Composition of nebivolol and amlodipine, preparation method therefor and use thereof

Abstract

The present invention provides a composition of nebivolol and amlodipine, comprising nebivolol, amlodipine and a pharmaceutical excipient. The nebivolol comprises one or more of nebivolol, a pharmaceutically acceptable salt thereof, and a solvate thereof. The amlodipine comprises one or more of amlodipine, a pharmaceutically acceptable salt thereof, and a solvate thereof. The pharmaceutical excipient is selected from one or more of a filler, a binder, a disintegrant, a lubricant, and a glidant. The composition does not contain a colorant and a film coating. The compound preparation of the present invention has good stability, and is beneficial to improving the antihypertensive efficacy, enhancing safety and tolerability, and reducing side effects. Compared to monotherapy, the present invention reduces the number of administered medications and improves the compliance of patients, is beneficial to improving the medication compliance of the elderly patients and individuals with dysphagia, maintains a stable plasma drug concentration, maintains long-term stable blood pressure in hypertensive patients, prevents the patients from discontinuing medication arbitrarily, and prevents disease recurrence and the progression of severe complications.

Description

Nebivolol and Amlodipine Combination, Preparation Method and Application

[0001] This application claims priority to the earlier application filed by the applicant on June 21, 2024 with the China National Intellectual Property Administration, patent application number 202410815064.0, entitled "A Composition of Nebivolol and Amlodipine, Its Preparation Method and Application". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical compositions, specifically relating to a combination of nebivolol and amlodipine, its preparation method, and its application. Background Technology

[0003] Hypertension is one of the most common cardiovascular diseases, with a prevalence of 25% to 30% in adults. If hypertension is not effectively controlled over a long period, it increases the risk of coronary atherosclerosis, left ventricular hypertrophy, carotid artery atherosclerosis, and kidney disease. Currently, the diagnosis and treatment of hypertension mainly rely on drug intervention, which has significant clinical effects, effectively suppressing the disease and alleviating patients' clinical symptoms. Therefore, developing drug formulations for treating hypertension and cardiovascular diseases while reducing toxic side effects is of positive significance for clinical medication.

[0004] Naibiluoer's chemical name 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, with a molecular weight of 405.43, has the following structural formula:

[0005] Nebivolol, a potent and highly selective (cardiac-selective) β1-adrenergic receptor blocker with vasodilatory activity, lacks alpha-adrenergic antagonism and also possesses vasodilatory effects, offering some protection to cardiac function and reducing cardiac preload. It is primarily used to treat essential hypertension and chronic heart failure, with indications including cardiovascular diseases such as hypertension, angina pectoris, myocardial infarction, and congestive heart failure. Nebivolol hydrochloride tablets have significant efficacy, convenient administration, and few adverse reactions, making them a promising new antihypertensive drug. It was first approved for marketing in Germany in 1997 for the treatment of essential hypertension. However, common adverse reactions of β-blockers include headache, nausea, bradycardia, orthostatic hypotension, and bronchospasm.

[0006] Amlodipine's chemical name is methyl ethyl 6-methyl-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate, with the molecular formula C2. 20 H 25 CIN2O5, with a molecular weight of 408.88, has the following structural formula:

[0007] Amlodipine is a dihydropyridine calcium channel blocker (a slow-acting channel blocker or calcium channel antagonist) that inhibits the transmembrane influx of calcium ions into the heart and vascular smooth muscle. The antihypertensive mechanism of amlodipine is its direct relaxation effect on vascular smooth muscle. The exact mechanism by which amlodipine relieves angina is not fully understood, but it reduces the overall ischemic load through two mechanisms: 1. Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload) during cardiac work. This unloading of the heart reduces myocardial energy consumption and oxygen demand as the heart rate remains stable. 2. The mechanism of action of amlodipine may also involve dilation of the main coronary arteries and coronary arterioles in both 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, existing technologies are single-component formulations. Therefore, there is an urgent need to develop a new compound formulation with good synergistic effects, good stability, few side effects, good antihypertensive efficacy, and good patient compliance. Summary of the Invention

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

[0010] This invention provides a nebivolol and amlodipine composition comprising nebivolol, amlodipine, and pharmaceutical excipients; wherein the nebivolol is provided by one or more of nebivolol, pharmaceutically acceptable salts thereof, and solvates thereof; wherein the amlodipine is provided by one or more of amlodipine, pharmaceutically acceptable salts thereof, and solvates thereof; wherein the pharmaceutical excipients are selected from one or more of fillers, binders, disintegrants, lubricants, and glidants; and wherein the nebivolol and amlodipine composition is free of colorants and coating films.

[0011] According to an embodiment of the present invention, the bulk density of the nebivolol and amlodipine composition is 0.35 g / ml to 0.65 g / ml, preferably 0.40 g / ml to 0.60 g / ml;

[0012] And / or, the tap density of the nebivolol and amlodipine composition is 0.45 g / ml to 0.70 g / ml, preferably 0.50 g / ml to 0.65 g / ml.

[0013] According to embodiments of the present invention, the nebivolol and amlodipine composition is a physical mixture comprising nebivolol, amlodipine, and pharmaceutical excipients, or a physical mixture consisting of nebivolol, amlodipine, and pharmaceutical excipients. For example, the physical mixture may be in the form of granules (e.g., capsule granules), powders (e.g., micro powders, nano powders), pills, and tablets.

[0014] According to embodiments of the present invention, the nebivolol and amlodipine composition is in the form of granules, preferably non-compression granules (e.g., physical mixing, wet granulation, and / or fluidized bed granulation), in dosage forms such as granules, capsules, dry suspensions, powders, or bilayer tablets; more preferably, the nebivolol and amlodipine composition is in the form of capsule granules, preferably non-compression granules (e.g., physical mixing, wet granulation, and / or fluidized bed granulation).

[0015] According to an embodiment of the present invention, the nebivolol and amlodipine composition comprises an inner structure and an outer structure covering the inner structure, or the particles consist of an inner structure and an outer structure covering the inner structure. Further, the nebivolol is located in the inner structure, and the amlodipine is located in the outer structure. Further, the covering is a non-compression-molded covering.

[0016] According to an embodiment of the present invention, the internal structure comprises nebivolol, a filler, a disintegrant, and a binder; or, the internal structure is composed of nebivolol, a filler, a disintegrant, and a binder; or, the internal structure is a physical mixture of nebivolol, a filler, a disintegrant, and a binder. Further, the internal structure is obtained by physical mixing (e.g., non-pressure mixing, or wet granulation and / or fluidized bed granulation) of a material comprising nebivolol, a filler, a disintegrant, and a binder, or a material composed of nebivolol, a filler, a disintegrant, and a binder.

[0017] According to an embodiment of the present invention, the outer structure comprises amlodipine, a filler, a disintegrant, a lubricant, and a flow aid; or, the outer structure is composed of amlodipine, a filler, a disintegrant, a lubricant, and a flow aid; or, the outer structure is a physical mixture of amlodipine, a filler, a disintegrant, a lubricant, and a flow aid. Further, the outer structure is obtained by physical mixing (e.g., non-pressure mixing) of a material comprising amlodipine, a filler, a disintegrant, a lubricant, and a flow aid, or a material composed of amlodipine, a filler, a disintegrant, a lubricant, and a flow aid.

[0018] According to embodiments of the present invention, the total impurity content of the nebivolol and amlodipine composition is not higher than 1.5%, for example, not higher than 1.0%, 0.8%, 0.5%, or 0.3%; preferably, it is sealed at 50°C (e.g., sealed in aluminum blister packaging) for 30 days, and / or sealed at 40°C / RH 75% for 30 days, with the total impurity content not higher than 1.5%, for example, not higher than 1.0%, 0.8%, 0.5%, or 0.3%.

[0019] According to an embodiment of the present invention, the pharmaceutically acceptable salt of nebivolol can be nebivolol hydrochloride.

[0020] According to embodiments of the present invention, the pharmaceutically acceptable salt of amlodipine can be amlodipine besylate and / or amlodipine maleate. For example, the amlodipine besylate can be levamlodipine besylate and / or dextroamlodipine besylate.

[0021] According to an embodiment of the present invention, the nebivolol and amlodipine composition can be a combination of nebivolol hydrochloride and amlodipine besylate.

[0022] According to an embodiment of the present invention, the filler refers to a solid substance that, when added to a material, can improve the material's properties, or increase its solubility, weight, and reduce its cost. It is selected from one or more of microcrystalline cellulose (e.g., microcrystalline cellulose 101 or microcrystalline cellulose 102), dicalcium phosphate, mannitol, pregelatinized starch, corn starch, sucrose, glucose, maltose, lactose (e.g., lactose monohydrate), sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose. For example, the filler is selected from one or more of microcrystalline cellulose, lactose (e.g., lactose monohydrate), pregelatinized starch, and corn starch.

[0023] According to embodiments of the present invention, the fillers in the inner and outer structures may be the same or different, for example, different. Exemplarily, the filler in the inner structure is selected from one or more of lactose (e.g., lactose monohydrate), pregelatinized starch, and corn starch, and the filler in the outer structure is selected from microcrystalline cellulose (e.g., microcrystalline cellulose 101).

[0024] According to embodiments of the present invention, the adhesive may be a conventional additive in the art capable of increasing the viscosity of the dispersion medium to reduce the settling velocity of the particles or increase the hydrophilicity of the particles, selected from one or more of polysorbate (selected from polysorbate 80 and / or polysorbate 20), sodium lauryl sulfate, polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, copovidone, povidone (e.g., povidone K30), gum arabic, polyvinylpyrrolidone, and sodium alginate; for example, the adhesive may be selected from one or more of hydroxypropyl methylcellulose, polysorbate (e.g., polysorbate 80), and sodium lauryl sulfate.

[0025] According to an embodiment of the present invention, the disintegrant is a substance that can cause the formulation (e.g., granules) prepared from the composition to disintegrate during dissolution, and is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose and sodium carboxymethyl starch, for example, crospovidone sodium carboxymethyl cellulose.

[0026] According to an embodiment of the present invention, the disintegrant in the inner structure and the disintegrant in the outer structure may be the same or different, for example, the same, such as cross-linked carboxymethyl cellulose sodium.

[0027] According to embodiments of the present invention, the lubricant can be a conventional lubricating substance in the art, selected from one or more of stearate metal salts, stearic acid, talc, stearate esters, stearoyl fumarate, and micronized silica gel. Preferably, the stearate metal salt is one or more of magnesium stearate, calcium stearate, and sodium stearate fumarate. Preferably, the stearate ester is glyceryl stearate. Preferably, the lubricant is selected from stearate metal salts, such as magnesium stearate.

[0028] According to an embodiment of the present invention, the flow aid can be a conventional excipient in the art that can reduce the friction between particles and improve the flowability of powder or granules, selected from one or more of talc, micronized silica and colloidal silica, for example, colloidal silica.

[0029] According to an embodiment of the present invention, the mass percentage of nebivolol is 1.0% to 10.0%, for example 1.5% to 7.0% or 1.5% to 5.0%, exemplary being 1.0%, 2.0%, 2.3%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5% or 6.0%, wherein the mass percentage refers to the percentage of the mass of nebivolol to the total mass of the nebivolol and amlodipine composition.

[0030] According to an embodiment of the present invention, the mass percentage of amlodipine is 1.0% to 20.0%, for example 1.5% to 6.0%, exemplary of 2.0%, 2.9%, 3.0%, 4.0%, 5.0% or 6.0%, wherein the mass percentage refers to the percentage of the mass of amlodipine to the total mass of the composition of nebivolol and amlodipine.

[0031] According to an embodiment of the present invention, the mass percentage of the filler is 40.0% to 95.0%, for example 60.0% to 90.0%, exemplary being 60.0%, 65.0%, 70.0%, 75.0%, 78.4%, 80.0%, 85.0%, 85.2%, 85.4%, or 90.0%, where the mass percentage refers to the percentage of the mass of the filler relative to the total mass of the nebivolol and amlodipine composition.

[0032] According to an embodiment of the present invention, the mass percentage of the filler in the inner structure is 50.0% to 90.0%, for example 60.0% to 90.0% or 65.0% to 85.0%, exemplary being 70.0%, 71.0%, 71.8%, 72.0%, 73.0%, 74.0%, 75.0%, 76.0%, 77.0%, 78.0%, 78.6%, 79.0%, 80.0%, 81.0%, 82.0%, 83.0%, or 84.0%, where the mass percentage refers to the percentage of the mass of the filler in the inner structure relative to the total mass of the nebivolol and amlodipine composition.

[0033] According to an embodiment of the present invention, the mass percentage of the filler in the outer structure is 1.0% to 15.0%, for example 1.0% to 10.0%, exemplary being 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 6.6%, 6.7%, 7.0%, 8.0%, or 9.0%, wherein the mass percentage refers to the percentage of the mass of the filler in the outer structure relative to the total mass of the nebivolol and amlodipine composition.

[0034] According to an embodiment of the present invention, the mass percentage of the adhesive is 1.0% to 30.0%, or it can be 1.0% to 20.0% or 1.0% to 10.0%, for example 1.0% to 5.0%, exemplary values ​​are 1.0%, 2.0%, 2.2%, 2.3%, 2.5%, 3.0%, 4.0% or 5.0%, and the mass percentage refers to the percentage of the mass of the adhesive relative to the total mass of the nebivolol and amlodipine composition.

[0035] According to embodiments of the present invention, the mass percentage of the disintegrant is 1.0% to 30.0%, or it can be 1.0% to 25.0% or 1.0% to 20.0%, for example 1.0% to 15.0%, exemplary values ​​are 1.0%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.6%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.3%, 13.5%, 14.05%, 14.5%, or 15.0%, where the mass percentage refers to the percentage of the mass of the disintegrant relative to the total mass of the nebivolol and amlodipine composition.

[0036] According to an embodiment of the present invention, the mass percentage of the disintegrant in the internal structure is 1.0% to 10.0%, for example, 1.0% to 8.0%, exemplarily 1.0%, 2.0%, 2.5%, 2.9%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 5.8%, 6.0%, 6.6%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, and 10.0%, where the mass percentage refers to the percentage of the mass of the disintegrant in the internal structure relative to the total mass of the nebivolol and amlodipine composition.

[0037] According to an embodiment of the present invention, the mass percentage of the disintegrant in the outer structure is 1.0% to 10.0%, for example 2.0% to 9.0%, exemplary values ​​being 1.0%, 2.0%, 2.5%, 3.0%, 3.5%, 3.7%, 4.0%, 4.5%, 5.0%, 5.5%, 5.8%, 6.0%, 6.6%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, and 10.0%, where the mass percentage refers to the percentage of the mass of the disintegrant in the outer structure relative to the total mass of the nebivolol and amlodipine composition.

[0038] According to an embodiment of the present invention, the mass percentage of the lubricant is 0.1% to 5.0%, for example 0.1% to 2.0% or 0.5% to 3.0%, exemplary being 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, 1.5% or 2.0%, wherein the mass percentage refers to the percentage of the mass of the lubricant relative to the total mass of the nebivolol and amlodipine composition.

[0039] According to an embodiment of the present invention, the mass percentage of the gliding agent is 0.1% to 5.0%, for example 0.2% to 3.0%, exemplarily 0.2%, 0.3%, 0.4%, 0.5%, 1.0% or 2.0%, wherein the mass percentage refers to the percentage of the mass of the gliding agent relative to the total mass of the nebivolol and amlodipine composition.

[0040] According to an embodiment of the present invention, the nebivolol and amlodipine composition can be any of the following formulations:

[0041] Formula 1: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 59.4% Lactose monohydrate, 19.2% Corn starch, 2.9% Sodium croscarmellose (added internally), 2.0% Hydroxypropyl methylcellulose, 0.2% Polysorbate 80, 3.7% Sodium croscarmellose (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.5% Magnesium stearate. The percentages refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition.

[0042] Preferably, the nebivolol and amlodipine composition of Formula 1 is a non-compressed granule, consisting of an inner structure and an outer structure covering the inner structure, with nebivolol hydrochloride located in the inner structure and amlodipine besylate located in the outer structure;

[0043] Preferably, the inner structure consists of 2.3% nebivolol hydrochloride, 59.4% lactose monohydrate, 19.2% corn starch, 2.9% croscarmellose sodium (added internally), 2.0% hydroxypropyl methylcellulose and 0.2% polysorbate 80, and the outer structure consists of 2.9% amlodipine besylate, 3.7% croscarmellose sodium (added externally), 0.3% colloidal silica, 6.6% microcrystalline cellulose 101 and 0.5% magnesium stearate;

[0044] Prescription 2: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 52.6% Lactose monohydrate, 19.2% Pregelatinized starch, 5.8% Croscarmellose sodium (added internally), 1.6% Hydroxypropyl methylcellulose, 0.4% Polysorbate 80, 0.3% Sodium dodecyl sulfate, 7.5% Croscarmellose sodium (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.5% Magnesium stearate. The percentages mentioned refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition.

[0045] Preferably, the nebivolol and amlodipine composition of Formula 2 is a non-compressed granule, consisting of an inner structure and an outer structure covering the inner structure, with nebivolol hydrochloride located in the inner structure and amlodipine besylate located in the outer structure;

[0046] Preferably, the inner structure consists of 2.3% nebivolol hydrochloride, 52.6% lactose monohydrate, 19.2% pregelatinized starch, 5.8% croscarmellose sodium (added internally), 1.6% hydroxypropyl methylcellulose, 0.4% polysorbate 80, and 0.3% sodium dodecyl sulfate, and the outer structure consists of 2.9% amlodipine benzylsulfonate, 7.5% croscarmellose sodium (added externally), 0.3% colloidal silica, 6.6% microcrystalline cellulose 101, and 0.5% magnesium stearate;

[0047] Formula 3: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 59.6% Lactose monohydrate, 19.2% Pregelatinized starch, 2.9% Croscarmellose sodium (added internally), 1.6% Hydroxypropyl methylcellulose, 0.4% Polysorbate 80, 3.7% Croscarmellose sodium (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.5% Magnesium stearate. The percentages mentioned refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition.

[0048] Preferably, the nebivolol and amlodipine composition of the formulation 3 is a non-compressed granule, consisting of an inner structure and an outer structure covering the inner structure, with nebivolol hydrochloride located in the inner structure and amlodipine besylate located in the outer structure;

[0049] Preferably, the inner structure consists of 2.3% nebivolol hydrochloride, 59.6% lactose monohydrate, 19.2% pregelatinized starch, 2.9% croscarmellose sodium (added internally), 1.6% hydroxypropyl methylcellulose and 0.4% polysorbate 80, and the outer structure consists of 2.9% amlodipine besylate, 3.7% croscarmellose sodium (added externally), 0.3% colloidal silica, 6.6% microcrystalline cellulose 101 and 0.5% magnesium stearate;

[0050] Formula 4: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 59.4% Lactose monohydrate, 19.2% Pregelatinized starch, 2.9% Croscarmellose sodium (added internally), 2.0% Hydroxypropyl methylcellulose, 0.2% Polysorbate 80, 3.7% Croscarmellose sodium (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.5% Magnesium stearate. The percentages mentioned refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition.

[0051] Preferably, the nebivolol and amlodipine composition of Formula 4 is a non-compressed granule, consisting of an inner structure and an outer structure covering the inner structure, with nebivolol hydrochloride located in the inner structure and amlodipine besylate located in the outer structure;

[0052] Preferably, the inner structure consists of 2.3% nebivolol hydrochloride, 59.4% lactose monohydrate, 19.2% pregelatinized starch, 2.9% croscarmellose sodium (added internally), 2.0% hydroxypropyl methylcellulose and 0.2% polysorbate 80, and the outer structure consists of 2.9% amlodipine besylate, 3.7% croscarmellose sodium (added externally), 0.3% colloidal silica, 6.6% microcrystalline cellulose 101 and 0.5% magnesium stearate.

[0053] According to an embodiment of the present invention, the nebivolol and amlodipine composition may contain 2.5 mg to 20.0 mg of nebivolol, for example 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 15.0 mg or 20.0 mg.

[0054] According to an embodiment of the present invention, the nebivolol and amlodipine composition may contain amlodipine in doses ranging from 2.5 mg to 20.0 mg, such as 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 15.0 mg or 20.0 mg.

[0055] According to an embodiment of the present invention, the dissolution rate of both nebivolol and amlodipine in the nebivolol and amlodipine composition is 90% or more, preferably 100% or more, within 30 minutes. Dissolution test conditions: acidic solution medium, dissolution test conducted using the USP second method at a rotation speed of 50 rpm or 75 rpm.

[0056] The present invention also provides the use of the described nebivolol and amlodipine composition in the preparation of medicaments for the treatment and / or prevention of cardiovascular diseases.

[0057] 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.

[0058] The present invention also provides a method for treating and / or preventing cardiovascular disease, comprising administering a therapeutically effective amount of the said nebivolol and amlodipine composition, the said drug, or a pharmaceutical preparation thereof to a patient in need.

[0059] The present invention also provides the use of the described nebivolol and amlodipine composition in the preparation of pharmaceutical formulations.

[0060] According to embodiments of the present invention, the pharmaceutical preparation can be an oral pharmaceutical preparation; for example, the dosage form of the oral pharmaceutical preparation includes, but is not limited to, capsules, granules, dry suspensions, powders, bilayer tablets, etc. For example, the nebivolol and amlodipine composition of the present invention is used together with a capsule shell to form a capsule.

[0061] The present invention also provides a pharmaceutical formulation prepared from the above-described combination of nebivolol and amlodipine. Preferably, the pharmaceutical formulation has the limitations described above.

[0062] The present invention also provides a method for preparing the aforementioned nebivolol and amlodipine composition, including but not limited to wet granulation or fluidized bed granulation.

[0063] According to an embodiment of the present invention, the wet granulation method or fluidized bed granulation method may include the following steps:

[0064] Step 1: Mix nebivolol, filler, binder and disintegrant, and then mix with binder aqueous solution for fluidized granulation and dry granulation to obtain nebivolol dry granules (i.e. internal structure);

[0065] Step 2: Mix the nebivolol dry granules obtained in Step 1 with amlodipine and filler, and then mix with lubricant and flow aid to obtain a nebivolol and amlodipine composition.

[0066] The present invention also provides a method for preparing the above-mentioned capsule, comprising further filling the nebivolol and amlodipine composition into a (gelatin) empty capsule to prepare a capsule.

[0067] The reagents and raw materials used in this invention are all commercially available. Beneficial effects

[0068] This invention provides a compound preparation of nebivolol and amlodipine for the treatment and / or prevention of cardiovascular diseases. The nebivolol and amlodipine compound preparation provided by this invention has good dissolution, high chemical stability, and good synergistic effect, which is beneficial for improving antihypertensive effects, enhancing safety and tolerability, and reducing side effects. Compared with monotherapy, the advantages of combined use of nebivolol and amlodipine are: (1) reducing the number of doses and improving patient compliance; (2) improving medication adherence for the elderly or those with swallowing difficulties; (3) maintaining stable blood drug concentrations, maintaining long-term stable blood pressure in hypertensive patients, and reducing the side effects of each drug; (4) preventing patients from arbitrarily discontinuing medication, and preventing disease recurrence and the progression of malignant complications.

[0069] Terminology Definitions and Explanations

[0070] The term "non-compression-formed particles" refers to a particle system in which material particles are agglomerated or solidified without relying on mechanical pressure (such as compression, extrusion, rolling, stamping) during the preparation process, but rather through physical actions (such as stirring, flow, vibration, diffusion). The core characteristics are: (1) The forming driving force is not mechanical pressure: for example, it relies on the adhesion of adhesives rather than external pressure; (2) The particle structure is loose and porous: the internal porosity is high and the density is lower than that of compression-formed particles.

[0071] The term "non-pressure mixing" refers to a mixing method in which raw materials are not bound by external mechanical pressure (such as compression, extrusion, rolling, etc.) but are uniformly distributed by physical forces (such as stirring, flow, vibration, diffusion). Its core characteristics are: (1) no additional pressure is applied: during the mixing process, the materials are mainly subjected to shear force, convection force, gravity, etc., rather than mechanical pressure; (2) the raw materials remain loose: the mixed raw materials are granules and do not undergo compression molding or structural densification. For example, non-pressure mixing can be achieved through wet granulation or fluidized bed granulation.

[0072] "Physical mixing" refers to a mixing method in which substances do not undergo chemical reactions, but are mixed in a uniform manner by physical forces (such as stirring, flowing, vibration, and diffusion) so that different components are evenly distributed, and each component retains its original chemical properties and molecular structure.

[0073] The term "multiple" refers to two or more physical mixtures, such as two, three or more physical mixtures.

[0074] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0075] The term "therapeutic effective amount" refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are looking for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. Detailed Implementation

[0076] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0077] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0078] Example 1

[0079] 1) Prescription composition

[0080] Table 1

[0081] 2) Preparation method

[0082] Adhesive preparation: Hydroxypropyl methylcellulose is prepared into an adhesive by using purified water, and then polysorbate 80 is added and stirred evenly for later use;

[0083] Step 1: Add nebivolol hydrochloride, lactose monohydrate, corn starch, and croscarmellose sodium (added internally) to a mixing pot and mix for 20 minutes. Then place the mixture in a fluidized bed, set the inlet air volume, inlet air temperature, atomization temperature, and feed rate parameters, and use a peristaltic pump to add the binder aqueous solution for fluidized granulation. The granulated material is then dry-granulated using a granulator to obtain nebivolol dry granules.

[0084] Step 2: Add the nebivolol dry granules obtained in Step 1, amlodipine besylate, croscarmellose sodium (added), colloidal silica, and microcrystalline cellulose 101 to a mixing pot and mix for 10 minutes. Then, use a granulator to granulate the granules. After granulation, continue mixing for 10 minutes, add magnesium stearate, and mix for 5 minutes. Finally, use a capsule filling machine to fill the capsules to obtain the final product.

[0085] Example 2

[0086] 1) Prescription composition

[0087] Table 2

[0088] 2) Preparation method

[0089] Adhesive preparation: Hydroxypropyl methylcellulose is prepared into an adhesive by using purified water, and then polysorbate 80 and sodium dodecyl sulfate are added and stirred evenly for later use;

[0090] Step 1: Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium (added internally) to a mixing pot and mix for 20 minutes. Then place the mixture in a fluidized bed, set the inlet air volume, inlet air temperature, atomization temperature, and feed rate parameters, and use a peristaltic pump to add the binder aqueous solution for fluidized granulation. The granulated material is then dry-granulated using a granulator to obtain nebivolol dry granules.

[0091] Step 2: Add the nebivolol dry granules obtained in Step 1, amlodipine besylate, croscarmellose sodium (added), colloidal silica, and microcrystalline cellulose 101 to a mixing pot and mix for 10 minutes. Then, use a granulator to granulate the granules. After granulation, continue mixing for 10 minutes, add magnesium stearate, and mix for 5 minutes. Finally, use a capsule filling machine to fill the capsules to obtain the final product.

[0092] Example 3

[0093] 1) Prescription composition

[0094] Table 3

[0095] 2) Preparation method

[0096] Adhesive preparation: Hydroxypropyl methylcellulose is prepared into an adhesive by using purified water, and then polysorbate 80 is added and stirred evenly for later use;

[0097] Step 1: Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium (added internally) to a mixing pot and mix for 20 minutes. Then place the mixture in a fluidized bed, set the inlet air volume, inlet air temperature, atomization temperature, and feed rate parameters, and use a peristaltic pump to add the binder aqueous solution for fluidized granulation. The granulated material is then dry-granulated using a granulator to obtain nebivolol dry granules.

[0098] Step 2: Add the nebivolol dry granules obtained in Step 1, amlodipine besylate, croscarmellose sodium (added), colloidal silica, and microcrystalline cellulose 101 to a mixing pot and mix for 10 minutes. Then, use a granulator to granulate the granules. After granulation, continue mixing for 10 minutes, add magnesium stearate, and mix for 5 minutes. Finally, use a capsule filling machine to fill the capsules to obtain the final product.

[0099] Example 4

[0100] 1) Prescription composition

[0101] Table 4

[0102] 2) Preparation method

[0103] Adhesive preparation: Hydroxypropyl methylcellulose is prepared into an adhesive by using purified water, and then polysorbate 80 is added and stirred evenly for later use;

[0104] Step 1: Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium (added internally) to a mixing pot and mix for 20 minutes. Then place the mixture in a fluidized bed, set the inlet air volume, inlet air temperature, atomization temperature, and feed rate parameters, and use a peristaltic pump to add the binder aqueous solution for fluidized granulation. The granulated material is then dry-granulated using a granulator to obtain nebivolol dry granules.

[0105] Step 2: Add the nebivolol dry granules obtained in Step 1, amlodipine besylate, croscarmellose sodium (added), colloidal silica, and microcrystalline cellulose 101 to a mixing pot and mix for 10 minutes. Then, use a granulator to granulate the granules. After granulation, continue mixing for 10 minutes, add magnesium stearate, and mix for 5 minutes. Finally, use a capsule filling machine to fill the capsules to obtain the final product.

[0106] Test Example 1: Dissolution Test

[0107] The amlodipine-nebivolol combination preparation of Example 2 was dissolved in 900 ml of pH 4.5 acetate buffer using the USP Method II at 50 rpm. The amlodipine-nebivolol combination preparation in Example 2 was in the form of 5 mg (as amlodipine) / 5 mg (as nebivolol). The dissolution results are shown in Table 5.

[0108] The amlodipine and nebivolol combination preparations of Examples 1 and 3-4 were subjected to dissolution tests in 900 ml of pH 2.0 hydrochloric acid solution using the USP Method II at 75 rpm. The amlodipine and nebivolol combination preparations in Examples 1 and 3-4 were in the form of 5 mg (calculated as amlodipine) / 5 mg (calculated as nebivolol). The dissolution results are shown in Table 6.

[0109] Table 5 - Dissolution results of amlodipine and nebivolol compound preparation in pH 4.5 medium.

[0110] Table 6 - Dissolution results of amlodipine and nebivolol compound preparation in pH 2.0 medium

[0111] Experimental results show that the compound preparation of nebivolol and amlodipine provided by this invention has a good synergistic effect, which is beneficial to improving the antihypertensive effect, improving safety and tolerability, and reducing side effects.

[0112] Test Example 2 Stability Test

[0113] Test conditions: High performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), solvent: acetonitrile-6.8 g / L potassium dihydrogen phosphate solution, using an octadecylsilane-bonded silica column.

[0114] Table 7 compares the results of influencing factors (high temperature) and acceleration conditions of the capsules (aluminum-aluminum blister packaging) of Example 1 of this invention and the tablets (aluminum-aluminum blister packaging) of Example 5 disclosed in CN118043047A.

[0115] The following experimental results demonstrate that, compared with the tablets of Example 5 disclosed in CN118043047A, the capsules of Example 1 of this invention exhibit relatively slower growth of related substances and better stability during day 0 and the stability test.

[0116] Table 7

[0117] Sample 1 was obtained by directly mixing the active ingredient and pharmaceutical excipients of Example 1. Sample 2 was obtained by directly mixing the contents of the capsule of Example 1. Sample 3 was obtained by directly mixing the powder of the compound tablet in Example 5 of CN118043047A. The above samples were subjected to a high-temperature destruction experiment. The test conditions were 105°C for 24 hours. The comparison of the growth results of related substances is shown in Table 8.

[0118] Table 8

[0119] The results showed that the related substances in the contents of Example 1 of this invention were significantly lower than those in the tablet grinding powder of Example 5 of CN118043047A. This indicates that the close contact between amlodipine besylate and nebivolol hydrochloride after compaction would accelerate the growth of impurities and result in poor stability. In contrast, the capsule formulation proposed in this invention, through process design, ensures that amlodipine and nebivolol are not in close contact, with nebivolol located in the inner structure and amlodipine in the outer structure. This reduces the contact surface area between the two active ingredients, lowers the impurity level, and results in good product stability with minimal impurity growth.

[0120] Test Example 3

[0121] The bulk density of the capsule contents in Examples 1 to 4 was tested, and the results are shown in Table 9.

[0122] Table 9

[0123] It can be seen that the bulk density of Examples 1 to 4 is in the range of 0.35 g / ml to 0.65 g / ml, and more preferably in the range of 0.40 g / ml to 0.60 g / ml.

[0124] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A composition of nebivolol and amlodipine, characterized in that, The nebivolol and amlodipine composition comprises nebivolol, amlodipine, and pharmaceutical excipients; the nebivolol is provided by one or more of nebivolol, pharmaceutically acceptable salts thereof, and solvates thereof; the amlodipine is provided by one or more of amlodipine, pharmaceutically acceptable salts thereof, and solvates thereof; the pharmaceutical excipients are selected from one or more of fillers, binders, disintegrants, lubricants, and glidants; the nebivolol and amlodipine composition is free of colorants and coating films.

2. The nebivolol and amlodipine composition as described in claim 1, characterized in that: The bulk density of the nebivolol and amlodipine composition is 0.35 g / ml to 0.65 g / ml; And / or, the tap density of the nebivolol and amlodipine composition is 0.45 g / ml to 0.70 g / ml; Preferably, the nebivolol and amlodipine composition is a physical mixture comprising nebivolol, amlodipine, and pharmaceutical excipients, or a physical mixture consisting of nebivolol, amlodipine, and pharmaceutical excipients. For example, the physical mixture may be in the form of granules, powder, pills, or tablets, among others. Preferably, the nebivolol and amlodipine composition is in the form of granules, and more preferably non-compression molded granules; Preferably, the nebivolol and amlodipine composition comprises an inner structure and an outer structure covering the inner structure, or the particles are composed of an inner structure and an outer structure covering the inner structure; the nebivolol is located in the inner structure, and the amlodipine is located in the outer structure; Preferably, the inner structure comprises nebivolol, a filler, a disintegrant, and a binder; or, the inner structure is composed of nebivolol, a filler, a disintegrant, and a binder; or, the inner structure is a physical mixture of nebivolol, a filler, a disintegrant, and a binder. The outer structure comprises amlodipine, a filler, a disintegrant, a lubricant, and a flow aid; or, the outer structure is composed of amlodipine, a filler, a disintegrant, a lubricant, and a flow aid; or, the outer structure is a physical mixture of amlodipine, a filler, a disintegrant, a lubricant, and a flow aid. Preferably, the total impurity content of the nebivolol and amlodipine composition is not higher than 1.5%.

3. The nebivolol and amlodipine composition as described in claim 1 or 2, characterized in that: The pharmaceutically acceptable salt of nebivolol is nebivolol hydrochloride; And / or, The pharmaceutically acceptable salts of amlodipine mentioned above are amlodipine besylate and / or amlodipine maleate; For example, the amlodipine besylate is levamlodipine besylate and / or dextroamlodipine besylate; And / or, The filler is selected from one or more of the following: microcrystalline cellulose, dicalcium phosphate, mannitol, pregelatinized starch, corn starch, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose. And / or, The adhesive is selected from one or more of polysorbate, sodium lauryl sulfate, polyoxyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, copovidone, povidone, gum arabic, polyvinylpyrrolidone, and sodium alginate; And / or, The disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch; And / or, The lubricant is selected from one or more of the following: metal stearate, stearic acid, talc, stearate, stearoyl fumarate, and micronized silica. And / or, The flow aid is selected from one or more of talc, micronized silica gel, and colloidal silica.

4. The nebivolol and amlodipine composition according to any one of claims 1-3, characterized in that: The mass percentage of nebivolol is 1.0% to 10.0%, and the mass percentage refers to the percentage of the mass of nebivolol to the total mass of the nebivolol and amlodipine composition; And / or, The mass percentage of amlodipine is 1.0% to 20.0%, and the mass percentage refers to the percentage of the mass of amlodipine in the total mass of the composition of nebivolol and amlodipine; And / or, The filler accounts for 40.0% to 95.0% of the mass percentage of the nebivolol and amlodipine composition; for example, the filler in the inner structure accounts for 50.0% to 90.0% of the mass percentage, and / or, the filler in the outer structure accounts for 1.0% to 15.0% of the mass percentage; And / or, The adhesive constitutes 1.0% to 30.0% of the mass percentage of the nebivolol and amlodipine composition; And / or, The disintegrant constitutes 1.0% to 30.0% of the composition of nebivolol and amlodipine by mass; for example, the disintegrant in the inner structure constitutes 1.0% to 10.0% by mass, and / or the disintegrant in the outer structure constitutes 1.0% to 10.0% by mass. And / or, The lubricant constitutes 0.1% to 5.0% of the mass percentage of the nebivolol and amlodipine composition; And / or, The flow aid comprises 0.1% to 5.0% by mass of the nebivolol and amlodipine composition.

5. The nebivolol and amlodipine composition according to any one of claims 1-4, characterized in that: The nebivolol and amlodipine composition is selected from any of the following formulations: Formula 1: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 59.4% Lactose monohydrate, 19.2% Corn starch, 2.9% Sodium croscarmellose (added internally), 2.0% Hydroxypropyl methylcellulose, 0.2% Polysorbate 80, 3.7% Sodium croscarmellose (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.50% Magnesium stearate. The percentages refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition. Prescription 2: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 52.6% Lactose monohydrate, 19.2% Pregelatinized starch, 5.8% Croscarmellose sodium (added internally), 1.6% Hydroxypropyl methylcellulose, 0.4% Polysorbate 80, 0.3% Sodium dodecyl sulfate, 7.5% Croscarmellose sodium (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.50% Magnesium stearate. The percentages mentioned refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition. Formula 3: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 59.6% Lactose monohydrate, 19.2% Pregelatinized starch, 2.9% Croscarmellose sodium (added internally), 1.6% Hydroxypropyl methylcellulose, 0.4% Polysorbate 80, 3.7% Croscarmellose sodium (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.50% Magnesium stearate. The percentages mentioned refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition. Formula 4: 2.3% Nebivolol hydrochloride, 2.9% Amlodipine besylate, 59.4% Lactose monohydrate, 19.2% Pregelatinized starch, 2.9% Croscarmellose sodium (added internally), 2.0% Hydroxypropyl methylcellulose, 0.2% Polysorbate 80, 3.7% Croscarmellose sodium (added externally), 0.3% Colloidal silica, 6.6% Microcrystalline cellulose 101, 0.50% Magnesium stearate. The percentages refer to the mass percentage of each component relative to the total mass of the nebivolol and amlodipine composition.

6. The nebivolol and amlodipine composition as described in claim 5, characterized in that: The nebivolol and amlodipine composition of Formula 1 is a non-compression molded granule, consisting of an inner structure and an outer structure covering the inner structure. Nebivolol hydrochloride is located in the inner structure, and amlodipine besylate is located in the outer structure. The inner structure consists of 2.3% nebivolol hydrochloride, 59.4% lactose monohydrate, 19.2% corn starch, 2.9% croscarmellose sodium, 2.0% hydroxypropyl methylcellulose, and 0.2% polysorbate 80. The outer structure consists of 2.9% amlodipine besylate, 3.7% croscarmellose sodium, 0.3% colloidal silica, 6.6% microcrystalline cellulose 101, and 0.5% magnesium stearate. The nebivolol and amlodipine composition of Formula 2 is a non-compression molded granule, consisting of an inner structure and an outer structure encapsulating the inner structure. Nebivolol hydrochloride is located in the inner structure, and amlodipine besylate is located in the outer structure. The inner structure consists of 2.3% nebivolol hydrochloride, 52.6% lactose monohydrate, 19.2% pregelatinized starch, 5.8% croscarmellose sodium, 1.6% hydroxypropyl methylcellulose, 0.4% polysorbate 80, and 0.3% sodium dodecyl sulfate. The outer structure consists of 2.9% amlodipine besylate, 7.5% croscarmellose sodium, 0.3% colloidal silica, 6.6% microcrystalline cellulose 101, and 0.5% magnesium stearate. The nebivolol and amlodipine composition of Formula 3 is a non-compression molded granule, consisting of an inner structure and an outer structure covering the inner structure. Nebivolol hydrochloride is located in the inner structure, and amlodipine besylate is located in the outer structure. The inner structure consists of 2.3% nebivolol hydrochloride, 59.6% lactose monohydrate, 19.2% pregelatinized starch, 2.9% croscarmellose sodium, 1.6% hydroxypropyl methylcellulose, and 0.4% polysorbate 80. The outer structure consists of 2.9% amlodipine besylate, 3.7% croscarmellose sodium, 0.3% colloidal silica, 6.6% microcrystalline cellulose 101, and 0.5% magnesium stearate. The nebivolol and amlodipine composition of Formula 4 is a non-compression molded granule, consisting of an inner structure and an outer structure covering the inner structure. Nebivolol hydrochloride is located in the inner structure, and amlodipine besylate is located in the outer structure. The inner structure consists of 2.3% nebivolol hydrochloride, 59.4% lactose monohydrate, 19.2% pregelatinized starch, 2.9% croscarmellose sodium, 2.0% hydroxypropyl methylcellulose, and 0.2% polysorbate 80. The outer structure consists of 2.9% amlodipine besylate, 3.7% croscarmellose sodium, 0.3% colloidal silica, 6.6% microcrystalline cellulose 101, and 0.5% magnesium stearate.

7. The use of the nebivolol and amlodipine composition according to any one of claims 1 to 6 in the preparation of a medicament for the treatment and / or prevention of cardiovascular diseases; Preferably, the cardiovascular diseases include hypertension, heart failure, coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, congenital heart disease, and valvular heart disease; Preferably, the drug is an oral pharmaceutical preparation, including but not limited to capsules, granules, dry suspensions, powders, and bilayer tablets.

8. A pharmaceutical preparation comprising the nebivolol and amlodipine composition according to any one of claims 1 to 6, or prepared from the nebivolol and amlodipine composition according to any one of claims 1 to 6; Preferably, the pharmaceutical preparation is an oral pharmaceutical preparation, including but not limited to capsules, granules, dry suspensions, powders, and bilayer tablets.

9. The pharmaceutical formulation as described in claim 8, characterized in that: The pharmaceutical preparation is a capsule, and the combination of nebivolol and amlodipine is the contents of the capsule.

10. The method for preparing the nebivolol and amlodipine composition according to any one of claims 1 to 6, characterized in that, The preparation method includes wet granulation or fluidized bed granulation.

11. A method for treating and / or preventing cardiovascular diseases, characterized in that: To administer to a patient in need a therapeutically effective amount of the nebivolol and amlodipine combination as described in any one of claims 1 to 6, or the pharmaceutical preparation as described in any one of claims 8 to 9; Preferably, the cardiovascular diseases include hypertension, heart failure, coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, congenital heart disease, and valvular heart disease; Preferably, the pharmaceutical preparation is an oral pharmaceutical preparation, including but not limited to capsules, granules, dry suspensions, powders, and bilayer tablets.

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