Pharmaceutical compositions comprising azilsartan medoxomil potassium and calcium channel blockers, methods of preparation thereof, and uses thereof

Abstract

The present invention provides a pharmaceutical composition containing azilsartan medoxomil potassium and a calcium channel blocker, as well as a method for preparing and using the same. The development of a combination formulation using azilsartan medoxomil potassium and a calcium channel blocker is advantageous in terms of improving antihypertensive effects, improving safety and tolerability, and reducing side effects. Azilsartan medoxomil potassium can alleviate amlodipine-induced peripheral edema by dilating peripheral venous blood vessels, while amlodipine can alleviate adverse reactions such as angioedema and dry cough caused by azilsartan medoxomil potassium. Compared with single drugs, the advantages of combination drugs include: (1) reducing medication dosage and improving patient compliance; (2) improving compliance for elderly people and those with dysphagia; and (3) preventing frequent fluctuations in blood drug concentrations, maintaining stable blood drug concentrations, stabilizing blood pressure in hypertensive patients over the long term, and reducing the side effects of each drug. (4) Avoid patients discontinuing medication on their own, and prevent disease recurrence and progression of malignant complications.

Description

Detailed Description of the Invention

[0001] This application claims priority to a Chinese patent application bearing application number 202211484130.8 and entitled "Pharmaceutical composition comprising azilsartan medoxomil potassium and a calcium channel blocker, its preparation method, and use," filed by the applicant with the State Intellectual Property Office of the People's Republic of China on November 24, 2022, the entire text of which is incorporated herein by reference.

[0002] [Technical Field] The present invention relates to a pharmaceutical composition comprising azilsartan medoxomil potassium and a calcium channel blocker, a method for preparing the same, and uses thereof.

[0003] [Background technology] Hypertension is one of the most common cardiovascular diseases, with a prevalence rate of 25% to 30% among adults. If hypertension is not effectively controlled over a long period of time, it increases the risk of developing coronary atherosclerosis, left ventricular hypertrophy, carotid atherosclerosis, and kidney disease. According to the 2019 China Cardiovascular Health and Disease Report, the number of people suffering from hypertension in China is 245 million, of which the adult prevalence rate is approximately 27.9%, showing a yearly increasing trend. However, the hypertension control rate in China is only 16.8%, meaning that a significant number of people with hypertension are unable to effectively control their condition. Therefore, the development of drugs to treat hypertension and cardiovascular disease and reduce toxicity and side effects is of positive significance for clinical medicine.

[0004] Azilsartan medoxomil potassium is an angiotensin II receptor blocker (ARB) developed by Takeda Pharmaceutical Co., Ltd. (Takeda Pharmaceuticals). Because this drug is a prodrug, it is rapidly converted to the active ingredient, azilsartan, after oral absorption. Azilsartan selectively blocks the binding of angiotensin II to the AT1 receptor in multiple tissues, thereby inhibiting the effects of angiotensin II. Angiotensin II is the primary hypertensive substance in the RAAS, and its effects include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal sodium reabsorption. Azilsartan medoxomil potassium selectively blocks the binding of angiotensin II to the AT1 receptor in many tissues (e.g., vascular smooth muscle and adrenal glands), thereby blocking angiotensin II-induced vasoconstriction and aldosterone secretion.

[0005] Azilsartan medoxomil potassium has the chemical name (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate monopotassium salt, a molecular weight of 606.62, and the structural formula: [ka]

[0006] Calcium channel blockers, also known as calcium antagonists, are drugs that selectively act on calcium channels, blocking the influx of extracellular calcium ions into cells and affecting cellular function. Intracellular calcium ions play a very important role in cellular function. As an important intracellular second messenger, they can regulate many cellular responses and activities, including neurotransmitter release, muscle contraction, glandular secretion, and platelet activation, and play a particularly important role in cardiovascular function.

[0007] Amlodipine is a calcium channel blocker. Because cardiac and smooth muscle contraction depends on the entry of extracellular calcium ions into cells through specific ion channels, amlodipine can selectively inhibit the transmembrane entry of calcium ions into smooth muscle cells and cardiac myocytes, with its effect being greater on smooth muscle than on cardiac muscle. The interaction of amlodipine with calcium channels is determined by the rate of binding and dissociation at receptor sites, so its pharmacological effect is gradual. Amlodipine is a peripheral arterial dilator that acts directly on vascular smooth muscle to reduce peripheral vascular resistance and lower blood pressure. Amlodipine has the chemical name methylethyl 6-methyl-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate, a molecular weight of 408.88, and the structural formula is shown below. [ka]

[0008] Levamlodipine is a dihydropyridine calcium channel blocker that acts directly on peripheral arterial smooth muscle to reduce peripheral vascular resistance and lower blood pressure. Levamlodipine inhibits the entry of extracellular calcium ions into cardiac myocytes and vascular smooth muscle cells through calcium ion channels (slow channels) in the cell membrane, directly relaxing vascular smooth muscle and lowering blood pressure. Amlodipine also reduces the vasoconstrictor effects of angiotensin II and adrenergic receptors and reduces sodium reabsorption by renal tubules.

[0009] Currently, common adverse reactions of azilsartan medoxomil potassium include dizziness, hypotension, diarrhea, angioedema, etc., and common adverse reactions of amlodipine include arrhythmia, bradycardia, chest pain, hypotension, peripheral ischemia, syncope, etc. Therefore, there is a need to develop a pharmaceutical composition, manufacturing method, and use comprising azilsartan medoxomil potassium and a calcium channel blocker that has fewer side effects and good compliance.

[0010] Summary of the Invention [Problem to be solved by the invention] The object of the present invention is to provide a pharmaceutical composition comprising azilsartan medoxomil potassium and a calcium channel blocker, which has fewer side effects and better compliance, unlike the prior art, and a method for producing the same and use thereof.

[0011] [Means for solving the problem] The present invention comprises azilsartan medoxomil potassium and a calcium channel blocker, The azilsartan medoxomil potassium includes one or more of azilsartan medoxomil potassium, a pharmaceutically acceptable salt thereof, and a solvate thereof; The calcium channel blocker provides a pharmaceutical composition comprising one or more of a calcium channel blocker, a pharmaceutically acceptable salt, and a solvate thereof.

[0012] According to embodiments of the present invention, the calcium channel blocker may be one or more of amlodipine, levamlodipine, and pharmaceutically acceptable salts thereof (e.g., amlodipine benzenesulfonate or levamlodipine benzenesulfonate).

[0013] According to an embodiment of the present invention, the content of azilsartan medoxomil potassium, a pharmaceutically acceptable salt and / or solvate thereof in the pharmaceutical composition may be 20 mg to 80 mg, for example, 20 mg, 40 mg, or 80 mg. Preferably, the content of azilsartan medoxomil potassium, a pharmaceutically acceptable salt and / or solvate thereof in a unit dose form of the pharmaceutical composition may be 20 mg to 80 mg, for example, 20 mg, 40 mg, or 80 mg.

[0014] Alternatively, as an alternative, the content of azilsartan medoxomil potassium, a pharmaceutically acceptable salt and / or solvate thereof in the pharmaceutical composition, based on the total weight of the pharmaceutical composition, may be 1% by mass to 50% by mass, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50% by mass, for example, 14.23%, 21.33%, or 21.34% by mass.

[0015] According to an embodiment of the present invention, the content of the calcium channel blocker, its pharmaceutically acceptable salt, and / or solvate contained in the pharmaceutical composition may be 2.5 mg to 20 mg, for example, 2.5 mg to 20 mg, preferably 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 20 mg. Alternatively, the content of levamlodipine contained in the pharmaceutical composition is 2.5 mg to 10 mg, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 20 mg, preferably 2.5 mg, 5 mg, or 10 mg. Preferably, the content of the calcium channel blocker, its pharmaceutically acceptable salt, and / or solvate in a unit dose form of the pharmaceutical composition may be 2.5 mg to 20 mg, for example, 2.5 mg to 20 mg, preferably 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 20 mg. Alternatively, the content of levamlodipine in the unit dosage form of the pharmaceutical composition is 2.5 mg to 10 mg, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 20 mg, preferably 2.5 mg, 5 mg, or 10 mg.

[0016] Alternatively, the content of the calcium channel blocker, pharmaceutically acceptable salt and / or solvate thereof contained in the pharmaceutical composition is 0.5% by mass to 10% by mass, for example, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, or 2% by mass, based on the total weight of the pharmaceutical composition. Amount%, 1.6% by mass, 1.7% by mass, 1.8% by mass, 1.9% by mass, 2% by mass, 2.5% by mass, 3% by mass, 3.5% by mass, 4% by mass, 4.5% by mass, 5% by mass, 5.5% by mass, 6% by mass, 6. It may be 5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% by weight, such as 1.74%, 2.31%, or 3.47% by weight.

[0017] According to an embodiment of the present invention, in the pharmaceutical composition, the ratio of the total weight of azilsartan medoxomil potassium, its pharmaceutically acceptable salt and / or solvate to the total weight of the calcium channel blocker, its pharmaceutically acceptable salt and / or solvate may be 1 to 32:1, and may be 1:1, 2:1, 2.7:1, 4:1, 5.3:1, 8:1, 16:1, or 32:1.

[0018] According to an embodiment of the present invention, the pharmaceutical composition may further comprise one or more of a pH adjuster, a diluent, a binder, a disintegrant, a lubricant, a flow aid, a tableting aid, a colorant, and a coating premix.

[0019] According to an embodiment of the present invention, the pH adjuster refers to a substance for adjusting the pH of the composition, and is one or more selected from fumaric acid, sodium fumarate, citric acid, sodium citrate, tartaric acid, sodium hydroxide, potassium dihydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate, and sodium carbonate. The content of the pH adjuster is preferably 0 to 10% by mass, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, or 3% by mass. %, 3 mass%, 3.5 mass%, 4 mass%, 4.5 mass%, 5 mass%, 5.5 mass%, 6 mass%, 6.5 mass%, 7 mass%, 7.5 mass%, 8 mass%, 8.5 mass%, 9 mass%, 9.5 mass%, or 10 mass%, wherein the content refers to the percentage of the mass of the pH adjuster to the total mass of the azilsartan medoxomil potassium and calcium channel blocker composition.

[0020] According to an embodiment of the present invention, the diluent refers to a solid substance that can be added to a material to improve the properties of the material, increase the volume, increase the weight, and reduce the cost of the material, and is one or more selected from mannitol, anhydrous calcium hydrogen phosphate, sucrose, glucose, maltose, lactose (e.g., lactose monohydrate), microcrystalline cellulose, and sorbitol. The content of the diluent is preferably 0 to 80% by mass, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 54%, 54.63%, 55%, 60%, 64%, 64.63%, 65%, 70%, 75%, or 80% by mass, where the content refers to the percentage of the mass of the diluent relative to the total mass of the azilsartan medoxomil potassium and calcium channel blocker composition.

[0021] According to an embodiment of the present invention, the binder (also referred to as a thickener) refers to an additive known in the art that increases the viscosity of a dispersion medium, reduces the sedimentation rate of microparticles, or increases the hydrophilicity of microparticles, and is one or more selected from hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, copovidone, povidone, and pregelatinized starch. The content of the binder is preferably 0 to 20% by weight, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight, where the content refers to the percentage of the weight of the binder relative to the total weight of the azilsartan medoxomil potassium and calcium channel blocker composition.

[0022] According to an embodiment of the present invention, the disintegrant refers to a substance that disintegrates tablets or granules during dissolution, and is one or more selected from the group consisting of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, and cornstarch. The content of the disintegrant is preferably 0 to 20% by weight, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight, where the content refers to the percentage of the mass of the disintegrant relative to the total mass of the azilsartan medoxomil potassium and calcium channel blocker composition.

[0023] According to an embodiment of the present invention, the lubricant may be a substance known in the art having a lubricating effect, such as one or more selected from metal stearates (e.g., magnesium stearate), stearic acid, talc, stearates, stearoyl fumarate, and finely powdered silica gel. The content of the lubricant is preferably 0 to 10% by weight, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight, where the content refers to the percentage of the weight of the lubricant relative to the total weight of the azilsartan medoxomil potassium and calcium channel blocker composition.

[0024] According to an embodiment of the present invention, the flow aid may be an auxiliary material known in the art that can improve the flowability of powders or granules by reducing interparticle friction, and may be one or more selected from talc, finely powdered silica gel, colloidal silica, and pregelatinized starch. The content of the flow aid is preferably 0 to 10% by mass, and the content refers to the percentage of the mass of the flow aid to the total mass of the azilsartan medoxomil potassium and calcium channel blocker composition.

[0025] According to an embodiment of the present invention, the tableting aid is an auxiliary material that can improve flowability and / or compressibility, and increase tablet hardness and wear resistance, and is selected from microcrystalline cellulose and / or lactose monohydrate.

[0026] According to an embodiment of the present invention, the colorant may be a substance known in the art that can achieve the purpose of coloring, and may be selected from red iron oxide and / or yellow iron oxide. The content of the colorant is preferably 0 to 5% by mass, and the content refers to the percentage of the mass of the colorant to the total mass of the azilsartan medoxomil potassium and calcium channel blocker composition.

[0027] According to an embodiment of the present invention, the coating premix is ​​known in the art. For example, the coating premix is ​​a film coating premix containing one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, lactose, titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide. For example, the coating premix may be selected from film coating premixes provided by COLORCON.

[0028] The pharmaceutical composition of the present invention may be a composition containing azilsartan medoxomil potassium and amlodipine (e.g., azilsartan medoxomil potassium-amlodipine tablets), or a composition containing azilsartan medoxomil potassium and levamlodipine (e.g., azilsartan medoxomil potassium-levamlodipine tablets).

[0029] According to an embodiment of the present invention, the azilsartan medoxomil potassium and calcium channel blocker in the pharmaceutical composition may be distributed in a monolayer core or a bilayer core structure, where if the pharmaceutical composition has a monolayer core structure, the monolayer core contains the azilsartan medoxomil potassium and the calcium channel blocker, or if the pharmaceutical composition has a bilayer core structure, one layer of the core contains azilsartan medoxomil potassium and the other layer of the core contains the calcium channel blocker.

[0030] When the pharmaceutical composition has a bilayer core structure, the core layer containing azilsartan medoxomil potassium and the core layer containing a calcium channel blocker may independently contain one or more of the above-mentioned pH adjusters, diluents, binders, disintegrants, lubricants, flow aids, tableting aids, colorants, and coating premixes.

[0031] For example, the core layer containing azilsartan medoxomil potassium may independently comprise one or more of the pH adjusters, diluents, binders, disintegrants, lubricants, and colorants described above, and the core layer containing a calcium channel blocker may independently comprise one or more of the diluents, disintegrants, lubricants, flow aids, and colorants described above.

[0032] According to an embodiment of the present invention, the pharmaceutical composition may be in any of the following formulations:

[0033] Formulation 1: 21.33% azilsartan medoxomil potassium, 3.47% amlodipine benzenesulfonate, 54.00% mannitol, 0.80% fumaric acid, 0.40% sodium hydroxide, 3.00% hydroxypropyl cellulose, 6.00% sodium carboxymethyl starch, 10.00% microcrystalline cellulose, and 1.00% magnesium stearate. The percentages refer to the weight of each component as a percentage of the total weight of the composition containing azilsartan medoxomil potassium and a calcium channel blocker.

[0034] Formulation 2: 21.33% azilsartan medoxomil potassium, 1.74% levamlodipine benzenesulfonate, 54.63% mannitol, 0.80% fumaric acid, 0.50% sodium hydroxide, 3.00% hydroxypropyl cellulose, 7.00% sodium carboxymethyl starch, 10.00% microcrystalline cellulose, and 1.00% magnesium stearate. The percentages refer to the weight of each component as a percentage of the total weight of the composition containing azilsartan medoxomil potassium and a calcium channel blocker.

[0035] Formulation 3: Amlodipine layer: amlodipine benzenesulfonate 6.93%, microcrystalline cellulose 58.07%, lactose monohydrate 30.00%, sodium carboxymethyl starch 4.00%, and magnesium stearate 1.00%, where the percentages refer to the weight of each component as a percentage of the total mass of the amlodipine layer. Azilsartan medoxomil potassium layer: 21.34% azilsartan medoxomil potassium, 52.31% mannitol, 6.00% croscarmellose sodium, 3.00% hydroxypropyl cellulose, 1.00% fumaric acid, 0.35% sodium hydroxide, 15.00% microcrystalline cellulose, and 1.00% magnesium stearate, where the percentages refer to the weight of each component as a percentage of the total mass of the azilsartan medoxomil potassium layer.

[0036] Formulation 4: Amlodipine layer: amlodipine benzenesulfonate 6.93%, microcrystalline cellulose 66.07%, anhydrous calcium hydrogen phosphate 20.00%, sodium carboxymethyl starch 6.00%, and magnesium stearate 1.00%, where the percentages refer to the weight of each component as a percentage of the total mass of the amlodipine layer. Azilsartan medoxomil potassium layer: 21.34% azilsartan medoxomil potassium, 25.00% lactose monohydrate, 38.31% mannitol, 7.00% hydroxypropyl cellulose, 1.00% fumaric acid, 0.35% sodium hydroxide, 6.00% sodium carboxymethyl starch, and 1.00% magnesium stearate, where the percentages refer to the weight of each component relative to the total mass of the azilsartan medoxomil potassium layer.

[0037] Formulation 5: Azilsartan medoxomil potassium 21.34%, mannitol 50.05%, fumaric acid 1.00%, sodium hydroxide 0.35%, hydroxypropyl cellulose 2.70%, amlodipine benzenesulfonate 3.47%, microcrystalline cellulose 12.50%, croscarmellose sodium 7.50%, magnesium stearate 1.10%. The percentages refer to the weight of each component as a percentage of the total weight of the composition containing azilsartan medoxomil potassium and a calcium channel blocker.

[0038] Formulation 6: Azilsartan medoxomil potassium 21.34%, mannitol 50.19%, fumaric acid 0.87%, sodium hydroxide 0.35%, hydroxypropyl cellulose 2.70%, amlodipine benzenesulfonate 3.47%, microcrystalline cellulose 12.50%, croscarmellose sodium 7.50%, magnesium stearate 1.10%. The percentages refer to the weight of each component as a percentage of the total weight of the composition containing azilsartan medoxomil potassium and a calcium channel blocker.

[0039] Formulation 7 or 8: Azilsartan medoxomil potassium 21.34%, mannitol 51.00%, fumaric acid 0.88%, sodium hydroxide 0.33%, hydroxypropyl cellulose 2.00%, amlodipine benzenesulfonate 3.47%, microcrystalline cellulose 12.50%, croscarmellose sodium 7.50%, magnesium stearate 1.10%. The percentages refer to the weight of each component as a percentage of the total weight of the composition containing azilsartan medoxomil potassium and a calcium channel blocker.

[0040] Formulation 9: Amlodipine layer: amlodipine benzenesulfonate 2.31%, microcrystalline cellulose 33.33%, croscarmellose sodium 3.69%, and magnesium stearate 0.67%, where the percentages refer to the weight of each component as a percentage of the total mass of the amlodipine layer. Azilsartan medoxomil potassium layer: 14.23% azilsartan medoxomil potassium, 33.97% mannitol, 1.33% hydroxypropyl cellulose, 0.58% fumaric acid, 0.22% sodium hydroxide, 5.00% microcrystalline cellulose, 4.00% croscarmellose sodium, and 0.67% magnesium stearate, where the percentages refer to the weight of each component as a percentage of the total mass of the azilsartan medoxomil potassium layer.

[0041] The present invention also provides a method for preparing the pharmaceutical composition, comprising the step of preparing the above ingredients into the pharmaceutical composition by a method selected from direct powder compression, wet granulation or fluidized bed granulation, dry granulation, extrusion-spheronization, and pellet coating.

[0042] The present invention also provides use of the pharmaceutical composition in the treatment and / or prevention of cardiovascular disease. The present invention also provides a method for treating and / or preventing cardiovascular disease, comprising administering a therapeutically effective amount of the pharmaceutical composition to a mammal (e.g., a human) in need thereof.

[0043] The present invention also provides the use of the pharmaceutical composition in the manufacture of a medicament or pharmaceutical formulation.

[0044] According to an embodiment of the invention, the drug or pharmaceutical preparation is used for the treatment and / or prevention of cardiovascular diseases.

[0045] According to an embodiment of the present invention, the pharmaceutical formulation may be an oral pharmaceutical formulation, for example, dosage forms of the pharmaceutical formulation include, but are not limited to, composite tablets, bilayer tablets, capsules, pellets, and microtablets.

[0046] According to an embodiment of the present invention, the cardiovascular disease is at least one selected from, for example, hypertension, heart failure, coronary artery disease, angina pectoris, arrhythmia, myocardial infarction, congenital heart disease, and valvular heart disease.

[0047] All reagents and raw materials used in the present invention are commercially available.

[0048] [Effects of the Invention] The present invention develops a pharmaceutical composition or combined preparation using azilsartan medoxomil potassium in combination with a calcium channel blocker, which is advantageous in terms of improving antihypertensive effects, improving safety and tolerability, and reducing side effects. In the pharmaceutical composition or combined preparation, azilsartan medoxomil potassium can alleviate amlodipine-induced peripheral edema by dilating peripheral venous blood vessels, and amlodipine can alleviate adverse reactions, such as angioedema and dry cough, caused by azilsartan medoxomil potassium. Compared with drugs containing each active ingredient alone, the pharmaceutical composition of the present invention has at least the following advantages: (1) It reduces medication dosage and improves patient compliance; (2) It is advantageous for improving medication compliance for the elderly and those with dysphagia; (3) It prevents frequent fluctuations in blood drug concentrations in the body, maintaining stable blood drug concentrations in the body, stabilizing blood pressure in hypertensive patients for the long term, and reducing side effects of each drug; and (4) It avoids patients from discontinuing medication without permission, preventing disease recurrence and the progression of malignant complications.

[0049] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the dissolution curves of azilsartan medoxomil potassium of the formulations of Examples 5 to 10 in a phosphate buffer medium at pH 7.2.

[0050] [Mode for Carrying Out the Invention] The present invention will be further described below with reference to examples, but the present invention is not limited to these examples. In the following examples, experimental methods for which specific conditions are not specified are selected according to conventional methods and conditions or product instructions.

[0051] Unless otherwise specified, the following film coating premixes are supplied by COLORCON.

[0052] Example 1 1) Prescription composition [Table 1] 2) Manufacturing method Preparation of binder: Hydroxypropyl cellulose, fumaric acid, and sodium hydroxide were dissolved in purified water to prepare a 5% solids solution (the percentage refers to the weight of hydroxypropyl cellulose, fumaric acid, and sodium hydroxide as a percentage of the total weight of the solution), and the solution was stirred uniformly for use. Azilsartan medoxomil potassium, amlodipine benzenesulfonate, and mannitol were placed in a hopper mixer and mixed for 10 minutes. The mixture was subjected to fluidized bed granulation, and parameters such as intake air volume, intake air temperature, atomization temperature, and peristaltic pump speed were set. An aqueous binder solution was added using the peristaltic pump, followed by fluidized bed granulation and drying. The granulated material was sieved through a 1.5 mm sieve. The dried particles were added to the mixing hopper, and sodium carboxymethyl starch and microcrystalline cellulose were added and mixed for 10 minutes. Magnesium stearate was then added and mixed for 5 minutes to obtain azilsartan medoxomil potassium-amlodipine mixed particles. The entire azilsartan medoxomil potassium-amlodipine mixed particles were placed in a rotary tablet press and compressed into tablets using a circular shallow arc die. The compressed azilsartan medoxomil potassium-amlodipine plain tablets were coated with an aqueous film coating premix solution (13% solids content) (the percentage refers to the percentage of the weight of the film coating premix to the total mass of the aqueous film coating premix solution), to obtain azilsartan medoxomil potassium-amlodipine tablets.

[0053] Example 2 [Table 2] 2) Manufacturing method Preparation of binder: Hydroxypropyl cellulose, fumaric acid, and sodium hydroxide were dissolved in purified water to prepare a 5% solids solution (the percentage refers to the weight of hydroxypropyl cellulose, fumaric acid, and sodium hydroxide as a percentage of the total weight of the solution), and the solution was stirred uniformly for use. Azilsartan medoxomil potassium, levamlodipine benzenesulfonate, mannitol, microcrystalline cellulose, and croscarmellose sodium were added to a wet granulation mixer, and the stirring and chopping speeds were adjusted for 10 minutes. Hydroxypropyl cellulose, fumaric acid, and an aqueous solution of sodium hydroxide were then added and wet granulated. The granulated material was then wet-sieved through a 1.5 mm sieve and dried in an oven until the moisture content was less than 3.0%. The dried particles were then dry-sieved through a 1.2 mm sieve to obtain azilsartan medoxomil potassium-levamlodipine dried particles. The azilsartan medoxomil potassium-levamlodipine dried particles were added to a mixing kettle, and magnesium stearate was added. After mixing for 5 minutes, the mixture was compressed into tablets using a rotary tablet press. The compressed azilsartan medoxomil potassium-levamlodipine plain tablets were coated with an aqueous film-coating premix solution (solid content 13%) (the percentage refers to the weight of the film-coating premix as a percentage of the total mass of the aqueous film-coating premix solution) to obtain azilsartan medoxomil potassium-levamlodipine tablets.

[0054] Example 3 1) Prescription composition [Table 3] 2) Manufacturing method Preparation of all mixed materials for the amlodipine layer: Amlodipine benzenesulfonate, microcrystalline cellulose, lactose monohydrate, and sodium carboxymethyl starch were mixed in a three-dimensional mixer for 20 minutes. Using a dry granulator, dry granulation was performed by adjusting the roll press pressure, roll press speed, and feed rate, and the mixture was then dry sized using a 20-mesh sieve. Next, magnesium stearate was added and mixed for 5 minutes to obtain amlodipine whole mixed particles. Preparation of the total mixed material for the azilsartan medoxomil potassium layer: Binder preparation: Hydroxypropyl cellulose, fumaric acid, and sodium hydroxide were mixed with purified water to prepare a 5% solids solution, which was then stirred uniformly and prepared for use. Azilsartan medoxomil potassium, mannitol, and croscarmellose sodium were added to a hopper mixer and mixed for 10 minutes. The mixture was subjected to fluidized bed granulation, and parameters such as intake air volume, intake air temperature, atomization temperature, and peristaltic pump speed were set. Hydroxypropyl cellulose, fumaric acid, and aqueous sodium hydroxide solution were added using a peristaltic pump, and fluidized bed granulation was performed while drying was also performed. The granulated material was sieved through a 1.5 mm sieve. The dried particles were added to a mixing hopper, and microcrystalline cellulose was added and mixed for 10 minutes. Next, magnesium stearate was added and mixed for 5 minutes to obtain azilsartan medoxomil potassium fully mixed particles. The amlodipine total mixed particles and the azilsartan medoxomil potassium total mixed particles were compressed in a bilayer tableting machine to obtain azilsartan medoxomil potassium-amlodipine plain tablets, which were then film-coated to obtain azilsartan medoxomil potassium-amlodipine tablets.

[0055] Example 4 1) Prescription composition [Table 4] 2) Manufacturing method Preparation of all mixed materials for the amlodipine layer: Amlodipine benzenesulfonate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sodium carboxymethyl starch were mixed in a three-dimensional mixer for 20 minutes, followed by adding magnesium stearate and mixing for 5 minutes to obtain amlodipine whole mixed particles. Preparation of the total mixed material for the azilsartan medoxomil potassium layer: Binder preparation: Hydroxypropyl cellulose, fumaric acid, and sodium hydroxide were mixed with purified water to prepare a 5% solids solution, which was then stirred uniformly and prepared for use. Azilsartan medoxomil potassium, mannitol, and lactose monohydrate were added to a wet granulation mixer, and the stirring and chopping speeds were adjusted for 10 minutes. Hydroxypropyl cellulose, fumaric acid, and an aqueous solution of sodium hydroxide were then added and wet granulated. The granulated material was then wet-sieved through a 1.5 mm sieve and dried in an oven until the moisture content was less than 3.0%. The dried particles were then dry-sieved through a 1.0 mm sieve. The dried azilsartan medoxomil potassium particles were then added to a hopper mixer, and sodium carboxymethyl starch and magnesium stearate were added. The mixture was mixed for 5 minutes to obtain a fully mixed azilsartan medoxomil potassium particle mixture. The amlodipine total blend material and the azilsartan medoxomil potassium total blend particles were compressed in a bilayer tablet press to obtain azilsartan medoxomil potassium-amlodipine plain tablets, which were then film-coated to obtain azilsartan medoxomil potassium-amlodipine tablets.

[0056] Example 5 1) Prescription composition [Table 5] 2) Manufacturing method Binder preparation: Hydroxypropyl cellulose, fumaric acid, and sodium hydroxide were mixed in purified water to a 5% solids solution, which was then mixed uniformly for use. Premixing: Mannitol and azilsartan medoxomil potassium were placed in a hopper mixer and mixed for 20 minutes. Granulation: The mixed mannitol and azilsartan medoxomil potassium were added to the fluidized bed, and the intake air volume and temperature were adjusted for preheating. Next, an aqueous solution of hydroxypropyl cellulose, fumaric acid, and sodium hydroxide was added and fluidized granulation was performed. After granulation was completed, the material was removed when its moisture content was less than 3.0%. The granulated material was sieved through a 1.5 mm sieve. External addition and total mixing: Next, the dried azilsartan medoxomil potassium particles were added to a hopper mixer, and amlodipine benzenesulfonate, microcrystalline cellulose, and croscarmellose sodium were added and mixed for 10 minutes. After that, magnesium stearate was added and mixing continued for 5 minutes to obtain azilsartan medoxomil potassium-amlodipine total mixed particles. Tableting: Finally, the entire azilsartan medoxomil potassium-amlodipine mixed particles were compressed in a tablet press to obtain azilsartan medoxomil potassium-amlodipine tablets.

[0057] Example 6 1) Prescription composition [Table 6] 2) Manufacturing method Binder preparation: Hydroxypropyl cellulose, fumaric acid, and sodium hydroxide were mixed in purified water to a 4% solids solution, which was then mixed uniformly for use. Premixing: Mannitol and azilsartan medoxomil potassium were placed in a hopper mixer and mixed for 20 minutes. Granulation: The mixed mannitol and azilsartan medoxomil potassium were added to the fluidized bed, and the intake air volume and temperature were adjusted for preheating. Next, an aqueous solution of hydroxypropyl cellulose, fumaric acid, and sodium hydroxide was added and fluidized granulation was performed. After granulation was completed, the material was removed when its moisture content was less than 3.0%. The granulated material was sieved through a 1.5 mm sieve. External addition and total mixing: Next, the dried azilsartan medoxomil potassium particles were added to a hopper mixer, and amlodipine benzenesulfonate, microcrystalline cellulose, and croscarmellose sodium were added and mixed for 10 minutes. After that, magnesium stearate was added and mixing continued for 5 minutes to obtain azilsartan medoxomil potassium-amlodipine total mixed particles. Tableting: Finally, the entire azilsartan medoxomil potassium-amlodipine mixed particles were compressed in a tablet press to obtain azilsartan medoxomil potassium-amlodipine tablets.

[0058] Example 7 1) Prescription composition [Table 7] 2) Manufacturing method Binder preparation: Hydroxypropyl cellulose, fumaric acid, and sodium hydroxide were mixed in purified water to a 4% solids solution, which was then mixed uniformly for use. Premixing: Mannitol and azilsartan medoxomil potassium were placed in a hopper mixer and mixed for 20 minutes. Granulation: The mixed mannitol and azilsartan medoxomil potassium were added to the fluidized bed, and the intake air volume and temperature were adjusted for preheating. Next, an aqueous solution of hydroxypropyl cellulose, fumaric acid, and sodium hydroxide was added and fluidized granulation was performed. After granulation was completed, the material was removed when its moisture content was less than 3.0%. The granulated material was sieved through a 1.5 mm sieve. External addition and total mixing: Next, the dried azilsartan medoxomil potassium particles were added to a hopper mixer, and amlodipine benzenesulfonate, microcrystalline cellulose, and croscarmellose sodium were added and mixed for 10 minutes. The mixed material was sieved again through a 1.5 mm sieve. Finally, magnesium stearate was added and mixed for 10 minutes to obtain azilsartan medoxomil potassium-amlodipine total mixed particles. Tableting: Finally, the entire azilsartan medoxomil potassium-amlodipine mixed particles were compressed in a tablet press to obtain azilsartan medoxomil potassium-amlodipine tablets.

[0059] Example 8 1) Prescription composition [Table 8] 2) Manufacturing method Preparation of pH adjuster: Fumaric acid and sodium hydroxide were dissolved in purified water to prepare a 4% solids solution, which was then stirred uniformly for use. Premixing: Mannitol, azilsartan medoxomil potassium, and hydroxypropyl cellulose were added to a hopper mixer and mixed for 20 minutes. Granulation: The mixed mannitol and azilsartan medoxomil potassium were added to a fluidized bed, and the inlet air volume and temperature were adjusted for preheating. Next, an aqueous solution of hydroxypropyl cellulose, fumaric acid, and sodium hydroxide was added and fluidized bed granulation was performed. After granulation was completed, the material was removed when its moisture content was less than 3.0%. The granulated material was sieved through a 1.5 mm sieve. External addition and total mixing: Next, the dried azilsartan medoxomil potassium particles were added to the hopper mixer, and amlodipine benzenesulfonate, microcrystalline cellulose, and croscarmellose sodium were added and mixed for 10 minutes. The mixed material was sieved again through a 1.5 mm sieve. Finally, magnesium stearate was added and mixed for 10 minutes to obtain azilsartan medoxomil potassium-amlodipine total mixed particles. Tableting: Finally, the entire azilsartan medoxomil potassium-amlodipine mixed particles were compressed in a tablet press to obtain azilsartan medoxomil potassium-amlodipine tablets.

[0060] Example 9 1) Prescription composition [Table 9] 2) Manufacturing method Preparation of all mixed materials for the amlodipine layer: Microcrystalline cellulose, croscarmellose sodium, and amlodipine benzenesulfonate were placed in a hopper mixer and mixed for 20 minutes, followed by adding magnesium stearate and mixing for 5 minutes to obtain amlodipine whole mixed particles. Preparation of the total mixed material for the azilsartan medoxomil potassium layer: Binder preparation: Fumaric acid and sodium hydroxide were mixed with purified water to prepare a 4% solids solution, which was then stirred uniformly and prepared for use. Mannitol, azilsartan medoxomil potassium, and hydroxypropyl cellulose were added to the fluidized bed, and the intake air volume and temperature were adjusted for preheating. Next, an aqueous solution of fumaric acid and sodium hydroxide was added, and fluidized bed granulation was performed. After granulation was completed, the material was removed when its moisture content was less than 3.0%. The granulated material was sieved through a 1.5 mm sieve. Next, the dried azilsartan medoxomil potassium particles were added to a hopper mixer, and microcrystalline cellulose and croscarmellose sodium were added. After mixing for 10 minutes, magnesium stearate was added and mixing continued for 10 minutes to obtain fully mixed azilsartan medoxomil potassium particles. The amlodipine total blend material and the azilsartan medoxomil potassium total blend particles were compressed into tablets using a bilayer tableting machine to obtain azilsartan medoxomil potassium-amlodipine bilayer tablets.

[0061] Example 10 1) Prescription composition [Table 10] 2) Manufacturing method Preparation of pH adjuster: Fumaric acid and sodium hydroxide were dissolved in purified water to prepare a 4% solids solution, which was then stirred uniformly for use. Premixing: Mannitol, azilsartan medoxomil potassium, and hydroxypropyl cellulose were added to a hopper mixer and mixed for 20 minutes. Granulation: The mixed mannitol and azilsartan medoxomil potassium were added to a fluidized bed, and the inlet air volume and temperature were adjusted for preheating. Next, an aqueous solution of hydroxypropyl cellulose, fumaric acid, and sodium hydroxide was added and fluidized bed granulation was performed. After granulation was completed, the material was removed when its moisture content was less than 3.0%. The granulated material was sieved through a 1.5 mm sieve. External addition and total mixing: Next, the dried azilsartan medoxomil potassium particles were added to the hopper mixer, and amlodipine benzenesulfonate, microcrystalline cellulose, and croscarmellose sodium were added and mixed for 10 minutes. The mixed material was sieved again through a 1.5 mm sieve. Finally, magnesium stearate was added and mixed for 10 minutes to obtain azilsartan medoxomil potassium-amlodipine total mixed particles. Capsule filling: Finally, all the azilsartan medoxomil potassium-amlodipine mixed particles were filled into capsule No. 1 to obtain azilsartan medoxomil potassium-amlodipine capsules.

[0062] Test Example 1: Test of dissolution characteristics The following table and Figure 1 summarize the results of the dissolution test of azilsartan medoxomil potassium for the formulations of Examples 5 to 10 in 900 mL of a pH 7.2 phosphate buffer medium using the paddle method at 75 rpm. [Table 11]

[0063] As can be seen from the above dissolution results, the dissolution degree and dissolution effect of azilsartan medoxomil potassium in Examples 7, 8 and 9 are superior.

[0064] Test Example 2: Stability test Based on the above dissolution results, the azilsartan medoxomil potassium-amlodipine tablets obtained in Example 8 were packaged in oral solid medicine high-density polyethylene bottles and then subjected to stability tests to detect related substances using the proposed HPLC liquid phase method. The test conditions and results are shown below. [Table 12]

[0065] From the above stability results, it was found that Example 8 had relatively good stability and a slow rate of increase in impurities. Therefore, the azilsartan medoxomil potassium-amlodipine tablet obtained in the present invention had relatively good dissolution properties and good stability.

[0066] The above is an illustrative description of the embodiments of the present invention. Of course, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the scope of protection of the claims of this application. [Brief explanation of the drawings]

[0067] [Figure 1] 1 shows dissolution curves of azilsartan medoxomil potassium of the formulations of Examples 5 to 10 in a phosphate buffer medium at pH 7.2.

Claims

1. azilsartan medoxomil potassium, and calcium channel blockers, The azilsartan medoxomil potassium includes one or more of azilsartan medoxomil potassium, a pharmaceutically acceptable salt thereof, and a solvate thereof; The pharmaceutical composition, wherein the calcium channel blocker comprises one or more of a calcium channel blocker, a pharmaceutically acceptable salt thereof, and a solvate thereof.

2. the calcium channel blocker is one or more of amlodipine, levamlodipine, and pharmaceutically acceptable salts thereof; and / or the amount of azilsartan medoxomil potassium contained in the pharmaceutical composition is 20 mg to 80 mg; and / or 2. The pharmaceutical composition according to claim 1, wherein the amount of the calcium channel blocker in the pharmaceutical composition is 2.5 mg to 20 mg.

3. The content of azilsartan medoxomil potassium in the pharmaceutical composition is 20 mg, 40 mg, or 80 mg, and / or The content of amlodipine in the pharmaceutical composition is 2.5 mg to 20 mg, and / or 3. The pharmaceutical composition according to claim 2, wherein the content of levamlodipine in the pharmaceutical composition is 2.5 mg to 10 mg.

4. 10. The pharmaceutical composition of claim 1, further comprising one or more of a pH adjuster, a diluent, a binder, a disintegrant, a lubricant, a flow aid, a tableting aid, a colorant, and a coating premix.

5. the pH adjuster is one or more selected from fumaric acid, sodium fumarate, citric acid, sodium citrate, tartaric acid, sodium hydroxide, potassium dihydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate, and sodium carbonate; and / or the diluent is one or more selected from mannitol, anhydrous calcium hydrogen phosphate, sucrose, glucose, maltose, lactose (e.g., lactose monohydrate), microcrystalline cellulose, and sorbitol; and / or the binder is one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, copovidone, povidone, and pregelatinized starch; and / or the disintegrant is one or more selected from sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, and corn starch; and / or the lubricant is one or more selected from metal stearates (e.g., magnesium stearate), stearic acid, talc, stearates, stearoyl fumarate, and finely powdered silica gel; and / or the flow aid is one or more selected from talc, finely powdered silica gel, colloidal silica, and pregelatinized starch; and / or the tableting aid is selected from microcrystalline cellulose and / or lactose monohydrate; and / or the colorant is selected from red iron oxide and / or yellow iron oxide; and / or 5. The pharmaceutical composition of claim 4, wherein the coating premix is ​​a film coating premix provided by Colorcon.

6. 2. The pharmaceutical composition according to claim 1, comprising azilsartan medoxomil potassium and amlodipine, or azilsartan medoxomil potassium and levamlodipine.

7. the pharmaceutical composition is an azilsartan medoxomil potassium-amlodipine tablet, and / or The pharmaceutical composition according to claim 6, which is an azilsartan medoxomil potassium-levamlodipine tablet.

8. 8. A method for producing the pharmaceutical composition according to any one of claims 1 to 7, comprising the step of preparing the components of the pharmaceutical composition into the pharmaceutical composition by one of direct powder compression, wet granulation, fluidized bed granulation, dry granulation, extrusion-spheronization, and pellet coating.

9. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament, wherein the medicament is used for the treatment and / or prevention of cardiovascular diseases, Preferably, the cardiovascular disease is at least one selected from, for example, hypertension, heart failure, coronary artery disease, angina pectoris, arrhythmia, myocardial infarction, congenital heart disease, and valvular heart disease.

10. the drug is a pharmaceutical formulation, preferably an oral pharmaceutical formulation; The use according to claim 9, characterized in that the dosage form of the pharmaceutical preparation is selected from the group consisting of a compound tablet, a bilayer tablet, a capsule, a pellet, and a microtablet.

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