A pharmaceutical composition of ARNi and calcium ion antagonist and its application

Abstract

A pharmaceutical composition of ARNi and a calcium ion antagonist and its application. The pharmaceutical composition can be used for diseases such as hypertension and heart failure.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical compositions and relates to a pharmaceutical composition of ARNi and a calcium ion antagonist and its application. Background Art

[0002] WO2007056546A1 discloses a sodium salt complex of valsartan and sacubitril (AHU377) (LCZ696) and its preparation method, which was approved for marketing in China in 2017 under the trade name: (The overseas marketed product is called 2015) for heart failure. Its molecular structure unit is as follows:

[0003]

[0004] In addition, WO2017125031A1 discloses a series of complexes composed of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), the molecular structural units of which are as follows:

[0005]

[0006] Amlodipine is a calcium channel blocker that acts directly on peripheral arterial smooth muscle, reducing peripheral vascular resistance and thereby lowering blood pressure. It exists in the form of racemic amlodipine, levamlodipine, dextroamlodipine, or mixtures of levamlodipine and dextroamlodipine in any ratio. Furthermore, amlodipine can exist in the form of salts, including amlodipine besylate and amlodipine maleate.

[0007] Prior art Hsiu-ling Hsiao, Pharmacokinetic drug–drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol, Clinical Pharmacology in Drug Development, 2015.02.11, doi:10.1002 / cpdd.183, disclosed PK data for the combined use of LCZ696 and amlodipine. The results showed that LCZ696 + amlodipine did not increase the exposure of valsartan compared to LCZ696 alone. Summary of the Invention

[0008] In view of the problems existing in the prior art, the object of the present invention is to provide a pharmaceutical composition, characterized in that the pharmaceutical composition is composed of ARNi and a calcium ion antagonist, wherein the structural unit of ARNi is as follows:

[0009] (EXP3174·AHU377)·1.5Ca·nH2O, where n=1-3;

[0010] The structural formula of ARNi is as follows:

[0011]

[0012] As a preferred technical solution of the present invention, n is selected from 1, 1.5, 2, 2.5 and 3.

[0013] As a preferred technical solution of the present invention, ARNi can be obtained by the preparation methods of WO2017125031A1 and WO2021143898A1. The relevant preparation methods and the obtained substances are introduced into this patent. Specifically, ARNi is preferably selected from:

[0014]

[0015]

[0016] As a preferred technical solution of the present invention, the calcium ion antagonist is selected from amlodipine.

[0017] As a preferred technical solution of the present invention, the ARNi (in the form of anhydrous free acid C 46 H 50 ClN7O7) and amlodipine (in C 20 H 25 The mass ratio of N2O5Cl) is 240:1.25~20.

[0018] As a preferred technical solution of the present invention, the ARNi (in the form of anhydrous free acid C 46 H 50 ClN7O7) and amlodipine (in C 20 H 25 The mass ratio of N2O5Cl) is 240:1.25, 240:2.5, 240:5, 240:7.5 and 240:10, preferably 240:5.

[0019] As a preferred technical solution of the present invention, the ARNi (in the form of anhydrous free acid C 46 H 50 ClN7O7) is selected from 60 to 480 mg.

[0020] As a preferred technical solution of the present invention, the ARNi (in the form of anhydrous free acid C 46 H 50 ClN7O7) is selected from 60, 120, 240, 300, 360, 420 and 480 mg.

[0021] As a preferred technical solution of the present invention, the amlodipine (in C 20 H 25 N2O5Cl) is selected from 2.5 to 10 mg.

[0022] As a preferred technical solution of the present invention, the amlodipine (in C 20 H 25 N2O5Cl) is selected from 2.5, 5, 7.5 and 10 mg.

[0023] As a preferred technical solution of the present invention, the pharmaceutical composition consists of ARNi and a calcium ion antagonist, which includes:

[0024] ARNi (in anhydrous free acid C 46 H 50 ClN7O7) 120mg, amlodipine (in C 20 H 25 N2O5Cl) 2.5 mg;

[0025] or ARNi (in anhydrous free acid C 46 H 50 ClN7O7) 240 mg, amlodipine (in C 20 H 25 N2O5Cl) 5mg;

[0026] or ARNi (in anhydrous free acid C 46 H 50 ClN7O7) 360mg, amlodipine (in C 20 H 25 N2O5Cl) 7.5 mg;

[0027] or ARNi (in anhydrous free acid C 46 H 50 ClN7O7) 480mg, amlodipine (in C 20 H 25 N2O5Cl) 10mg.

[0028] As a preferred technical solution of the present invention, the amlodipine Selected from racemic amlodipine, levamlodipine Dextroamlodipine, or a mixture of levtroamlodipine and dextroamlodipine in any proportion; amlodipine is in the form of a salt selected from amlodipine besylate Amlodipine maleate, levamlodipine besylate, and levamlodipine maleate wait.

[0029] As a preferred technical solution of the present invention, the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers, and the pharmaceutical composition is prepared into a suitable pharmaceutical dosage form by formulation means, and the dosage form includes a solid oral dosage form.

[0030] The present invention further provides a use of a pharmaceutical composition, wherein the pharmaceutical composition is used in the preparation of a medicament for treating heart failure and / or hypertension, wherein the hypertension includes essential hypertension, and the heart failure includes heart failure with decreased ejection fraction and heart failure with preserved ejection fraction.

[0031] The use includes the use in medicine for patients with hypertension / heart failure who are not well controlled by ARNi alone, or the use in medicine for patients with hypertension / heart failure who are not well controlled by calcium channel blockers alone.

[0032] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0033] (1) The present invention provides a combination of ARNi and a calcium ion antagonist, which achieves a synergistic effect through a specific mass ratio of ARNi to the calcium ion antagonist, which is beneficial to improving the effect of treating heart failure and / or hypertension.

[0034] (2) After administration of the ARNi of the present invention and amlodipine at a mass ratio of 240:1.25-20, the exposure of EXP3174 increased significantly, especially at a mass ratio of 240:5.

[0035] (3) Compared with the combination of amlodipine and the drug of the present invention, the exposure of angiotensin receptor antagonist ARB (EXP3174 of the ARNi complex of the present invention compared with valsartan of LCZ696) was significantly increased in the combination of amlodipine and the drug of the present invention.

[0036] (4) The use of the drug combination further includes its application in the treatment of patients with hypertension / heart failure who are poorly controlled by ARNi alone, or in the treatment of patients with hypertension / heart failure who are poorly controlled by calcium ion antagonist alone, both of which have better effects. DETAILED DESCRIPTION

[0037] The present invention will be further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0038] The raw materials used in the present invention can be obtained by preparation methods known in the prior art, including the methods described in WO2017125031A1 and WO2021143898A1.

[0039] Unless otherwise specified, the ARNi of the present invention is a compound of the following formula, and its usage amount is based on the anhydrous free acid C 46 H 50 ClN7O7 meter:

[0040]

[0041] The amlodipine used was amlodipine besylate, and its dosage was based on the free concentration C 20 H 25 N2O5Cl meter:

[0042]

[0043] Example 1

[0044] 1.1 Preparation of dosing solution:

[0045] ARNi, LCZ696 and amlodipine besylate were accurately weighed, and 0.5% CMC-Na was added and vortexed to disperse them respectively, so that the concentration of ARNi or LCZ696 was 48 mg / mL and the concentration of amlodipine (free concentration) was 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+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. An equal volume of LCZ696 was mixed with 1.0 mg / mL amlodipine suspension to obtain LCZ696+amlodipine suspension with a drug concentration of 24+0.5. 48 mg / mL ARNi or LCZ696 suspensions were diluted 2-fold with 0.5% CMC-Na to obtain a concentration of 24 mg / mL for the ARNi and LCZ696 suspensions.

[0046] 1.2 Drug administration and blood collection in SD rats:

[0047] Twenty-five male Sprague-Dawley rats weighing 200-300 g were randomly divided into three groups: ARNi and ARNi combined with amlodipine (groups of three rats each); and LCZ696 and LCZ696 combined with amlodipine (groups of two rats each). The dosages for each group are shown in Table 1. Each group was gavaged with the corresponding drug at a volume of 10 mL / kg. Approximately 100 μL of whole blood was collected via the tail vein at 0.25, 0.5, 1, 2, 5, 7, and 24 hours after administration. The blood was collected into EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 2 minutes. Plasma was separated, and plasma concentrations of EXP3174 or valsartan were determined by LC / MS / MS.

[0048] Table 1

[0049]

[0050] 1.3 Statistics:

[0051] WinNonlin software was used to calculate the pharmacokinetic parameters of EXP3174 or valsartan.

[0052] 1.4 Experimental results are shown in Table 2 below:

[0053] Table 2

[0054]

[0055] 1.5 Conclusion of rat PK experiment:

[0056] After ARNi and amlodipine were co-administered orally in different ratios to rats, the exposure of EXP3174 showed different changes compared with the same dose of ARNi alone. After ARNi and amlodipine were co-administered in a ratio of 240:0.625, the exposure of EXP3174 decreased compared with 240 mg / kg ARNi alone (decreased by about 11.5%). However, as the ratio of ARNi to amlodipine increased, the exposure of EXP3174 increased compared with the ARNi alone group. Among them, the increase in EXP3174 exposure was the highest when ARNi and amlodipine were administered in a ratio of 240:5 (the increase was 35.8%).

[0057] However, after oral administration of LCZ696 and amlodipine in a ratio of 240:5 to rats, the increase in valsartan exposure was only 4.6%, which was significantly lower than the increase in exposure when ARNi and amlodipine were administered in equal ratios.

[0058] In summary, the rat PK experiment demonstrated that the combination of ARNi and amlodipine of the present invention is superior to ARNi alone, and is also superior to the combination of LCZ696 and amlodipine.

[0059] Example 2

[0060] The preparation methods described in WO2017125031A1 and WO2021143898A1 were used to obtain ARNi of the following structural formulas, which were respectively combined with amlodipine at a ratio of 240:1.25-20 to obtain experimental results basically consistent with those in Example 1, showing a synergistic effect in the exposure amount of EXP3174.

[0061]

[0062] In summary, EXP3174 and AHU377 achieve a synergistic effect in EXP3174 exposure through the combination of ARNi composed of 1.5Ca and amlodipine (according to the free concentration mass ratio of 240:1.25-20, especially the mass ratio of 240:5). It is expected that the combined use can enhance the effect for hypertension and / or heart failure.

[0063] Example 3 Effects of ARNi+Amlodipine Administration on SHR Rats Poorly Controlled by Amlodipine Alone

[0064] Experimental animals: WKY rats and SHR rats were purchased from Beijing Weitonglihua Biotechnology Co., Ltd. They were admitted to the animal room at the age of 13 weeks, and the experiments were carried out after the suitable period of about 2 weeks.

[0065] Test substances: ARNi, amlodipine and LCZ696 were all provided by Shenzhen Xinlitai Pharmaceutical Co., Ltd.

[0066] Drug preparation: 0.5% CMC-Na was used for preparation, and the prepared drug concentrations were all calculated based on the anhydrous free form.

[0067] Experimental groups: One day before administration, the animals were randomly divided into 4 groups according to their basal blood pressure and body weight. The specific groups and administration schedules are shown in Table 3.

[0068] Table 3 Animal groups

[0069]

[0070] After 7 days of continuous administration in each dose group, rats with poor blood pressure control (SBP ≥ 140 mmHg) were selected from Groups 3 and 4 according to the 24-h blood pressure control situation to continue the experiment. Group 4 was randomly divided into three groups (Group 4, Group 5, Group 6). The specific grouping and dosing schedule are shown in Table 4.

[0071] Table 4 Animal grouping and drug administration

[0072]

[0073] Experimental Methods: Weigh animals on Day 0, Day 7, and Day 14. Basal blood pressure was measured on Day 0 before dosing. Blood pressure was measured 1, 3, 7, and 24 hours per week after dosing. For blood pressure measurements, animals were placed in a rat bag equipped with a BP-2010A non-invasive blood pressure monitor in a 37.5°C insulated container for 2-3 minutes. Blood pressure measurements were then started after the animals stabilized. Blood pressure was measured 1-3 times per animal.

[0074] Experimental results: For hypertension that is poorly controlled by amlodipine alone, the administration of the compound pharmaceutical composition composed of the ARNi complex of the present invention and amlodipine has a synergistic effect in blood pressure control, performs better in 24-hour blood pressure control, and is superior to the antihypertensive effect of the compound pharmaceutical composition composed of LCZ696 and amlodipine, indicating that the compound pharmaceutical composition of the present ARNi and amlodipine can more effectively prevent the occurrence of cardiovascular and cerebrovascular complications.

[0075] Table 5 24h blood pressure data after amlodipine monotherapy was poorly controlled and combined with ARNi complex

[0076]

[0077] Note: * P<0.05, *** P < 0.001 (vs SHR vehicle group); # P < 0.05 (vsARNi); $$$ P<0.001 (vs amlodipine).

[0078] @ The amount of ARNi complex used in this example is based on anhydrous free acid C 46 H 50 The amlodipine used is amlodipine besylate, and its usage is based on the free concentration C 20 H 25 N2O5Cl meter.

[0079] Example 4 Effects of ARNi+Amlodipine Administration on SHR Rats with Poor ARNi Control

[0080] Experimental animals: WKY rats and SHR rats were purchased from Beijing Weitonglihua Biotechnology Co., Ltd. They were admitted to the animal room at the age of 13 weeks, and the experiments were carried out after the suitable period of about 2 weeks.

[0081] Test substances: ARNi and amlodipine were provided by Shenzhen Xinlitai Pharmaceutical Co., Ltd.

[0082] Drug preparation: 0.5% CMC-Na was used for preparation, and the prepared drug concentrations were all calculated based on the anhydrous free form.

[0083] Experimental groups: One day before administration, the animals were randomly divided into 4 groups according to their basal blood pressure and body weight. The specific groups and administration schedules are shown in Table 6.

[0084] Table 6 Animal grouping

[0085]

[0086] After 7 days of continuous administration in each dose group, rats with poor blood pressure control (SBP ≥ 140 mmHg) were selected from Groups 3 and 4 according to the 24-h blood pressure control situation to continue the experiment. Group 3 was randomly divided into two groups (Group 3 and Group 5). The specific grouping and dosing schedule are shown in the table.

[0087] Table 7 Animal grouping and drug administration

[0088]

[0089] Experimental Methods: Weigh animals on Day 0, Day 7, and Day 14. Basal blood pressure was measured on Day 0 before dosing. Blood pressure was measured 1, 3, 7, and 24 hours per week after dosing. For blood pressure measurements, animals were placed in a rat bag equipped with a BP-2010A non-invasive blood pressure monitor in a 37.5°C insulated container for 2-3 minutes. Blood pressure measurements were then started after the animals stabilized. Blood pressure was measured 1-3 times per animal.

[0090] Experimental results: The results indicate that for hypertension poorly controlled by ARNi alone, the combination of the ARNi complex of the present invention and amlodipine exhibits a synergistic effect in controlling blood pressure, demonstrating superior 24-hour blood pressure control. This suggests that the combination of ARNi and amlodipine is more effective in preventing cardiovascular and cerebrovascular complications.

[0091] Table 8 24-hour blood pressure data after ARNi monotherapy was poorly controlled and combined with amlodipine

[0092]

[0093] Note: * P<0.05, *** P < 0.001 (vs SHR vehicle group); ## P<0.01 (vs amlodipine).

[0094] @ The amount of ARNi complex used in this example is based on anhydrous free acid C 46 H 50 The amlodipine used is amlodipine besylate, and its usage is based on the free concentration C 20 H 25 N2O5Cl meter.

[0095] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition is composed of ARNi and a calcium ion antagonist, wherein the structural unit of ARNi is as follows: (EXP3174·AHU377)·1.5Ca·nH2O, where n=1-3; The structural formula of ARNi is as follows: ， The calcium ion antagonist is selected from amlodipine, and the mass ratio of the ARNi to amlodipine is 240:1.25-20, wherein the ARNi is in the form of anhydrous free acid C 46 H 50 Amlodipine is calculated as ClN7O7. 20 H 25 N2O5Cl meter.

2. The pharmaceutical composition according to claim 1, characterized in that ARNi is selected from: ； ； 。 3. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the ARNi to amlodipine is 240:1.25, 240:2.5, 240:5, 240:7.5 and 240:10, wherein the ARNi is in the form of anhydrous free acid C 46 H 50 Amlodipine is calculated as ClN7O7. 20 H 25 N2O5Cl meter.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The ARNi in the pharmaceutical composition is selected from 60 to 480 mg, wherein the ARNi is in the form of anhydrous free acid C 46 H 50 ClN7O7 meter.

5. The pharmaceutical composition according to claim 4, characterized in that The ARNi is selected from 60, 120, 240, 300, 360, 420 and 480 mg, wherein the ARNi is in the form of anhydrous free acid C 46 H 50 ClN7O7 meter.

6. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The amlodipine in the pharmaceutical composition is selected from 2.5 to 10 mg, wherein the amlodipine is C 20 H 25 N2O5Cl meter.

7. The pharmaceutical composition according to claim 6, characterized in that The amlodipine is selected from 2.5, 5, 7.5 and 10 mg, wherein the amlodipine is C 20 H 25 N2O5Cl meter.

8. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The amlodipine is selected from racemic amlodipine, levamlodipine, dextroamlodipine, or a mixture of levamlodipine and dextroamlodipine in any proportion.

9. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The amlodipine is in the form of a salt selected from amlodipine besylate, amlodipine maleate, levamlodipine besylate, and levamlodipine maleate.

10. A use of a pharmaceutical composition, characterized in that: The pharmaceutical composition according to any one of claims 1 to 9 is used in the preparation of a medicament for treating heart failure and / or hypertension.

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