Pharmaceutical composition for treating diabetes mellitus complicated with nephropathy and application thereof

Abstract

The invention relates to the technical field of drugs for treating diabetic nephropathy, and particularly discloses a pharmaceutical composition for treating diabetes mellitus complicated with nephropathy and application. The invention provides a pharmaceutical composition for treating diabetes mellitus complicated with nephropathy. The pharmaceutical composition comprises fenerenone and a potassium-excreting diuretic in a mass ratio of (1-4): (1-10), the potassium-excreting diuretic is selected from at least one of thiazine diuretic, thiazine-like diuretic or loop diuretic. According to the pharmaceutical composition for treating diabetes mellitus complicated with nephropathy provided by the invention, the fenerenone and the potassium-excreting diuretic in a specific ratio are adopted, and in the process of using the fenerenone to treat and control the progress of chronic kidney diseases, the potassium-excreting diuretic which is compounded and combined not only reduces the occurrence of adverse reactions of hyperkalemia, but also enhances the effect of reducing urine protein, so that the curative effect of treating diabetes mellitus complicated with nephropathy is enhanced, and the curative effect of treating diabetes mellitus complicated with nephropathy is improved. Good market application values are realized.

Description

Technical Field

[0001] The present invention relates to the technical field of drugs for treating diabetic nephropathy, and in particular to a drug composition for treating diabetes combined with nephropathy and its application. Background Art

[0002] Finerenone (BAY 94-8862) is a nonsteroidal, selective mineralocorticoid receptor (MR) antagonist. MR is expressed in the kidney, heart, and blood vessels. In preclinical studies, finerenone can block the harmful effects caused by MR overactivation and reduce inflammation and fibrosis mediated by MR overactivation. In diabetic patients, MR overactivation is believed to lead to the progression of chronic kidney disease (CKD) and cardiovascular damage, which may be driven by metabolic, hemodynamic, or inflammatory and fibrotic factors.

[0003] Finerenone has a significant therapeutic effect in reducing the occurrence of adverse renal and cardiovascular events in patients with diabetes and CKD. However, there is a risk of persistent hyperkalemia during finerenone treatment, which is mainly manifested as muscle weakness, paralysis, and decreased myocardial contractility. In severe cases, it can lead to arrhythmia and cardiac arrest, and the electrocardiogram will also show special manifestations. Therefore, in the process of controlling the progression of CKD, how to enhance the effect of reducing urine protein and reduce the occurrence of adverse reactions of hyperkalemia is the focus of current research work. Summary of the invention

[0004] In view of the above problems, the present invention provides a pharmaceutical composition for treating diabetes combined with nephropathy and its application. The present invention reduces the occurrence of hyperkalemia and enhances the effect of reducing urine protein by compounding finerenone and potassium-excreting diuretics for combined use.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions: In a first aspect, the present invention provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, comprising finerenone and a potassium-excreting diuretic.

[0006] Compared with the prior art, the pharmaceutical composition for treating diabetes combined with nephropathy provided by the present invention (hereinafter referred to as the pharmaceutical composition) is compounded with finerenone and a potassium-excreting diuretic. In the process of using finerenone to treat and control the progression of CKD, the compounded potassium-excreting diuretic not only reduces the occurrence of adverse reactions of hyperkalemia, but also enhances the effect of reducing urine protein, and has good market application value.

[0007] Preferably, the mass ratio of finerenone to the potassium-excreting diuretic is (1-4):(1-10).

[0008] Preferably, the potassium-excreting diuretic is selected from at least one of thiazide diuretics, thiazide-like diuretics or loop diuretics.

[0009] Further preferably, the mass ratio of the finerenone to the thiazide diuretic is (1-4):1.

[0010] More preferably, the thiazide diuretic is hydrochlorothiazide.

[0011] Further preferably, the mass ratio of the finerenone to the thiazide-like diuretic is (1-3.5):1.

[0012] More preferably, the thiazide-like diuretic is indapamide.

[0013] Further preferably, the mass ratio of the finerenone to the loop diuretic is 1:(3-10).

[0014] Further preferably, the loop diuretic is furosemide.

[0015] The present invention adopts finerenone and potassium-excreting diuretics in a specific ratio for compounding, so that the two can produce a synergistic effect, which not only further reduces the occurrence of adverse reactions of hyperkalemia, but also further enhances the effect of reducing urine protein.

[0016] In a second aspect, the present invention provides a pharmaceutical preparation for treating diabetes mellitus combined with nephropathy, comprising the pharmaceutical composition for treating diabetes mellitus combined with nephropathy and pharmaceutically acceptable excipients.

[0017] Preferably, the auxiliary material is selected from at least one of lactose, microcrystalline cellulose, povidone, cross-linked povidone or magnesium stearate.

[0018] For example, the povidone is povidone K30.

[0019] Preferably, the mass content of the pharmaceutical composition for treating diabetes combined with nephropathy is 2% to 20%, more preferably 3% to 12%, and even more preferably 4% to 8%.

[0020] In a third aspect, the present invention provides a method for using the pharmaceutical composition for treating diabetes combined with nephropathy, wherein the dosage of finerenone is 1 mg / kg to 10 mg / kg, and the dosage of potassium-excreting diuretics is 1 mg / kg to 100 mg / kg.

[0021] Preferably, the potassium-excreting diuretic is selected from at least one of thiazide diuretics, thiazide-like diuretics or loop diuretics.

[0022] More preferably, the dosage of the thiazide diuretic is 1 mg / kg to 5 mg / kg.

[0023] More preferably, the dosage of the thiazide-like diuretic is 1 mg / kg to 10 mg / kg.

[0024] More preferably, the dosage of the loop diuretic is 10 mg / kg to 100 mg / kg. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0026] In the embodiment of the present invention, the experimental subjects are male SD rats, SPF grade, 6 weeks to 8 weeks old, 180g / rat to 220g / rat, purchased from Beijing Huafukang Biotechnology Co., Ltd., the production unit license number is SCXK (Beijing) 2019-0008, and the animal quality certificate number is No.110322220103040415.

[0027] The rats were randomly divided into control group, model group and drug administration group according to body weight, 8 rats / group. Except for the control group, rats in the model group and drug administration group underwent left nephrectomy and were subcutaneously injected with DOCA 50mg / kg every week for 4 consecutive weeks. At the same time, 10g / L NaCl was contained in the drinking water to prepare the DOCA-salt hypertensive rat nephropathy model.

[0028] In order to better illustrate the present invention, further examples are given below.

[0029] Example 1 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and hydrochlorothiazide in a mass ratio of 1:1.

[0030] Example 2 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and hydrochlorothiazide in a mass ratio of 3:1.

[0031] Example 3 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and hydrochlorothiazide in a mass ratio of 1.2:1.

[0032] Example 4 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and hydrochlorothiazide in a mass ratio of 4:1.

[0033] Example 5 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and hydrochlorothiazide in a mass ratio of 2:1.

[0034] Application Example 1 This application example provides the effects of the pharmaceutical composition for treating diabetes combined with nephropathy in Examples 1 to 5 on blood pressure, urine protein and serum potassium in rats with DOCA-salt hypertension-induced nephropathy model. The drug administration group was intragastrically administered with the doses shown in Table 1. After 20 weeks of administration, the tail vein pressure of rats in each group was measured, venous blood was collected to determine serum potassium levels, and urine was collected to detect urine protein. The results are shown in Tables 1 to 2.

[0035] Table 1 Effect of finerenone combined with hydrochlorothiazide on blood pressure in rats

[0036] Note: Compared with the normal group, **p<0.01; compared with the model group, #p<0.05, ##p<0.01.

[0037] Table 2 Effects of finerenone combined with hydrochlorothiazide on urine protein and serum potassium levels in rats

[0038] Note: Compared with the normal group, **p<0.01; compared with the model group, #p<0.05, ##p<0.01.

[0039] As can be seen from Table 1, finerenone and hydrochlorothiazide alone did not significantly reduce systolic blood pressure after 20 weeks of administration. The combination of 3mg / kg~10mg / kg finerenone and 1mg / kg~5mg / kg hydrochlorothiazide can significantly reduce the blood pressure of rats; the combined medication index CI of 1mg / kg~10mg / kg finerenone and 1mg / kg~5mg / kg hydrochlorothiazide is less than 1, indicating that the two drugs have a synergistic effect. As can be seen from Table 2, compared with the control group, the urine protein of the model group rats was significantly increased. When 3mg / kg~10mg / kg of finerenone was given alone, urine protein decreased by 39%, but there was no significant difference compared with the model group; when 1mg / kg~5mg / kg of hydrochlorothiazide was given alone, urine protein decreased significantly, with the highest decrease of 71%; when 1mg / kg~10mg / kg of finerenone was used in combination with 1mg / kg~5mg / kg of hydrochlorothiazide, urine protein in each group decreased significantly, with the highest decrease of 89%; when 1mg / kg~10mg / kg of finerenone was used in combination with 1mg / kg~5mg / kg of hydrochlorothiazide, serum potassium in each group was lower than 4.2 mEq -1 , effectively reducing the adverse reaction of hyperkalemia caused by the use of the non-steroidal MR receptor antagonist finerenone alone; 1mg / kg~10mg / kg of finerenone combined with 1mg / kg~5mg / kg of hydrochlorothiazide produced a synergistic effect.

[0040] Example 6 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and indapamide in a mass ratio of 1:1.

[0041] Example 7 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and indapamide in a mass ratio of 3:1.

[0042] Example 8 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and indapamide in a mass ratio of 3.33:1.

[0043] Application Example 2 This application example provides the effects of the pharmaceutical composition for treating diabetes combined with nephropathy in Examples 6 to 8 on blood pressure, urine protein and serum potassium in rats with DOCA-salt hypertension-induced nephropathy model. The drug administration group was intragastrically administered with the doses shown in Table 3. After 20 weeks of administration, the tail vein pressure of rats in each group was measured, venous blood was collected to determine serum potassium levels, and urine was collected to detect urine protein. The results are shown in Tables 3 to 4.

[0044] Table 3 Effect of finerenone combined with indapamide on blood pressure in rats

[0045] Note: Compared with the normal group, **p<0.01; compared with the model group, #p<0.05, ##p<0.01.

[0046] Table 4 Effect of finerenone combined with indapamide on urine protein and blood potassium levels in rats

[0047] Note: Compared with the normal group, **p<0.01; compared with the model group, #p<0.05, ##p<0.01.

[0048] As can be seen from Table 3, 1mg / kg~10mg / kg finerenone alone did not significantly reduce systolic blood pressure after 20 weeks of administration, 3mg / kg~10mg / kg indapamide could significantly reduce systolic blood pressure; 1mg / kg~10mg / kg finerenone combined with 1mg / kg~10mg / kg indapamide could significantly reduce blood pressure in rats; the combination index CI of the two was <1, indicating that the two drugs had a synergistic effect. As can be seen from Table 4, compared with the control group, the urine protein of the model group rats was significantly increased; when 1mg / kg~10mg / kg of finerenone was given alone, the urine protein decreased by 28%, but there was no significant difference compared with the model group; when 1mg / kg~10mg / kg of indapamide was given alone, the urine protein could be significantly reduced, with the maximum reduction of 55%; when 1mg / kg~10mg / kg of finerenone was combined with 1mg / kg~10mg / kg of indapamide, the urine protein of each group was significantly reduced, with the maximum reduction of 85%; when 1mg / kg~10mg / kg of finerenone was combined with 1mg / kg~10mg / kg of indapamide, a synergistic effect occurred; when 1mg / kg~10mg / kg of finerenone was given alone, the serum potassium level increased with the dose, reaching a maximum of 4.63 mEq -1 , combined with 1mg / kg~10mg / kg indapamide, can significantly improve the increase in serum potassium caused by finerenone.

[0049] Example 9 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and furosemide in a mass ratio of 1:10.

[0050] Example 10 This embodiment provides a pharmaceutical composition for treating diabetes mellitus combined with nephropathy, which is composed of finerenone and furosemide in a mass ratio of 1:3.33.

[0051] Embodiment 11 This embodiment provides a pharmaceutical composition for treating diabetic nephropathy, which is composed of finerenone and furosemide in a mass ratio of 1:3.

[0052] Application Example 3 This application example provides the effects of the pharmaceutical composition for treating diabetes combined with nephropathy in Examples 9 to 11 on blood pressure, urine protein and serum potassium in rats with DOCA-salt hypertension-induced nephropathy model. The drug administration group was intragastrically administered with the doses shown in Table 3. After 20 weeks of administration, the tail vein pressure of rats in each group was measured, venous blood was collected to determine serum potassium levels, and urine was collected to detect urine protein. The results are shown in Tables 5 to 6.

[0053] Table 5 Effect of finerenone combined with furosemide on blood pressure in rats

[0054] Note: Compared with the normal group, **p<0.01; compared with the model group, #p<0.05, ##p<0.01.

[0055] Table 6 Effect of finerenone combined with furosemide on urine protein and blood potassium levels in rats

[0056] Note: Compared with the normal group, **p<0.01; compared with the model group, #p<0.05, ##p<0.01.

[0057] As can be seen from Table 5, 1mg / kg~10mg / kg finerenone alone did not significantly reduce systolic blood pressure after 20 weeks of administration, while 30mg / kg~100mg / kg furosemide could significantly reduce systolic blood pressure; 1mg / kg~10mg / kg finerenone combined with 10mg / kg~100mg / kg furosemide could significantly reduce blood pressure in rats; their combined drug index CI was <1, indicating that the two drugs had a synergistic effect. As can be seen from Table 6, when 1mg / kg~10mg / kg of finerenone was given alone, urine protein decreased by 24%, but there was no significant difference with the model group; when 10mg / kg~100mg / kg of furosemide was given alone, urine protein was significantly reduced, with the highest reduction of 76%; when 1mg / kg~10mg / kg of finerenone was used in combination with 10mg / kg~100mg / kg of furosemide, urine protein in each group was significantly reduced, with the highest reduction of 82%; the combination of the two had a synergistic effect; when 1mg / kg~10mg / kg of finerenone was given alone, the highest serum potassium level reached 4.58mEq -1 , combined with 10mg / kg~100mg / kg furosemide, serum potassium levels are basically normal.

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition for treating diabetes combined with nephropathy, characterized in that: These include finerenone and potassium-wasting diuretics.

2. The pharmaceutical composition for treating diabetes combined with nephropathy according to claim 1, characterized in that: The mass ratio of the finerenone to the potassium-excreting diuretic is (1-4):(1-10); The potassium-excreting diuretic is selected from at least one of thiazide diuretics, thiazide-like diuretics or loop diuretics.

3. The pharmaceutical composition for treating diabetes combined with nephropathy according to claim 2, characterized in that: The thiazide diuretic is hydrochlorothiazide; and / or The thiazide-like diuretic is indapamide; and / or The loop diuretic is furosemide.

4. The pharmaceutical composition for treating diabetes combined with nephropathy according to claim 2 or 3, characterized in that: The mass ratio of the finerenone to the thiazide diuretic is (1-4):

1.

5. The pharmaceutical composition for treating diabetes combined with nephropathy according to claim 2 or 3, characterized in that: The mass ratio of the finerenone to the thiazide-like diuretic is (1-3.5):

1.

6. The pharmaceutical composition for treating diabetes combined with nephropathy according to claim 2 or 3, characterized in that: The mass ratio of the finerenone to the loop diuretic is 1:(3-10).

7. A pharmaceutical preparation for treating diabetes combined with nephropathy, characterized in that: The invention comprises the pharmaceutical composition for treating diabetes combined with nephropathy according to any one of claims 1 to 6 and pharmaceutically acceptable excipients.

8. The pharmaceutical preparation for treating diabetes combined with nephropathy according to claim 7, characterized in that: The auxiliary material is selected from at least one of lactose, microcrystalline cellulose, povidone, cross-linked povidone or magnesium stearate.

9. The pharmaceutical preparation for treating diabetes combined with nephropathy according to claim 7, characterized in that: The mass content of the pharmaceutical composition for treating diabetes combined with nephropathy is 2% to 20%.

10. A method for using the pharmaceutical composition for treating diabetes combined with nephropathy according to any one of claims 1 to 6, characterized in that: The dosage of finerenone is 1mg / kg~10mg / kg, and the dosage of potassium-excreting diuretics is 1mg / kg~100mg / kg.

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