Pharmaceutical compositions and applications of ARNi and calcium ion antagonists

Abstract

A pharmaceutical composition of ARNi and a calcium ion antagonist for use in the treatment of diseases such as hypertension and heart failure, and its application.

Description

[Technical Field]

[0001] The present invention belongs to the technical field of pharmaceutical compositions, and relates to pharmaceutical compositions of ARNi and calcium ion antagonists and their applications. [Background technology]

[0002] WO2007056546A1 discloses a valsartan-sacubitril (AHU377) sodium salt complex (LCZ696) and a method for producing the same. This valsartan-sacubitril sodium salt complex received manufacturing and marketing approval in China in 2017 under the product name ENTRESTO (registered trademark) (sold overseas under the product name ENTRESTO (registered trademark) in 2015) and is used for the treatment of heart failure. Its molecular structural unit is as follows:

[0003] [ka]

[0004] Furthermore, WO2017125031A1 discloses a series of complexes of an angiotensin receptor antagonist metabolite (EXP3174) and an NEP inhibitor (Sacubitril), the molecular structural units of which are as follows:

[0005] [ka]

[0006] Amlodipine is a calcium ion antagonist that acts directly on peripheral arterial vascular smooth muscle, lowering peripheral vascular resistance and thereby lowering blood pressure. Its existing forms include racemic amlodipine, levo-amlodipine, dextro-amlodipine, or a mixture of levo-amlodipine and dextro-amlodipine in any ratio. Amlodipine can also exist as a salt, including amlodipine benzenesulfonate, amlodipine maleate, etc.

[0007] The prior art, Hsiu-ling Hsiao, Pharmacokinetic drug-drug interaction assessment between LCZ696, a N-terminal agonist receptor inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol, Clinical Pharmacology iNDrug Development, 2015.02.11, doi:10.1002 / cpdd.183, discloses PK data for the combination of LCZ696 and amlodipine, and found that the combination of LCZ696 and amlodipine did not increase the exposure of valsartan compared to LCZ696 alone. Summary of the Invention

[0008] In view of the problems of the prior art, the present invention provides an ARNi and a calcium ion antagonist, wherein the structural unit of ARNi is (EXP3174·AHU377)·1.5Ca·nH2O, where n=1 to 3; The structural formula of ARNi is: [ka] The object of the present invention is to provide a pharmaceutical composition characterized by:

[0009] In a preferred technical implementation of the present invention, n is selected from 1, 1.5, 2, 2.5 and 3.

[0010] As a preferred technical solution of the present invention, ARNi can be obtained by the manufacturing methods of WO2017125031A1 and WO2021143898A1, and the related manufacturing methods and obtained materials are incorporated into the present patents. Specifically, ARNi can be obtained by: [ka] [ka] or [ka] It is preferably selected from:

[0011] In a preferred technical solution of the present invention, the calcium ion antagonist is selected from amlodipine.

[0012] As a preferred technical solution of the present invention, the ARNi (free acid anhydride C 46 H 50 ClN7O7 equivalent) and amlodipine (C 20 H 25 The mass ratio of N2O5Cl (as converted amount) to N2O5Cl is 240:1.25-20.

[0013] As a preferred technical solution of the present invention, the ARNi (free acid anhydride C 46 H 50 ClN7O7 equivalent) and amlodipine (C 20 H 25 The mass ratio of the HCl to the HCl (as converted into N2O5Cl) is 240:1.25, 240:2.5, 240:5, 240:7.5, or 240:10, and is preferably 240:5.

[0014] As a preferred technical solution of the present invention, ARNi (free acid anhydride C 46 H 50 The dose (in terms of ClN7O7 equivalent) is selected from 60 to 480 mg.

[0015] As a preferred technical solution of the present invention, the ARNi (free acid anhydride C 46 H 50 The dose of 100 mg ...

[0016] As a preferred technical solution of the present invention, amlodipine (C 20 H 25 The dose (as N2O5Cl equivalent) is selected from 2.5 to 10 mg.

[0017] As a preferred technical solution of the present invention, the amlodipine (C 20 H 25 The dose of N2O5Cl (as N2O5Cl equivalent) is selected from 2.5, 5, 7.5 and 10 mg.

[0018] As a preferred technical solution of the present invention, the pharmaceutical composition comprises an ARNi and a calcium ion antagonist, wherein the pharmaceutical composition comprises: ARNi(free acid anhydride C 46 H 50 ClN7O7 equivalent) 120mg and amlodipine (C 20 H 25 Contains 2.5 mg (equivalent to N2O5Cl) ARNi(free acid anhydride C 46 H 50 ClN7O7 equivalent) 240mg and amlodipine (C 20 H 25 Contains 5 mg (equivalent to N2O5Cl) ARNi(free acid anhydride C 46 H 50 ClN7O7 equivalent) 360mg and amlodipine (C 20 H 25 Contains 7.5 mg (equivalent to N2O5Cl) or ARNi(free acid anhydride C 46 H 50 ClN7O7 equivalent) 480mg and amlodipine (C 20 H 25Contains 10 mg (equivalent to N2O5Cl).

[0019] As a preferred technical solution of the present invention, [ka] racemic amlodipine, levorotatory amlodipine [ka] Dextrorotatory amlodipine or a mixture of levorotatory amlodipine and dextrorotatory amlodipine in any ratio, wherein amlodipine is present as a salt, and amlodipine benzenesulfonate [ka] Amlodipine maleate and amlodipine levobenzenesulfonate, Amlodipine Maleate Levorotatory [ka] is selected from among others.

[0020] In a preferred technical solution of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, and the pharmaceutical composition is prepared into a suitable pharmaceutical dosage form by a formulation means, and the suitable pharmaceutical dosage form includes dosage forms such as solid oral dosage forms.

[0021] The present invention further provides a use of the pharmaceutical composition, wherein the use of the pharmaceutical composition is use of the pharmaceutical composition in the preparation of a medicament for treating heart failure and / or hypertension, wherein the hypertension includes primary hypertension, and the heart failure includes heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.

[0022] Said uses include applications in medicine for hypertension / heart failure patients who are inadequately controlled by ARNi alone, or in medicine for hypertension / heart failure patients who are inadequately controlled by calcium ion antagonists alone.

[0023] The present invention has the following advantages and beneficial effects over the prior art:

[0024] (1) The present invention provides a combination of ARNi and a calcium ion antagonist, which achieves a synergistic effect by using a specific mass ratio of ARNi and a calcium ion antagonist, and is advantageous in improving the therapeutic effect of heart failure and / or hypertension.

[0025] (2) In the present invention, when ARNi and amlodipine are administered at a mass ratio of 240:1.25-20, the exposure to EXP3174 is significantly increased in both cases, and administration at a mass ratio of 240:5 is most preferable.

[0026] (3) The combination of amlodipine and the pharmaceutical agent of the present invention clearly increases the exposure of the angiotensin receptor antagonist ARB (EXP3174, an ARNi complex of the present invention, is compared to valsartan, an LCZ696) compared to the combination of amlodipine and LCZ696.

[0027] (4) The use of the pharmaceutical composition further includes application in medicine for patients with hypertension / heart failure who are insufficiently controlled by ARNi alone, or in medicine for patients with hypertension / heart failure who are insufficiently controlled by calcium ion antagonists alone, both of which have excellent effects. DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention will be described in more detail below with reference to examples, but the embodiments of the present invention are not limited to these.

[0029] The raw materials used in the present invention can be obtained by manufacturing methods known in the art, including those described in WO2017125031A1 and WO2021143898A1.

[0030] Unless otherwise specified, ARNi in the examples of the present invention is a compound of the following formula, and its amount is free acid anhydride C 46 H 50 It is based on ClN7O7.

[0031] [ka]

[0032] The amlodipine used is amlodipine benzenesulfonate, and the amount used is the free concentration C 20 H 25 It is based on N2O5Cl. [ka]

[0033] Example 1 1.1 Preparation of dosing solutions ARNi, LCZ696, and amlodipine benzenesulfonate were precisely weighed, and each was dispersed in 0.5% CMC-Na using a vortex mixer to give ARNi or LCZ696 concentrations of 48 mg / mL, and amlodipine (free) concentrations of 0.125, 0.25, 0.5, 1.0, 2.0, and 4.0 mg / mL. An equal volume of ARNi was mixed with 0.125, 0.25, 0.5, 1.0, 2.0, and 4.0 mg / mL amlodipine suspensions to obtain ARNi and amlodipine suspensions with pharmaceutical concentrations of 24 + 0.0625, 24 + 0.125, 24 + 0.25, 24 + 0.5, 24 + 1.0, and 24 + 2.0 mg / mL. An equal volume of LCZ696 was mixed with 1.0 mg / mL amlodipine suspension to obtain LCZ696 and amlodipine suspensions with pharmaceutical concentrations of 24 + 0.5 mg / mL. The 48 mg / mL ARNi or LCZ696 suspensions were each diluted 2-fold with 0.5% CMC-Na to obtain a 24 mg / mL ARNi and LCZ696 suspension.

[0034] 1.2 Administration to SD rats and blood sampling Twenty-five male SD rats weighing 200-300 g were randomly assigned to groups. The ARNi group and the ARNi plus amlodipine group each had three rats, while the LCZ696 group and the LCZ696 plus amlodipine group each had two rats. The doses for each group are shown in Table 1 below. Each group received the corresponding drug via intragastric administration at a volume of 10 mL / kg. Approximately 100 μL of whole blood samples were collected from the tail vein into EDTA-K2 blood collection tubes at 0.25, 0.5, 1, 2, 5, 7, and 24 h after each administration. The samples were centrifuged at 10,000 rpm for 2 min to separate the plasma, and the blood concentrations of EXP3174 or valsartan were detected by LC / MS / MS.

[0035] [Table 1]

[0036] 1.3 Data Statistics Pharmacokinetic parameters of EXP3174 or valsartan were calculated using WinNonlin software.

[0037] 1.4 The experimental results are shown in Table 2 below.

[0038] [Table 2]

[0039] 1.5 Conclusions of the rat PK study EXP3174 exposure after intragastric administration of different ARNi and amlodipine combinations to rats showed different changes compared to the same dose of ARNi administered alone. After coadministration of ARNi and amlodipine at a 240:0.625 ratio, the EXP3174 exposure was reduced (approximately 11.5%) compared to 240 mg / kg ARNi alone. However, as the ARNi / amlodipine ratio increased, the EXP3174 exposure increased compared to the ARNi alone group. The 240:5 ARNi / amlodipine combination showed the highest increase in EXP3174 exposure (35.8%).

[0040] However, after intragastric administration of LCZ696 and amlodipine at a 240:5 ratio to rats, the increase in valsartan exposure was only 4.6%, which was significantly lower than that observed when ARNi and amlodipine were coadministered at the same ratio.

[0041] From the above, it was found from the rat PK experiments that the combination of ARNi and amlodipine of the present invention is superior to ARNi alone, and also superior to the combination of LCZ696 and amlodipine.

[0042] Example 2 Using the manufacturing methods described in WO2017125031A1 and WO2021143898A1, ARNi with the following structural formulas were obtained, each of which was combined with amlodipine in a ratio of 240:1.25-20. Experimental results were almost identical to those in Example 1, demonstrating a synergistic effect at the exposure dose of EXP3174.

[0043] [ka]

[0044] [ka]

[0045] From the above, it is expected that the combination of ARNi, a complex formed by EXP3174 and AHU377 with 1.5Ca, and amlodipine (at a mass ratio of 240:1.25-20 at free concentrations, particularly at a mass ratio of 240:5), will achieve a synergistic effect on the exposure of EXP3174, and that the combined use will enhance the efficacy of the drug for the treatment of hypertension and / or heart failure.

[0046] Example 3: Effects of ARNi + amlodipine administration to SHR rats with poor control with amlodipine alone Experimental animals: WKY rats and SHR rats were purchased from Beijing Weitong Lihua Biotechnology Co., Ltd. They were introduced into the animal room at the age of 13 weeks, and the experiment was conducted after an acclimation period of about 2 weeks.

[0047] Test substances: ARNi, amlodipine and LCZ696 were all provided by Shenzhen Xinli Tai Pharmaceutical Co., Ltd.

[0048] Preparation of pharmaceuticals: 0.5% CMC-Na was used for preparation, and the concentrations of the prepared pharmaceuticals were all based on the anhydrous free form.

[0049] Experimental grouping: On the day before administration, the animals were randomly divided into four groups according to their basal blood pressure and body weight. The specific grouping and administration schedule are shown in Table 3.

[0050] [Table 3]

[0051] After seven days of administration in each dose group, rats with insufficient blood pressure control (SBP ≥ 140 mmHg) were selected for groups 3 and 4 based on the 24-hour blood pressure control status, and the experiment was continued. Group 4 was randomly divided into three groups (groups 4, 5, and 6). The specific group divisions and administration schedules are shown in Table 4.

[0052] [Table 4]

[0053] Experimental method: Animals were weighed on days 0, 7, and 14. Basal blood pressure was measured before administration, i.e., on day 0, and then measured weekly at 1, 3, 7, and 24 hours after administration. When measuring blood pressure, the animals were placed in a rat bag attached to a BP-2010A non-invasive blood pressure monitor and placed in a holding vessel at 37.5°C for 2-3 minutes. Blood pressure measurements were started once the animals' condition stabilized, with each animal being measured 1-3 times.

[0054] Experimental results: For hypertension that is insufficiently controlled with amlodipine alone, the pharmaceutical composition of the complex consisting of the ARNi complex and amlodipine of the present invention has a synergistic effect in controlling blood pressure, is excellent in controlling blood pressure over 24 hours, and has a superior antihypertensive effect than the pharmaceutical composition of the complex consisting of LCZ696 and amlodipine, suggesting that this complex consisting of ARNi and amlodipine can more effectively prevent the occurrence of cerebrovascular complications.

[0055] [Table 5]

[0056] remarks: * P<0.05, *** P<0.001 (vs. SHR vehicle group). # P<0.05 (vs. ARNi), $$$ P<0.001 (vs. amlodipine).

[0057] @ The amount of ARNi complex used in this example was 100% free acid anhydride C 46 H 50 The amlodipine used was amlodipine benzenesulfonate, and the amount used was the free concentration C 20 H 25 The standard was N2O5Cl.

[0058] Example 4: Effects of ARNi + amlodipine administration to SHR rats with poor control with ARNi alone

[0059] Experimental animals: WKY rats and SHR rats were purchased from Beijing Weitong Lihua Biotechnology Co., Ltd. They were introduced into the animal room at the age of 13 weeks and were allowed to acclimate for approximately two weeks before the experiment.

[0060] Test substances: ARNi and amlodipine were both provided by Shenzhen Xinli Tai Pharmaceutical Co., Ltd.

[0061] Preparation of pharmaceuticals: 0.5% CMC-Na was used for preparation, and the concentrations of the prepared pharmaceuticals were all based on the anhydrous free form.

[0062] Experimental grouping: On the day before administration, the animals were randomly divided into four groups according to their basal blood pressure and body weight. The specific grouping and administration schedule are shown in Table 6.

[0063] [Table 6]

[0064] After 7 days of continuous administration for each dose group, rats with insufficient blood pressure control (SBP ≥ 140 mmHg) were selected for Groups 3 and 4 based on the 24-hour blood pressure control status, and the experiment was continued. Group 3 was randomly divided into two groups (Group 3 and Group 5). The specific group divisions and administration schedules are shown in Table 7.

[0065] [Table 7]

[0066] Experimental method: Animals were weighed on days 0, 7, and 14. Basal blood pressure was measured before administration, i.e., on day 0, and then measured weekly at 1, 3, 7, and 24 hours after administration. When measuring blood pressure, the animals were placed in a rat bag attached to a BP-2010A non-invasive blood pressure monitor and placed in a holding vessel at 37.5°C for 2-3 minutes. Blood pressure measurements were started once the animals' condition stabilized, with each animal being measured 1-3 times.

[0067] Experimental Results: The test results showed that in cases of hypertension where ARNi alone is insufficient, the pharmaceutical composition of the present invention, which is a complex of ARNi and amlodipine, has a synergistic effect in controlling blood pressure and is superior in 24-hour blood pressure control. This suggests that the complex of ARNi and amlodipine can more effectively prevent the occurrence of cerebrovascular complications.

[0068] [Table 8]

[0069] remarks: * P<0.05, *** P<0.001 (vs. SHR vehicle group). ## P<0.01 (vs. amlodipine).

[0070] @ The amount of ARNi complex used in this example was 100% free acid anhydride C 46 H 50 The amlodipine used was amlodipine benzenesulfonate, and the amount used was the free concentration C 20 H 25 The standard was N2O5Cl.

[0071] The above-mentioned examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above-mentioned examples, and it should be understood that any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention are equivalent replacement methods, and all fall within the protection scope of the present invention.

Claims

1. ARNi and a calcium ion antagonist, The structural unit of ARNi is (EXP3174 AHU377) 1.5Ca nH ２ O, n=1 to 3, The structural formula of ARNi is: 【Chemical 1】 and the calcium ion antagonist is amlodipine; A pharmaceutical composition characterized in that the mass ratio of ARNi (equivalent to free acid anhydride C 46 H 50 ClN 7 O 7 ) to amlodipine (equivalent to C 20 H 25 N 2 O 5 Cl) is 240:1.25-20.

2. ARNi is, 【Chemistry 2】 、 【Chemistry 3】 ,or 【Chemistry 4】 The pharmaceutical composition according to claim 1, characterized in that it is selected from the group consisting of:

3. The ARNi (free acid anhydride C ４６ H ５０ ClN ７ O ７ (as equivalent) and amlodipine (C ２０ H ２５ N ２ O ５ 2. The pharmaceutical composition according to claim 1, wherein the mass ratio of HCl to HCl (as converted amount) is 240:1.25, 240:2.5, 240:5, 240:7.5, or 240:

10.

4. ARNi (free acid anhydride C ４６ H ５０ ClN ７ O ７ The pharmaceutical composition according to claim 1, characterized in that the dose (as an equivalent amount) is selected from the range of 60 to 480 mg.

5. The ARNi (free acid anhydride C ４６ H ５０ ClN ７ O ７ 5. The pharmaceutical composition according to claim 4, characterized in that the dose (as equivalent) is selected from the group consisting of 60, 120, 240, 300, 360, 420 and 480 mg.

6. The amlodipine (C ２０ H ２５ N ２ O ５ The pharmaceutical composition according to claim 1, wherein the dose of the compound (as Cl equivalent) is selected from the range of 2.5 to 10 mg.

7. The amlodipine (C ２０ H ２５ N ２ O ５ 7. The pharmaceutical composition according to claim 6, wherein the dose of the compound (as Cl equivalent) is selected from 2.5, 5, 7.5 and 10 mg.

8. 2. The pharmaceutical composition of claim 1, wherein the amlodipine is selected from racemic amlodipine, levo-amlodipine, dextro-amlodipine, or a mixture of levo-amlodipine and dextro-amlodipine in any ratio, and the amlodipine is present as a salt selected from amlodipine benzenesulfonate, amlodipine maleate, amlodipine levo-amlodipine benzenesulfonate, and amlodipine maleate.

9. Use of a pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for the treatment of patients with heart failure and / or hypertension.

10. The use according to claim 9, characterized in that the patient is a patient with hypertension and / or heart failure that is inadequately controlled with an ARNi alone, or a patient with hypertension and / or heart failure that is inadequately controlled with a calcium ion antagonist alone.

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