Bisoprolol-amlodipine composition and preparation method thereof

Abstract

The present invention discloses a bisoprolol amlodipine composition and a preparation method thereof. Bisoprolol and amlodipine are prepared into specific micropills respectively as two active ingredients, and the micropills are mixed with excipients and compressed into tablets to obtain tablets or filled into capsules after homogenization with the excipients, wherein the bisoprolol coating is provided on a drug layer on the surface of the micropills, and an isolation layer is further provided, thereby completely isolating bisoprolol from amlodipine, thereby avoiding the mutual contact of the active ingredients and the generation of impurities, and effectively controlling the impurity IMP-57 to be less than 0.1%. In addition, in the composition of the present invention, the bisoprolol micropills are treated with medicine and isolation, and the isolation layer formed can bear the pressure during tableting without causing rupture or cracks.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a bisoprolol-amlodipine composition and a preparation method thereof. Background Art

[0002] Hypertension is one of the most common chronic diseases. Currently, the main medications used to treat hypertension include calcium ion antagonists, beta-blockers, ACEIs, ARBs, diuretics, and alpha-blockers. The "Guidelines for the Management of Hypertension in the Elderly in China 2019" indicate that more than half of the elderly suffer from hypertension. Furthermore, due to the complex pathogenesis of hypertension, it is difficult to effectively control it with a single medication. Therefore, combination therapy or the use of single-pill combination preparations (SPCs) is clinically indicated.

[0003] Bisoprolol is a beta-blocker that selectively blocks the binding of adrenaline to β1 receptors while sparing β2 receptors. It is a beta-blocker with high affinity and selectivity for cardiac β1 receptors, with a higher β1 selectivity than cardioselective beta-blockers such as atenolol and metoprolol. Amlodipine besylate tablets are a calcium ion antagonist, comprising 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate. Currently, a combination of bisoprolol and amlodipine has been published. While this combination has excellent efficacy, impurities can be generated by contact between bisoprolol and amlodipine during formulation. The impurity content of the original drug (patent application number 200980138060.7) is controlled to below 0.5%. This content level is still relatively high, and how to better control the generation of impurities is one of the technical problems that need to be solved.

[0004] Chinese patent application CN 101674811A discloses a dosage form for administering two or more active pharmaceutical ingredients to an individual, the dosage form comprising a first pharmaceutical composition comprising the first active pharmaceutical ingredient and optionally one or more pharmaceutically acceptable excipients, in a first physical form selected from the group consisting of a powder, granules, pellets, beads, or tablets; and at least a second pharmaceutical composition comprising a second active pharmaceutical ingredient and optionally one or more pharmaceutically acceptable excipients, in a third physical form selected from the group consisting of granules, pellets, beads, tablets, or tablets. The composition is characterized in that the first and third physical forms are selected to be different to minimize interaction between the first and third pharmaceutical compositions and to enable separation of the first and second pharmaceutical compositions based on size differences for analysis. In other words, the document discloses a dosage form of two or more APIs in different physical forms, minimizing interaction between the APIs. In addition, Chinese patent application CN 101766611A discloses a pharmaceutical composition comprising levamlodipine or a pharmaceutically acceptable salt thereof and a beta-blocker, and its use. The active ingredients of the pharmaceutical composition include levamlodipine or a pharmaceutically acceptable salt thereof and a beta-blocker, wherein the beta-blocker is selected from nebivolol, bisoprolol, betaxolol, celiprolol, or vedolol. This pharmaceutical composition exhibits significant efficacy and is convenient for use. However, these two documents only discuss combined drug use and fail to address the issue of impurities generated by drug interactions when different active ingredients coexist.

[0005] Chinese patent application CN102164585A discloses a pharmaceutical composition packaged in moisture-proof packaging, comprising amlodipine or a pharmaceutically acceptable salt thereof, bisoprolol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The composition comprises less than 0.5% impurities derived from the amlodipine and bisoprolol. The composition is produced by a direct compression method, and when the tablets are stored in a glass container sealed with a polyethylene cap at 30°C and 65% relative humidity, degradation products remain below the detection limit.

[0006] Chinese patent application CN114668760A discloses a pharmaceutical formulation containing amlodipine and bisoprolol and its preparation method. By preparing amlodipine and bisoprolol separately and then combining them into a SPC formulation, the likelihood of contact between the two components is effectively reduced, significantly reducing the amount of reaction products produced, and improving storage stability. The disclosed pharmaceutical formulation has a total impurity level of over 0.2% at day 0 and reaches over 0.7% after one month of storage. The AML-2 impurity is present at over 0.02% or not detected.

[0007] There is still a need for a combined formulation of amlodipine and bisoprolol with controlled impurity levels.

[0008] The information in the background technology is only intended to illustrate the general background of the invention and should not be regarded as an admission or any form of suggestion that this information constitutes the prior art known to a person skilled in the art. Summary of the Invention

[0009] To solve at least some of the technical problems in the prior art, the present invention provides a bisoprolol-amlodipine composition and a preparation method thereof. Specifically, the present invention includes the following contents.

[0010] In a first aspect of the present invention, a bisoprolol amlodipine composition is provided, which comprises, based on 100 parts by weight of the composition, 40-50 parts by weight of bisoprolol micropellets with a diameter of 100-300 μm, preferably 120-180 μm, 40-50 parts by weight of amlodipine micropellets with a diameter of 100-300 μm, preferably 120-180 μm, and 0.01-2 parts by weight of a lubricant.

[0011] In certain embodiments, according to the bisoprolol amlodipine composition of the present invention, the bisoprolol micropellets include a pellet core, a drug layer wrapping the pellet core, and a separation layer wrapping the drug layer.

[0012] In certain embodiments, according to the bisoprolol amlodipine composition of the present invention, the pellet core comprises at least one of calcium hydrogen phosphate, microcrystalline cellulose and sucrose, and preferably, the weight ratio of calcium hydrogen phosphate, microcrystalline cellulose and sucrose is 2:1:2.

[0013] In certain embodiments, according to the bisoprolol amlodipine composition of the present invention, the drug layer is prepared from a drug-loading solution comprising bisoprolol fumarate, hydroxypropylcellulose and a solvent.

[0014] In certain embodiments, according to the bisoprolol amlodipine composition of the present invention, the solvent is an alcohol-water mixed solvent with an alcohol content of 70-90%.

[0015] In certain embodiments, according to the bisoprolol amlodipine composition of the present invention, the isolation layer comprises hypromellose and glycerin, and preferably, the isolation layer accounts for 5%-20% by weight of the pellet core.

[0016] In certain embodiments, the bisoprolol amlodipine composition according to the present invention, wherein the amlodipine micropellets comprise amlodipine besylate, microcrystalline cellulose and sodium starch glycolate.

[0017] In certain embodiments, according to the bisoprolol amlodipine composition of the present invention, the lubricant is selected from at least one of magnesium stearate, micronized silica gel, talc and magnesium lauryl sulfate.

[0018] In certain embodiments, the bisoprolol amlodipine composition according to the present invention is in the form of a tablet or capsule.

[0019] A second aspect of the present invention provides a method for preparing a bisoprolol-amlodipine composition, comprising the steps of:

[0020] The bisoprolol fumarate solution is suspended in a fluidized state and sprayed onto the surface of the blank pellets to form a drug-loaded layer to obtain drug-loaded pellets, and a solution of hypromellose and glycerol is sprayed onto the surface of the drug-loaded pellets to form an isolation layer, and dried to obtain bisoprolol-coated pellets, wherein the blank pellets contain calcium hydrogen phosphate, microcrystalline cellulose, and sucrose;

[0021] preparing amlodipine pellets from raw materials comprising amlodipine besylate, microcrystalline cellulose, and sodium starch glycolate; and

[0022] The bisoprolol pellets, amlodipine pellets and lubricant are mixed and tableted to obtain bisoprolol amlodipine tablets, or the bisoprolol pellets, amlodipine pellets, lubricant and optional excipients are homogenized, anti-adhesive agents are added for further homogenization and then filled into capsules to obtain bisoprolol amlodipine capsules.

[0023] In certain embodiments, according to the method for preparing a bisoprolol-amlodipine composition of the present invention, the solvent of the bisoprolol fumarate solution is a 70-90% ethanol-water mixed solvent.

[0024] The present invention prepares a preparation for a capsule preparation by preparing two active ingredients, bisoprolol and amlodipine, into specific micropellets, mixing the micropellets with excipients, and compressing the pellets into tablets or filling the mixed pellets into capsules. The bisoprolol is coated on a drug layer disposed on the surface of the micropellets, and an isolation layer is further provided to completely isolate the bisoprolol and amlodipine, thereby preventing contact between the active ingredients and the generation of impurities. Furthermore, the bisoprolol micropellets in the composition of the present invention undergo drug coating and isolation treatment, and the isolation layer formed can withstand the pressure during tableting without breaking or cracking. DETAILED DESCRIPTION

[0025] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0026] It should be understood that the terms described in the present invention are only for describing particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges in the present invention, it should be understood that the upper and lower limits of the ranges and each intermediate value therebetween are specifically disclosed. Each smaller range between any stated value or intermediate value within a stated range and any other stated value or intermediate value within the stated range is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0027] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of any conflict with any incorporated document, the content of this specification shall prevail.

[0028] Herein, IMP-57 is a compound having the following structure:

[0029]

[0030] Herein, impurity D is a compound having the following structure:

[0031]

[0032] Herein, when the active ingredient is a compound salt, the dosage is the weight of the compound salt. For example, when bisoprolol fumarate is used as the active ingredient, the weight is the weight of bisoprolol fumarate.

[0033] The present invention provides a bisoprolol-amlodipine composition, which comprises bisoprolol micropellets, amlodipine micropellets and a lubricant.

[0034] In the present invention, the diameter of the bisoprolol micropills and the amlodipine micropills is not limited, and is generally 100-300 μm, such as 100-250 μm, 110-200 μm, 120-150 μm, etc., such as 125 μm, 130 μm, 135 μm, 140 μm, 145 μm, etc. Preferably, the bisoprolol micropills and the amlodipine micropills have the same diameter, which is conducive to uniform mixing of the two. If the micropill diameter is too small, on the one hand, it is not conducive to the coating of the bisoprolol drug, and on the other hand, the micropills tend to stick together. If the micropill diameter is too large, greater force is required during compression, and the micropills are easily broken or the coating layer tends to rupture.

[0035] In the present invention, based on 100 parts by weight of the composition, the amount of bisoprolol micropellets is generally 40-50 parts by weight, such as 42 parts by weight, 44 parts by weight, 46 parts by weight, 48 parts by weight, etc. The amount of amlodipine micropellets is generally 40-50 parts by weight, such as 42 parts by weight, 44 parts by weight, 46 parts by weight, 48 parts by weight, etc. In certain embodiments, the amounts of bisoprolol micropellets and amlodipine micropellets are equal or substantially equal.

[0036] In the present invention, the bisoprolol micropellets comprise, from the inside out, a core, a drug layer, and a barrier layer. The core comprises at least one of dicalcium phosphate, microcrystalline cellulose, and sucrose. Microcrystalline cellulose plastically deforms under pressure, providing good compressibility, but it is elongated and has poor fluidity. Calcium phosphate and / or sucrose have a rounded shape and good fluidity, but as brittle materials, they are susceptible to brittle deformation under pressure.

[0037] In a preferred embodiment, the core of the bisoprolol micropellets of the present invention comprises microcrystalline cellulose and at least one selected from calcium hydrogen phosphate and sucrose. That is, the core comprises both a brittle material and a plastic material, and the combination of the two achieves excellent mixing uniformity and tableting requirements.

[0038] In certain embodiments, the pellet core of the bisoprolol micropills of the present invention comprises microcrystalline cellulose and sucrose. At this time, based on 100 parts by weight of the pellet core, the amount of microcrystalline cellulose is usually lower than the amount of sucrose. Generally speaking, the amount of microcrystalline cellulose is 0.1-30 parts by weight, such as 1-20 parts by weight, 5-15 parts by weight, 8-10 parts by weight, etc. The amount of sucrose is generally 75-99.9 parts by weight, such as 80 parts by weight, 85 parts by weight, 90 parts by weight, and 95 parts by weight. If the amount of microcrystalline cellulose is too large, the pellet core obtained tends to become larger in elasticity, which is unfavorable for tableting, and even produces rupture of the coating layer during tableting. If the amount of microcrystalline cellulose is too large, the sucrose content as a brittle material is too high, and the pellets tend to break during tableting.

[0039] In certain embodiments, the pellet core of the bisoprolol micropills of the present invention comprises calcium hydrogen phosphate, microcrystalline cellulose and sucrose. At this time, based on 100 parts by weight of the pellet core, the amount of microcrystalline cellulose is generally lower than the amount of sucrose. Generally speaking, the amount of microcrystalline cellulose is 0.1-25 parts by weight, such as 1-20 parts by weight, 5-15 parts by weight, 8-10 parts by weight, etc. The total amount of sucrose and calcium hydrogen phosphate is generally 75-99.9 parts by weight, such as 80 parts by weight, 85 parts by weight, 90 parts by weight, and 95 parts by weight. The weight ratio of sucrose to calcium hydrogen phosphate is generally (1-5): 1. The water solubility of calcium hydrogen phosphate is lower than that of sucrose, and the hardness of calcium hydrogen phosphate powder is higher than that of sucrose powder. By using calcium hydrogen phosphate to replace part of the sucrose, the adverse effect of water in the drug-carrying solvent on the pellet core when it is adsorbed to the pellet core can be avoided. If the proportion of sucrose is too high, the wettability of the water in the drug-carrying solvent to the pellet core becomes larger, and the pellet core tends to adhere, affecting subsequent processes. In this case, it is necessary to control the water content in the drug-loading solvent or use anhydrous solvent. On the other hand, if the proportion of sucrose is too low, the wettability of the drug-loading solvent on the pellet core tends to deteriorate, which is not conducive to the adhesion of the drug layer.

[0040] In the present invention, the drug layer is prepared by a drug-loaded solution comprising bisoprolol fumarate, hydroxypropyl cellulose and a solvent, preferably by applying the drug-loaded solution to the surface of the pellet core. The concentration of bisoprolol fumarate in the drug-loaded solution of the present invention is not limited and can be freely set as needed. Exemplarily, the concentration of bisoprolol fumarate is 1-40 mg / L, preferably 5-35 mg / L, more preferably 10-30 mg / L, and also preferably 15-25 mg / L. The concentration of hydroxypropyl cellulose in the drug-loaded solution of the present invention is not limited and can be freely set as needed. Exemplarily, the concentration of hydroxypropyl cellulose is 1.0-20.0 mg / L, such as 1.5-12.0 mg / L, 2.0-10.0 mg / L, and also preferably 5.0-8.0 mg / L. In an exemplary embodiment, the weight ratio of bisoprolol fumarate and hydroxypropyl cellulose is 1.5-2.5:1.

[0041] The solvent used in the drug-loaded solution of the present invention generally comprises an alcohol, such as methanol, ethanol, or the like. In certain embodiments, particularly when the pellet core contains a high sucrose content, an alcohol is preferably used as the solvent. In certain embodiments, particularly when the pellet core contains a low sucrose content, an aqueous alcohol solvent is preferably used as the solvent. In this case, the alcohol content is generally 70-90% by volume, such as 75%, 80%, or 85%. The amount of solvent used is not limited, but is generally 7-8 times the weight of the active ingredient and excipients.

[0042] In the present invention, the amount of the drug-loaded layer is not limited, but based on 650 parts by weight of the pellet core, the dry weight of the drug layer is 6-10 parts, such as 6.5 parts, 7 parts, 7.5 parts, 8 parts, 8.5 parts, 9 parts, 9.5 parts, etc.

[0043] In the present invention, the isolation layer comprises hypromellose and glycerol. In the present invention, the hypromellose does not react with the active pharmaceutical ingredient and does not adsorb the drug, so it does not affect drug release. On the other hand, the glycerol in the isolation layer forms hydrogen bonds or van der Waals forces with the hypromellose, thereby increasing the interaction between the molecular chains, improving the softness and ductility of the molecular chains, and avoiding the isolation layer from cracking during tableting. The usage ratio of glycerol to hypromellose is generally 1:1.5-5 based on weight, preferably 1:1.5-3, etc.

[0044] In the present invention, the amlodipine micropellets contain amlodipine besylate, microcrystalline cellulose, and sodium starch glycolate. Based on 100 parts by weight of amlodipine besylate, the amount of microcrystalline cellulose used is generally 800-1500 parts by weight, preferably 900-1400 parts by weight, and more preferably 1000-1200 parts by weight. The amount of sodium starch glycolate used is generally 15-50 parts by weight, preferably 18-40 parts by weight, and further preferably 20-30 parts by weight, such as 25 parts by weight.

[0045] In the present invention, amlodipine micropellets can be prepared using known micropellet preparation methods or processes. Exemplary preparation processes include extrusion-spheronization using an extruder and spheronizer, centrifugal-fluidized pelleting, fluidized bed pelleting, coating pan pelleting, and liquid medium pelleting. Depending on the type of pelleting equipment and the preparation process, pelleting types include rotary pelleting, layered pelleting, compression pelleting, and spherical pelleting. The first stage of rotary pelleting technology involves random collisions of raw powder particles to form larger particles (nucleation) and subsequent agglomeration, ultimately forming fine pellet cores. The size of the pellet cores depends on the size of the raw powder particles, the moisture content, the viscosity of the binder solution, the humidity of the matrix, the rolling and drying speeds, and other factors that affect pellet core formation. Layered pelleting refers to the process in which the drug is deposited on the surface of a prefabricated pellet core in the form of a solution, suspension, or dry powder. The deposited material may be crystals, particles, or pellet cores. There are two exemplary process technologies: one is the liquid phase layering method in which the drug is continuously layered onto the pellet core from a solution or suspension, and the other is the powder layering method in which dry powder is layered onto the pellet core. Compression pelleting refers to the process of using mechanical force to compress the drug and excipients into pellets of a certain size. Spheroidization pelleting technology is the process of spraying a hot melt, solution or suspension to form spherical particles or pellets. Atomized liquid is also used in other pelleting technologies (such as liquid phase layering), but it is only used for the pellet growth process. In spheroidization pelleting technology, the atomization process can obtain spherical particles directly from hot melt solutions and suspensions through evaporation or cooling. After the liquid is atomized, a large surface area is generated, which further increases the drying and cooling effect of the droplets.

[0046] In the present invention, the lubricant is not limited, and illustrative examples include but are not limited to magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycols, and magnesium lauryl sulfate. The present invention can use any one of these or a combination of two or more. In the case of a combination, the amount ratio of each lubricant is not limited and can be freely set by a technician as needed. In a preferred embodiment, the present invention uses a hydrophobic lubricant, such as magnesium stearate, which is easy to mix with the particles and has a smooth and beautiful tablet surface after tableting.

[0047] In the present invention, the amount of lubricant used is generally 0.01-2 parts by weight based on the weight of the composition, for example, 0.05 parts by weight, 0.08 parts by weight, 0.1 parts by weight, 0.2 parts by weight, 0.4 parts by weight, 0.5 parts by weight, 0.8 parts by weight, 1 part by weight, 1.5 parts by weight, or 1.8 parts by weight. If the amount is too large, the tablet may disintegrate or dissolve slowly due to its hydrophobicity.

[0048] In the present invention, an exemplary method for preparing a bisoprolol amlodipine composition comprises the following steps:

[0049] (1) suspending a bisoprolol fumarate solution into a fluidized state and spraying the suspension onto the surface of the blank pellet core to form a drug-loaded layer to obtain drug-loaded micropellets, spraying a solution of hydroxypropyl methylcellulose and glycerol onto the surface of the drug-loaded micropellets to form an isolation layer, and drying the suspension to obtain bisoprolol micropellets, wherein the blank pellet core contains calcium hydrogen phosphate, microcrystalline cellulose, and sucrose;

[0050] (2) preparing amlodipine pellets from raw materials comprising amlodipine besylate, microcrystalline cellulose, and sodium starch glycolate; and

[0051] (3) The bisoprolol pellets, amlodipine pellets and lubricant are mixed and then compressed into tablets to obtain bisoprolol amlodipine tablets, or the bisoprolol pellets, amlodipine pellets, lubricant and other excipients are homogenized and then filled into capsules to obtain a capsule preparation.

[0052] Those skilled in the art will understand that the numbers (1), (2), etc. are only for the purpose of distinguishing different steps and do not indicate the order of the steps. As long as the purpose of the present invention can be achieved, the order of the above steps is not particularly limited. In addition, those skilled in the art will also understand that other steps or operations may be included before or after the above steps (1)-(3), or between these arbitrary steps, for example, to further optimize and / or improve the method described in the present invention.

[0053] Example 1

[0054] This example is a method for preparing an exemplary bisoprolol amlodipine tablet, and its formula is as follows:

[0055] Table 1

[0056]

[0057]

[0058] Said include:

[0059] 1. Preparation of Bisoprolol Pellets

[0060] 1.1 Blank pellet cores (particle size 100-120 μm) were prepared by compounding calcium hydrogen phosphate, microcrystalline cellulose CEOLUS UF-702, and sucrose, wherein the weight ratio of calcium hydrogen phosphate, microcrystalline cellulose, and sucrose was 40:20:40.

[0061] 1.2 Grind the bisoprolol fumarate API and hydroxypropyl cellulose separately and pass through a 30-mesh sieve to obtain a powder. Dissolve an appropriate amount of bisoprolol fumarate in half the prescribed solvent (70% ethanol, i.e., 4 times the amount of API + excipients). Heat the remaining half of the prescribed solvent to 40°C and dissolve an appropriate amount of hydroxypropyl cellulose. Mix the two resulting solutions to prepare a drug-loaded solution. Adjust the amounts of each component so that the drug-loaded solution contains 7.3 mg / L hydroxypropyl cellulose and 25 mg / L bisoprolol fumarate. Place blank pellet cores into the fluidized bed, set the fan speed to 1500-2000 rpm, and the inlet air temperature to 40-50°C. Specific parameters should be adjusted according to actual conditions. Preheat the pellets to approximately 38°C, then apply an atomizing pressure of 0.15 MPa. Start the peristaltic pump spraying, increasing the spray speed from slow to fast. Control the peristaltic pump speed to 8-12 rpm (tube inner diameter 5 mm). Monitor the temperature and fluidization state of the material throughout the process, adjust parameters according to actual conditions to prevent pellets from sticking.

[0062] 1.3 Heat half of the prescribed amount of purified water to about 60°C, stir into a vortex, slowly add hydroxypropyl methylcellulose to disperse, add the remaining water at room temperature, stir until the solution is clear, add glycerol and stir for further 30 minutes. Put the upper drug pellets obtained in step 1.2 into the fluidized bed, set the fan speed to 1800-2200rpm, the inlet air temperature to 42-49°C, preheat the pellets, control the material temperature to 36-41°C, then turn on the atomization pressure to 0.11-0.18Mpa, turn on the peristaltic pump to spray, and increase the spray speed from slow to fast. The peristaltic pump speed is controlled at 8-12rpm (tube inner diameter 5mm). Monitor the temperature and fluidization state of the material throughout the process, adjust the parameters according to the actual situation to prevent the pellets from sticking.

[0063] 1.4 The granules obtained in step 1.3 were sieved through a 100-120 mesh sieve and subjected to intermediate testing to obtain bisoprolol pellets.

[0064] 2. Preparation of Amlodipine Pellets

[0065] The amlodipine besylate API was passed through an oscillating granulator and screened through a 30-mesh sieve for pretreatment. The pretreated API, half the formulated amount of microcrystalline cellulose, and sodium carboxymethyl starch were weighed and added to a wet granulator. The stirring blade speed was adjusted to 10-20 rpm and the cutting blade speed to 20-50 rpm. Mixing was continued under these conditions for 5 minutes, after which stirring and cutting were stopped. The prepared soft material was extruded through a 0.12-0.15 mm orifice plate using an extruder spheronizer. Spheronization was then performed at 600-1600 rpm and then 100-500 rpm, respectively. During the spheronization process, an appropriate amount of 75% ethanol was sprayed to promote pellet formation. The pellets (wet material) obtained by spheronization were dried in a fluidized bed with an inlet air temperature of 30-45°C and a material temperature of 35-45°C for approximately 10-30 minutes. Further granulation and intermediate testing were performed to obtain amlodipine pellets.

[0066] 3. Tablet preparation

[0067] The obtained bisoprolol micropellets and amlodipine micropellets are mixed in equal amounts, and magnesium stearate is further added and fully mixed, and then tablets are obtained by tableting.

[0068] Example 2

[0069] This example is a method for preparing an exemplary bisoprolol amlodipine tablet. The formulation and method are the same as those in Example 1 except for the following differences:

[0070] 1. Preparation of Bisoprolol Pellets

[0071] 1.1 Blank pellet cores (particle size 100-120 μm) were prepared by compounding calcium hydrogen phosphate, microcrystalline cellulose CEOLUS UF-702, and sucrose, wherein the weight ratio of calcium hydrogen phosphate, microcrystalline cellulose, and sucrose was 20:10:70.

[0072] 1.2 Grind the bisoprolol fumarate API and hydroxypropyl cellulose separately and pass through a 30-mesh sieve to obtain a powder. Dissolve an appropriate amount of bisoprolol fumarate in half the prescribed amount of solvent (70% ethanol, i.e., 4 times the amount of API + excipients). Heat the remaining solvent to 40°C and dissolve an appropriate amount of hydroxypropyl cellulose. Mix the two resulting solutions to prepare a drug-loaded solution. Adjust the amounts of each component so that the drug-loaded solution contains 7.3 mg / L hydroxypropyl cellulose and 25 mg / L bisoprolol fumarate. Place the blank pellet cores into the fluidized bed, set the fan speed to 1500-2000 rpm, and the inlet air temperature to 40-50°C. Specific parameters should be adjusted according to actual conditions. Preheat the pellets to approximately 38°C, then activate the atomization pressure at 0.15 MPa. Start the peristaltic pump spray, increasing the spray speed from slow to fast. Control the peristaltic pump speed to 8-12 rpm (tube inner diameter 5 mm). Monitor the temperature and fluidization state of the material throughout the process, and adjust the parameters according to actual conditions to prevent pellets from sticking.

[0073] 1.3 Heat half of the prescribed amount of purified water to about 60°C, stir into a vortex, slowly add hydroxypropyl methylcellulose to disperse, add the remaining water at room temperature, stir until the solution is clear, add glycerol and stir for another 30 minutes. Put the drug pellets obtained in step 1.2 into the fluidized bed, set the fan speed to 1800-2200rpm, the inlet air temperature to 42-49°C, preheat the pellets, control the material temperature to 36-41°C, then turn on the atomization pressure to 0.11-0.18Mpa, turn on the peristaltic pump to spray, and increase the spray speed from slow to fast. The peristaltic pump speed is controlled at 8-12rpm (tube inner diameter 5mm). Monitor the temperature and fluidization state of the material throughout the process, and adjust the parameters according to the actual situation to prevent the pellets from sticking.

[0074] 1.4 The granules obtained in step 1.3 were sieved through a 100-120 mesh sieve and subjected to intermediate testing to obtain bisoprolol pellets.

[0075] 2. Preparation of Amlodipine Pellets

[0076] The amlodipine besylate API was passed through an oscillating granulator, screened with a 30-mesh sieve, and pretreated for later use. The pretreated API, microcrystalline cellulose, and sodium carboxymethyl starch were weighed and added to a wet granulator. The stirring blade speed was adjusted to 10-20 rpm and the cutting blade speed to 20-50 rpm. Mixing was continued under these conditions for 5 minutes, followed by cessation of stirring and cutting. The prepared soft material was extruded through a 0.12-0.15 mm orifice plate using an extruder spheronizer. Spheronization was then performed at 600-1600 rpm and then 100-500 rpm, respectively. During the spheronization process, an appropriate amount of 75% ethanol was sprayed to promote pellet formation. The pellets (wet material) obtained by spheronization were dried in a fluidized bed with an inlet air temperature of 30-45°C and a material temperature of 35-45°C for approximately 10-30 minutes. Further granulation and intermediate testing were performed to obtain amlodipine pellets.

[0077] 3. Tablet preparation

[0078] The obtained bisoprolol micropellets and amlodipine micropellets are mixed in equal amounts, and magnesium stearate is further added and fully mixed, and then tablets are obtained by tableting.

[0079] Example 3

[0080] This example is a method for preparing an exemplary bisoprolol amlodipine tablet, wherein the method is the same as Example 1 except for the following differences:

[0081] 1. Preparation of Bisoprolol Pellets

[0082] 1.1 Blank pellet cores (particle size 100-120 μm) were prepared by compounding microcrystalline cellulose CEOLUS UF-702 and sucrose, wherein the weight ratio of microcrystalline cellulose to sucrose was 20:80.

[0083] 1.2 Grind the bisoprolol fumarate API and hydroxypropyl cellulose separately and pass through a 30-mesh sieve to obtain a powder. Dissolve an appropriate amount of bisoprolol fumarate in half the prescribed amount of pure ethanol (i.e., 4 times the amount of API + excipients). Heat the remaining half of the prescribed amount of ethanol to 40°C and dissolve an appropriate amount of hydroxypropyl cellulose. Mix the two resulting solutions to prepare a drug-loaded solution. Adjust the amounts of each component to achieve a hydroxypropyl cellulose content of 7.3 mg / L and a bisoprolol fumarate content of 25 mg / L. Place blank pellet cores into the fluidized bed, set the fan speed to 1500-2000 rpm, and the inlet air temperature to 40-50°C. Specific parameters should be adjusted according to actual conditions. Preheat the pellets to approximately 38°C, then apply an atomizing pressure of 0.15 MPa. Start the peristaltic pump spraying, increasing the spray speed from slow to fast. Control the peristaltic pump speed to 8-12 rpm (tube inner diameter 5 mm). Monitor the temperature and fluidization state of the material throughout the process, and adjust the parameters according to actual conditions to prevent pellets from sticking.

[0084] 1.3 Heat half of the prescribed amount of purified water to about 60°C, stir into a vortex, slowly add hydroxypropyl methylcellulose to disperse, add the remaining water at room temperature, stir until the solution is clear, add glycerol and stir for another 30 minutes. Put the drug pellets obtained in step 1.2 into the fluidized bed, set the fan speed to 1800-2200rpm, the inlet air temperature to 42-49°C, preheat the pellets, control the material temperature to 36-41°C, then turn on the atomization pressure to 0.11-0.18Mpa, turn on the peristaltic pump to spray, and increase the spray speed from slow to fast. The peristaltic pump speed is controlled at 8-12rpm (tube inner diameter 5mm). Monitor the temperature and fluidization state of the material throughout the process, and adjust the parameters according to the actual situation to prevent the pellets from sticking.

[0085] 1.4 The granules obtained in step 1.3 were sieved through a 100-120 mesh sieve and subjected to intermediate testing to obtain bisoprolol pellets.

[0086] 2. Preparation of Amlodipine Pellets

[0087] The amlodipine besylate raw material is passed through a swing granulator, screened with a 30-mesh sieve, and pretreated for later use. The pretreated raw material, microcrystalline cellulose, and sodium carboxymethyl starch are weighed and added to a wet granulator. The stirring blade speed is adjusted to 10 rps and the cutting blade speed is adjusted to 20-50 rps. Mix under these conditions for 5 minutes, and then stop stirring and cutting. The prepared soft material is extruded through a 0.12-0.15 mm orifice plate using an extruder spheronizer, and then spheronized at 600-1600 rpm and 100-500 rpm respectively. During the spheronization process, an appropriate amount of 75% ethanol can be sprayed to help the micropills form. The micropills (wet material) prepared by spheronization are dried in a fluidized bed with an inlet air temperature of 45°C and a material temperature controlled at 35-45°C for approximately 30 minutes. Further granulation and intermediate testing are performed to obtain amlodipine micropills.

[0088] 3. Tablet preparation

[0089] The obtained bisoprolol micropellets and amlodipine micropellets are mixed in equal amounts, and magnesium stearate is further added and fully mixed, and then tablets are obtained by tableting.

[0090] Comparative Example 1

[0091] This comparative example is a method for preparing an exemplary bisoprolol amlodipine tablet, which is the same as Example 1 except for the following differences:

[0092] 1. Preparation of Bisoprolol Pellets

[0093] 1.1 Blank pellets (particle size 100-120 μm) were prepared by compounding microcrystalline cellulose CEOLUS UF-702 and sucrose. The blank pellet formula was 117 mg / tablet, and the weight ratio of microcrystalline cellulose to sucrose was 20:80.

[0094] 1.2 Grind the bisoprolol fumarate API and hydroxypropyl cellulose separately and pass through a 30-mesh sieve to obtain a powder. Dissolve an appropriate amount of bisoprolol fumarate in half the prescribed solvent (50% ethanol, i.e., 4 times the amount of API + excipients). Heat the remaining half of the prescribed solvent to 40°C and dissolve an appropriate amount of hydroxypropyl cellulose. Mix the two resulting solutions to prepare a drug-loaded solution. Adjust the amounts of each component so that the drug-loaded solution contains 7.3 mg / L hydroxypropyl cellulose and 25 mg / L bisoprolol fumarate. Place blank pellet cores into the fluidized bed, set the fan speed to 1500-2000 rpm, and the inlet air temperature to 40-50°C. Adjust according to actual conditions. Preheat the pellets, control the material temperature to approximately 38°C, then activate the atomizing pressure at 0.15 MPa. Start the peristaltic pump spraying, increasing the spray speed from slow to fast. Control the peristaltic pump speed to 8-12 rpm (tube inner diameter 5 mm). Monitor the material temperature and fluidization state throughout the process. Adjust parameters according to actual conditions to prevent pellets from sticking together.

[0095] 1.3 Heat half of the prescribed amount of purified water to about 60°C, stir into a vortex, slowly add hydroxypropyl methylcellulose to disperse, add the remaining water at room temperature, stir until the solution is clear, add glycerol and stir for further 30 minutes. Put the upper drug pellets obtained in step 1.2 into the fluidized bed, set the fan speed to 1800-2200rpm, the inlet air temperature to 42-49°C, preheat the pellets, control the material temperature to 36-41°C, then turn on the atomization pressure to 0.11-0.18Mpa, turn on the peristaltic pump to spray, and increase the spray speed from slow to fast. The peristaltic pump speed is controlled at 8-12rpm (tube inner diameter 5mm). Monitor the temperature and fluidization state of the material throughout the process. Adjust the parameters according to the actual situation to prevent the pellets from sticking.

[0096] 1.4 The granules obtained in step 1.3 were sieved through a 100-120 mesh sieve and subjected to intermediate testing to obtain bisoprolol pellets.

[0097] 2. Preparation of Amlodipine Pellets

[0098] The amlodipine besylate raw material is passed through a swing granulator, screened with a 30-mesh sieve, and pretreated for later use. The pretreated raw material, microcrystalline cellulose, and sodium carboxymethyl starch are weighed and added to a wet granulator. The stirring blade speed is adjusted to 10 rps and the cutting blade speed is adjusted to 20-50 rps. Mix under these conditions for 5 minutes, and then stop stirring and cutting. The prepared soft material is extruded through a 0.12-0.15 mm orifice plate using an extruder spheronizer, and then spheronized at 600-1600 rpm and 100-500 rpm respectively. During the spheronization process, an appropriate amount of 75% ethanol can be sprayed to help the micropills form. The micropills (wet material) prepared by spheronization are dried in a fluidized bed with an inlet air temperature of 45°C and a material temperature controlled at 35-45°C for approximately 30 minutes. Further granulation and intermediate testing are performed to obtain amlodipine micropills.

[0099] 3. Tablet preparation

[0100] The obtained bisoprolol micropellets and amlodipine micropellets are mixed in equal amounts, and magnesium stearate is further added and fully mixed, and then tablets are obtained by tableting.

[0101] Comparative Example 2

[0102] This comparative example is a method for preparing an exemplary bisoprolol amlodipine tablet, which is the same as Example 1 except for the following differences:

[0103] 1. Preparation of Bisoprolol Pellets

[0104] 1.1 Blank pellet cores (particle size 100-120 μm) were prepared by compounding calcium hydrogen phosphate, microcrystalline cellulose CEOLUS UF-702, and sucrose, wherein the weight ratio of calcium hydrogen phosphate, microcrystalline cellulose, and sucrose was 40:20:40.

[0105] 1.2 Grind the bisoprolol fumarate API and hydroxypropylcellulose separately and pass through a 30-mesh sieve to obtain a powder. Dissolve an appropriate amount of bisoprolol fumarate in half the prescribed amount of water (i.e., 4 times the amount of API + excipients). Heat the remaining half of the prescribed amount of solvent to 40°C and dissolve an appropriate amount of hydroxypropylcellulose. Mix the two resulting solutions to prepare a drug-loaded solution. Adjust the amounts of each component to achieve a hydroxypropylcellulose content of 7.3 mg / L and a bisoprolol fumarate content of 25 mg / L. Place blank pellet cores into the fluidized bed, set the fan speed to 1500-2000 rpm, and the inlet air temperature to 40-50°C. Specific parameters should be adjusted based on actual conditions. Preheat the pellets to approximately 38°C, then apply an atomizing pressure of 0.15 MPa. Start the peristaltic pump spraying, increasing the spray speed from slow to fast. Control the peristaltic pump speed to 8-12 rpm (tube inner diameter 5 mm). Monitor the material temperature and fluidization state throughout the process. Adjust parameters according to actual conditions to prevent pellets from sticking together.

[0106] 1.3 Heat half of the prescribed amount of purified water to about 60°C, stir into a vortex, slowly add hydroxypropyl methylcellulose to disperse, add the remaining water at room temperature, stir until the solution is clear, add glycerol and stir for further 30 minutes. Put the upper drug pellets obtained in step 1.2 into the fluidized bed, set the fan speed to 1800-2200rpm, the inlet air temperature to 42-49°C, preheat the pellets, control the material temperature to 36-41°C, then turn on the atomization pressure to 0.11-0.18Mpa, turn on the peristaltic pump to spray, and increase the spray speed from slow to fast. The peristaltic pump speed is controlled at 8-12rpm (tube inner diameter 5mm). Monitor the temperature and fluidization state of the material throughout the process. Adjust the parameters according to the actual situation to prevent the pellets from sticking.

[0107] 1.4 The granules obtained in step 1.3 were sieved through a 100-120 mesh sieve and subjected to intermediate testing to obtain bisoprolol pellets.

[0108] 2. Preparation of Amlodipine Pellets

[0109] The amlodipine besylate raw material is passed through a swing granulator, screened with a 30-mesh sieve, and pretreated for later use. The pretreated raw material, microcrystalline cellulose, and sodium carboxymethyl starch are weighed and added to a wet granulator. The stirring blade speed is adjusted to 10 rps and the cutting blade speed is adjusted to 20-50 rps. Mix under these conditions for 5 minutes, and then stop stirring and cutting. The prepared soft material is extruded through a 1-1.5 mm orifice plate using an extrusion spheronizer, and then spheronized at 600-1600 rpm and 100-500 rpm respectively. During the spheronization process, an appropriate amount of 75% ethanol can be sprayed to help the micropills form. The micropills (wet material) prepared by spheronization are dried in a fluidized bed with an inlet air temperature of 45°C, a material temperature controlled at 35-45°C, and a drying time of approximately 30 minutes. Further granulation and intermediate testing are performed to obtain amlodipine micropills.

[0110] 3. Tablet preparation

[0111] The obtained bisoprolol micropellets and amlodipine micropellets are mixed in equal amounts, and magnesium stearate is further added and fully mixed, and then tablets are obtained by tableting.

[0112] Comparative Example 3

[0113] This comparative example is a method for preparing an exemplary bisoprolol amlodipine tablet, which is the same as Example 1 except for the following differences:

[0114] 1. Preparation of Bisoprolol Pellets

[0115] 1.1 Blank pellet cores (particle size 100-120 μm) were prepared by compounding calcium hydrogen phosphate, microcrystalline cellulose CEOLUS UF-702, and sucrose, wherein the weight ratio of calcium hydrogen phosphate, microcrystalline cellulose, and sucrose was 40:20:40.

[0116] 1.2 Grind the bisoprolol fumarate API and hydroxypropyl cellulose separately and pass through a 30-mesh sieve to obtain a powder. Dissolve an appropriate amount of bisoprolol fumarate in half the prescribed solvent (70% ethanol, i.e., 4 times the amount of API + excipients). Heat the remaining half of the prescribed solvent to 40°C and dissolve an appropriate amount of hydroxypropyl cellulose. Mix the two resulting solutions to prepare a drug-loaded solution. Adjust the amounts of each component so that the drug-loaded solution contains 7.3 mg / L hydroxypropyl cellulose and 25 mg / L bisoprolol fumarate. Place blank pellet cores into the fluidized bed, set the fan speed to 1500-2000 rpm, and the inlet air temperature to 40-50°C. Specific parameters should be adjusted according to actual conditions. Preheat the pellets to approximately 38°C, then apply an atomizing pressure of 0.15 MPa. Start the peristaltic pump spraying, increasing the spray speed from slow to fast. Control the peristaltic pump speed to 8-12 rpm (tube inner diameter 5 mm). Monitor the temperature and fluidization state of the material throughout the process, adjust parameters according to actual conditions to prevent pellets from sticking.

[0117] 1.3 Heat half of the prescribed amount of purified water to about 60°C, stir it into a vortex, slowly add hydroxypropyl methylcellulose to disperse it, add the remaining water at room temperature, stir until the solution is clear and set aside. Put the upper medicine pellets obtained in step 1.2 into the fluidized bed, set the fan speed to 1800-2200rpm, the inlet air temperature to 42-49°C, preheat the pellets, control the material temperature to 36-41°C, then turn on the atomization pressure to 0.11-0.18Mpa, turn on the peristaltic pump to spray the liquid, and increase the spray speed from slow to fast. The peristaltic pump speed is controlled at 8-12rpm (tube inner diameter 5mm). Monitor the temperature and fluidization state of the material throughout the process, adjust the parameters according to the actual situation, and prevent the pellets from sticking.

[0118] 1.4 The granules obtained in step 1.3 were sieved through a 100-120 mesh sieve and subjected to intermediate testing to obtain bisoprolol pellets.

[0119] 2. Preparation of Amlodipine Pellets

[0120] The amlodipine besylate API was passed through an oscillating granulator, screened with a 30-mesh sieve, and pretreated for later use. The pretreated API, microcrystalline cellulose, and sodium carboxymethyl starch were weighed and added to a wet granulator. The stirring blade speed was adjusted to 10-20 rpm and the cutting blade speed to 20-50 rpm. Mixing was continued under these conditions for 5 minutes, followed by cessation of stirring and cutting. The prepared soft material was extruded through a 0.12-0.15 mm orifice plate using an extruder spheronizer. Spheronization was then performed at 600-1600 rpm and then 100-500 rpm, respectively. During the spheronization process, an appropriate amount of 75% ethanol was sprayed to promote pellet formation. The pellets (wet material) obtained by spheronization were dried in a fluidized bed with an inlet air temperature of 30-45°C and a material temperature of 35-45°C for approximately 10-30 minutes. Further granulation and intermediate testing were performed to obtain amlodipine pellets.

[0121] 3. Tablet preparation

[0122] The obtained bisoprolol micropellets and amlodipine micropellets were mixed in equal amounts, and magnesium stearate was further added and fully mixed before tableting. The bisoprolol micropellets were severely broken.

[0123] Table 2 Test results of influencing factors (high temperature condition 60℃)

[0124]

[0125] Table 3 Test results of influencing factors (high humidity conditions 25℃ / 75%RH)

[0126]

[0127] Although the present invention has been described with reference to exemplary embodiments, it should be understood that the invention is not limited to the disclosed exemplary embodiments. Various modifications and variations may be made to the exemplary embodiments of the present specification without departing from the scope or spirit of the present invention. The scope of the claims is to be given the broadest interpretation so as to encompass all such modifications and equivalent structures and functions.

Claims

1. A method for preparing bisoprolol amlodipine tablets, characterized in that, Based on 100 parts by weight of the composition, the tablet comprises 40-50 parts by weight of bisoprolol micropellets with a diameter of 100-300 μm, 40-50 parts by weight of amlodipine micropellets with a diameter of 100-300 μm, and 0.01-2 parts by weight of a lubricant. The method comprises the following steps: (1) suspending a bisoprolol fumarate solution into a fluidized state and spraying it onto the surface of the blank pill core to form a drug-loaded layer to obtain drug-loaded micropellets, spraying a hydroxypropyl methylcellulose and glycerol solution onto the surface of the drug-loaded micropellets to form an isolation layer, and drying to obtain bisoprolol coated micropellets, wherein the blank pill core contains calcium hydrogen phosphate, microcrystalline cellulose and sucrose, based on 100 parts by weight of the blank pill core, the amount of the microcrystalline cellulose is 0.1-25 parts by weight, the total amount of the sucrose and the calcium hydrogen phosphate is 75-99.9 parts by weight, and the amount of the microcrystalline cellulose is lower than the amount of sucrose, the weight ratio of the sucrose to calcium hydrogen phosphate is (1-5):1, and the bisoprolol fumarate solution contains bisoprolol fumarate, hydroxypropyl cellulose and a solvent, and the solvent is a 70-90% ethanol-water mixed solvent; (2) preparing amlodipine pellets from raw materials comprising amlodipine besylate, microcrystalline cellulose, and sodium starch glycolate; and (3) The bisoprolol pellets, amlodipine pellets and lubricant are mixed and tableted to obtain bisoprolol amlodipine tablets.

2. The method according to claim 1, characterized in that The weight ratio of calcium hydrogen phosphate, microcrystalline cellulose and sucrose is 2:1:

2.

3. The method according to claim 1, characterized in that The isolation layer is 5%-20% based on the weight of the pellet core.

4. The method according to claim 1, wherein The lubricant is selected from at least one of magnesium stearate, micropowder silica gel, talc and magnesium lauryl sulfate.

5. A bisoprolol amlodipine tablet, characterized in that: It is prepared by the method according to any one of claims 1 to 4.

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