Composition of nebivolol and amlodipine, its preparation method and application

Abstract

The present invention provides a composition comprising nebivolol and amlodipine, wherein the nebivolol comprises one or more of nebivolol and its pharmaceutically acceptable salts and solvates, and the amlodipine comprises one or more of amlodipine and its pharmaceutically acceptable salts and solvates. The nebivolol and amlodipine combination formulation of the present invention is advantageous in terms of improved antihypertensive effect, improved safety and tolerability, and reduced side effects. Compared with either of these single agents, the combination of nebivolol and amlodipine has the advantages of reducing the dosage and increasing patient compliance, which is advantageous for elderly people and those with dysphagia, maintaining a moderate blood drug concentration in the body, stabilizing blood pressure in hypertensive patients for a long period of time, reducing side effects of each drug, avoiding the need for patients to voluntarily discontinue medication, and preventing disease recurrence and the progression of malignant complications.

Description

Detailed Description of the Invention

[0001] This application claims priority from a prior application filed by the applicant with the State Intellectual Property Office of the People's Republic of China on September 14, 2022, bearing application number 202211112943.4 and entitled "Composition of nebivolol and amlodipine, its preparation method and application," the entire contents of which are incorporated herein by reference.

[0002] [Technical Field] The present invention relates to a composition of nebivolol and amlodipine, its preparation method and application.

[0003] [Background technology] Hypertension is one of the most common cardiovascular diseases, with a prevalence rate of 25% to 30% in adults. If hypertension is not effectively controlled over a long period of time, it increases the risk of developing coronary artery atherosclerosis, left ventricular hypertrophy, carotid artery atherosclerosis, and renal disease. Currently, the treatment of hypertension mainly involves drug intervention, which has significant clinical efficacy, effectively inhibiting the disease and delaying clinical symptoms in patients. Therefore, the development of pharmaceutical preparations that treat hypertension and cardiovascular disease and reduce toxic side effects is of positive significance for clinical administration.

[0004] The chemical name of nebivolol is 2,2'-[iminodi(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]bis[2-hydroxy-2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-)]ethylamine, with the molecular formula C 22 H 25 F2NO4, molecular weight 405.43, its structural formula is as follows: [ka]

[0005] Nebivolol is a potent, highly selective (cardioselective) adrenergic beta-1 receptor blocker with vasodilatory activity, lacking alpha-adrenergic antagonism and possessing vasodilatory activity, providing some cardiac protection and reducing cardiac preload. It is primarily used for the treatment of primary hypertension and chronic heart failure, with indications including cardiovascular diseases such as hypertension, angina pectoris, myocardial infarction, and congestive heart failure. Nebivolol hydrochloride boasts significant therapeutic effects, convenient administration, and few adverse reactions, making it a promising new antihypertensive drug. It was first approved for sale in Germany in 1997 for the treatment of primary hypertension. However, common adverse reactions associated with beta-receptor blockers include headache, nausea, bradycardia, postural hypotension, and bronchospasm.

[0006] The chemical name of amlodipine is ethyl methyl 6-methyl-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate, molecular formula C 20 H 25 CIN2O5, molecular weight 408.88, its structural formula is as follows: [ka]

[0007] Amlodipine is a dihydropyridine calcium ion entry inhibitor (slow channel blocker or calcium antagonist) that can inhibit transmembrane influx of calcium ions into the heart and vascular smooth muscle. The mechanism of amlodipine's antihypertensive action is its direct relaxation effect on vascular smooth muscle. Although the exact mechanism by which amlodipine relieves angina has not yet been fully determined, amlodipine reduces the overall ischemic load through the following two actions: 1. Amlodipine dilates small peripheral arteries, thereby reducing the total peripheral resistance (afterload) the heart faces. This offloading of the heart reduces myocardial energy expenditure and oxygen demand, as the heart rate remains stable. 2. Amlodipine's mechanism of action may also involve dilation of the main and small coronary arteries in normal and ischemic areas. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina). Amlodipine is a long-acting calcium channel blocker used to treat hypertension, chronic stable angina, and vasospastic angina.

[0008] However, since the conventional technology is a single-drug formulation, there is an urgent need to develop a new combination formulation that has good synergistic effects, good stability, few side effects, good blood pressure lowering effect, and good patient compliance.

[0009] Summary of the Invention The technical problem solved by the present invention is to provide a composition of nebivolol and amlodipine that is different from the prior art, its preparation method and application.

[0010] The present invention provides a nebivolol and amlodipine composition comprising the active ingredients nebivolol and amlodipine, wherein the active ingredient nebivolol comprises one or more of nebivolol, pharmaceutically acceptable salts, and solvates thereof, and the active ingredient amlodipine comprises one or more of amlodipine, pharmaceutically acceptable salts, and solvates thereof.

[0011] According to an embodiment of the present invention, the pharmaceutically acceptable salt of nebivolol may be nebivolol hydrochloride.

[0012] According to an embodiment of the present invention, the pharmaceutically acceptable salt of amlodipine may be amlodipine benzenesulfonate and / or amlodipine maleate.

[0013] According to an embodiment of the present invention, the nebivolol and amlodipine composition may be a composition of nebivolol hydrochloride and amlodipine benzenesulfonate.

[0014] According to an embodiment of the present invention, the nebivolol and amlodipine composition further comprises one or more of a surfactant, a filler, an adhesive, a disintegrant, a lubricant, a glidant, a colorant, and a coating.

[0015] According to an embodiment of the present invention, the surfactant may be sodium dodecyl sulfate and / or polysorbate, for example, the polysorbate may be selected from polysorbate 80 and / or polysorbate 20.

[0016] According to an embodiment of the present invention, the filler refers to a solid substance that can be added to a material to improve the performance of the material, or to solubilize, weight, or reduce the cost of the material, and is selected from one or more of microcrystalline cellulose (e.g., microcrystalline cellulose 101 or microcrystalline cellulose 102), calcium hydrogen phosphate, mannitol, sucrose, glucose, maltose, lactose (e.g., lactose monohydrate), sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose.

[0017] According to an embodiment of the present invention, the adhesive may be an additive that can increase the viscosity of a dispersion medium commonly used in the art in order to reduce the sedimentation rate of the microparticles or increase the hydrophilicity of the microparticles, and is selected from one or more of polyoxyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, copovidone, povidone (e.g., povidone K30), pregelatinized starch, gum arabic, polyvinylpyrrolidone, and sodium alginate.

[0018] According to an embodiment of the present invention, the disintegrant refers to a substance that can disintegrate a formulation (e.g., a tablet or granules) produced by the composition during dissolution, and is selected from one or more of crospovidone, cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, and corn starch.

[0019] According to an embodiment of the present invention, the lubricant may be a substance having a lubricating effect commonly used in the art, and may be selected from one or more of metal stearates, stearic acid, talc powder, stearic acid esters, stearoyl fumarate, and finely powdered silica gel. The metal stearates are preferably selected from one or more of magnesium stearate, calcium stearate, and sodium stearyl fumarate. The stearic acid ester is preferably glyceryl stearate.

[0020] According to an embodiment of the present invention, the glidant may be an adjuvant commonly used in the art that can improve the flowability of powders or particles by reducing the frictional force between particles, and is selected from one or more of talc powder, finely powdered silica gel, and colloidal silica.

[0021] According to an embodiment of the present invention, the colorant may be any conventional material in the art that can achieve the purpose of coloring, and is selected from red iron oxide and / or yellow iron oxide.

[0022] According to an embodiment of the present invention, in the above-mentioned composition of nebivolol and amlodipine, the components other than the coating film together constitute the core.

[0023] According to an embodiment of the present invention, the mass percentage of the nebivolol, its pharmaceutically acceptable salt or solvate in the core is 1 to 10%, for example 1.5 to 7%, illustratively 1.60%, 1.82%, 2.00%, 2.18%, 2.27%, 2.50%, 2.73%, 3.00%, 3.50%, 4.00%, 5.00%, 5.45%, or 6.00%.

[0024] According to an embodiment of the present invention, the mass percentage of the amlodipine, pharmaceutically acceptable salt or solvate thereof in the core is 1 to 20%, for example, 1.5 to 15%, and examples thereof include 2.00%, 2.31%, 2.77%, 2.89%, 3.00%, 4.00%, 5.00%, 5.45%, 6.00%, 6.93%, 8.00%, 10.00%, 12.00%, 13.86%, and 14.00%.

[0025] According to an embodiment of the present invention, the mass percentage of the surfactant in the core is 0.05 to 10%, for example 0.1 to 5%, e.g., 0.19%, 0.25%, 0.38%, 0.50%, 1.20%, 2.00%, or 3.00%.

[0026] According to an embodiment of the present invention, the mass percentage of the filler in the core is 40 to 95%, for example 60 to 90%, and illustratively 68.25%, 79.70%, 88.07%, 78.77%, 79.14%, 81.05%, 66.06%, 66.00%, and 65.81%.

[0027] According to an embodiment of the present invention, the mass percentage of the adhesive in the core is 1 to 30%, for example, 5 to 25%, and illustratively 5.00%, 6.67%, 8.00%, 10.00%, 18.00%, or 20.80%.

[0028] According to an embodiment of the present invention, the mass percentage of the disintegrant in the core is 1 to 10%, for example, 2 to 8%, illustratively 4.00%, 5.00%, 6.00%, 6.60%, or 7.00%.

[0029] According to an embodiment of the present invention, the mass percentage of the lubricant in the core is 0.1 to 5%, for example, 0.5 to 3%, illustratively 1.00%, 1.50%, or 2.00%.

[0030] According to an embodiment of the present invention, the mass percentage of the glidant in the core is 0.1-5%, for example 0.2-3%, illustratively 0.25%, 0.30%, 0.40%, 0.50%, 1.00%, 2.00%.

[0031] According to an embodiment of the present invention, the coating film of the present invention may be selected from a film coating premix (gastric type).

[0032] According to an embodiment of the present invention, the core may have any one of the following formulations: Formulation 1 2.77% amlodipine benzenesulfonate, 2.18% nebivolol hydrochloride, 44.25% microcrystalline cellulose 101, 16.00% lactose monohydrate, 12.00% pregelatinized starch, 6.00% sodium carboxymethyl starch, 6.00% hydroxypropyl cellulose, 1.20% polysorbate 80, 8.00% microcrystalline cellulose 102, 0.60% colloidal silica, 1.00% magnesium stearate, the above percentages refer to the percentage of the mass of each component relative to the total mass of the core.

[0033] Formulation 2 2.31% amlodipine benzenesulfonate, 1.82% nebivolol hydrochloride, 39.70% mannitol, 20.00% lactose monohydrate, 6.67% hypromellose, 6.00% cross-linked sodium carboxymethylcellulose, 2.00% sodium dodecyl sulfate, 10.00% microcrystalline cellulose 102, 10.00% anhydrous calcium hydrogen phosphate, 0.50% colloidal silica, 1.00% magnesium stearate, the above percentages refer to the percentage of the mass of each component relative to the total mass of the core.

[0034] Formulation 3 Amlodipine layer: 6.93% amlodipine benzenesulfonate, 60.00% microcrystalline cellulose 102, 28.07% lactose monohydrate, 4.00% sodium carboxymethyl starch, and 1.00% magnesium stearate, the percentages above indicating the weight percentage of each component relative to the total mass of the amlodipine layer. Nebivolol layer: 2.73% nebivolol hydrochloride, 63.77% microcrystalline cellulose 101, 15.00% lactose monohydrate, 6.00% cross-linked sodium carboxymethylcellulose, 8.00% pregelatinized starch, 3.00% polysorbate 80, 0.50% colloidal silica, and 1.00% magnesium stearate, the percentages above referring to the weight percentage of each component relative to the total mass of the nebivolol layer.

[0035] Formulation 4 Amlodipine layer: 13.86% amlodipine benzenesulfonate, 54.14% microcrystalline cellulose 102, 25.00% anhydrous calcium hydrogen phosphate, 6.00% sodium carboxymethyl starch, and 1.00% magnesium stearate, the percentages above referring to the weight percentage of each component relative to the total mass of the amlodipine layer. Nebivolol layer: 5.45% nebivolol hydrochloride, 56.05% microcrystalline cellulose 101, 25.00% mannitol, 5.00% cross-linked sodium carboxymethylcellulose, 5.00% hydroxypropyl cellulose, 2.00% polysorbate 80, 0.50% colloidal silica, and 1.00% magnesium stearate, the percentages above indicating the weight percentage of each component relative to the total mass of the nebivolol layer.

[0036] Formulation 5 2.27% nebivolol hydrochloride, 2.89% amlodipine benzenesulfonate, 59.41% lactose monohydrate, 19.16% pregelatinized starch, 2.87% cross-linked sodium carboxymethylcellulose (internal addition), 1.63% hypromellose, 0.38% polysorbate 80, 0.25% sodium dodecyl sulfate, 3.74% cross-linked sodium carboxymethylcellulose (external addition), 0.25% colloidal silica, 6.65% microcrystalline cellulose 101, 0.50% magnesium stearate. The above percentages refer to the percentage of the mass of each component relative to the total mass of the core.

[0037] Formulation 6 2.27% nebivolol hydrochloride, 2.89% amlodipine benzenesulfonate, 59.35% lactose monohydrate, 19.16% pregelatinized starch, 2.87% cross-linked sodium carboxymethylcellulose (internal addition), 1.63% hypromellose, 0.19% polysorbate 80, 3.74% cross-linked sodium carboxymethylcellulose (external addition), 0.25% colloidal silica, 6.65% microcrystalline cellulose 101, 0.50% sodium dodecyl sulfate, 0.50% magnesium stearate. The above percentages refer to the mass of each component relative to the total mass of the core.

[0038] Formulation 7 2.27% nebivolol hydrochloride, 2.89% amlodipine benzenesulfonate, 59.16% lactose monohydrate, 19.16% pregelatinized starch, 2.87% cross-linked sodium carboxymethylcellulose (internal addition), 1.63% hypromellose, 0.38% polysorbate 80, 0.50% sodium dodecyl sulfate, 3.74% cross-linked sodium carboxymethylcellulose (external addition), 0.25% colloidal silica, 6.65% microcrystalline cellulose 101, 0.50% magnesium stearate. The above percentages refer to the mass of each component as a percentage of the total mass of the core.

[0039] Formulation 8 1.56% nebivolol hydrochloride, 1.98% amlodipine benzenesulfonate, 22.85% microcrystalline cellulose (internal addition), 11.43% anhydrous calcium hydrogen phosphate, 38.25% lactose monohydrate, 11.43% pregelatinized starch, 1.29% hypromellose, 0.26% polysorbate 80, 0.17% sodium dodecyl sulfate, 4.28% microcrystalline cellulose (external addition), 5.00% cross-linked sodium carboxymethylcellulose (external addition), 0.50% colloidal silica, 1.00% magnesium stearate. The above percentages refer to the percentage of the mass of each component relative to the total mass of the core.

[0040] According to an embodiment of the present invention, the dosage of nebivolol contained in the nebivolol and amlodipine composition may be 2.5 mg to 20.0 mg, for example, 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 15.0 mg, or 20.0 mg.

[0041] According to an embodiment of the present invention, the dosage of amlodipine contained in the nebivolol and amlodipine composition may be 2.5 mg to 20.0 mg, for example, 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 15.0 mg, or 20.0 mg.

[0042] According to an embodiment of the present invention, the above-mentioned composition of nebivolol and amlodipine has a dissolution amount of nebivolol and amlodipine of 70% or more within 30 minutes, for example, 75% or more, and preferably 80% or more.

[0043] The present invention further provides the use of the above composition of nebivolol and amlodipine in the manufacture of a medicament for treating and / or preventing cardiovascular diseases.

[0044] According to an embodiment of the present invention, the cardiovascular diseases include hypertension, heart failure, coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, congenital heart disease, and valvular heart disease.

[0045] The present invention further provides a method for treating and / or preventing cardiovascular disease by administering a therapeutically effective amount of the above-mentioned nebivolol and amlodipine composition, the above-mentioned drug, or the below-mentioned pharmaceutical formulation to a mammal (e.g., a human) in need thereof.

[0046] The present invention further provides the application of the above composition of nebivolol and amlodipine in the manufacture of pharmaceutical preparations.

[0047] According to an embodiment of the present invention, the pharmaceutical formulation may be an oral pharmaceutical formulation, for example, dosage forms of the oral pharmaceutical formulation include, but are not limited to, compound tablets, double tablets, capsules, micropellets, and microtablets.

[0048] The present invention further provides a pharmaceutical formulation prepared from the above-described nebivolol and amlodipine composition, preferably having the limitations as described above.

[0049] The present invention further provides methods for preparing the above nebivolol and amlodipine compositions, including, but not limited to, direct powder compression, wet granulation, dry granulation, fluidized bed granulation, extrusion-spheronization, or micropellet coating.

[0050] According to an embodiment of the present invention, the wet granulation or fluidized bed granulation method may comprise the following steps: Step 1: Nebivolol hydrochloride, a filler, an adhesive, and a disintegrant are mixed, and then further mixed with an aqueous solution of the adhesive, followed by wet granulation, wet sieving, drying, and dry sieving to obtain nebivolol dried granules.

[0051] Step 2: The nebivolol dried granules obtained in Step 1 are mixed with amlodipine and a filler, and then further mixed with a lubricant and a glidant, followed by tableting to obtain nebivolol amlodipine uncoated tablets.

[0052] Step 3: The nebivolol amlodipine uncoated tablets obtained in Step 2 are coated with an aqueous solution of the film coating premix to obtain nebivolol amlodipine tablets.

[0053] According to an embodiment of the present invention, the dry granulation method may comprise the following steps:

[0054] Step (1) Nebivolol hydrochloride, a filler, an adhesive, and a disintegrant are mixed, and then granulated with an aqueous solution of the adhesive. The mixture is then wet-granulated, dried, and dry-granulated to obtain nebivolol dried granules. The obtained nebivolol dried granules are then further mixed with a lubricant and a glidant to obtain total mixed nebivolol granules.

[0055] Step (2) After amlodipine, a filler, and a disintegrant are uniformly mixed, the mixture is granulated using a dry granulator and uniformly mixed with a lubricant to obtain amlodipine total mixed granules.

[0056] Step (3) The total mixed granules of nebivolol obtained in step (1) and the total mixed granules of amlodipine obtained in step (2) are compressed into tablets to obtain nebivolol-amlodipine plain tablets, which are then further film-coated to obtain nebivolol-amlodipine tablets.

[0057] The order of steps (1) and (2) above may be changed.

[0058] All reagents and raw materials used in the present invention are commercially available.

[0059] Beneficial effects The present invention provides a combination formulation of nebivolol and amlodipine for treating and / or preventing cardiovascular disease.

[0060] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0061] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be prepared by known methods.

[0062] Example 1 1)Blend composition [Table 1]

[0063] 2) Manufacturing method Preparation of adhesive Hypromellose is mixed with purified water to prepare an adhesive (solid content 5%), and polysorbate 80 is added, followed by stirring uniformly for use.

[0064] Step 1: Place nebivolol hydrochloride, microcrystalline cellulose 101, lactose monohydrate, pregelatinized starch, and sodium carboxymethyl starch into a wet granulation kettle, start the stirring and chopping speeds, mix for 5 minutes, add an aqueous solution of adhesive, and wet granulate. The granulated material is wet-sized using a 16-mesh screen, and the sized material is placed in an oven and dried until the moisture content is less than 3.0%. The dried granules are then dry-sized using a 20-mesh screen to obtain nebivolol hydrochloride dried granules.

[0065] Step 2: Add the dried nebivolol hydrochloride granules obtained in Step 1, amlodipine benzenesulfonate, and microcrystalline cellulose 102 to a mixing kettle and mix for 20 minutes. Add colloidal silica and magnesium stearate and mix for 5 minutes. Then, compress the mixture into tablets using a rotary press to obtain nebivolol amlodipine uncoated tablets.

[0066] Step 3: The nebivolol amlodipine plain tablets obtained in Step 2 are coated with an aqueous solution of film coating premix (solid content 12%, percentage refers to the percentage of the mass of the coating premix to the total mass of the aqueous solution of the coating premix) to obtain nebivolol amlodipine tablets.

[0067] Example 2 1)Blend composition [Table 2]

[0068] 2) Manufacturing method Preparation of adhesive: Hypromellose is prepared into an adhesive (solid content 5%) with purified water, and sodium dodecyl sulfate is added, stirred and dissolved, and then it is ready for use.

[0069] Step 1: Add nebivolol hydrochloride, mannitol, lactose monohydrate, and cross-linked sodium carboxymethylcellulose to a mixing kettle and mix for 20 minutes. Then, place the mixed material in a fluidized bed. Set the parameters of air volume, air temperature, atomization temperature, and feed rate, and use a peristaltic pump to add an aqueous solution of adhesive to perform fluid granulation. After granulation, sieve the material through a 30-mesh sieve to obtain dry nebivolol granules.

[0070] Step 2: Add the dried nebivolol granules obtained in Step 1, amlodipine benzenesulfonate, microcrystalline cellulose 102, anhydrous calcium hydrogen phosphate, and colloidal silica to a mixing kettle and mix for 15 minutes. Then add magnesium stearate and mix for 10 minutes. Then, compress the mixture into tablets using a rotary press to obtain nebivolol amlodipine uncoated tablets.

[0071] Step 3: The nebivolol amlodipine plain tablets obtained in Step 2 are coated with an aqueous solution of film coating premix (solid content 12%, percentage refers to the percentage of the mass of the coating premix to the total mass of the aqueous solution of the coating premix) to obtain nebivolol amlodipine tablets.

[0072] Example 3 1)Blend composition [Table 3]

[0073] 2) Manufacturing method Step A. Preparation of the total blend material for the nebivolol layer Slowly add pregelatinized starch to the stirred purified water and dissolve, then add polysorbate 80 and stir evenly until ready for use.

[0074] Add nebivolol hydrochloride, microcrystalline cellulose 101, lactose monohydrate, and cross-linked sodium carboxymethylcellulose to a wet granulator, begin stirring and chopping, and mix for 10 minutes. Add an aqueous solution of adhesive to form a slurry and granulate. The granulated soft material is wet-sized through a 16-mesh sieve, and the wet granules are then placed in a thermostatic oven, dried to a moisture content of 3.0% or less, and sized through a 20-mesh sieve. Then, add the dried nebivolol granules, colloidal silica, and magnesium stearate to a three-dimensional mixer and mix for 5 minutes to obtain a total mixed nebivolol granules.

[0075] Step B: Preparation of total blend material for amlodipine layer Amlodipine benzenesulfonate, microcrystalline cellulose 102, lactose monohydrate, and carboxymethylcellulose are placed in a three-dimensional mixer and mixed for 20 minutes. A dry granulator is used to dry granulate the mixture by adjusting the roll press pressure, roll press speed, and feed rate. The mixture is then dry-granulated through a 24-mesh sieve. Magnesium stearate is added and mixed for 5 minutes to obtain amlodipine mixed granules.

[0076] Step C The nebivolol total mixed granules obtained in step A and the amlodipine total mixed granules obtained in step B are tableted using a double-layer tablet press to obtain nebivolol amlodipine plain tablets, which are then further film-coated to obtain nebivolol amlodipine tablets.

[0077] Example 4 1)Blend composition [Table 4]

[0078] 2) Manufacturing method Preparation of total mixed material for amlodipine layer Amlodipine benzenesulfonate, microcrystalline cellulose 102, lactose monohydrate, microcrystalline cellulose 102, and sodium carboxymethyl starch are placed in a three-dimensional mixer and mixed for 20 minutes, and magnesium stearate is added and mixed for 5 minutes.

[0079] Preparation of the total mixed material for the nebivolol layer Slowly add hypromellose to the stirred purified water and dissolve, then add polysorbate 80 and stir until homogenous, and prepare for use.

[0080] Nebivolol hydrochloride, microcrystalline cellulose 101, mannitol, and cross-linked sodium carboxymethylcellulose were added to a three-dimensional mixer and mixed for 10 minutes. The mixed material was then placed in a fluidized bed, and the parameters for airflow, airflow temperature, atomization temperature, and feed rate were set. An aqueous solution of adhesive was added using a peristaltic pump to perform fluid granulation. The granulated material was sieved through a 30-mesh sieve to obtain dried nebivolol granules. Magnesium stearate and colloidal silica were then mixed for 5 minutes to obtain total mixed nebivolol granules.

[0081] The amlodipine total mixed material and the nebivolol total mixed granules are tableted using a double-layer tableting machine to obtain nebivolol amlodipine plain tablets, which are then further film-coated to obtain nebivolol amlodipine tablets.

[0082] Example 5 1)Blend composition [Table 5]

[0083] 2) Manufacturing method Preparation of adhesive Hypromellose is prepared into an adhesive with purified water, and polysorbate 80 and sodium dodecyl sulfate are added and stirred until homogenous, ready for use.

[0084] Step 1: Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and cross-linked sodium carboxymethylcellulose (internal additive) to a mixing kettle and mix for 20 minutes. Then, place the mixed material in a fluidized bed. Set the parameters for airflow, air temperature, atomization temperature, and feed rate, and use a peristaltic pump to add an aqueous solution of adhesive to perform fluid granulation. The granulated material is then dry-sized using a sieving machine to obtain nebivolol dry granules.

[0085] Step 2: The dried nebivolol granules obtained in Step 1, amlodipine benzenesulfonate, cross-linked sodium carboxymethylcellulose (externally added), colloidal silica, and microcrystalline cellulose 101 are added to a mixing kettle and mixed for 10 minutes, then sized using a sizing machine. After sizing is complete, mixing is continued for 10 minutes, magnesium stearate is added, and the mixture is mixed for 5 minutes. Tablets are then produced using a rotary press.

[0086] Example 6 1)Blend composition [Table 6]

[0087] 2) Manufacturing method Preparation of adhesive: Hypromellose is mixed with purified water to form an adhesive, and polysorbate 80 is added and stirred until homogenous, ready for use.

[0088] Step 1: Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and cross-linked sodium carboxymethylcellulose (internal additive) to a mixing kettle and mix for 20 minutes. Then, place the mixed material in a fluidized bed. Set the parameters of airflow, air temperature, spray temperature, and feed rate, and use a peristaltic pump to add an aqueous solution of adhesive to perform fluid granulation. Then, pass the granulated material through a 20-mesh sieve to obtain dry nebivolol granules.

[0089] Step 2: The dried nebivolol granules obtained in Step 1, amlodipine benzenesulfonate, cross-linked sodium carboxymethylcellulose (externally added), colloidal silica, microcrystalline cellulose 101, and sodium dodecyl sulfate are added to a mixing kettle and mixed for 10 minutes, after which magnesium stearate is added and mixed for 5 minutes, and the mixture is compressed into tablets using a rotary press.

[0090] Example 7 1)Blend composition [Table 7]

[0091] 2) Manufacturing method Preparation of adhesive Hypromellose is prepared into an adhesive with purified water, and polysorbate 80 and sodium dodecyl sulfate are added and stirred until homogenous, ready for use.

[0092] Step 1: Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and cross-linked sodium carboxymethylcellulose (internal additive) to a mixing kettle and mix for 20 minutes. Then, place the mixed material in a fluidized bed. Set the parameters for airflow, air temperature, atomization temperature, and feed rate, and use a peristaltic pump to add an aqueous solution of adhesive to perform fluid granulation. The granulated material is then dry-sized using a sieving machine to obtain nebivolol dry granules.

[0093] Step 2: The dried nebivolol granules obtained in Step 1, amlodipine benzenesulfonate, cross-linked sodium carboxymethylcellulose (externally added), colloidal silica, and microcrystalline cellulose 101 are added to a mixing kettle and mixed for 10 minutes, then sized using a sizing machine. After sizing, mixing is continued for 10 minutes, magnesium stearate is added, and the mixture is mixed for 5 minutes. Tablets are then produced using a rotary press.

[0094] Example 8 1)Blend composition [Table 8]

[0095] 2) Manufacturing method Manufacturing of amlodipine granules Amlodipine benzenesulfonate, microcrystalline cellulose (internal addition), and anhydrous calcium hydrogen phosphate are placed in a mixer and mixed for 20 minutes, and then pressed using a dry granulator by adjusting the roll press and feed parameters, and then sieved through a 24-mesh sieve to obtain amlodipine granules.

[0096] Manufacturing of nebivolol granules Preparation of adhesive solution Hypromellose is slowly added to stirred purified water to dissolve, and sodium dodecyl sulfate and polysorbate 80 are then added and stirred to dissolve, ready for use.

[0097] Nebivolol hydrochloride, lactose monohydrate, and pregelatinized starch are added to a three-dimensional mixer and mixed for 10 minutes. The mixed material is then placed in a fluidized bed, and the parameters of air flow, air temperature, atomization temperature, and feed rate are set. An aqueous solution of adhesive is added using a peristaltic pump to perform fluid granulation. After granulation, the material is sieved through a 30-mesh sieve to obtain nebivolol granules.

[0098] Amlodipine granules, nebivolol granules, microcrystalline cellulose (externally added), cross-linked sodium carboxymethylcellulose (externally added), and colloidal silica are added to a mixing kettle and mixed for 10 minutes, and then magnesium stearate is added and mixed for 5 minutes to obtain a total mixed granule of nebivolol and amlodipine. The total mixed granules are then filled into capsules to obtain nebivolol and amlodipine capsules.

[0099] The amlodipine-nebivolol combination formulations of Examples 1 to 8 were subjected to dissolution tests in a 900 mL volume of pH 4.5 acetate buffer solution at a rotation speed of 50 rpm using the second method of the USP. The specifications of the amlodipine-nebivolol combination formulation in Example 4 were 10 mg (calculated as amlodipine) / 10 mg (calculated as nebivolol), and the specifications of the amlodipine-nebivolol combination formulations in Examples 1 to 3 and Examples 5 to 8 were 5 mg (calculated as amlodipine) / 5 mg (calculated as nebivolol). The dissolution results are shown in Table 1. [Table 9] JPEG2025531213000012.jpg255165 JPEG2025531213000013.jpg255165

[0100] The combination formulation of nebivolol and amlodipine provided by the present invention has a high synergistic effect, which is advantageous in terms of improving antihypertensive effects, improving safety and tolerance, and reducing side effects. The combination of nebivolol and amlodipine has the following advantages over either drug alone: ​​(1) reducing the dosage and increasing patient compliance; (2) being advantageous in improving medication compliance for the elderly and those with dysphagia; (3) gently maintaining blood drug concentrations in the body, stabilizing blood pressure in hypertensive patients for a long period of time, and reducing the side effects of each drug; and (4) avoiding the need for patients to voluntarily discontinue medication, thereby preventing disease recurrence and the progression of malignant complications.

[0101] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A composition of nebivolol and amlodipine, wherein the composition of nebivolol and amlodipine comprises the active ingredients nebivolol and amlodipine, wherein the active ingredient nebivolol comprises one or more of nebivolol, its pharmaceutically acceptable salts, and solvates, and the active ingredient amlodipine comprises one or more of amlodipine, its pharmaceutically acceptable salts, and solvates. A composition of nebivolol and amlodipine.

2. The pharmaceutically acceptable salt of nebivolol is nebivolol hydrochloride; and / or The pharmaceutically acceptable salt of amlodipine is amlodipine benzenesulfonate and / or amlodipine maleate.

2. The composition of claim 1 comprising nebivolol and amlodipine.

3. The nebivolol and amlodipine composition further comprises one or more of a surfactant, a filler, an adhesive, a disintegrant, a lubricant, a glidant, a colorant, and a coating.

2. The composition of claim 1 comprising nebivolol and amlodipine.

4. the surfactant is selected from sodium dodecyl sulfate and / or polysorbate; and / or the filler is selected from one or more of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose; and / or the adhesive is selected from one or more of polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, copovidone, povidone, pregelatinized starch, gum arabic, polyvinylpyrrolidone, and sodium alginate; and / or the disintegrant is selected from one or more of crospovidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and corn starch; and / or the lubricant is selected from one or more of metal stearates, stearic acid, talc powder, stearic acid esters, stearoyl fumarate, and finely powdered silica gel; and / or the glidant is selected from one or more of talc powder, finely powdered silica gel, and colloidal silica; and / or the colorant is selected from red iron oxide and / or yellow iron oxide; and / or The coating film is a film coating premix.

4. The composition of claim 3 comprising nebivolol and amlodipine.

5. In the composition of nebivolol and amlodipine, the components other than the coating film together constitute a core, and the core is selected from any one of the following formulations: Formulation 1: 2.77% amlodipine benzenesulfonate, 2.18% nebivolol hydrochloride, 44.25% microcrystalline cellulose 101, 16.00% lactose monohydrate, 12.00% pregelatinized starch, 6.00% sodium carboxymethyl starch, 6.00% hydroxypropyl cellulose, 1.20% polysorbate 80, 8.00% microcrystalline cellulose 102, 0.60% colloidal silica, 1.00% magnesium stearate and coating material, the percentages referring to the weight percentage of each component relative to the total weight of the core; Formulation 2: 2.31% amlodipine benzenesulfonate, 1.82% nebivolol hydrochloride, 39.70% mannitol, 20.00% lactose monohydrate, 6.67% hypromellose, 6.00% cross-linked sodium carboxymethylcellulose, 2.00% sodium dodecyl sulfate, 10.00% microcrystalline cellulose 102, 10.00% anhydrous calcium hydrogen phosphate, 0.50% colloidal silica, 1.00% magnesium stearate and coating material, the percentages indicating the percentage of the mass of each component relative to the total mass of the core; Formulation 3 Amlodipine layer: 6.93% amlodipine benzenesulfonate, 60.00% microcrystalline cellulose 102, 28.07% lactose monohydrate, 4.00% sodium carboxymethyl starch, and 1.00% magnesium stearate, the percentages indicating the weight percentage of each component relative to the total weight of the amlodipine layer; Nebivolol layer: 2.73% nebivolol hydrochloride, 63.77% microcrystalline cellulose 101, 15.00% lactose monohydrate, 6.00% cross-linked sodium carboxymethylcellulose, 8.00% pregelatinized starch, 3.00% polysorbate 80, 0.50% colloidal silica, and 1.00% magnesium stearate, the percentages representing the weight of each component relative to the total weight of the nebivolol layer; Formulation 4 Amlodipine layer: 13.86% amlodipine benzenesulfonate, 54.14% microcrystalline cellulose 102, 25.00% anhydrous calcium hydrogen phosphate, 6.00% sodium carboxymethyl starch, and 1.00% magnesium stearate, the percentages indicating the weight percentage of each component relative to the total weight of the amlodipine layer; Nebivolol layer: 5.45% nebivolol hydrochloride, 56.05% microcrystalline cellulose 101, 25.00% mannitol, 5.00% cross-linked sodium carboxymethylcellulose, 5.00% hydroxypropyl cellulose, 2.00% polysorbate 80, 0.50% colloidal silica, and 1.00% magnesium stearate, the percentages indicating the weight percentage of each component relative to the total weight of the nebivolol layer; Formulation 5: 2.27% nebivolol hydrochloride, 2.89% amlodipine benzenesulfonate, 59.41% lactose monohydrate, 19.16% pregelatinized starch, 2.87% cross-linked sodium carboxymethylcellulose (internal addition), 1.63% hypromellose, 0.38% polysorbate 80, 0.25% sodium dodecyl sulfate, 3.74% cross-linked sodium carboxymethylcellulose (external addition), 0.25% colloidal silica, 6.65% microcrystalline cellulose 101, 0.50% magnesium stearate, the percentages referring to the mass of each component relative to the total mass of the core, Formulation 6: 2.27% nebivolol hydrochloride, 2.89% amlodipine benzenesulfonate, 59.35% lactose monohydrate, 19.16% pregelatinized starch, 2.87% cross-linked sodium carboxymethylcellulose (internal addition), 1.63% hypromellose, 0.19% polysorbate 80, 3.74% cross-linked sodium carboxymethylcellulose (external addition), 0.25% colloidal silica, 6.65% microcrystalline cellulose 101, 0.50% sodium dodecyl sulfate, 0.50% magnesium stearate, the percentages referring to the mass of each component relative to the total mass of the core, Formulation 7: 2.27% nebivolol hydrochloride, 2.89% amlodipine benzenesulfonate, 59.16% lactose monohydrate, 19.16% pregelatinized starch, 2.87% cross-linked sodium carboxymethylcellulose (internal addition), 1.63% hypromellose, 0.38% polysorbate 80, 0.50% sodium dodecyl sulfate, 3.74% cross-linked sodium carboxymethylcellulose (external addition), 0.25% colloidal silica, 6.65% microcrystalline cellulose 101, 0.50% magnesium stearate, the percentages indicating the mass of each component relative to the total mass of the core. Formulation 8: 1.56% nebivolol hydrochloride, 1.98% amlodipine benzenesulfonate, 22.85% microcrystalline cellulose (internal addition), 11.43% anhydrous calcium hydrogen phosphate, 38.25% lactose monohydrate, 11.43% pregelatinized starch, 1.29% hypromellose, 0.26% polysorbate 80, 0.17% sodium dodecyl sulfate, 4.28% microcrystalline cellulose (external addition), 5.00% cross-linked sodium carboxymethylcellulose (external addition), 0.50% colloidal silica, 1.00% magnesium stearate, wherein the percentages refer to the percentage of the mass of each component relative to the total mass of the core. A composition of nebivolol and amlodipine according to any one of claims 1 to 4.

6. Use of the composition of nebivolol and amlodipine according to any one of claims 1 to 5 in the manufacture of a medicament for treating and / or preventing cardiovascular diseases.

7. 7. The application according to claim 6, wherein the cardiovascular diseases include hypertension, heart failure, coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, congenital heart disease and valvular heart disease.

8. Use of the composition of nebivolol and amlodipine according to any one of claims 1 to 5 in the manufacture of a pharmaceutical preparation, said pharmaceutical preparation being preferably an oral pharmaceutical preparation.

9. The application according to claim 8, characterized in that the dosage forms of the oral pharmaceutical preparation include, but are not limited to, compound tablets, double tablets, capsules, micropellets and microtablets.

10. 6. The method for preparing the composition of nebivolol and amlodipine according to any one of claims 1 to 5, characterized in that the preparation method includes, but is not limited to, direct powder compression, wet granulation, dry granulation, fluidized bed granulation, extrusion-spheronization, and micropellet coating.

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