Pharmaceutical composition containing ARNi and calcium ion antagonist

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing sartan drugs or esters thereof, NEPi and CCB. The pharmaceutical composition can be used for treating cardiovascular diseases such as hypertension and / or heart failure. On one hand, the combination of the sartan medicine or the ester thereof, the NEPi and the CCB obtains a better curative effect than the curative effect obtained by independently administering the sartan medicine or the NEP inhibitor and the CCB; on the other hand, the dosage can be reduced by using the lower dosage of the combined drugs of the invention.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a pharmaceutical composition containing a sartan drug or an ester thereof, a NEPi, and a CCB. Background Art

[0002] Angiotensin II interacts with specific receptors on the surface of target cells. Receptor subtypes, such as the AT1 and AT2 receptors, have been identified. Recently, considerable effort has been devoted to identifying substances that bind to the AT1 receptor. These active ingredients are often referred to as angiotensin II antagonists. Because of their inhibitory effect on the AT1 receptor, these antagonists can be used, for example, as antihypertensives or for the treatment of other conditions such as congestive heart failure. Thus, angiotensin II antagonists are understood to be active ingredients that bind to the AT1 receptor subtype.

[0003] Currently, AT1 receptor antagonists (sartans) are selected from abisartan, candesartan, elisartan, embusartan, eprosartan, fonsartan, forasartan, irbesartan, losartan, milfasartan, olmesartan, The group consisting of Pratosartan, Ripisartan, Saprisartan, Tasosartan, Telmisartan, Zolasartan, Enoltasosartan, Glycyllosartan, Opomisartan, etc. or any physiologically compatible salts, solvates, prodrugs or esters thereof are being used in clinical or preclinical studies for patients with cardiovascular and cerebrovascular diseases such as hypertension or heart failure.

[0004] Neutral endopeptidase (EC 3.4.24.11; enkephalinase; nephrin residue lysing enzyme; NEP) is a zinc-containing metalloproteinase that cleaves peptide substrates at the amino terminus of a variety of hydrophobic residues [see Pharmacol Rev, Vol. 45, p. 87 (1993)]. Infusion of ANP into normal subjects results in a reproducible and significant increase in natriuresis and diuresis, including an increase in the fractional excretion of sodium, urine flow rate, and glomerular filtration rate [see J Clin Pharmacol, Vol. 27, p. 927 (1987)]. Therefore, NEP inhibitors (neutral endopeptidase inhibitors, enkephalin inhibitors, NEPi) will increase the plasma level of ANP and are therefore expected to induce natriuresis and diuresis.

[0005] Currently, NEP inhibitors (neutral endopeptidase inhibitors, enkephalin inhibitors, NEPi) selected from the group consisting of or any physiologically compatible salts, solvates, prodrugs or esters thereof are being used in clinical or preclinical studies for patients with cardiovascular and cerebrovascular diseases such as hypertension or heart failure.

[0006] Long-term, uncontrolled hypertensive vascular disease ultimately leads to various pathological changes in target organs such as the heart and kidneys. Sustained hypertension can also lead to an increased incidence of stroke. Therefore, there is a strong need to evaluate the efficacy of antihypertensive treatments, that is, to examine cardiovascular endpoints other than blood pressure lowering to further explore the benefits of combined treatments.

[0007] Hypertensive vascular disease is multifactorial in nature. In some cases, drugs with different mechanisms of action have been combined. However, it should be noted that any combination of drugs with different modes of action does not necessarily result in a beneficial combination. Therefore, more effective combination therapies with fewer harmful side effects are needed. Summary of the Invention

[0008] One aspect of the present invention relates to a pharmaceutical composition comprising an ARNi and a calcium ion antagonist in the presence or absence of a pharmaceutically acceptable carrier, wherein ARNi refers to a drug combination comprising a sartan drug or its ester and a NEPi, and a pharmaceutical composition comprising the drug combination, specifically, a drug combination comprising a sartan drug or its ester, a NEP inhibitor (NEPi), and a calcium ion antagonist (CCB), and a pharmaceutical composition comprising the drug combination.

[0009] Specifically, the pharmaceutical composition containing sartan drugs or their esters, NEPi, and CCB includes more than one sartan drugs, more than one NEP inhibitor, and more than one CCB, and the presence or absence of a pharmaceutically acceptable carrier.

[0010] The weight ratio or molar ratio of the sartan drug and the one or more NEP inhibitors is 1:100-100:1, preferably 1:50-50:1, 1:45-45:1, 1:40-40:1, 1:35-35:1, 1:30-30:1, 1:25-25:1, 1:20-20:1, 1:15-15:1, 1:14-14:1, 1:13-13:1, 1:12-12:1, 1:11-11:1, more preferably 1:10-10:1, 1:9.5 -9.5:1, 1:9-9:1, 1:8.5-8.5:1, 1:8-8:1, 1:7.5-7.5:1, 1:7-7:1, 7:3-3:7, 1:6.5-6.5:1, 1:6-6:1, 1:5.5-5.5:1, 1:5-5:1, 1:4.5-4.5:1, 1:4-4:1, 1:3.5-3.5:1, 1:3-3:1, 1:2.5-2.5:1, 1:2-2:1, 1:1.5-1.5:1, or 1:1, etc.;

[0011] Alternatively, when the total weight of the sartan drug or its ester and the NEP inhibitor is 50 mg or 100 mg, the sartan drug or its ester or the NEP inhibitor is independently 21 mg, 22 mg, 23 mg, 24 mg, 26 mg, 27 mg, 28 mg, 29 mg, 41 mg, 42 mg, 43 mg, 44 mg, 46 mg, 47 mg, 48 mg, or 49 mg, respectively; or when the total weight of the sartan drug or its ester and the NEP inhibitor is 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, the above ratio of 50 mg or 100 mg is multiplied by 3, 1.5, 4, 2, 5, 2.5, 6, 3, 7, 3.5, 8, or 4, respectively.

[0012] The sartan drug (AT1 receptor antagonist) or its ester is selected from Azilsartan, Amisartan, Abitesartan, Candesartan, Elisartan, Embusartan, Eprosartan, Fonsartan, Forasartan, Irbesartan, Losartan, Milfasartan, Olmesartan, Pratosartan, Ripisartan, Saprisartan, Tasosartan, Telmisartan, Zolasartan, Enoltasosartan, Glycyllosartan, Opomisartan or its ester.

[0013] The amount of the sartan drug (AT1 receptor antagonist) or its ester is calculated based on sartan, for example, the amount of azilsartan medoxomil is calculated based on azilsartan.

[0014] The amount of the sartan drug or its ester is about 0.1 mg to about 1000 mg, preferably about 5 mg to about 800 mg, preferably about 20 mg to about 700 mg, more preferably about 50 mg to about 600 mg, and more preferably 100 mg to about 300 mg, calculated as sartan.

[0015] More preferably, the sartan drug (AT1 receptor antagonist) or its ester is used in an amount of 800 mg, 600 mg, 400 mg, 300 mg, 200 mg, 150 mg, 125 mg, 100 mg, 80 mg, 75 mg, 60 mg, 50 mg, 40 mg, 32 mg, 30 mg, 25 mg, 20 mg, 16 mg, 15 mg, 12.5 mg, 10 mg, 9 mg, 8 mg, 7 mg, 7.5 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2.5 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, or 0.25 mg, etc., calculated as sartan.

[0016] Preferably, it further includes Telmisartan or its ester calculated as Telmisartan (20, 40, 80 mg), Candesartan or its ester calculated as Candesartan (4, 8, 16, 32 mg), Olmesartan medoxomil or its ester calculated as Olmesartan (5, 20, 40 mg), Eprosartan or its ester calculated as Eprosartan (400, 600 mg), and Valsartan or its ester calculated as Valsartan (80, 160 mg).

[0017] The NEPi is selected from the group consisting of Sacubitril (AHU377), Candoxatril, Daglutril, Ilepatril, Cadotril, Fasidotril, etc. or any physiologically compatible salts, solvates, prodrugs or esters thereof, more preferably Sacubitril (AHU377).

[0018] The NEPi is used in an amount of about 0.1 mg to about 1000 mg, preferably about 5 mg to about 800 mg, preferably about 20 mg to about 700 mg, more preferably about 50 mg to about 600 mg, and more preferably 100 mg to about 300 mg.

[0019] More preferably, the specific dosage of NEPi is 1000 mg, 800 mg, 600 mg, 400 mg, 300 mg, 200 mg, 150 mg, 125 mg, 100 mg, 80 mg, 75 mg, 60 mg, 50 mg, 40 mg, 32 mg, 30 mg, 25 mg, 20 mg, 16 mg, 15 mg, 12.5 mg, 10 mg, 9 mg, 8 mg, 7 mg, 7.5 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2.5 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, or 0.25 mg, etc.

[0020] More specifically, sacubitril (AHU377) is preferred. The specific dosage of sacubitril (AHU377) is 1000 mg, 800 mg, 600 mg, 400 mg, 300 mg, 200 mg, 150 mg, 125 mg, 100 mg, 80 mg, 75 mg, 60 mg, 50 mg, 40 mg, 32 mg, 30 mg, 25 mg, 20 mg, 16 mg, 15 mg, 12.5 mg, 10 mg, 9 mg, 8 mg, 7 mg, 7.5 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2.5 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, or 0.25 mg.

[0021] In another embodiment, the present invention relates to a method for treating heart and kidney related conditions by administering a pharmaceutical composition comprising a sartan or its ester, and a NEPi, and a CCB or to the use of a pharmaceutical composition comprising a sartan or its ester, and a NEPi, and a CCB.

[0022] In another embodiment of the present invention, the calcium ion antagonist of the present invention is selected from nifedipine, amlodipine, lercanidipine, nimodipine, nicardipine, nitrendipine, nisoldipine, felodipine, benidipine, lacidipine or any physiologically compatible salt thereof, more preferably amlodipine.

[0023] 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.

[0024] The amlodipine (C 20 H 25 N2O5Cl) is selected from 2.5 to 10 mg.

[0025] 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.

[0026] It can be shown that the combination therapy using the pharmaceutical composition of the sartan or its ester, and NEPi, and CCB of the present invention produces a more effective antihypertensive treatment by improving efficacy and having a higher response rate (whether for malignant hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, isolated systolic hypertension or other secondary hypertension, including hypertension for which the monotherapy is not effective, such as hypertension for which sartan alone is not effective, hypertension for which calcium ion antagonists alone are not effective, etc.). The combination can also be used to treat or prevent heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter or harmful vascular remodeling. It can also be shown that the treatment of sartans and NEP inhibitors is beneficial in the treatment and prevention of myocardial infarction and its sequelae. The combination of sartans plus NEP inhibitors can also be used to treat atherosclerosis, angina (whether stable or unstable angina), and renal insufficiency (diabetic and non-diabetic). In addition, combination therapy with sartans and NEP inhibitors can improve endothelial dysfunction, thereby providing benefits in diseases where normal endothelial function is disrupted, such as heart failure, angina, and diabetes. In addition, the combination of the present invention can also be used for the treatment or prevention of secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria in primary nephropathy, and renal vascular hypertension, diabetic retinopathy, other vascular disorders such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's disease), glaucoma, and stroke.

[0027] Among them, some preferred sartan drugs or their esters have the following structural formula, which are prepared according to the preparation methods of CN200680000397.8, CN200580013073.3 and CN201310042669.2:

[0028]

[0029]

[0030] The structural formulas of some preferred NEPi drugs are as follows:

[0031]

[0032] The carrier includes one or more components such as a filler, a binder, a disintegrant, a lubricant, a glidant, etc.

[0033] The filler is selected from one of microcrystalline cellulose, lactose, mannitol, starch, pregelatinized starch, sucrose, dextrin, calcium hydrogen phosphate, and sorbitol, or a mixture of two or more of the above in any proportion.

[0034] The binder is selected from one of povidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and hypromellose, or a mixture of two or more of the two in any ratio.

[0035] The disintegrant is selected from one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, or a mixture of two or more of the two in any ratio.

[0036] The pharmaceutical composition may further contain a glidant, which is selected from one of silicon dioxide and talc or a mixture of two or more thereof in any ratio.

[0037] The pharmaceutical composition of the present invention may further comprise a lubricant as required by the prescription. The lubricant is selected from one or a mixture of two or more of magnesium stearate, hydrogenated vegetable oil, polyethylene glycols, stearic acid, palmitic acid, and carnauba wax in any ratio.

[0038] The pharmaceutical composition of the present invention may further comprise one or a mixture of two or more of plasticizers, preservatives, flavoring agents, solubilizers, colorants, dispersants, release rate regulators, etc., depending on the prescription requirements.

[0039] The plasticizer includes but is not limited to polyethylene glycol, propylene glycol, and glycerin.

[0040] The preservatives include, but are not limited to, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, potassium sodium sorbate, calcium propionate, sodium propionate, parahydroxybenzoic acid, and isopropyl parahydroxybenzoate.

[0041] The flavoring agents include sweeteners, aromatics, mucilages and effervescents, wherein the sweeteners can be sucrose, stevioside, monosaccharide syrup, aromatic syrup, glycerin, sorbitol, saccharin sodium, and protein sugar; the mucilages can be sodium alginate, gum arabic, gelatin, methylcellulose, and sodium carboxymethylcellulose; and the effervescents can be organic acids such as citric acid, tartaric acid, and sodium bicarbonate.

[0042] The solubilizers include, but are not limited to, sorbitan fatty acids, polysorbates, polyoxyethylene fatty acid esters, phospholipids, cholesterol, stearates (such as sodium stearate), oleates (such as sodium oleate), sodium lauryl sulfate, and sodium lauryl sulfonate.

[0043] The coloring agents include but are not limited to beet red, carmine, carotene, lemon yellow, pine needle blue, sodium copper chlorophyllin, caramel, aluminum lake, yellow iron oxide, and brilliant blue.

[0044] The dispersant includes but is not limited to sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, silicates, triethylhexyl phosphate, methyl amyl alcohol, cellulose derivatives, polyacrylamide, guar gum, and fatty acid polyethylene glycol esters.

[0045] Sunscreens include, but are not limited to, titanium dioxide, zinc oxide, and yellow iron oxide.

[0046] The release rate regulator is selected from sucrose, sodium chloride, surfactants, and polyethylene glycol (PEG).

[0047] In order to make the effect of the specific formulation more perfect, the present invention will appropriately add one or more of the above-mentioned excipients. For those of ordinary skill in the art, the above-mentioned excipients can be appropriately used according to their common technical knowledge and common common sense, and the present invention will not be further explained.

[0048] The dosage of each excipient can be adjusted according to actual needs and preparation experience. Preferably, the dosage of each excipient is 0.01-10 times, preferably 0.1-5 times, more preferably any value between 0.5-3 times the active ingredient in the pharmaceutical composition.

[0049] The pharmaceutical composition containing sartan drugs or their esters, NEPi, and CCB can be prepared into oral solid preparations; the oral solid preparations are tablets (including ordinary tablets, coated tablets), capsules, granules, and pills.

[0050] A method for preparing a pharmaceutical composition containing a sartan drug or its ester, a NEPi, and a CCB, the method comprising a wet and / or dry process, and requiring or not requiring a granulation process.

[0051] Above-mentioned pharmaceutical composition can further carry out coating, tabletting step, prepare common tablet, coated tablet, granule and capsule or adopt extrusion spheronization to prepare micropill.Prepared preparation product stability is good, thereby effectively guarantees the safety and effectiveness of drug use.Coating adopts conventional coating method, and its coating material can be selected from cellulose acetate, ethyl cellulose, hypromellose, hydroxypropyl cellulose, polyethylene glycol, cellulose acetate benzene trimer, cellulose acetate phthalate, polyvinyl pyrrolidone, polypropylene resin, methacrylic acid copolymer, polyvinyl acetate phthalate, hypromellose phthalate, hydroxypropyl methylcellulose acetate, succinic acid hydroxypropyl methylcellulose, zein ethanol solution, shellac ethanol solution, gelatin, methacrylic acid-methyl acrylate (or ethyl ester, butyl ester) copolymer, methacrylic acid-methyl methacrylate copolymer, ethyl acrylate-methacrylate copolymer, ethyl acrylate-methyl methacrylate (2:1) copolymer.

[0052] The drying can be drum drying, box drying, vacuum drying, fluidized bed drying, spray drying, freeze drying, or infrared drying.

[0053] The beneficial effects of the present invention compared to the prior art include but are not limited to:

[0054] Surprisingly, it was found that the combination of a sartan or its ester, a NEPi, and a CCB achieved greater efficacy than the efficacy achieved by administering the sartan, NEP inhibitor, or CCB alone, and that the angioedema observed was less than that observed when the vasopeptidase inhibitor was administered alone. The greater efficacy was demonstrated by a prolonged duration of action. The duration of action can be monitored by the time to return to baseline or the area under the curve (AUC) before the next dose and expressed as the product of the change in blood pressure in millimeters of mercury (mmHg change) and the duration of action (minutes, hours, or days).

[0055] An additional benefit is that the dosage can be reduced by using lower doses of the combined drugs of the present invention, for example, the required dose is not only often smaller, but can also be applied less frequently, or it can be used to reduce the incidence of side effects. Regardless of the etiology of the condition, the combined administration of a pharmaceutical composition of a sartan or ester thereof, and a NEPi, and a CCB produces a significant therapeutic effect in a higher percentage of treated patients, i.e., has a higher response rate. This is consistent with the wishes and needs of the patients being treated. DETAILED DESCRIPTION

[0056] 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.

[0057] The experimental compounds of the present invention are obtained by commercially available or prior art preparation methods, wherein the sartan drugs or their esters have the following structural formula, which are prepared with reference to the preparation methods of CN200680000397.8, CN200580013073.3 and CN201310042669.2:

[0058]

[0059]

[0060] Example 1 Pharmaceutical composition containing sartan drugs or their esters, NEPi, and CCB according to mass ratio

[0061]

[0062]

[0063]

[0064] Among them, compound S is Sacubitril (AHU377), compound CCB1 is amlodipine, and the dosage is 2.5 mg and 5 mg; CCB2 is levamlodipine, and the dosage is 2.5 mg and 5 mg.

[0065] Example 2 The formulation of Example 2 is the same as that of Example 1, wherein the compound Sacubitril is replaced by Candoxatril.

[0066] Example 3 The formulation of Example 3 is the same as that of Example 1, wherein the compound Sacubitril is replaced by Daglutril.

[0067] Example 4 The formulation of Example 4 is the same as that of Example 1, wherein the compound Sacubitril is replaced by Ilepatril.

[0068] Example 5 The proportions of Example 5 are the same as those of Example 1, wherein the compound Sacubitril is replaced by Cadotril.

[0069] Example 6 The proportions of Example 6 are the same as those of Example 1, wherein the compound Sacubitril is replaced by Fasidotril.

[0070] Example 7 A pharmaceutical composition containing a sartan drug or its ester, a NEPi, and a CCB in a molar ratio

[0071]

[0072]

[0073] Wherein, compound S is Sacubitril, compound CCB1 is amlodipine, and the pharmaceutical composition contains CCB1 2.5 mg and 5 mg; CCB2 is levamlodipine, and the pharmaceutical composition contains CCB2 2.5 mg and 5 mg.

[0074] Example 8 The formulation of Example 8 is the same as that of Example 7, wherein the compound Sacubitril is replaced by Candoxatril.

[0075] Example 9 The formulation of Example 9 is the same as that of Example 7, wherein the compound Sacubitril is replaced by Daglutril.

[0076] Example 10 The formulation of Example 10 is the same as that of Example 7, wherein the compound Sacubitril is replaced by Ilepatril.

[0077] Example 11 The formulation of Example 11 is the same as that of Example 7, wherein the compound Sacubitril is replaced by Cadotril.

[0078] Example 12 The formulation of Example 12 is the same as that of Example 7, wherein the compound Sacubitril is replaced by Fasidotril.

[0079] Example 13 Pharmaceutical composition containing sartan or its ester, NEPi, and CCB in a mass ratio

[0080]

[0081]

[0082]

[0083] Among them, compound S is Sacubitril (AHU377), compound CCB1 is amlodipine, and the dosage is 2.5 mg and 5 mg; CCB2 is levamlodipine, and the dosage is 2.5 mg and 5 mg.

[0084] Example 14 The formulation of Example 14 is the same as that of Example 13, wherein the compound Sacubitril is replaced by Candoxatril.

[0085] Example 15 The formulation of Example 15 is the same as that of Example 13, wherein the compound Sacubitril is replaced by Daglutril.

[0086] Example 16 The formulation of Example 16 is the same as that of Example 13, wherein the compound Sacubitril is replaced by Ilepatril.

[0087] Example 17 The formulation of Example 17 is the same as that of Example 13, wherein the compound Sacubitril is replaced by Cadotril.

[0088] Example 18 The formulation of Example 18 is the same as that of Example 13, wherein the compound Sacubitril is replaced by Fasidotril.

[0089] Example 19: A pharmaceutical composition containing a sartan drug or its ester, a NEPi, and a CCB in a molar ratio

[0090]

[0091]

[0092] Wherein, compound S is Sacubitril, compound CCB1 is amlodipine, and the pharmaceutical composition contains CCB1 2.5 mg and 5 mg; CCB2 is levamlodipine, and the pharmaceutical composition contains CCB2 2.5 mg and 5 mg.

[0093] Example 20 The formulation of Example 20 is the same as that of Example 19, wherein the compound Sacubitril is replaced by Candoxatril.

[0094] Example 21 The formulation of Example 21 is the same as that of Example 19, wherein the compound Sacubitril is replaced by Daglutril.

[0095] Example 22 The formulation of Example 22 is the same as that of Example 19, wherein the compound Sacubitril is replaced by Ilepatril.

[0096] Example 23 The formulation of Example 23 is the same as that of Example 19, wherein the compound Sacubitril is replaced by Cadotril.

[0097] Example 24 The formulation of Example 24 is the same as that of Example 19, wherein the compound Sacubitril is replaced by Fasidotril.

[0098] Example 25 Pharmaceutical composition containing sartan or its ester, NEPi, and CCB according to mass ratio

[0099]

[0100]

[0101]

[0102] Among them, compound S is Sacubitril (AHU377), compound CCB1 is amlodipine, and the dosage is 2.5 mg and 5 mg; CCB2 is levamlodipine, and the dosage is 2.5 mg and 5 mg.

[0103] Example 26 The formulation of Example 26 is the same as that of Example 25, wherein the compound Sacubitril is replaced by Candoxatril.

[0104] Example 27 The formulation of Example 27 is the same as that of Example 25, wherein the compound Sacubitril is replaced by Daglutril.

[0105] Example 28 The formulation of Example 28 is the same as that of Example 25, wherein the compound Sacubitril is replaced by Ilepatril.

[0106] Example 29 The formulation of Example 29 is the same as that of Example 25, wherein the compound Sacubitril is replaced by Cadotril.

[0107] Example 30 The formulation of Example 30 is the same as that of Example 25, wherein the compound Sacubitril is replaced by Fasidotril.

[0108] Example 31 A pharmaceutical composition containing a sartan drug or its ester, a NEPi, and a CCB in a molar ratio

[0109]

[0110]

[0111] Wherein, compound S is Sacubitril, compound CCB1 is amlodipine, and the pharmaceutical composition contains CCB1 2.5 mg and 5 mg; CCB2 is levamlodipine, and the pharmaceutical composition contains CCB2 2.5 mg and 5 mg.

[0112] Example 32 The formulation of Example 32 is the same as that of Example 31, wherein the compound Sacubitril is replaced by Candoxatril.

[0113] Example 33 The formulation of Example 33 is the same as that of Example 31, wherein the compound Sacubitril is replaced by Daglutril.

[0114] Example 34 The formulation of Example 34 is the same as that of Example 31, wherein the compound Sacubitril is replaced by Ilepatril.

[0115] Example 35 The formulation of Example 35 is the same as that of Example 31, wherein the compound Sacubitril is replaced by Cadotril.

[0116] Example 36 The formulation of Example 36 is the same as that of Example 31, wherein the compound Sacubitril is replaced by Fasidotril.

[0117] Example 37 Pharmaceutical Composition Containing Sartan Drugs or Their Esters, NEPi, and CCB in a Mass Ratio

[0118]

[0119]

[0120]

[0121] Among them, compound S is Sacubitril (AHU377), compound CCB1 is amlodipine, and the dosage is 2.5 mg and 5 mg; CCB2 is levamlodipine, and the dosage is 2.5 mg and 5 mg.

[0122] Example 38 The formulation of Example 38 is the same as that of Example 37, wherein the compound Sacubitril is replaced by Candoxatril.

[0123] Example 39 The formulation of Example 39 is the same as that of Example 37, wherein the compound Sacubitril is replaced by Daglutril.

[0124] Example 40 The formulation of Example 40 is the same as that of Example 37, wherein the compound Sacubitril is replaced by Ilepatril.

[0125] Example 41 The formulation of Example 41 is the same as that of Example 37, wherein the compound Sacubitril is replaced by Cadotril.

[0126] Example 42 The formulation of Example 42 is the same as that of Example 37, wherein the compound Sacubitril is replaced by Fasidotril.

[0127] Example 43: A pharmaceutical composition containing a sartan drug or its ester, a NEPi, and a CCB in a molar ratio

[0128]

[0129]

[0130] Wherein, compound S is Sacubitril, compound CCB1 is amlodipine, and the pharmaceutical composition contains CCB1 2.5 mg and 5 mg; CCB2 is levamlodipine, and the pharmaceutical composition contains CCB2 2.5 mg and 5 mg.

[0131] Example 44 The formulation of Example 44 is the same as that of Example 43, wherein the compound Sacubitril is replaced by Candoxatril.

[0132] Example 45 The formulation of Example 45 is the same as that of Example 43, wherein the compound Sacubitril is replaced by Daglutril.

[0133] Example 46 The formulation of Example 46 is the same as that of Example 43, wherein the compound Sacubitril is replaced by Ilepatril.

[0134] Example 47 The formulation of Example 47 is the same as that of Example 43, wherein the compound Sacubitril is replaced by Cadotril.

[0135] Example 48 The formulation of Example 48 is the same as that of Example 43, wherein the compound Sacubitril is replaced by Fasidotril.

[0136] Example 49 Pharmaceutical composition containing sartan or its ester, NEPi, and CCB in a mass ratio

[0137]

[0138]

[0139] Among them, compound S is Sacubitril (AHU377), compound CCB1 is amlodipine, and the dosage is 2.5 mg and 5 mg; CCB2 is levamlodipine, and the dosage is 2.5 mg and 5 mg.

[0140] Example 50 The proportions of Example 49 are the same as those of Example 49, wherein the compound Sacubitril is replaced by Candoxatril.

[0141] Example 51 The formulation of Example 49 is the same as that of Example 49, wherein the compound Sacubitril is replaced by Daglutril.

[0142] Example 52 The formulation of Example 49 is the same as that of Example 49, wherein the compound Sacubitril is replaced by Ilepatril.

[0143] Example 53 The formulation of Example 49 is the same as that of Example 49, wherein the compound Sacubitril is replaced by Cadotril.

[0144] Example 54 The proportions of Example 49 are the same as those of Example 49, wherein the compound Sacubitril is replaced by Fasidotril.

[0145] Example 55 A pharmaceutical composition containing a sartan drug or its ester, a NEPi, and a CCB in a molar ratio

[0146]

[0147]

[0148] Wherein, compound S is Sacubitril, compound CCB1 is amlodipine, and the pharmaceutical composition contains CCB1 2.5 mg and 5 mg; CCB2 is levamlodipine, and the pharmaceutical composition contains CCB2 2.5 mg and 5 mg.

[0149] Example 56 The ratio of Example 55 is the same as that of Example 55, wherein the compound Sacubitril is replaced by Candoxatril.

[0150] Example 57 The ratio of Example 55 is the same as that of Example 55, wherein the compound Sacubitril is replaced by Daglutril.

[0151] Example 58 The ratio of Example 55 is the same as that of Example 55, wherein the compound Sacubitril is replaced by Ilepatril.

[0152] Example 59 The ratio of Example 55 is the same as that of Example 55, wherein the compound Sacubitril is replaced by Cadotril.

[0153] Example 60 The proportions of Example 55 are the same as those of Example 55, wherein the compound Sacubitril is replaced by Fasidotril.

[0154] Example 61 Preparation method of pharmaceutical composition

[0155] The sartan ester of the composition of any ratio in any of the foregoing embodiments is replaced by one of Azilsartan, Amisartan, Abitesartan, Candesartan, Elisartan, Embusartan, Eprosartan, Fonsartan, Forasartan, Irbesartan, Losartan, Milfasartan, Olmesartan, Pratosartan, Ripisartan, Saprisartan, Tasosartan, Telmisartan, Zolasartan, Enoltasosartan, Glycyllosartan, and Opomisartan.

[0156] Example 62

[0157] According to any ratio of the composition in any of the above examples, the corresponding active ingredients are weighed, one or more carriers are added or not added, and the mixture is filled into capsules to prepare capsules.

[0158] Example 63 Preparation method of pharmaceutical composition

[0159] According to any of the composition ratios of any of the aforementioned embodiments, the corresponding substances are weighed, one or more carriers are added, and the tablet composition is prepared by dry or wet granulation, tablet compression, and coating.

[0160] The carrier comprises a filler, a binder, and a disintegrant; the filler is microcrystalline cellulose; the binder is povidone; and the disintegrant is cross-linked povidone. The amounts of the filler, binder, and disintegrant are 0.5, 1, and 0.3 of the total weight of the active ingredients of the pharmaceutical composition, respectively.

[0161] The above-mentioned carrier may further contain auxiliary materials of other properties; the auxiliary materials may be replaced with various auxiliary materials described in the instructions as needed.

[0162] Example 64: Drug Efficacy Experiment

[0163] The pharmaceutical composition of any of the above embodiments is used in an anti-hypertension and / or heart failure model experiment,

[0164] The experimental method is as follows: The effects of the pharmaceutical composition are studied using SHR. The hypertensive background of SHR is altered by chronic salt loading to inhibit the renin-angiotensin system (RAS) or by chronic salt deprivation to activate the RAS in SHR. These procedures allow for a more extensive evaluation of the efficacy of various test substances.

[0165] Spontaneously hypertensive rats (SHR) were used in the experiments. A radiotelemetry device was implanted in the lower abdominal aorta of all 14- to 16-week-old experimental animals. All SHRs were allowed to recover for at least 2 weeks after the implantation procedure before the experiments began. Cardiovascular parameters were continuously monitored using the radio transmitter and transmitted to a receiver that collected the digital signals and stored them using a computerized data acquisition system. Blood pressure (mean arterial pressure, systolic pressure, and diastolic pressure) and heart rate were monitored in conscious, freely moving SHRs in their home cages. Arterial blood pressure and heart rate were measured for 10 seconds every 10 minutes and recorded. Data reported for each rat are expressed as a 24-hour mean and are composed of 144 10-minute samples collected daily. Baseline blood pressure and heart rate values ​​were composed of the average of three consecutive 24-hour readings before the start of drug treatment. All rats were housed individually in a temperature- and humidity-controlled room on a 12-hour light-dark cycle. In addition to cardiovascular parameters, body weight was measured weekly for all rats.

[0166] Treatment was administered daily via oral gavage in the drinking water or via the mini-osmotic pump described above. If drinking water was administered, water consumption was measured five times per week. The dosage of the pharmaceutical composition was then calculated based on each rat's water consumption, drug concentration in the drinking water, and individual body weight. All drug solutions in the drinking water were refreshed every three to four days.

[0167] Among them, the single use of sartan drugs, NEPi or calcium ion antagonist is used as a positive control, and the dosage of each sartan drug, NEPi or calcium ion antagonist is the single dosage in the composition of the above-mentioned pharmaceutical composition.

[0168] The results showed that surprisingly, the combination of the sartan, NEP inhibitor and calcium ion antagonist achieved a higher therapeutic effect than that achieved by administering the sartan, NEP inhibitor or calcium ion antagonist alone.

[0169] Greater efficacy can be demonstrated by an increased duration of action. The duration of action can be monitored by the time to return to baseline before the next dose or the area under the curve (AUC) and expressed as the product of the change in blood pressure in millimeters of mercury (mmHg change) and the duration of action (minutes, hours, or days).

[0170] An additional benefit is that the dosage can be reduced by using lower doses of the combined drugs of the present invention. For example, the required dose is not only often smaller, but can also be applied less frequently, or the incidence of side effects can be reduced. Regardless of the etiology of the condition, the combination of a sartan or its ester, a NEP inhibitor, and a calcium ion antagonist produces a significant therapeutic effect in a higher percentage of treated patients, i.e., has a higher response rate. This is consistent with the wishes and needs of the patients being treated.

[0171] 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 comprising a sartan or its ester, a NEPi, and a CCB, comprising one or more sartan or its ester, one or more NEP inhibitors, one or more calcium ion antagonists, and the presence or absence of a pharmaceutically acceptable carrier, characterized in that: The weight ratio or molar ratio of the sartan drug or its ester to the one or more NEP inhibitors is 1:100-100:1, preferably 1:50-50:1, 1:45-45:1, 1:40-40:1, 1:35-35:1, 1:30-30:1, 1:25-25:1, 1:20-20:1, 1:15-15:1, 1:14-14:1, 1:13-13:1, 1:12-12:1, 1:11-11:1, and more preferably 1:10-10:

1. , 1:9.5-9.5:1,1:9-9:1,1:8.5-8.5:1,1:8-8:1,1:7.5-7.5:1,1:7-7:1,1:6.5-6.5:1,1:6-6:1,1:5.5-5.5:1,1:5-5:1,1:4.5-4.5:1,1:4-4:1,1:3.5-3.5:1,1:3-3:1,1:2.5-2.5:1,1:2-2:1,1:1.5-1.5:1, or 1:1; Alternatively, when the total weight of the sartan drug or its ester and the NEP inhibitor is 50 mg or 100 mg, the sartan drug or its ester or the NEP inhibitor is independently 21 mg, 22 mg, 23 mg, 24 mg, 26 mg, 27 mg, 28 mg, 29 mg, 41 mg, 42 mg, 43 mg, 44 mg, 46 mg, 47 mg, 48 mg, or 49 mg, respectively; or when the total weight of the sartan drug or its ester and the NEP inhibitor is 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, the above ratio of 50 mg or 100 mg is multiplied by 3, 1.5, 4, 2, 5, 2.5, 6, 3, 7, 3.5, 8, or 4, respectively.

2. The pharmaceutical composition according to claim 1, characterized in that The sartan drug (AT1 receptor antagonist) or its ester is selected from Azilsartan, Amisartan, Abitesartan, Candesartan, Elisartan, Embusartan, Eprosartan, Fonsartan, Forasartan, Irbesartan, Losartan, Milfasartan, Olmesartan, Pratosartan, Ripisartan, Saprisartan, Tasosartan, Telmisartan, Zolasartan, Enoltasosartan, Glycyllosartan, Opomisartan or its ester; preferably, the sartan drug or its ester is calculated as sartan; The NEPi is selected from the group consisting of Sacubitril (AHU377), Candoxatril, Daglutril, Ilepatril, Cadotril, Fasidotril, etc. or any physiologically compatible salts, solvates, prodrugs or esters thereof; The calcium ion antagonist is selected from nifedipine, amlodipine, lercanidipine, nimodipine, nicardipine, nitrendipine, nisoldipine, felodipine, benidipine, lacidipine or any physiologically compatible salt thereof, more preferably amlodipine, levamlodipine or any physiologically compatible salt thereof.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The sartan or its ester is used in an amount of about 0.1 mg to about 1000 mg, preferably about 5 mg to about 800 mg, preferably about 20 mg to about 700 mg, more preferably about 50 mg to about 600 mg, and more preferably 100 mg to about 300 mg, calculated as sartan; And / or the NEPi is used in an amount of about 0.1 mg to about 1000 mg, preferably about 5 mg to about 800 mg, preferably about 20 mg to about 700 mg, more preferably about 50 mg to about 600 mg, and more preferably 100 mg to about 300 mg.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that The dosage of the sartan drug or its ester calculated as sartan is specifically 800mg, 600mg, 400mg, 300mg, 200mg, 150mg, 125mg, 100mg, 80mg, 75mg, 60mg, 50mg, 40mg, 32mg, 30mg, 25mg, 20mg, 16mg, 15mg, 12.5mg, 10mg, 9mg, 8mg, 7mg, 7.5mg, 6mg, 5mg, 4mg, 3mg, 2.5mg, 2mg, 1mg, 0.75mg, 0.5mg, 0.25mg, etc.; And / or the specific dosage of the NEPi is 1000 mg, 800 mg, 600 mg, 400 mg, 300 mg, 200 mg, 150 mg, 125 mg, 100 mg, 80 mg, 75 mg, 60 mg, 50 mg, 40 mg, 32 mg, 30 mg, 25 mg, 20 mg, 16 mg, 15 mg, 12.5 mg, 10 mg, 9 mg, 8 mg, 7 mg, 7.5 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2.5 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, or 0.25 mg, etc.

5. The pharmaceutical composition according to claim 1 or 2, characterized in that When the total weight of the sartan drug or its ester and the NEP inhibitor is 50 mg or 100 mg, the sartan drug or its ester or the NEP inhibitor is independently 21 mg, 22 mg, 23 mg, 24 mg, 26 mg, 27 mg, 28 mg, 29 mg, 41 mg, 42 mg, 43 mg, 44 mg, 46 mg, 47 mg, 48 mg, 49 mg respectively; or when the total weight of the sartan drug or its ester and the NEP inhibitor is 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, the above ratio of 50 mg or 100 mg is multiplied by 3, 1.5, 4, 2, 5, 2.5, 6, 3, 7, 3.5, 8 or 4, etc.

6. The pharmaceutical composition according to claim 1 or 2, characterized in that The sartan is valsartan or its ester (80, 160, 300 mg according to valsartan), telmisartan or its ester (20, 40, 80 mg according to telmisartan), candesartan or its ester (4, 8, 16, 32 mg according to candesartan), olmesartan or its ester (5, 20, 40 mg according to olmesartan), eprosartan or its ester (400, 600 mg according to eprosartan), or losartan or its ester (25, 50, 100 mg according to losartan).

7. The pharmaceutical composition according to claim 1 or 2, characterized in that The pharmaceutical composition further contains amlodipine (in the form of C 20 H 25 N2O5Cl) is selected from 2.5 to 10 mg, preferably amlodipine (in C 20 H 25 N2O5Cl) is selected from 2.5, 5, 7.5 and 10 mg.

8. The pharmaceutical composition according to claim 1 or 2, characterized in that The carrier includes one or more components such as filler, binder, disintegrant, lubricant, glidant, etc.; The filler is selected from one or a mixture of two or more of microcrystalline cellulose, lactose, mannitol, starch, pregelatinized starch, sucrose, dextrin, calcium hydrogen phosphate, and sorbitol in any ratio; The binder is selected from one of povidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and hypromellose, or a mixture of two or more in any ratio; The disintegrant is selected from one or a mixture of two or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose in any ratio; The pharmaceutical composition may further contain a glidant, which is selected from one of silicon dioxide and talc or a mixture of two or more thereof in any ratio. The pharmaceutical composition of the present invention may further comprise a lubricant as required by the prescription. The lubricant is selected from one or a mixture of two or more of magnesium stearate, hydrogenated vegetable oil, polyethylene glycols, stearic acid, palmitic acid, and carnauba wax in any ratio.

9. The pharmaceutical composition according to claim 1 or 2, characterized in that further comprising one or a mixture of two or more of plasticizers, preservatives, flavoring agents, solubilizers, colorants, dispersants, release rate regulators, etc.; The plasticizers include but are not limited to polyethylene glycol, propylene glycol, and glycerin; The preservatives include but are not limited to benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, potassium sodium sorbate, calcium propionate, sodium propionate, parahydroxybenzoic acid, and isopropyl parahydroxybenzoate; The flavoring agent includes a sweetener, a fragrance, a mucilage and an effervescent agent, wherein the sweetener can be sucrose, stevioside, monosaccharide syrup, aromatic syrup, glycerin, sorbitol, saccharin sodium, and protein sugar; the mucilage can be sodium alginate, gum arabic, gelatin, methylcellulose, and sodium carboxymethylcellulose; the effervescent agent can be an organic acid such as citric acid, tartaric acid, and sodium bicarbonate; The solubilizer includes but is not limited to sorbitan fatty acids, polysorbates, polyoxyethylene fatty acid esters, phospholipids, cholesterol, stearates (such as sodium stearate), oleates (such as sodium oleate), sodium lauryl sulfate, sodium lauryl sulfonate; The coloring agents include but are not limited to beetroot red, carmine, carotene, lemon yellow, pine needle blue, sodium copper chlorophyllin, caramel, aluminum lake, yellow iron oxide, and brilliant blue; The dispersants include, but are not limited to, sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, silicates, triethylhexyl phosphate, methyl amyl alcohol, cellulose derivatives, polyacrylamide, guar gum, and polyethylene glycol esters of fatty acids; Sunscreens include, but are not limited to, titanium dioxide, zinc oxide, and yellow iron oxide; The release rate regulator is selected from sucrose, sodium chloride, surfactants, and polyethylene glycol (PEG). Preferably, the amount of each excipient is 0.01-10 times, preferably 0.1-5 times, more preferably any value between 0.5-3 times the active ingredient in the pharmaceutical composition.

10. The use of the pharmaceutical composition of any one of claims 1 to 7 in the preparation of a drug for the prevention and / or treatment of a disease, including antihypertensive therapy (whether for malignant hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, isolated systolic hypertension or other secondary hypertension); the combination can also be used to treat or prevent heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter or adverse vascular remodeling. Sartans and NEP inhibitors can also be shown to be beneficial in the treatment and prevention of myocardial infarction and its sequelae. The combination of sartans and NEP inhibitors can also be used to treat atherosclerosis, angina (whether stable or unstable angina), and renal insufficiency (diabetic and non-diabetic). In addition, combination therapy with sartans and NEP inhibitors can improve endothelial dysfunction, thereby providing benefits in diseases where normal endothelial function is disrupted, such as heart failure, angina, and diabetes. In addition, the combination of the present invention can also be used for the treatment or prevention of secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria in primary nephropathy, and renal vascular hypertension, diabetic retinopathy, other vascular disorders such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's disease), glaucoma, and stroke.