Pharmaceutical composition of ARNi and indapamide and application

Abstract

The invention provides a pharmaceutical composition of ARNi and indapamide and application of the pharmaceutical composition. The pharmaceutical composition can be used for diseases such as hypertension and / or heart failure.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical composition technology, and relates to a pharmaceutical composition and application of ARNi and indapamide. This pharmaceutical composition 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]

[0004] In addition, WO2017125031A1 discloses a series of complexes consisting of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), with the following molecular structural units:

[0005]

[0006] 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

[0007] 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 indapamide, wherein the structural units of ARNi are as follows:

[0008] (EXP3174·AHU377)·1.5Ca·nH2O, where n=1~3;

[0009] Specifically, the structural formula of the ARNi is as follows:

[0010]

[0011] As a preferred embodiment of the present invention, n is selected from 1, 1.5, 2, 2.5 and 3.

[0012] The structural formulas of EXP3174 and AHU377 (Sakubaqu) are as follows:

[0013]

[0014] As a preferred embodiment of the present invention, the ARNi compound can be obtained by the preparation methods of WO2017125031A1, WO2021143898A1, CN202380014343.0, etc., and the relevant preparation methods and the obtained substances are introduced in this patent. Specifically, ARNi is preferably selected from:

[0015]

[0016]

[0017] As a preferred technical solution of the present invention, the ARNi (in anhydrous free acid C) 46 H 50 (calculated as ClN7O7) and indapamide (calculated as C) 16 H 16 The mass ratio of ClN3O3S to 240:0.5 to 240:6 is given.

[0018] As a preferred technical solution of the present invention, the ARNi (in anhydrous free acid C) 46 H 50 (calculated as ClN7O7) and indapamide (calculated as C) 16 H 16 The mass ratios of ClN3O3S (calculated as ClN3O3S) are 240:0.5, 240:0.6, 240:0.75, 240:1, 240:1.5, 240:3, and 240:6, with 240:0.75, 240:1, and 240:1.5 being more preferred.

[0019] 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.

[0020] As a preferred technical solution of the present invention, the ARNi (in 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.

[0021] As a preferred embodiment of the present invention, indapamide (in C...) in the pharmaceutical composition 16 H 16 The ClN3O3S (calculated as 0.5mg-6mg) is selected from 0.5mg-6mg.

[0022] As a preferred technical solution of the present invention, the indapamide (in C 16 H 16The concentration of ClN3O3S is selected from 6mg, or 5mg, or 4mg, or 3mg, or 2.5mg, or 2mg, or 1.75mg, or 1.5mg, or 1.25mg, or 1mg, or 0.75mg, or 0.6mg, or 0.5mg.

[0023] The indapamide used in this invention is The molecular formula is C 16 H 16 ClN3O3S has a molecular weight of 365.83.

[0024] Another object of the present invention is to provide a pharmaceutical composition selected from combinations of LCZ696 and indapamide, LCZ696 and amlodipine or their salts, LCZ696 and levamlodipine or their salts, wherein the structural units of LCZ696 are as follows:

[0025]

[0026] LCZ696, calculated as sacubitril / valsartan, is selected from: (1) 50 mg (sacubitril 24 mg / valsartan 26 mg); (2) 100 mg (sacubitril 49 mg / valsartan 51 mg); (3) 200 mg (sacubitril 97 mg / valsartan 103 mg). Indapamide (as C 16 H 16 Indapamide (calculated as C1N3O3S) is selected from 6 mg, or 5 mg, or 4 mg, or 3 mg, or 2.5 mg, or 2 mg, or 1.75 mg, or 1.5 mg, or 1.25 mg, or 1 mg, or 0.75 mg, or 0.6 mg, or 0.5 mg, more specifically, when LCZ696 is 200 mg, indapamide (calculated as C1N3O3S) is selected from 6 mg, or 5 mg, or 4 mg, or 3 mg, or 2.5 mg, or 2 mg, or 1.75 mg, or 1.5 mg, or 1.25 mg, or 1 mg, or 0.75 mg, or 0.6 mg, or 0.5 mg. More specifically, when LCZ696 is 200 mg, indapamide (calculated as C1N3O3S) is selected 16 H 16 The concentration of ClN3O3S is selected from 6mg, or 5mg, or 4mg, or 3mg, or 2.5mg, or 2mg, or 1.75mg, or 1.5mg, or 1.25mg, or 1mg, or 0.75mg, or 0.6mg, or 0.5mg.

[0027] Amlodipine or its salts (in C 20 H 25 The concentration of amlodipine (calculated as ClN2O5) is selected from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, or 10 mg. More specifically, when LCZ696 is 200 mg, amlodipine or its salts (calculated as C) are selected from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, or 10 mg. 20 H 25The salt (calculated as ClN2O5) is selected from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg or 10 mg, preferably from 2.5 mg, 5 mg or 10 mg, and the salt is selected from benzenesulfonate, maleate, fumarate, etc.

[0028] Levoamlodipine (levamlodipine) or its salts (as C) 20 H 25 The concentration of levamlodipine (calculated as C1N2O5) is selected from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, or 10 mg. More specifically, when LCZ696 is 200 mg, levamlodipine (levamlodipine) or its salt (calculated as C1N2O5) is selected from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, or 10 mg. 20 H 25 The salt (calculated as ClN2O5) is selected from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg or 10 mg, preferably from 2.5 mg, 5 mg or 10 mg, and the salt is selected from benzenesulfonate, maleate, fumarate, etc.

[0029] 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.

[0030] 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 primary, mild, moderate and severe hypertension, and the heart failure includes heart failure with decreased ejection fraction and heart failure with preserved ejection fraction.

[0031] As a preferred embodiment of the present invention, the uses include applications in medicaments for patients with hypertension / heart failure who do not respond well to ARNi monotherapy, applications in medicaments for patients with hypertension / heart failure who do not respond well to indapamide monotherapy, or applications in medicaments for patients with hypertension / heart failure who do not respond well to amlodipine or its salts, or levamlodipine or its salts monotherapy. The ARNi monotherapy includes LCZ696, and compounds with the ARNi structural formula of the present invention.

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

[0033] (1) The present invention provides a combination of ARNi and indapamide, which achieves synergistic effect through ARNi and indapamide, which is beneficial to improve the treatment effect of heart failure and / or hypertension.

[0034] (2) When the drug composition ARNi of the present invention is mixed with indapamide at a mass ratio of 240:0.5 to 240:6, the EXP3174 exposure is significantly increased, especially at a mass ratio of 240:0.75 to 240:1.5.

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

[0036] (4) 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 indapamide monotherapy. Detailed Implementation

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

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

[0039] 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:

[0040]

[0041] The indapamide is an amino acid with the molecular formula C10. 16 H 16 ClN3O3S, with a molecular weight of 365.83, has the following structural formula:

[0042] Example

[0043] 1.1 Preparation of the drug delivery solution:

[0044] Accurately weigh ARNi compound, LCZ696 and indapamide, and vortex disperse them in 1% HPMC to make the concentration of ARNi or LCZ696 48 mg / mL, and the concentration of indapamide 0.08, 0.1, 0.12, 0.15, 0.2, 0.3, 0.6 and 1.2 mg / mL, respectively. Equal volumes of ARNi were mixed with indapamide at concentrations of 0.08, 0.1, 0.12, 0.15, 0.2, 0.3, 0.6, and 1.2 mg / mL to obtain ARNi+indapamide suspensions with drug concentrations of 24+0.04, 24+0.05, 24+0.06, 24+0.075, 24+0.1, 24+0.15, 24+0.3, and 24+0.6 mg / mL. Equal volumes of LCZ696 were mixed with indapamide at concentrations of 0.15 and 0.3 mg / mL to obtain LCZ696+indapamide suspensions with drug concentrations of 24+0.075 and 24+0.15 mg / mL. The 48 mg / mL ARNi or LCZ696 suspension was diluted 1-fold with 1% HPMC to obtain an ARNi and LCZ696 suspension concentration of 24 mg / mL.

[0045] 1.2 Drug administration and blood collection in SD rats:

[0046] Twenty-four male SD rats weighing 200–300 g were randomly divided into two groups (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 determined by LC / MS / MS.

[0047]

[0048] 1.3 Data Statistics:

[0049] Pharmacokinetic parameters of EXP3174 or valsartan were calculated using WinNonlin software.

[0050] 1.4 Experimental Results:

[0051]

[0052]

[0053] 1.5 Conclusions of the rat PK experiment:

[0054] In this invention, when ARNi and indapamide were administered to rats via gavage in a ratio of 240:0.5 to 240:6, the EXP3174 exposure was increased to varying degrees compared with that after administration of the same dose of ARNi alone. The increase was relatively higher in the ratio range of 240:0.75 to 240:1.5, with an increase rate ranging from 37% to 52%, and the highest increase rate of 52% was observed at the 240:1.5 ratio.

[0055] However, when LCZ696 was administered to rats in combination with indapamide at ratios of 240:0.75 and 240:1.5 via gavage, valsartan exposure did not increase; on the contrary, exposure decreased by 10%–16%, which was significantly lower than the increase in exposure when combined with ARNi and indapamide at the same ratio.

[0056] In summary, the rat pharmacokinetic (PK) experiment demonstrated that the combination of ARNi and indapamide in this invention exerts a synergistic effect, which is superior to ARNi alone, and also superior to the combination of LCZ696 and indapamide in the corresponding proportions.

[0057] Note: The amount of ARNi complex used in this embodiment is based on anhydrous free acid C. 46 H 50 The amount of indapamide used is calculated as ClN7O7. The amount of indapamide used is expressed as the free concentration C. 16 H 16 ClN3O3S is used for calculation.

[0058] Example 2

[0059] ARNi with the following structural formulas was obtained using the preparation methods described in WO2017125031A1 and WO2021143898A1:

[0060]

[0061] 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 in that, The pharmaceutical composition comprises ARNi and indapamide, wherein the structural units of ARNi are as follows: (EXP3174·AHU377)·1.5Ca·nH2O, where n=1~3; Specifically, the structural formula of ARNi is as follows:

2. The pharmaceutical composition according to claim 1, characterized in that, n = 1, 1.5, 2, 2.5 and 3.

3. The pharmaceutical composition according to claim 1, characterized in that, The ARNi (in anhydrous free acid C) 46 H 50 (calculated as ClN7O7) and indapamide (calculated as C) 16 H 16 The mass ratio of ClN3O3S to 240:0.5 to 240:6 is given.

4. The pharmaceutical composition according to claim 1, characterized in that, The ARNi (in anhydrous free acid C) 46 H 50 (calculated as ClN7O7) and indapamide (calculated as C) 16 H 16 The mass ratios of ClN3O3S (calculated as ClN3O3S) are 240:0.5, 240:0.6, 240:0.75, 240:1, 240:1.5, 240:3, and 240:6, with 240:0.75, 240:1, and 240:1.5 being more preferred.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition contains ARNi (in anhydrous free acid C). 46 H 50 (Calculated as ClN7O7) is selected from 60 to 480 mg.

6. The pharmaceutical composition according to claim 1, characterized in that, The ARNi (in 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.

7. The pharmaceutical composition according to claim 1, characterized in that, Indapamide (in C) in the pharmaceutical composition 16 H 16 The ClN3O3S (calculated as 0.5mg-6mg) is selected from 0.5mg-6mg.

8. The pharmaceutical composition according to claim 1, characterized in that, The indapamide (in C 16 H 16 The concentration of ClN3O3S is selected from 6mg, or 5mg, or 4mg, or 3mg, or 2.5mg, or 2mg, or 1.75mg, or 1.5mg, or 1.25mg, or 1mg, or 0.75mg, or 0.6mg, or 0.5mg.

9. The 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. The use of the 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 indapamide monotherapy.

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