79 (0.539)% and 6.78 (0.617)%, respectively. The least square mean (standard error) of the changes from baseline were -1.68 (0.093)%, -1.69 (0.102)% and -1.63 (0.095)%, respectively. Compared with the baseline, the drug composition 1 injection combined with 1 dose of Ruixiulin Group, pharmaceutical composition 1 injection combined with 2 doses of Ruixiulin The HbA1c decrease in the two groups was greater than that in the degludec and insulin aspart injection groups.

[0256] Table 14: HbA1c (%) Analysis

[0257] Note: Baseline is defined as the last nonmissing measurement before the subject's first dose of trial medication.

[0258] (2) Venous fasting plasma glucose analysis

[0259] Based on the FAS, an ANCOVA model (with MI imputed) was used to compare the changes in fasting plasma glucose from baseline between the two groups after 16 weeks of treatment. The changes in fasting plasma glucose from baseline at each visit were analyzed graphically using the unimputed ANCOVA model (Figure 2).

[0260] After 16 weeks of treatment, the mean (SD) venous fasting plasma blood glucose levels in group B1, group B2, and group B3 were 7.591 (2.1949) mmol / L, 7.463 (1.7462) mmol / L, and 7.269 (2.6958) mmol / L, respectively. The least squares mean (standard error) changes from baseline were -1.422 (0.4423) mmol / L, -1.780 (0.4385) mmol / L, and -2.086 (0.4215) mmol / L, respectively. The reductions in venous fasting plasma blood glucose in groups B1 and B2 were lower than that in group B3.

[0261] (3) Analysis of the proportion of subjects with decreased glycated hemoglobin

[0262] Based on the FAS, logistic regression analysis (MI imputed) was used to compare the proportions of subjects with HbA1c < 7.0% and HbA1c ≤ 6.5% after 16 weeks of treatment between the two groups.

[0263] After 16 weeks of treatment, the proportions of subjects with HbA1c < 7.0% in groups B1, B2 and B3 were 72.3%, 61.7% and 59.0%, respectively. The achievement rate of HbA1c < 7% was 1. The group was higher than the degludec insulin aspart injection group, and the drug composition 1 injection combined with 2 doses of Ruixiulin The results of the control group were similar to those of the degludec and insulin aspart injection group.

[0264] After 16 weeks of treatment, the proportions of subjects with HbA1c ≤ 6.5% in groups B1, B2, and B3 were 28.8%, 41.3%, and 45.5%, respectively. The proportions of subjects with HbA1c ≤ 6.5% in groups B2 and B3 were similar.

[0265] (4) Changes in weight of subjects at each visit compared to baseline

[0266] Based on the FAS, an ANCOVA model was used to compare the change in body weight from baseline between groups after 16 weeks of treatment. The least squares mean difference (95% CI) between groups B1 and B3 was -0.640 (-1.774, 0.493) kg, which was not statistically significant (P = 0.2642). The least squares mean difference (95% CI) between groups B2 and B3 was 0.018 (-1.153, 1.190) kg, which was not statistically significant (P = 0.9750). The results showed that after 16 weeks of treatment, the weight gain in group B1 was less than that in group B3, while the weight gain in groups B2 and B3 was similar.

[0267] Safety analysis results

[0268] Safety analysis was based on SS. Throughout the study, no TEAEs leading to premature withdrawal or death occurred in any group. Pharmaceutical Composition 1 injection was well-safe and well-tolerated, with most TEAEs being Grade 1 in severity. Common TEAEs were hypoglycemia and weight gain, similar to those observed with other similar insulin analogs.

[0269] PK studies have shown that the long-acting component of Pharmaceutical Composition 1 Injection, the compound of formula (I), has a longer half-life, which helps to lower blood sugar more effectively, thereby supporting the effect of long-acting products.

[0270] The immunogenicity risk of the injection of Pharmaceutical Composition 1 is low and has acceptable immunogenicity.

[0271] Example 3: Clinical trial of a pharmaceutical composition containing a compound of formula (I) and insulin aspart in combination with insulin aspart in adult patients with type 2 diabetes who were previously poorly controlled with basal / premixed insulin

[0272] This clinical trial is a randomized, double-blind, positive-controlled study to evaluate the efficacy, safety, and tolerability of Pharmaceutical Composition 1 combined with insulin aspart in adult patients with type 2 diabetes who were previously poorly controlled with basal / premixed insulin. The initial dosing regimen is shown in Table 15.

[0273] Table 15: Initial dosing of study drugs

[0274] The adjusted dosages were the same as those in Table 4 of Example 1. The inclusion criteria were the same as those in Example 1.

[0275] After receiving a full 16 weeks of trial drug treatment, the first day of W16 is the end of the visit, and the subjects need to return to the research center for relevant safety checks, etc.

[0276] The safety follow-up period lasts one week after the end of the treatment period. The investigator may decide to continue conventional treatment based on the subject's overall condition. It is recommended that patients switch to conventional treatment two days after the last dose or when their fasting blood glucose reaches ≥10 mmol / L. The timing of transition to conventional treatment will ultimately be determined by the investigator. At the end of the safety follow-up period, subjects will record hypoglycemic events, adverse events (AEs) / serious adverse events (SAEs), and concomitant medications / treatments.

[0277] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true scope of the invention.

Claims

1. A method for treating metabolic syndrome, the method comprising administering a combination of a compound having a structure of formula (I) and insulin aspart to a subject in need thereof, wherein the total dose of the compound having a structure of formula (I) and insulin aspart is about 5U-200U, preferably about 5U-50U, and preferably the total dose of each administration is independently the same or different; preferably, when administering the combination of the compound having a structure of formula (I) and insulin aspart, the compound having a structure of formula (I) and insulin aspart are administered together or separately; preferably, when administering the combination of the compound having a structure of formula (I) and insulin aspart, the compound having a structure of formula (I) and insulin aspart are administered simultaneously; preferably, the combination of the compound having a structure of formula (I) and insulin aspart is a pharmaceutical composition comprising the compound having a structure of formula (I) and insulin aspart; Preferably, the metabolic syndrome is diabetes; preferably, the diabetes is type 2 diabetes.

2. A method for treating metabolic syndrome, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of formula (I) and insulin aspart, wherein the total dose of the compound of formula (I) and insulin aspart is 5U-200U, preferably about 5U-50U; preferably, the total dose of each administration is independently the same or different; Preferably, the metabolic syndrome is diabetes; preferably, the diabetes is type 2 diabetes.

3. The method according to claim 1 or 2, wherein: In the combination of the compound of formula (I) and insulin aspart, and in the pharmaceutical composition containing the compound of formula (I) and insulin aspart, the molar percentage of the compound of formula (I) in the combination or pharmaceutical composition is about 50%-99%; preferably, the molar percentage of the compound of formula (I) in the combination or pharmaceutical composition is about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95%; preferably, the molar percentage of the compound of formula (I) in the combination or pharmaceutical composition is about 50%, about 60%, about 70% or about 80%; preferably, the molar ratio of the compound of formula (I) to insulin aspart is 1:1 or 7:

3.

4. The method according to any one of claims 1 to 3, wherein: The total daily dose of the compound of formula (I) and insulin aspart is about 5U-200U, preferably about 5U-50U, preferably about 5U, about 6U, about 7U, about 8U, about 9U, about 10U, about 11U, about 12U, about 13U, about 14U, about 15U, about 16U, about 17U, about 18U, about 19U, about 20U, about 21U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U , about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 55U, about 60U, about 65U, about 70U, about 75U, about 80U, about 85U, about 90U, about 95U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U; Preferably the total dose administered each day is independently the same or different.

5. The method according to any one of claims 1 to 4, wherein: The method comprises administering a combination of the compound of formula (I) and insulin aspart, or administering a pharmaceutical composition containing the compound of formula (I) and insulin aspart to a subject in need thereof once a day or less, preferably the total doses of each administration are independently the same or different.

6. The method according to any one of claims 1 to 5, wherein: The method comprises administering the compound of formula (I) and insulin aspart to a subject in need thereof once a day or less frequently and with a total administration dose of about 5-200 U, preferably about 5-50 U, preferably administering the compound of formula (I) and insulin aspart to a subject in need thereof once a day or less frequently and with a total administration dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 55U, about 60U, about 65U, about 70U, about 75U, about 80U, about 85U, about 90U, about 95U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U; Preferably, for subjects who have previously been administered once-daily basal or premixed insulin, when switching to the combination of the compound of formula (I) and insulin aspart, or the pharmaceutical composition containing the compound of formula (I) and insulin aspart, the total starting dose of the compound of formula (I) and insulin aspart is about 50%-90%, preferably about 60%-85%, preferably about 70%-80%, preferably about 50%, about 60%, about 70%, about 75% or about 80% of the total daily dose of the previous basal or premixed insulin.

7. The method according to any one of claims 1 to 6, wherein: The method further comprises administering the compound of formula (I) and insulin aspart to a subject in need thereof at the starting dose, and then administering the compound of formula (I) and insulin aspart once a day or less frequently. The total dose of each administration may be the same as or different from the starting dose. Preferably, the total dose of each administration is determined based on the individual condition of the subject.

8. The method according to any one of claims 1 to 7, wherein: The method comprises administering a combination of the compound of formula (I) and insulin aspart, or administering a pharmaceutical composition containing the compound of formula (I) and insulin aspart, to a subject in need thereof once a day or less frequently and with a total administration dose of about 5-200 U, preferably about 5-50 U, as a starting dose; preferably administering the compound of formula (I) and insulin aspart to a subject in need thereof once a day or less frequently and with a total administration dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 1U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U about 7U, about 48U, about 49U, about 50U, about 55U, about 60U, about 65U, about 70U, about 75U, about 80U, about 85U, about 90U, about 95U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U; After 1 day, 2 days, 3 days or 4 days of administration at the starting dose, or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks of administration, a total dose of M of the compound of formula (I) and insulin aspart is administered once a day, wherein the dose M administered daily is the same or different, and each is independently about 1U-200U, preferably about 1U-70U, preferably each is independently about 1U, about 2U, about 3U, about 4U, about 5U, about 6U, about 7U, about 8U, about 9U, about 10U, about 11U, about 12U, about 13U, about 14U, about 15U, about 16U, about 17U, about 18U, about 19U, about 20U, about 21U, about 22U, about 23U, about 24U, about 25U 3U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U About 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U.

9. The method according to any one of claims 1 to 8, wherein: The method comprises administering a compound of formula (I) and insulin aspart to a subject in need thereof once a day or less frequently at a total dose of about 5-200 U as a starting dose, preferably administering a compound of formula (I) and insulin aspart to a subject in need thereof once a day or less frequently at a total dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U , about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 55U, about 60U, about 65U, about 70U, about 75U, about 80U, about 85U, about 90U, about 95U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, or about 200U; After 1, 2, 3 or 4 days of administration at the initial dose, or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks of administration, the daily dose M administered is adjusted daily, weekly or more frequently.

10. The method according to claim 8 or 9, wherein: The daily dose M is adjusted daily, weekly or more frequently according to the following rules: a) When the fasting blood glucose value of the subject before administration is 3.9-4.3mmol / L, or when the average fasting peripheral blood glucose value of the subject before breakfast for 3 consecutive times starting from 2 days or 3 days before administration is 3.9-4.3mmol / L, the administered dose M needs to be adjusted to be reduced by about 1U-6U, preferably by about 1U-4U, preferably by about 1U, about 2U, about 3U or about 4U relative to the previous administered dose; or b) The subject's sky blood glucose value before administration is 4.4-6.1 mmol / L, or the subject's sky blood glucose value is 4.4-6.1 mmol / L 2 days before administration When the average value of fasting peripheral blood glucose before breakfast for 3 consecutive times is 4.4-6.1mmol / L, the dosage M is the previous dosage; or c) when the fasting blood glucose value of the subject before administration is 6.2-7.0mmol / L, or when the average fasting peripheral blood glucose value of the subject before breakfast for 3 consecutive times since 2 days or 3 days before administration is 6.2-7.0mmol / L, the administered dose M needs to be adjusted to increase by about 1U-4U, preferably by about 1U, about 2U, about 3U or about 4U relative to the previous administered dose; or d) when the fasting blood glucose value of the subject before administration is 7.1-8.0mmol / L, or when the average fasting peripheral blood glucose value of the subject before breakfast for 3 consecutive times starting from 2 days or 3 days before administration is 7.1-8.0mmol / L, the administered dose M needs to be adjusted to increase by about 2U-6U, preferably by about 3U, about 4U, about 5U or about 6U relative to the previous administered dose; or e) when the fasting blood glucose value of the subject before administration is 8.1-9.0mmol / L, or when the average fasting peripheral blood glucose value of the subject before breakfast for 3 consecutive times starting from 2 days or 3 days before administration is 8.1-9.0mmol / L, the administered dose M needs to be adjusted to increase by about 4U-8U, preferably by about 5U, about 6U, about 7U or about 8U relative to the previous administered dose; or f) When the subject's fasting blood glucose value before administration is greater than 9.0mmol / L, or when the average fasting peripheral blood glucose value before breakfast for three consecutive times 2 days or 3 days before administration is greater than 9.0mmol / L, the administered dose M needs to be adjusted to increase by about 6U-10U, preferably by about 7U, about 8U, about 9U or about 10U relative to the previous administered dose; or g) When the subject's fasting blood glucose value is ≤3.0mmol / L before administration, or when the subject's lowest fasting peripheral blood glucose value before breakfast is ≤3.0mmol / L for 3 consecutive times 2 days or 3 days before administration, the administered dose M needs to be adjusted to a dose reduced by about 1U-8U, preferably by about 2U-6U, preferably by about 3U, about 4U or about 5U relative to the previous administered dose, or when the previous administered dose is >45U, the administered dose M needs to be adjusted to a dose reduced by 5% to 15% relative to the previous administered dose, preferably by 10%; or h) When the fasting blood glucose value of the subject before administration is 3.1-3.8mmol / L, or when the lowest fasting peripheral blood glucose value of the subject before breakfast is 3.1-3.8mmol / L for 3 consecutive times starting from 2 days or 3 days before administration, the administered dose M needs to be adjusted to a dose reduced by about 1U-4U, preferably by about 1U-3U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose, or when the previous administered dose is greater than 45U, the administered dose M needs to be adjusted to a dose reduced by 2% to 10% relative to the previous administered dose, preferably by 5%.

11. The method according to any one of claims 1 to 10, wherein the subject is a patient with type II diabetes who is poorly controlled by oral hypoglycemic drugs; or the subject is a patient with diabetes who was previously poorly controlled using basal insulin or premixed insulin; or the subject is a patient with type II diabetes who was previously poorly controlled using basal insulin or premixed insulin; or the subject is a patient with type II diabetes who was previously poorly controlled using once-daily basal insulin or at least once-daily premixed insulin, with or without pre-dinner mealtime insulin.

12. The method according to any one of claims 1 to 11, wherein the subject has a BMI between 10 and 50 kg / m 2 Between, preferably 18.5-35kg / m 2 ; and / or Have an HbA1c of 7.5%-11.0%; and / or Fasting venous blood glucose ≥7.0mmol / L; and / or The patient has received one or more oral hypoglycemic drugs, preferably up to 3 oral hypoglycemic drugs, and the oral hypoglycemic drugs include metformin, and also include oral hypoglycemic drugs selected from DPP-4i, α-glucosidase inhibitors, SGLT2 inhibitors, and glucokinase activators in combination or not.

13. The method according to any one of claims 1 to 12, wherein the combination of the compound of formula (I) and insulin aspart, or the pharmaceutical composition comprising the compound of formula (I) and insulin aspart, is administered at a fixed or irregular time before any meal, preferably before breakfast.

14. The method according to any one of claims 1 to 13, wherein the combination of the compound of formula (I) and insulin aspart, or the pharmaceutical composition comprising the compound of formula (I) and insulin aspart, is administered by subcutaneous injection, preferably subcutaneous injection in the abdomen.

15. The method of any one of claims 1-14, wherein the combination of a compound of formula (I) and insulin aspart, or a pharmaceutical composition comprising a compound of formula (I) and insulin aspart, is administered long-term, preferably for at least 4 weeks, preferably for at least 8 weeks, preferably for at least 16 weeks, preferably for at least 20 weeks, preferably for at least 25 weeks, and preferably for at least 32 weeks.

16. The method according to any one of claims 1 to 15, when the subject is a diabetic patient whose diabetes was previously poorly controlled using basal and / or premixed insulin, wherein the method further comprises administering insulin aspart alone to the subject, preferably administering insulin aspart alone before dinner every day.

17. The method of claim 16, wherein the method comprises administering a compound of formula (I) and insulin aspart to a subject in need thereof once a day or less frequently at a total dose of 50% to 100% of the total daily dose of previous basal and / or premixed insulin as a starting dose; and / or Further, insulin aspart is administered once daily or twice daily at a total dose of 0% to 50% of the total daily dose of previous basal and / or premixed insulin as a starting dose; in, The compound of formula (I) and insulin aspart are administered at a first time point, the insulin aspart is administered at a second time point, and / or the insulin aspart is administered at a second time point and / or a third time point; Preferably, the method comprises administering a compound of formula (I) and insulin aspart to a subject in need thereof once a day or less at a first time point with a total dose of 60%, 70%, 80%, 90% or 100% of the total daily dose of previous basal and / or premixed insulin as a starting dose; and / or Further, insulin aspart is administered once a day or twice a day at the second time point and / or the third time point with a total dose of 5%, 10%, 15%, 20% or 40% of the total daily dose of previous basal and / or premixed insulin as a starting dose.

18. The method of claim 17, wherein the method comprises administering a compound having the structure of formula (I) and insulin aspart at a total dose of N once a day and / or further administering insulin aspart at a dose of O once a day or twice a day after administering the starting dose for 1 week, wherein the dose N administered each day is the same or different, and / or the dose O administered each day is the same or different, wherein N and O are each independently 0%-100% of the total daily dose of previous basal and / or premixed insulin, and preferably each independently 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the total daily dose of previous basal and / or premixed insulin.

19. The method of claim 17 or 18, wherein the method comprises administering a compound having a structure of formula (I) and insulin aspart at a total dose of N once a day after administering the starting dose for 1 week, and / or further administering insulin aspart at a dose of O once a day or twice a day, the dose N administered each day is the same or different, and / or the dose O administered each day is the same or different, wherein N and O are each independently 0%-100% of the total daily dose of previous basal and / or premixed insulin, preferably each independently 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the total daily dose of previous basal and / or premixed insulin; After 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks of administration at the initial dose, the daily doses of N and O are adjusted weekly or more frequently.

20. The method according to claim 18 or 19, wherein: The daily dose N is adjusted weekly or more frequently according to the following rules: a) when the subject's fasting blood glucose value before administration is 3.9-4.3mmol / L, or when the average value of the subject's peripheral blood glucose before three consecutive meals before administration is 3.9-4.3mmol / L, the administered dose N needs to be adjusted to be reduced by about 1U-6U, preferably by about 1U-4U, preferably by about 1U, about 2U, about 3U or about 4U relative to the previous administered dose; or b) when the subject's sky blood glucose value before administration is 4.4-6.1mmol / L, or when the average value of the subject's 3 consecutive pre-meal blood glucose values ​​before administration is 4.4-6.1mmol / L, the administered dose N is the previous administered dose; or c) when the subject's fasting blood glucose value is 6.2-7.0 mmol / L before administration, or when the subject's average peripheral blood glucose value before three consecutive meals before administration is 6.2-7.0 mmol / L, the administered dose N needs to be adjusted to increase by about 1U-4U, preferably by about 1U, about 2U, about 3U or about 4U relative to the previous administered dose; or d) when the subject's fasting blood glucose value is 7.1-8.0 mmol / L before administration, or when the subject's average peripheral blood glucose value before three consecutive meals before administration is 7.1-8.0 mmol / L, the administered dose N needs to be adjusted to increase by about 2U-6U, preferably by about 3U, about 4U, about 5U or about 6U relative to the previous administered dose; or e) when the subject's fasting blood glucose value is 8.1-9.0 mmol / L before administration, or when the subject's average peripheral blood glucose value before three consecutive meals before administration is 8.1-9.0 mmol / L, the administered dose N needs to be adjusted to increase by about 4U-8U, preferably by about 5U, about 6U, about 7U or about 8U relative to the previous administered dose; or f) When the subject's fasting blood glucose value before administration is greater than 9.0mmol / L, or when the average value of the subject's peripheral blood glucose before three consecutive meals before administration is greater than 9.0mmol / L, the administered dose N needs to be adjusted to increase by about 6U-10U, preferably by about 7U, about 8U, about 9U or about 10U relative to the previous administered dose; or g) When the subject's sky blood glucose value is ≤3.0mmol / L before administration, or when the subject's lowest peripheral blood glucose value before three consecutive meals before administration is ≤3.0mmol / L, the administered dose N needs to be adjusted to a dose reduced by about 1U-8U, preferably by about 2U-6U, preferably by about 3U, about 4U or about 5U relative to the previous administered dose, or when the previous administered dose is >45U, the administered dose M needs to be adjusted to a dose reduced by 5% to 15% relative to the previous administered dose, preferably by 10%; h) or when the subject's fasting blood glucose value is 3.1-3.8mmol / L before administration, or when the subject's lowest peripheral blood glucose value before meals for three consecutive times before administration is 3.1-3.8mmol / L, the administered dose N needs to be adjusted to a dose reduced by 1U-4U, preferably by 1U-3U, preferably by 1U, 2U or 3U relative to the previous dose, or when the previous dose is >45U, N needs to be adjusted to a dose reduced by 2% to 10% relative to the previous dose, preferably by 5%.

21. The method according to claim 18 or 19, wherein: The daily dose may be adjusted weekly or more frequently according to the following rules: a) When the lowest blood glucose level of the subject after 2 hours of meals is less than 6.1 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to be reduced by about 1U-4U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose; or b) When the lowest blood glucose level of the subject after 3 consecutive meals is 6.1-6.9 mmol / L at 2 hours before administration, the administered dose O is the previous administered dose; or c) when the lowest blood glucose level of the subject after 3 consecutive meals at 2 hours is 7.0-7.8 mmol / L before administration, the administered dose O needs to be adjusted to increase by about 0U-4U, preferably by about 0U, about 1U, about 2U or about 3U relative to the previous administered dose; or d) when the lowest blood glucose level of the subject 2 hours after meals for three consecutive times before administration is 7.9-10.0 mmol / L, the administered dose O needs to be adjusted to increase by about 0U-4U, preferably by about 0U, about 1U, about 2U or about 3U relative to the previous administered dose; or e) When the lowest blood glucose value of the subject 2 hours after meals for three consecutive times before administration is ≥10.0mmol / L, the administered dose O needs to be adjusted to increase by about 2U-5U relative to the previous administered dose, preferably by about 2U, about 3U, about 4U or about 5U.

22. The method of claim 21, wherein the adjustment rule is further adjusted according to the previous dose of insulin aspart, when the dose of insulin aspart is less than 15U, a) When the lowest blood glucose level of the subject after 2 hours of meals is less than 6.1 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to be reduced by about 1U-4U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose; or b) When the lowest blood glucose level of the subject after 3 consecutive meals is 6.1-7.8 mmol / L at 2 hours before administration, the administered dose O is the previous administered dose; or c) when the lowest blood glucose level of the subject after 3 consecutive meals at 2 hours is 7.9-10.0 mmol / L before administration, the administered dose O needs to be adjusted to increase by about 1U-4U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose; or d) when the lowest blood glucose level of the subject after 3 consecutive meals at 2 hours is ≥10.0mmol / L before administration, the administered dose O needs to be adjusted to increase the dose by about 2U-4U, preferably by about 2U, about 3U or about 4U relative to the previous dose; or When the insulin aspart dosage is ≥15U, a) When the lowest blood glucose level of the subject after 2 hours of meals is less than 6.1 mmol / L for three consecutive times before administration, the administered dose O needs to be adjusted to be reduced by about 1U-4U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose; or b) When the lowest blood glucose level of the subject after 3 consecutive meals is 6.1-6.9 mmol / L at 2 hours before administration, the administered dose O is the previous administered dose; or c) when the lowest blood glucose level of the subject after 3 consecutive meals at 2 hours is 7.0-7.8 mmol / L before administration, the administered dose O is increased by about 1U-3U, preferably by about 1U, about 2U or about 3U relative to the previous administered dose; or d) when the lowest blood glucose level of the subject after 3 consecutive meals at 2 hours is 7.9-10.0 mmol / L before administration, the administered dose O needs to be adjusted to increase the dose by about 2U-4U, preferably by about 2U, about 3U or about 4U relative to the previous dose; or e) When the lowest blood glucose value of the subject 2 hours after meals for three consecutive times before administration is ≥10.0mmol / L, the administered dose O needs to be adjusted to increase by about 3U-5U, preferably by about 3U, about 4U or about 5U relative to the previous administered dose.

23. The method according to any one of claims 16-22, wherein the first time point, the second time point and the third time point are arbitrarily selected from before breakfast, before lunch, and before dinner, respectively; preferably, the first time point is before breakfast, the second time point is before dinner, and the third time point is before lunch.

24. The method of any one of claims 16-23, wherein the subject has a BMI between 10-50 kg / m 2 Between, preferably 18.5-35kg / m 2 between; and / or Have an HbA1c of 7.5%-11.0%; and / or Fasting venous blood glucose ≥7.0mmol / L; and / or The patient has received one or more oral glucose-lowering drugs, preferably up to 3 oral glucose-lowering drugs combined with 1 basal insulin or premixed insulin, wherein the daily administration frequency of the basal insulin / premixed insulin does not exceed 2 times, the daily dosage is about 10U-100U, and the basal insulin / premixed insulin is combined with a stable dose of oral glucose-lowering drugs for ≥3 months.

25. The oral hypoglycemic drug of claim 24 comprises metformin, which is further combined with or not combined with an oral hypoglycemic drug, wherein the oral hypoglycemic drug comprises a DPP4 inhibitor (DPP-4i), an α-glucosidase inhibitor, a SGLT2 inhibitor, a glucokinase activator, a sulfonylurea, and a glinide.

26. The method according to any one of claims 16 to 25, wherein the pharmaceutical composition is administered by subcutaneous injection, preferably by subcutaneous injection in the abdomen.

27. The method of any one of claims 16-26, wherein the administration of the pharmaceutical composition in combination with insulin aspart is long-term, preferably for at least 4 weeks, preferably for at least 8 weeks, preferably for at least 16 weeks, preferably for at least 20 weeks, preferably for at least 25 weeks, preferably for at least 32 weeks.

28. The method according to any one of claims 1-27, wherein the subject further takes metformin orally daily.

29. The method according to any one of claims 1 to 28, wherein: In the pharmaceutical composition containing the compound of formula (I) and insulin aspart, the content of the compound of formula (I) is about 20-200 U / ml, preferably about 30-100 U / ml, preferably about 30 U / ml, about 40 U / ml, about 50 U / ml, about 60 U / ml, about 70 U / ml, about 80 U / ml, about 90 U / ml, about 100 U / ml, preferably about 30 U / ml, about 40 U / ml, about 50 U / ml, about 60 U / ml, or about 70 U / ml.

30. The method according to any one of claims 1 to 29, wherein: The pharmaceutical composition containing the compound of formula (I) and insulin aspart further contains 10-25 mg / ml glycerol, 1.5-6 mg / ml phenol, 0.5-3 mg / ml m-cresol, 5-50 μg / ml zinc ion and 0.5-2.0 mg / ml sodium chloride, and the pH of the composition is 7.0-8.0; Preferably, the pharmaceutical composition containing the compound of formula (I) and insulin aspart further contains 10-25 mg / ml glycerol, 1.5-3.5 mg / ml phenol, 0.5-2.0 mg / ml m-cresol, 5-50 μg / ml zinc ion and 0.5-2.0 mg / ml sodium chloride, and the pH of the composition is 7.0-8.0; Preferably, the pharmaceutical composition containing the compound of formula (I) and insulin aspart further contains 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 15-40 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8; Preferably, the pharmaceutical composition comprises 0.18 mM of the compound of formula (I), 0.18 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 18.75 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8; Or the pharmaceutical composition comprises 0.42 mM of the compound of formula (I), 0.18 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 35.9 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.8; Or the pharmaceutical composition comprises 0.3 mM compound of formula (I), 0.3 mM insulin aspart, 17 mg / ml glycerol, 2.82 mg / ml phenol, 1.08 mg / ml m-cresol, 31.25 μg / ml zinc ion and 1.17 mg / ml sodium chloride, and the pH of the composition is 7.2-7.

8.

31. A method for treating metabolic syndrome, comprising administering to a subject in need thereof a compound having a structure of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the metabolic syndrome is diabetes; preferably, the diabetes is type I diabetes or type II diabetes; Preferably, the subject is a diabetic patient whose diabetes is poorly controlled by oral hypoglycemic drugs, preferably a patient with type II diabetes; Preferably, the subject is a diabetic patient whose diabetes was poorly controlled using basal and / or premixed insulin, preferably a type II diabetic patient.

32. The method of claim 31, wherein: The single administration dose of the compound of formula (I) is calculated based on the body weight of the subject, and the single administration dose is 0.2-30 nmol / kg, preferably 0.45 nmol / kg, 0.9 nmol / kg, 1.8 nmol / kg, 3.6 nmol / kg, 7.2 nmol / kg, 14.4 nmol / kg or 28.8 nmol / kg.

33. The method of claim 32, wherein: The single administration dose of the compound of formula (I) is calculated based on the subject's body weight, and the single administration dose is about 0.03-5 U / kg, preferably, about 0.075 U / kg, about 0.15 U / kg, about 0.3 U / kg, about 0.6 U / kg, about 1.2 U / kg, about 2.4 U / kg or about 4.8 U / kg.

34. The method according to any one of claims 1 to 33, characterized in that After administering the combination or pharmaceutical composition containing the compound of formula (I) and insulin aspart, the subject can achieve a decrease in glycated hemoglobin by 0.1% or more relative to before administration, preferably 0.2% or more, preferably 0.3% or more, preferably 0.4% or more, preferably 0.5% or more, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20%; preferably, after administering the combination or pharmaceutical composition containing the compound of formula (I) and insulin aspart, the subject can achieve a decrease in glycated hemoglobin by 0.1% or more relative to before administration, preferably 0.2%, preferably 0.3%, preferably 0.4%, preferably 0.5%, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20%. The combination or pharmaceutical composition of a compound of formula (I) and insulin aspart can achieve a reduction in glycated hemoglobin of 0.1% or more, preferably 0.2% or more, preferably 0.3% or more, preferably 0.4% or more, preferably 0.5% or more, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20% after 16 weeks, 20 weeks, 25 weeks, 30 weeks or 35 weeks.

35. A medicine kit comprising: A compound of formula (I), or a pharmaceutically acceptable salt thereof, Packaging materials, and A label or package insert contained within the packaging material, the label or package insert indicating that the subject receiving treatment with the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be treated by the method of any one of claims 1-34.

Images