Pharmaceutical composition of arni and bisoprolol or salt thereof, and use thereof

Abstract

Provided in the present invention are a pharmaceutical composition of ARNi and bisoprolol or a salt thereof, and a use thereof. The pharmaceutical composition can be used for diseases such as hypertension and / or heart failure.

Description

A pharmaceutical composition of ARNi with bisoprolol or a salt thereof and its application Technical Field

[0001] This invention belongs to the field of pharmaceutical composition technology, and relates to a pharmaceutical composition and application of ARNi and bisoprolol or their salts, which can be used for diseases such as hypertension and / or heart failure. Background Technology

[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. Trade name: (The product name listed overseas is...) (2015) Used for heart failure. Its molecular structural units are as follows:

[0003] In addition, WO2017125031A1, WO2021143898A1, and WO2024027779A1 disclose a series of complexes consisting of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), with the following molecular structural units:

[0004] The aforementioned compounds are collectively referred to as ANRi drugs. However, with the advancement of clinical applications and disease progression, existing ANRi drugs may face drug resistance issues in applications for hypertension and / or heart failure. Summary of the Invention

[0005] In view of the problems existing in the prior art, the object of the present invention is to provide a pharmaceutical composition comprising ARNi and bisoprolol or a salt thereof, wherein the structural units of ARNi are as follows:

[0006] (EXP3174·AHU377)·1.5Ca·nH2O, where n=1~3;

[0007] Specifically, the structural formula of ARNi is as follows:

[0008] As a preferred embodiment of the present invention, n is selected from 1, 1.5, 2, 2.5 and 3.

[0009] As a preferred embodiment of the present invention, the ARNi compound can be obtained by the preparation methods of WO2017125031A1, WO2021143898A1, and WO2024027779A1. The relevant preparation methods and the obtained substances are introduced in this patent. Specifically, ARNi is preferably selected from:

[0010] As a preferred technical solution of the present invention, the ARNi (using anhydrous free acid C) 46 H 50 The mass ratio of ClN7O7 to bisoprolol or its salt is 240:2.5 to 240:20, preferably 240:2.5 to 240:10.

[0011] As a preferred technical solution of the present invention, the ARNi (using anhydrous free acid C) 46 H 50 The mass ratio of ClN7O7 to bisoprolol or its salt is 240:2.5, 240:5, or 240:10.

[0012] As a preferred embodiment of the present invention, ARNi (in anhydrous free acid C) in the pharmaceutical composition 46 H 50 (Calculated as ClN7O7) is selected from 60 to 480 mg.

[0013] As a preferred technical solution of the present invention, the ARNi (using anhydrous free acid C) 46 H 50 The concentrations of ClN7O7 (calculated as ClN7O7) are selected from 60, 120, 240, 300, 360, 420 and 480 mg.

[0014] The bisoprolol salt used in this invention is selected from bisoprolol fumarate, with the chemical name: (±)1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol fumarate, and its structural formula is:

[0015] The molecular formula is: (C 18 H 31 NO4)2×C4H4O4;

[0016] Molecular weight: 766.96.

[0017] The bisoprolol or its salt is 2.5 mg to 5 mg, preferably 2.5 mg or 5 mg as bisoprolol fumarate.

[0018] As a preferred embodiment 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, the dosage form including solid oral dosage forms, etc.

[0019] The present invention further provides the 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.

[0020] As a preferred embodiment of the present invention, the use includes its application in medicaments for patients with hypertension / heart failure who do not respond well to ARNi monotherapy, or in medicaments for patients with hypertension / heart failure who do not respond well to bisoprolol or its saline monotherapy. The ARNi monotherapy includes LCZ696, and compounds with the ARNi structural formula of the present invention.

[0021] The present invention has the following advantages and beneficial effects compared with the prior art:

[0022] (1) The present invention provides a combination of ARNi and bisoprolol or its salt, which achieves synergistic effect through ARNi and bisoprolol, which is beneficial to improve the treatment effect of heart failure and / or hypertension.

[0023] (2) When the pharmaceutical composition ARNi of the present invention is mixed with bisoprolol or its salt in a mass ratio of 240:2.5 to 240:10, it can increase the exposure of bisoprolol.

[0024] (3) The use of the drug combination further includes its use in the treatment of patients with hypertension and / or heart failure that are poorly controlled by ARNi monotherapy, or in the treatment of patients with hypertension and / or heart failure that are poorly controlled by bisoprolol or its salts monotherapy. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0026] The raw materials used in this invention can be obtained by preparation methods known in the prior art, including the methods described in WO2017125031A1, WO2021143898A1, and WO2024027779A1.

[0027] Unless otherwise stated, ARNi in the embodiments of the present invention is a compound of the following formula, and its amount used is based on anhydrous free acid C. 46 H 50 ClN7O7 calculation:

[0028] The fumarate bisoprolol has the chemical name: (±)1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol fumarate, and its structural formula is:

[0029] Example 1

[0030] 1.1 Preparation of the drug delivery solution:

[0031] Accurately weigh the ARNi complex and bisoprolol fumarate. Disperse the ARNi complex into a suspension using 1% HPMC solvent via vortexing. Prepare a bisoprolol solution using 5% DMSO + 60% PEG400 + 35% physiological saline via vortexing, resulting in ARNi complex concentrations of 6, 12, 24, 48, 96, and 192 mg / mL, and a bisoprolol concentration of 1.0 mg / mL. Mix equal volumes of bisoprolol with the ARNi complex suspensions at concentrations of 6, 12, 24, 48, 96, and 192 mg / mL, respectively, to obtain ARNi complex + bisoprolol suspensions with drug concentrations of 3 + 0.5, 6 + 0.5, 12 + 0.5, 24 + 0.5, 48 + 0.5, and 96 + 0.5 mg / mL. Dilute the 1.0 mg / mL bisoprolol solution 1:1 with 1% HPMC to obtain a bisoprolol concentration of 0.5 mg / mL.

[0032] 1.2 Drug administration and blood collection in SD rats:

[0033] Fourteen male SD rats weighing 200–300 g were randomly divided into seven groups of two rats each. The dosages for each group are shown in the table below. Each group was administered the corresponding drug by 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 after drug administration into EDTA-K2 anticoagulant tubes. The tubes were centrifuged at 10,000 rpm for 2 min, and the plasma was separated. The bisoprolol blood concentration was determined by LC / MS / MS.

[0034] Table 1

[0035] 1.3 Data Statistics:

[0036] Pharmacokinetic parameters of bisoprolol were calculated using WinNonlin software.

[0037] 1.4 Experimental Results:

[0038] Table 2

[0039] 1.5 Conclusions of the rat PK experiment:

[0040] The exposure of bisoprolol to rats after combined gavage administration of ARNi complex and bisoprolol at different ratios showed different changes compared with the same dose of bisoprolol monotherapy. When ARNi complex and bisoprolol were combined at a ratio of 240:40, the exposure of bisoprolol increased by only about 9% compared with 5 mg / kg bisoprolol monotherapy. As the ratio of ARNi complex to bisoprolol decreased, the exposure of bisoprolol increased significantly compared with the monotherapy group. However, when the ratio was 240:1.25, rats showed certain adverse reactions (drooling, respiratory sounds, prickly hairs, etc. after administration).

[0041] Note: The amount of ARNi complex used in this embodiment is based on anhydrous free acid C. 46 H 50 The calculation is based on ClN7O7; the bisoprolol used is calculated as bisoprolol fumarate.

[0042] Example 2

[0043] 2.1 Preparation of the drug delivery solution:

[0044] Accurately weigh ARNi complex, LCZ696, propranolol hydrochloride and bisoprolol fumarate. Disperse ARNi complex and LCZ696 into a suspension by vortexing in 1% HPMC solvent. Prepare a solution of propranolol and bisoprolol by vortexing in 5% DMSO + 60% PEG400 + 35% physiological saline solvent, so that the concentration of ARNi complex and LCZ696 is 48 mg / mL, and the concentration of bisoprolol and propranolol (in free form) is 1.0 mg / mL. Equal volumes of 48 mg / mL ARNi complex suspension and 1.0 mg / mL propranolol solution were mixed to obtain an ARNi complex + propranolol suspension with a drug concentration of 24 + 0.5 mg / mL. The 1.0 mg / mL propranolol was diluted 1-fold with 1% HPMC to obtain a propranolol concentration of 0.5 mg / mL. Equal volumes of 48 mg / mL LCZ696 suspension and 1.0 mg / mL bisoprolol solution were mixed to obtain an LCZ696 + bisoprolol suspension with a drug concentration of 24 + 0.5 mg / mL.

[0045] 2.2 Drug administration and blood collection in SD rats:

[0046] Six male SD rats weighing 200–300 g were randomly divided into three groups of two rats each. The dosages for each group are shown in the table below. Each group was administered the corresponding drug by 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 propranolol and bisoprolol were determined by LC / MS / MS.

[0047] Table 3

[0048] 2.3 Data Statistics:

[0049] Pharmacokinetic parameters of propranolol and bisoprolol were calculated using WinNonlin software.

[0050] 2.4 Experimental Results:

[0051] Table 4

[0052] 2.5 Conclusions of the rat PK experiment:

[0053] After combined oral administration of ARNi complex and propranolol in rats at a ratio of 240:5, the exposure of propranolol was not significantly different from that of propranolol monotherapy. After combined oral administration of LCZ696 and bisoprolol in rats at a ratio of 240:5, the exposure of bisoprolol was not significantly different from that of bisoprolol monotherapy.

[0054] Example 3: Effect of ARNi + bisoprolol administration on SHR rats with poor bisoprolol monotherapy control

[0055] Experimental animals: SHR rats were purchased from Beijing Vital River Biotechnology Co., Ltd., and were 13-14 weeks old when they entered the animal room. The experimental period was at least one week before the experiment was carried out.

[0056] Test substances: ARNi and bisoprolol were both provided by Shenzhen Salubris Pharmaceuticals Co., Ltd.

[0057] Drug preparation: 0.5% CMC-Na was used for preparation, and all drug concentrations were expressed in anhydrous free form.

[0058] 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 5.

[0059] Table 5 Animal grouping

[0060] Systolic blood pressure (SBP) was measured 1 hour after a single dose in each dose group. After three days of washout, rats in groups 3 and 4 were given bisoprolol and ARNi. The specific dosing regimen is shown in Table 6.

[0061] Table 6 Animal grouping and administration

[0062] Experimental methods: Animals were weighed on Day 0. Baseline blood pressure was measured on Day 0 before drug administration. SBP was measured 1 hour after drug administration. When measuring blood pressure, the animals were placed in the mouse bag of the non-invasive blood pressure monitor and placed in a 37.5℃ insulated container for 2-3 minutes. Blood pressure was measured after the animals were stable. Each animal was measured at least 3 times.

[0063] Experimental results: For hypertension that is poorly controlled by bisoprolol monotherapy, the use of the ARNi complex of this invention combined with bisoprolol to form a compound drug composition can significantly increase the blood pressure control effect of monotherapy.

[0064] Table 7. Efficacy data of bisoprolol monotherapy followed by combination therapy with ARNi complex after poor control.

[0065] Note: The amount of ARNi complex used in this embodiment is based on anhydrous free acid C. 46 H 50 ClN7O7 is used as a metric.

[0066] Example 4: Effect of ARNi + bisoprolol administration on SHR rats with poor ARNi monotherapy control

[0067] Experimental animals: SHR rats were purchased from Beijing Vital River Biotechnology Co., Ltd., and were 13-14 weeks old when they entered the animal room. The experimental period was at least one week before the experiment was carried out.

[0068] Test substances: ARNi and bisoprolol were both provided by Shenzhen Salubris Pharmaceuticals Co., Ltd.

[0069] Drug preparation: 0.5% CMC-Na was used for preparation, and all drug concentrations were expressed in anhydrous free form.

[0070] Experimental grouping: One day before administration, the animals were randomly divided into 3 groups based on their baseline blood pressure and weight. The specific grouping and administration regimen are shown in Table 8.

[0071] Table 8 Animal Grouping

[0072] SBP was measured 1 hour after a single dose in each dose group. After three days of washing, rats in group 2 were given ARNi and bisoprolol. The specific dosing regimen is shown in Table 9.

[0073] Table 9 Animal grouping and administration

[0074] Experimental methods: Animals were weighed on Day 0. Baseline blood pressure was measured on Day 0 before drug administration. SBP was measured 1 hour after drug administration. When measuring blood pressure, the animals were placed in the mouse bag of the non-invasive blood pressure monitor and placed in a 37.5℃ insulated container for 2-3 minutes. Blood pressure was measured after the animals were stable. Each animal was measured at least 3 times.

[0075] Experimental results: For hypertension that is poorly controlled by ARNi monotherapy, the use of the ARNi complex of this invention combined with bisoprolol to form a compound drug composition can significantly increase the blood pressure control effect of monotherapy.

[0076] Table 10 Efficacy data of ARNi monotherapy followed by combination therapy with bisoprolol when ARNi monotherapy was ineffective.

[0077] Note: The amount of ARNi complex used in this embodiment is based on anhydrous free acid C. 46 H 50 ClN7O7 is used as a metric.

[0078] 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. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises ARNi and bisoprolol or a salt thereof, wherein the structural units of ARNi are as follows: (EXP3174·AHU377)·1.5Ca·nH2O, where n=1~3; In particular, the ARNi has the following structural formula:

2. The pharmaceutical composition of claim 1, wherein, n = 1, 1.5, 2, 2.5 and 3.

3. The pharmaceutical composition of claim 1, wherein, The ARNi (in anhydrous free acid C) 46 H 50 The mass ratio of ClN7O7 to bisoprolol or its salt is 240:2.5 to 240:20, preferably 240:2.5 to 240:

10.

4. The pharmaceutical composition of claim 1, wherein, The ARNi (in anhydrous free acid C) 46 H 50 The mass ratio of ClN7O7 to bisoprolol or its salt is 240:2.5, 240:5, or 240:

10.

5. The pharmaceutical composition of claim 1, wherein, ARNi (as anhydrous free acid C 46 H 50 ClN7O7) is selected from 60-480 mg.

6. The pharmaceutical composition of claim 1, wherein, The ARNi (in anhydrous free acid C 46 H 50 ClN7O7) is selected from 60, 120, 240, 300, 360, 420, and 480 mg.

7. The pharmaceutical composition of claim 1, wherein, The bisoprolol or its salts in the pharmaceutical composition are selected from 2.5 mg to 5 mg.

8. The pharmaceutical composition of claim 1, wherein, The bisoprolol is selected from bisoprolol fumarate, preferably from 2.5 mg to 5 mg based on bisoprolol fumarate.

9. Use of a pharmaceutical composition, characterized in that, The pharmaceutical composition according to any one of claims 1-8 is used in the preparation of a medicament for treating, including heart failure and / or hypertension.

10. Use of a pharmaceutical composition according to claim 9, characterized in that, The uses include use in medications for patients with hypertension and / or heart failure that are poorly controlled by ARNi monotherapy, or use in medications for patients with hypertension and / or heart failure that are poorly controlled by bisoprolol monotherapy.

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