New uses of pharmaceutical compositions of arni complexes

Abstract

The present application provides a new application of a pharmaceutical composition containing an ARNi complex, and the new application is an application of the pharmaceutical composition containing the ARNi complex in the preparation of a medicine for treating a hypertension patient who is poorly controlled by amlodipine 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 pharmaceutical composition of ARNi complex. 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. The commonly used six categories of high blood pressure treatment drugs are: beta receptor blockers, angiotensin II receptor antagonists (ARB), angiotensin converting enzyme inhibitors (ACEi), diuretics, calcium ion channel antagonists (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 the bottleneck period of 60% of patients who are not ideal for single drug control. Under this condition, 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 has attracted more and more attention in the medical field at home and abroad.

[0003] At present, the ARNi (angiotensin receptor blocker 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, WO2017125031A1 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 purpose of the present application is to provide a new application of a pharmaceutical composition containing ARNi complex, and the new application is the application of the pharmaceutical composition containing ARNi complex in the preparation of a drug for treating high blood pressure patients who are not well controlled by amlodipine monotherapy.

[0009] Hypertensive patients who do not respond well to amlodipine monotherapy may also have other conditions such as heart failure, angina pectoris, diabetes, such as hypertension in diabetic patients, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria in primary kidney disease, and renal vascular hypertension.

[0010] This application includes administering a pharmaceutical composition containing an effective amount of the ARNi complex, or a combination pharmaceutical composition of the ARNi complex and amlodipine, to hypertensive patients requiring this treatment.

[0011] Specifically, the present invention is achieved through the following technical solution:

[0012] A novel application of a pharmaceutical composition containing an ARNi complex, wherein the application is in the preparation of a medicament for treating patients with hypertension poorly controlled by amlodipine monotherapy, the ARNi complex being selected from the complexes shown in formula (I):

[0013] Where n = 0 - 3.

[0014] In a preferred embodiment of the present invention, x = 0.5, 1, 1.5, or 2, and n = 0, 0.5, 1, 1.5, 2, 2.5, or 3. In a preferred embodiment of the present invention, the ARNi complex is selected from the complex shown in formula (Ia): Where n = 0, 0.5, 1, 1.5, 2, 2.5 or 3.

[0015] As a preferred technical solution of the present invention, n = 2 or 2.5 is preferred.

[0016] As a preferred embodiment of the present invention, amlodipine can be a pharmaceutically acceptable salt, selected from amlodipine maleate and amlodipine besylate.

[0017] As a preferred embodiment of the present invention, the dosage of amlodipine used when monotherapy is ineffective is 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.

[0018] As a preferred embodiment of the present invention, the dosage unit of the pharmaceutical composition may contain ARNi complex (calculated as anhydrous free acid of ARNi) 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, or 300 mg. The dosages of amlodipine are 0.5 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; the dosage of amlodipine used is 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.

[0019] As a preferred embodiment of the present invention, when the dosage unit of the pharmaceutical composition contains 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, or 480 mg of ARNi complex (calculated as anhydrous free acid of ARNi), the dosage of amlodipine is 2.5 mg, 5 mg, or 10 mg.

[0020] As a preferred embodiment of the present invention, the pharmaceutical composition is a compound pharmaceutical composition containing ARNi complex and amlodipine.

[0021] As a preferred embodiment of the present invention, the mass ratio of the ARNi complex (calculated as anhydrous free ARNi acid) to amlodipine is 1:1 to 200:1.

[0022] As a preferred embodiment of the present invention, specifically, the mass ratio of the ARNi complex (calculated as anhydrous free acid of ARNi) 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, and 192:1.

[0023] For example: ARNi + amlodipine = 60mg + 2.5mg, 60mg + 5mg, 60mg + 10mg; or 120mg + 2.5mg, 120mg + 5mg, 120mg + 10mg; or 180mg + 2.5mg, 180mg + 5mg, 180mg + 10mg; or 240mg + 2.5mg, 240mg + 5mg, 240mg + 10mg; or 300mg + 2.5mg, 3000mg + 5mg, 3000mg + 10mg; or 360mg + 2.5mg, 360mg + 5mg, 360mg + 10mg; or 420mg + 2.5mg, 420mg + 5mg, 420mg + 10mg; or 480mg + 2.5mg, 480mg + 5mg, 480mg + 10mg.

[0024] The ARNi complex can be obtained by methods known in the prior art, wherein the ARNi complex and its preparation method disclosed in WO2017125031A1 are incorporated herein by reference.

[0025] As a more preferred embodiment of the present invention, the composite is selected from:

[0026] (EXP3174·AHU377)·1.5Ca·1H2O;

[0027] (EXP3174·AHU377)·1.5Ca·1.5H2O;

[0028] (EXP3174·AHU377)·1.5Ca·2H2O;

[0029] (EXP3174·AHU377)·1.5Ca·2.5H2O;

[0030] (EXP3174·AHU377)·1.5Ca·3H2O;

[0031] (EXP3174·AHU377)·2Ca·1H2O;

[0032] (EXP3174·AHU377)·2Ca·1.5H2O;

[0033] (EXP3174·AHU377)·2Ca·2H2O;

[0034] (EXP3174·AHU377)·2Ca·2.5H2O;

[0035] (EXP3174·AHU377)·2Ca·3H2O.

[0036] Those skilled in the art will understand that the complex is a supramolecular complex, and in the unit cell of the supramolecular complex, the alisartan ester metabolite (EXP3174), AHU377, and calcium ions (Ca) are present. 2+ Solvent molecules and other molecules will fill it in the form of several structural units.

[0037] The supramolecular complex (complex) described in this invention differs from a mixture obtained by simply mixing two active ingredients physically. The XRD pattern of the resulting supramolecular complex (complex) is significantly different from that of the EXP3174 and AHU377 calcium salts, and its solubility in various solvents (such as water, ethanol, ethanol-water, etc.) also shows significant differences. Furthermore, significant differences are observed in other physicochemical properties such as hygroscopicity, melting point, and infrared spectrum.

[0038] The present invention has the following advantages and beneficial effects compared with the prior art:

[0039] 1. The pharmaceutical composition containing ARNi of the present invention is expected to have a good antihypertensive effect when used clinically to treat patients with hypertension that is not well controlled by amlodipine monotherapy.

[0040] 2. The pharmaceutical composition containing ARNi and amlodipine of the present invention is expected to have a good antihypertensive effect when used clinically to treat patients with hypertension that is not well controlled by amlodipine monotherapy. Detailed Implementation

[0041] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0042] In the following embodiments:

[0043] X-ray powder diffraction was performed using an Empyrean X-ray diffractometer. The detection conditions were: Cu target Kα rays, 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 size 0.02°, and dwell time per step 40 s.

[0044] Differential scanning calorimetry (DSC) spectra were detected using a NETZSCH DSC204F1 DSC calorimeter from Germany. Detection conditions: atmosphere: N2, 20 mL / min; scanning program: temperature increased from room temperature to 250 °C at 10 °C / min, and the temperature rise curve was recorded.

[0045] Moisture content was determined using a NETZSCH TG209 thermogravimetric analyzer from Germany. The testing conditions were: atmosphere: N2, 20 mL / min; scan program: room temperature - 700℃, heating rate: 10℃ / min.

[0046] The EXP3174 used in the examples was manufactured in-house and had a purity of 98.3%.

[0047] The AHU377 calcium salt used in the examples was manufactured in-house and had a purity of 99.4%.

[0048] Example 1

[0049] Preparation of anhydrous free acid AHU377:

[0050] Add 2.1 g of AHU377 calcium salt and 40 mL of isopropyl acetate to a 250 mL single-necked flask, and add 4.5 mL of 2 mol / L hydrochloric acid at room temperature, stirring until dissolved. Separate the layers, collect the organic layer, and wash the organic layer twice with 20 mL of water; remove the solvent under reduced pressure at 35 °C to obtain anhydrous free AHU377 acid.

[0051] Example 2

[0052] Preparation of the complex: (Prepared according to Example 2 of patent WO2017125031A1)

[0053]

[0054] At room temperature, 2.36 g of anhydrous free acid AHU377 obtained according to the method in Example 1, 2 g of EXP3174, and 40 mL of acetone were added to a 250 mL three-necked flask and dissolved. Then, at room temperature, 1.3 equivalents of calcium hydroxide solid relative to AHU377 and 1 mL of water were added, and the mixture was stirred at room temperature for 10 h. Another 40 mL of acetone was added, and the reaction was continued for 8 h. The mixture was then filtered through a Buchner funnel under nitrogen protection. The solid was washed with acetone to obtain a white solid, which was then dried under vacuum at 35 °C for 8 h to obtain 3.5 g of solid (EXP3174·AHU377).3 -·1.5Ca 2+ • 2.5H2O, HPLC purity was 99%. Repeat the experiment to obtain a sufficient amount for efficacy testing.

[0055] Example 3

[0056] Preparation of the complex: (Prepared according to Example 3 of patent WO2017125031A1)

[0057]

[0058] At room temperature, 2.36 g of anhydrous free acid AHU377 obtained according to the method in Example 1, 2 g of EXP3174, and 40 mL of acetone were added to a 250 mL three-necked flask and dissolved. At room temperature, 1.6 equivalents of calcium hydroxide solid relative to AHU377 and 0.6 mL of water were added, and the mixture was stirred at 35°C for 6 h. Another 40 mL of acetone was added, and the reaction was continued for 8 h. The mixture was filtered through a Buchner funnel under nitrogen protection. The solid was washed with acetone to obtain a white solid, which was then dried under vacuum at 50°C for 8 h to obtain 3.1 g of solid (EXP3174·AHU377). 3 -·1.5Ca 2+ • 2H₂O. Repeat the experiment to obtain a sufficient dosage for the efficacy test.

[0059] Example 4: Effect of ARNi + Amlodipine on SHR Rats with Poor Controlled Rats by Amlodipine Monotherapy

[0060] Experimental animals: WKY rats and SHR rats were purchased from Beijing Vital River Biotechnology Co., Ltd. They were 13 weeks old when they entered the animal room and were put into use for experiments after about 2 weeks.

[0061] Test substances: ARNi, amlodipine and LCZ696 were all provided by Shenzhen Salubris Pharmaceuticals Co., Ltd.

[0062] Drug preparation: 0.5% CMC-Na was used for preparation, and all drug concentrations were expressed in anhydrous free form.

[0063] Experimental grouping: One day before administration, the animals were randomly divided into 4 groups based on their baseline blood pressure and weight. The specific grouping and administration regimen are shown in Table 1.

[0064] Table 1 Animal grouping

[0065]

[0066] After each dose group was administered for 7 consecutive days, rats with poor blood pressure control (SBP≥140mmHg) were selected from groups 3 and 4 based on their 24-hour blood pressure control to continue the experiment. Group 4 was randomly divided into three groups (group 4, group 5, and group 6). The specific grouping and administration regimen are shown in Table 2.

[0067] Table 2 Animal grouping and administration

[0068]

[0069] Experimental Methods: Animals were weighed on Day 0, Day 7, and Day 14. Baseline blood pressure was measured on Day 0 before drug administration. Blood pressure was measured weekly at 1, 3, 7, and 24 hours after drug administration. During measurement, animals were placed in the BP-2010A non-invasive blood pressure monitor's accompanying mouse bag and placed in a 37.5℃ insulated container for 2-3 minutes. Blood pressure was measured 1-3 times per animal after the animal's condition stabilized.

[0070] Experimental results: For hypertension that is poorly controlled by amlodipine monotherapy, the combination drug composition of ARNi complex and amlodipine of this invention has a synergistic effect on blood pressure control, showing better performance in 24-hour blood pressure control and is superior to the antihypertensive effect of the combination drug composition of LCZ696 and amlodipine. This suggests that the combination drug composition of ARNi and amlodipine can more effectively prevent the occurrence of cardiovascular and cerebrovascular complications.

[0071] Table 3. 24-hour blood pressure data after combining with ARNi complex for treatment of inadequate amlodipine monotherapy

[0072]

[0073] Note: * P<0.05, *** P<0.001 (vs SHR solvent group); # P<0.05 (vs ARNi); $$$ P<0.001 (vs. amlodipine).

[0074] @The ARNi complex in this embodiment is the complex obtained in Example 3, and its usage is based on anhydrous free acid C 46 H 50 The dosage is calculated as ClN7O7. The amlodipine used is amlodipine besylate, and its dosage is expressed as the free concentration C. 20 H 25 N2O5Cl is used as a metric.

[0075] Example 5

[0076] 5.1 Preparation of drug delivery solution:

[0077] 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.

[0078] 5.2 Drug administration and blood collection in SD rats:

[0079] 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.

[0080]

[0081] 5.3 Data Statistics:

[0082] Pharmacokinetic parameters of EXP3174 or valsartan were calculated using WinNonlin software.

[0083] 5.4 Experimental Results:

[0084]

[0085] 5.5 Conclusions of the rat PK experiment:

[0086] The EXP3174 exposure in rats after combined gavage administration of ARNi and amlodipine at different ratios showed different changes compared with the same dose of ARNi monotherapy. The EXP3174 exposure was lower (approximately 11.5%) after combined administration of ARNi and amlodipine at a ratio of 240:0.625 compared with 240 mg / kg ARNi monotherapy. However, the EXP3174 exposure increased with increasing ARNi:amlodipine ratio compared with the ARNi monotherapy group. The highest increase in EXP3174 exposure was observed (35.8%) when ARNi and amlodipine were administered at a ratio of 240:5.

[0087] However, after rats were given LCZ696 and amlodipine in a 240:5 ratio via gavage, the increase in valsartan exposure was only 4.6%, which was significantly lower than that of ARNi + amlodipine in the same ratio.

[0088] In summary, the rat PK experiment demonstrated that the combination of ARNi and amlodipine of the present invention is superior to ARNi monotherapy, and also superior to the combination of LCZ696 and amlodipine.

[0089] Note: The ARNi complex in this example is the complex obtained in Example 3, and its usage is based on the amount of anhydrous free acid C. 46 H 50 The dosage is calculated as ClN7O7. The amlodipine used is amlodipine besylate, and its dosage is expressed as the free concentration C. 20 H 25 N2O5Cl is used as a metric.

[0090] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The use of a pharmaceutical composition containing an ARNi complex, characterized in that, The application refers to the use of pharmaceutical compositions containing the ARNi complex in the preparation of remedies for treating patients with hypertension who do not respond well to amlodipine monotherapy. The pharmaceutical composition is a combination pharmaceutical composition of ARNi complex and amlodipine, wherein the ARNi complex is selected from the complex shown in formula (I): (I), where x=1.5, n=0-3; the mass ratio of ARNi complex to amlodipine in the pharmaceutical composition is 5:1-192:1, and the ARNi complex is calculated as anhydrous free acid of ARNi.

2. The application of a pharmaceutical composition containing an ARNi complex according to claim 1, characterized in that, x = 1.5, n = 0, 0.5, 1, 1.5, 2, 2.5 or 3.

3. The application of a pharmaceutical composition containing an ARNi complex according to claim 1, characterized in that, The ARNi complex is selected from the complex shown in formula (Ia): (Ia), where n = 0, 0.5, 1, 1.5, 2, 2.5 or 3.

4. The application of a pharmaceutical composition containing an ARNi complex according to claim 1, characterized in that, n=2 or 2.

5.

5. The application of a pharmaceutical composition containing an ARNi complex 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.

6. The application of a pharmaceutical composition containing an ARNi complex according to claim 1, characterized in that, The dosage of amlodipine used for patients whose condition is not well controlled by monotherapy is 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.

7. The application of a pharmaceutical composition containing an ARNi complex 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. 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.

8. The application of a pharmaceutical composition containing an ARNi complex 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.

9. The application of a pharmaceutical composition containing an ARNi complex 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.

10. The application of a pharmaceutical composition containing an ARNi complex 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.

11. The application of a pharmaceutical composition containing an ARNi complex 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.

12. The application of a pharmaceutical composition containing an ARNi complex 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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