New use of a combination of an arni complex and amlodipine

Abstract

The present application provides a new application of a compound pharmaceutical composition of an ARNi complex and amlodipine, and the new application is an application of a pharmaceutical composition containing an ARNi complex in the preparation of a medicine for treating hypertensive patients who are poorly controlled by ARNi monotherapy.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, in particular, the present application relates to a new application of a compound pharmaceutical composition of ARNi complex and amlodipine. BACKGROUND

[0002] At present, the world's high blood pressure patients are estimated to be 1 billion, high blood pressure can cause patients' heart, brain, kidney and other organ damage, and is closely related to sugar, lipid metabolism disorder and diabetes, significantly reduces the quality of life of patients, and even endangers life in severe cases. There are six major categories of commonly used high blood pressure treatment drugs: beta receptor blockers, angiotensin II receptor antagonists (ARB), angiotensin converting enzyme inhibitors (ACEi), diuretics, calcium channel blockers (CCB), and peripheral vasodilators. Among them, angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors belong to renin-angiotensin-aldosterone system (RASS) inhibitors. However, the treatment of high blood pressure is currently facing a bottleneck period of 60% of patients who are not ideal for single drug control. In this case, the simultaneous use of two or more antihypertensive drugs has its needs and values, so the research on the combination of high blood pressure treatment drugs is increasingly valued by the medical community at home and abroad.

[0003] At present, the ARNi class (angiotensin receptor neprilysin inhibitor) drug for treating high blood pressure was only approved for listing in China in 2017, with the trade name: The molecular structure unit is as follows:

[0004]

[0005] In addition, WO2017125031Al discloses a series of complexes of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), which show certain effects on heart failure and high blood pressure, and the molecular structure unit is as follows:

[0006]

[0007] High blood pressure drugs may have drug resistance or drug resistance in clinical practice, and there is an unmet clinical need in clinical practice, and new drugs are needed to solve such problems. SUMMARY

[0008] The application aims to provide a new application of a compound pharmaceutical composition of an ARNi complex and amlodipine, and the new application is an application of a pharmaceutical composition containing an ARNi complex shown in formula (I) in the preparation of a medicine for treating hypertensive patients who are poorly controlled by ARNi monotherapy.

[0009] The hypertensive patients who are poorly controlled by ARNi monotherapy refer to hypertensive patients who are poorly controlled by the complex shown in formula (I) or formula (II),

[0010] wherein n = 0-3;

[0011]

[0012] The hypertensive patients who are poorly controlled by ARNi monotherapy may also have heart failure, angina pectoris, diabetes, hypertension in diabetic patients, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and renal vascular hypertension.

[0013] The application includes administering to a hypertensive patient in need of such treatment a compound pharmaceutical composition containing an effective amount of an ARNi complex shown in formula (I) and amlodipine.

[0014] Specifically, the application is achieved by the following technical solutions:

[0015] A new application of a compound pharmaceutical composition of an ARNi complex and amlodipine, and the new application is an application of a pharmaceutical composition containing an ARNi complex shown in formula (I) in the preparation of a medicine for treating hypertensive patients who are poorly controlled by ARNi monotherapy, and the ARNi complex is selected from the complex shown in formula (I):

[0016] wherein n = 0-3,

[0017] The hypertensive patients who are poorly controlled by ARNi monotherapy refer to hypertensive patients who are poorly controlled by the complex shown in formula (I) or formula (II),

[0018] wherein n = 0-3;

[0019]

[0020] As a preferred technical solution of the application, in the ARNi complex shown in formula (I), x = 0.5, 1, 1.5 or 2, and n = 0, 0.5, 1, 1.5, 2, 2.5 or 3.

[0021] As a preferred technical solution of the present application, the ARNi complex represented by formula (I) is selected from the complex represented by formula (la): wherein n = 0, 0.5, 1, 1.5, 2, 2.5, or 3.

[0022] As a preferred technical solution of the present application, in the ARNi complex represented by formula (I), n = 2 or 2.5 is preferred.

[0023] As a preferred technical solution of the present application, amlodipine can be a pharmaceutically acceptable salt selected from amlodipine maleate, amlodipine besylate.

[0024] As a preferred technical solution of the present application, the administration unit of the pharmaceutical composition can contain the ARNi complex (calculated as ARNi anhydrous free acid) in an amount of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, or 600 mg; and the amlodipine is in an amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0025] As a preferred technical solution of the present application, when the administration unit of the pharmaceutical composition contains the ARNi complex in an amount of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg (calculated as ARNi anhydrous free acid), the amlodipine is in an amount of 2.5 mg, or 5 mg, or 10 mg.

[0026] Specifically, ARNi + amlodipine = 60 mg + 2.5 mg, 60 mg + 5 mg, 60 mg + 10 mg; or 120 mg + 2.5 mg, 120 mg + 5 mg, 120 mg + 10 mg; or 180 mg + 2.5 mg, 180 mg + 5 mg, 180 mg + 10 mg; or 240 mg + 2.5 mg, 240 mg + 5 mg, 240 mg + 10 mg; or 300 mg + 2.5 mg, 3000 mg + 5 mg, 3000 mg + 10 mg; or 360 mg + 2.5 mg, 360 mg + 5 mg, 360 mg + 10 mg; or 420 mg + 2.5 mg, 420 mg + 5 mg, 420 mg + 10 mg; or 480 mg + 2.5 mg, 480 mg + 5 mg, 480 mg + 10 mg.

[0027] As a preferred technical solution of the present application, the mass ratio of ARNi complex (calculated as ARNi anhydrous free acid) to amlodipine in the pharmaceutical composition is 1:1 to 200:1.

[0028] As a preferred technical solution of the present application, specifically, the mass ratio of ARNi complex (calculated as ARNi anhydrous free acid) to amlodipine is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 18:1, 24:1, 30:1, 36:1, 42:1, 48:1, 54:1, 60:1, 66:1, 72:1, 78:1, 84:1, 90:1, 96:1, 102:1, 108:1, 114:1, 120:1, 126:1, 132:1, 138:1, 144:1, 150:1, 156:1, 162:1, 168:1, 174:1, 180:1, 186:1, 192:1.

[0029] The ARNi complex can be obtained by methods known in the art, wherein the ARNi complex and the preparation method thereof disclosed in WO2017125031A1 are incorporated into the present application.

[0030] As a more preferred technical solution of the present application, the complex is selected from:

[0031] (EXP3174·AHU377)·1.5Ca·1H2O;

[0032] (EXP3174·AHU377)·1.5Ca·1.5H2O;

[0033] (EXP3174·AHU377)·1.5Ca·2H2O;

[0034] (EXP3174·AHU377)·1.5Ca·2.5H2O;

[0035] (EXP3174·AHU377)·1.5Ca·3H2O;

[0036] (EXP3174·AHU377)·2Ca·1H2O;

[0037] (EXP3174·AHU377)·2Ca·1.5H2O;

[0038] (EXP3174·AHU377)·2Ca·2H2O;

[0039] (EXP3174·AHU377)·2Ca·2.5H2O;

[0040] (EXP3174·AHU377)·2Ca·3H2O.

[0041] Those skilled in the art can understand that the complex is a supramolecular complex (complex), in the unit cell of the supramolecular complex (complex), the aliskiren metabolite (EXP3174), AHU377, calcium ion (Ca 2+ ) and solvent molecules fill in the form of several structural units.

[0042] The supramolecular complex (complex) of the present application is distinguished from a mixture obtained by simply mixing two active ingredients. The XRD spectrum of the obtained supramolecular complex (complex) is obviously distinguished from the XRD spectrum of EXP3174 and AHU377 calcium salt, and there are obvious differences in the solubility in each solvent (such as water, ethanol, ethanol-water, etc.), and there are obvious differences in other physicochemical properties such as hygroscopicity, melting point, infrared spectrum, etc.

[0043] The present application has the following advantages and beneficial effects relative to the prior art:

[0044] According to the test results, the pharmaceutical composition containing the ARNi and amlodipine of the present application is expected to have good antihypertensive effect when used in the clinical treatment of hypertensive patients whose ARNi monotherapy is not well controlled. DETAILED DESCRIPTION

[0045] The present application will be further described in detail below in conjunction with examples, but the embodiments of the present application are not limited thereto.

[0046] In the following examples:

[0047] X-ray powder diffraction was detected by Empyrean X-ray diffractometer, detection conditions: Cu target Kα ray, voltage 40 KV, current 40 mA, emission slit 1 / 32°, anti-scattering slit 1 / 16°, anti-scattering slit 7.5 mm, 2θ range: 3°-60°, step 0.02°, each step stay time 40 s.

[0048] Differential scanning calorimetry spectrum was detected by DSC204F1 differential scanning calorimeter of Germany NETZSCH company, detection conditions: atmosphere: N2, 20 mL / min; scanning program: from room temperature to 250℃ at 10℃ / min, record the temperature rising curve.

[0049] Moisture content was detected by TG209 thermal gravimetric analyzer of Germany NETZSCH company, detection conditions: atmosphere: N2, 20 mL / min; scanning program: room temperature-700℃, temperature rising rate: 10℃ / min.

[0050] EXP3174 used in the examples was prepared by the company itself, with a purity of 98.3%.

[0051] AHU377 calcium salt used in the examples was prepared by the company itself, with a purity of 99.4%.

[0052] Example 1

[0053] Preparation of AHU377 anhydrous free acid:

[0054] 2.1 g of AHU377 calcium salt and 40 mL of isopropyl acetate were added to a 250 mL single-neck flask, 4.5 mL of 2 mol / L hydrochloric acid was added at room temperature and stirred to dissolve. The organic layer was collected and washed with 20 mL of water twice; the organic layer was dissolved under reduced pressure at 35℃ to obtain AHU377 anhydrous free acid.

[0055] Example 2

[0056] Preparation of the complex: (prepared according to Example 2 of patent WO2017125031A1)

[0057]

[0058] At room temperature, 2.36 g of AHU377 anhydrous free acid obtained according to the method of Example 1, 2 g of EXP3174 and 40 mL of acetone were added to a 250 mL three-neck flask, and the solution was dissolved; 1.3 equivalents of calcium hydroxide solid and 1 mL of water were added at room temperature relative to AHU377, and stirred at room temperature for 10 h, 40 mL of acetone was added, and reacted for another 8 h, and then filtered through a Buchner funnel under nitrogen protection, and the solid was washed with acetone to obtain a white solid, which was dried in a vacuum oven at 35℃ for 8 h to obtain a solid 3.5 g (EXP3174·AHU377)3- • 1.5 Ca 2+ • 2.5 H2O, HPLC purity 99%. Repeat the test to obtain enough amount for efficacy test.

[0059] Example 3

[0060] Preparation of the complex: (prepared according to Example 3 of patent WO2017125031A1)

[0061]

[0062] At room temperature, 2.36 g of AHU377 anhydrous free acid, 2 g of EXP3174 and 40 mL of acetone were added to a 250 mL three-necked flask, and dissolved; 1.6 equivalents of calcium hydroxide solid and 0.6 mL of water were added to the solution at room temperature, and stirred at 35°C for 6 h, 40 mL of acetone was added, and reacted for another 8 h, and then filtered through a Buchner funnel under nitrogen protection, and the solid was washed with acetone, to obtain a white solid, which was dried at 50°C under vacuum for 8 h, to obtain 3.1 g of solid (EXP3174·AHU377) 3- • 1.5 Ca 2+ • 2 H2O. Repeat the test to obtain enough amount for efficacy test.

[0063] Example 4 Effect of ARNi + amlodipine administration on SHR rats with poor control of ARNi monotherapy

[0064] Experimental animals: WKY rats and SHR rats were purchased from Beijing Vantianlihua Biotechnology Co., Ltd., and were introduced into the animal house at the age of 13 weeks, and the experiments were carried out after about 2 weeks of use period.

[0065] Test substances: ARNi and amlodipine were provided by Shenzhen Xintai Pharmaceutical Co., Ltd.

[0066] Drug preparation: 0.5% CMC-Na was used for preparation, and the concentration of the prepared drug was calculated in anhydrous free form.

[0067] Experimental grouping: one day before administration, the animals were randomly divided into 4 groups according to the basic blood pressure and body weight of the animals, and the specific grouping and administration scheme are shown in Table 1.

[0068] Table 1 Animal grouping

[0069]

[0070] After 7 days of continuous administration in each dose group, rats with poor blood pressure control (SBP≥140 mmHg) were selected according to the 24 h blood pressure control in group 3 and group 4, and the experiment was continued, and group 3 was randomly divided into two groups (group 3 and group 5), and the specific grouping and administration scheme are shown in Table 2.

[0071] Table 2 Animal grouping and dosing

[0072]

[0073] Experimental method: Weighed on Day 0 and Day 7, 14 respectively. The baseline blood pressure was measured on Day 0 before dosing, and the blood pressure of animals was measured at 1, 3, 7, 24 hours after dosing every week. When measuring blood pressure, the animals were placed in the mouse bag matched with BP-2010A non-invasive blood pressure meter, and placed in a 37.5°C incubator for 2-3 minutes. After the animal state was stable, blood pressure measurement was started, and each animal was measured 1-3 times.

[0074] Experimental results: From the test results, for high blood pressure controlled poorly by ARNi monotherapy, the application of ARNi complex and amlodipine compound pharmaceutical composition has a synergistic effect on blood pressure control, and performs better in 24h blood pressure control. It is suggested that the ARNi and amlodipine compound can more effectively prevent the occurrence of cardiovascular and cerebrovascular complications.

[0075] Table 3. 24h blood pressure data of ARNi monotherapy combined with amlodipine

[0076]

[0077]

[0078] Note: * P<0.05, *** P<0.001 (vs SHR vehicle group); ## P<0.01 (vs amlodipine).

[0079] The ARNi complex of the present embodiment is the complex obtained in Example 3, and the amount used is calculated based on the anhydrous free acid C 46 H 50 ClN7O7. The amlodipine used is amlodipine besylate, and the amount used is calculated based on the free concentration C 20 H 25 N2O5Cl.

[0080] Example 5

[0081] 5.1 Preparation of dosing solution:

[0082] Accurately weigh ARNi, LCZ696 and amlodipine besylate, and vortex disperse them in 0.5% CMC-Na to make the concentration of ARNi or LCZ696 48 mg / mL and the concentration of amlodipine (free concentration) 0.125, 0.25, 0.5, 1.0, 2.0 and 4.0 mg / mL. Equal volumes of ARNi were mixed with amlodipine suspensions at concentrations of 0.125, 0.25, 0.5, 1.0, 2.0, and 4.0 mg / mL to obtain ARNi+amlodipine suspensions with drug concentrations of 24 + 0.0625, 24 + 0.125, 24 + 0.25, 24 + 0.5, 24 + 1.0, and 24 + 2.0 mg / mL, respectively. Equal volumes of LCZ696 were mixed with amlodipine suspension at a concentration of 1.0 mg / mL to obtain LCZ696+amlodipine suspension with a drug concentration of 24 + 0.5%. The 48 mg / mL ARNi or LCZ696 suspension was diluted twice with 0.5% CMC-Na to make the concentration of ARNi and LCZ696 suspensions 24 mg / mL.

[0083] 5.2 Drug administration and blood collection in SD rats:

[0084] Twenty-five male SD rats weighing 200–300 g were randomly divided into two groups: ARNi and ARNi combined with amlodipine (n=3 per group), and LCZ696 and LCZ696 combined with amlodipine (n=2 per group). The dosages for each group are shown in the table below. Each group was administered the corresponding drug via gavage at a volume of 10 mL / kg. Approximately 100 μL of whole blood was collected via tail vein at 0.25, 0.5, 1, 2, 5, 7, and 24 h post-administration and placed in EDTA-K2 anticoagulant tubes. The tubes were centrifuged at 10,000 rpm for 2 min, and the plasma was separated. The blood concentrations of EXP3174 or valsartan were detected by LC / MS / MS.

[0085]

[0086]

[0087] 5.3 Data Statistics:

[0088] Pharmacokinetic parameters of EXP3174 or valsartan were calculated using WinNonlin software.

[0089] 5.4 Experimental Results:

[0090]

[0091] 5.5 Conclusions of the rat PK experiment:

[0092] The exposure of EXP3174 after the rats were given ARNi and amlodipine in different ratios by gavage was different from that after the rats were given ARNi at the same dose. After the rats were given ARNi and amlodipine at a ratio of 240:0.625 by gavage, the exposure of EXP3174 was lower (about 11.5% lower) than that after the rats were given ARNi at a dose of 240 mg / kg. However, after the rats were given ARNi and amlodipine at a ratio of 240:5 by gavage, the exposure of EXP3174 was higher than that after the rats were given ARNi at a dose of 240 mg / kg, and the increase was the highest (about 35.8% higher).

[0093] However, after the rats were given LCZ696 and amlodipine at a ratio of 240:5 by gavage, the exposure of valsartan was only increased by 4.6%, which was significantly lower than that after the rats were given ARNi and amlodipine at the same ratio.

[0094] In summary, the PK experiment on rats shows that the combination of ARNi and amlodipine is better than ARNi alone, and is also better than the combination of LCZ696 and amlodipine.

[0095] Note: The ARNi complex in this example is the complex obtained in Example 3, and the amount used is based on the anhydrous free acid C 46 H 50 ClN7O7. The amlodipine used is amlodipine besylate, and the amount used is based on the free concentration C 20 H 25 N2O5Cl.

[0096] The above examples are preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application are equivalent replacement methods and are included in the protection scope of the present application.

Claims

1. The use of a compound pharmaceutical composition of an ARNi complex and amlodipine, wherein the use is in the preparation of a medicament for treating patients with hypertension who do not respond well to ARNi monotherapy, wherein the mass ratio of the ARNi complex to amlodipine in the pharmaceutical composition is 5:1 to 192:1, and the ARNi complex is selected from the compound of formula (Ia), based on anhydrous free acid of ARNi. (Ia), where n = 0 - 3, in, The hypertension poorly controlled by ARNi monotherapy refers to hypertension poorly controlled by the complex shown in formula (Ia) or formula (II). (Ia), where n = 0 - 3; (II)。 2. The application of the ARNi complex and amlodipine compound pharmaceutical composition according to claim 1, characterized in that, n = 0, 0.5, 1, 1.5, 2, 2.5 or 3.

3. The application of the ARNi complex and amlodipine compound pharmaceutical composition according to claim 1, characterized in that, n=2 or 2.

5.

4. The application of the compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, characterized in that, Amlodipine is a pharmaceutically acceptable salt, selected from amlodipine maleate and amlodipine besylate, in terms of free concentration.

5. The application of the ARNi complex and amlodipine compound pharmaceutical composition according to claim 1, characterized in that, The dosage unit of the pharmaceutical composition contains amlodipine in doses of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

6. The application of the ARNi complex and amlodipine compound pharmaceutical composition according to claim 1, characterized in that, The dosage unit of the pharmaceutical composition contains ARNi complex in amounts of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, and 360 mg. mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg or 600mg, wherein the ARNi complex is calculated as anhydrous free acid of ARNi.

7. The application of the ARNi complex and amlodipine compound pharmaceutical composition according to claim 1, characterized in that, When the dosage of the ARNi complex is 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, or 480 mg, the dosage of amlodipine is 2.5 mg, 5 mg, or 10 mg, and the ARNi complex is calculated as anhydrous free acid of ARNi.

8. The application of the compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, characterized in that, The mass ratio of ARNi complex to amlodipine in the pharmaceutical composition is 5:1 to 48:1, and the ARNi complex is calculated as anhydrous free acid of ARNi.

9. The application of the compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, characterized in that, The mass ratio of ARNi complex to amlodipine in the pharmaceutical composition is 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 18:1, 24:1, 30:1, 36:1, 42:1, 48:1, 54:1, 60:1, 66:1, 72:1, 78:1, 84:1, 90:1, 96:1, 102:1, 108:1, 114:1, 120:1, 126:1, 132:1, 138:1, 144:1, 150:1, 156:1, 162:1, 168:1, 174:1, 180:1, 186:1, or 192:1, and the ARNi complex is calculated as anhydrous free acid of ARNi.

10. The application of the compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, characterized in that, The mass ratio of ARNi complex to amlodipine in the pharmaceutical composition is 48:1, and the ARNi complex is calculated as anhydrous free acid of ARNi.

11. The application of the compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, characterized in that, The complex is selected from: (EXP3174·AHU377)·1.5Ca·1H2O; (EXP3174·AHU377)·1.5Ca·1.5H2O; (EXP3174·AHU377)·1.5Ca·2H2O; (EXP3174·AHU377)·1.5Ca·2.5H2O; (EXP3174·AHU377)·1.5Ca·3H2O.

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