Bisoprolol amlodipine compound tablet and preparation process thereof

Abstract

The invention discloses a bisoprolol amlodipine compound tablet and a preparation process thereof, and the preparation method comprises the following steps: mixing bisoprolol or a pharmaceutically acceptable salt thereof with microcrystalline cellulose, carboxymethyl starch sodium, colloidal silicon dioxide and anhydrous citric acid according to a ratio, and carrying out dry granulation to obtain bisoprolol particles; the amlodipine or the pharmaceutically acceptable salt thereof, microcrystalline cellulose, carboxymethyl starch sodium, colloidal silicon dioxide and anhydrous citric acid are subjected to dry granulation in proportion, and amlodipine granules are obtained; the preparation method comprises the following steps: uniformly mixing bisoprolol particles and amlodipine particles, and uniformly mixing with a lubricant to obtain total mixed particles; and tabletting the total mixed particles to obtain the bisoprolol amlodipine compound tablet. According to the process, a relatively complex double-layer tablet process is not adopted, and the two active ingredients can be substantially separated, so that the operation can be effectively simplified, and the stability of the product can be improved.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a bisoprolol-amlodipine compound tablet and a preparation process thereof. Background Art

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] The combination preparation of bisoprolol and amlodipine is a long-acting antihypertensive drug. However, if the active substances of bisoprolol and amlodipine come into direct contact, a chemical reaction will occur to produce AML-2, an added impurity of amlodipine and fumaric acid in bisoprolol, posing risks to the stability and safety of the combination preparation.

[0004] The chemical formula of impurity AML-2 is C 24 H 29 ClN2O9, the structural formula is as follows:

[0005]

[0006] The existing preparation method of bisoprolol and amlodipine compound preparation includes: separating different active ingredients in different granules, further mixing the granules with excipients and filling them into capsules or sachets, or pressing them into so-called double-layer tablets. This method still has the following problems: the active ingredients are granulated separately and double-layer tablets are prepared, but there is still a large contact surface between the two active ingredients, and the chemical reaction between amlodipine base and fumaric acid to form impurity product AML-2 cannot be completely avoided.

[0007] Also have preparation method is to granulate amlodipine besylate and bisoprolol fumarate together, tablet, then pack the composition in moisture-proof packaging.In this production process, because after feeding, amlodipine besylate and bisoprolol fumarate promptly begin to contact, begin to react, produce degradation product AML-2, therefore need to carry out strict control to the ambient temperature and humidity in the whole production process, and shorten the production process duration as far as possible, to ensure that the preparation produced by this process can have good quality, have good stability during stability.Because need to control its whole production environment temperature and humidity and need to complete the whole production process with extremely short process duration, and use moisture-proof packaging, production pressure and production cost are greatly improved, process requirements are also higher, and the operability of process is greatly reduced. Summary of the invention

[0008] In view of the deficiencies in the prior art, the present invention aims to provide a bisoprolol-amlodipine compound tablet and a preparation process thereof.

[0009] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0010] In a first aspect, the present invention provides a method for preparing a bisoprolol-amlodipine compound tablet, comprising the following steps:

[0011] Mixing bisoprolol or a pharmaceutically acceptable salt thereof with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate in proportion and dry granulating the mixture to obtain bisoprolol granules;

[0012] Dry granulating amlodipine or a pharmaceutically acceptable salt thereof with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and anhydrous citric acid in proportion to obtain amlodipine granules;

[0013] After the bisoprolol granules and the amlodipine granules are uniformly mixed, in order to prevent the risk of sticking during tableting, they are mixed evenly with an external lubricant to obtain a total mixed granule.

[0014] The total mixed granules are tableted to obtain bisoprolol-amlodipine compound tablets.

[0015] In the above, microcrystalline cellulose is a filler, sodium starch glycolate is a disintegrant, colloidal silicon dioxide is a glidant, magnesium stearate is a lubricant, and anhydrous citric acid is a pH regulator.

[0016] The fillers, disintegrants, glidants and lubricants used in bisoprolol granules and amlodipine granules are consistent, the excipients of the two layers of materials are consistent, the API and the excipients are fully mixed before dry granulation, and the API and the excipients are roll-pressed in the dry granulation process to achieve full combination of the raw and excipients in each layer, thereby reducing the contact area between the two APIs. After dry granulation, the powder properties of the two layers of materials are basically consistent, which reduces the risk of material stratification during tableting and can also improve the stability of the drug.

[0017] The inventors have found through experiments that using anhydrous citric acid as a pH regulator can further improve the stability of the compound preparation.

[0018] In some embodiments, in the bisoprolol particles, the mass ratios of bisoprolol or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate are 5:30-40, 3-8:1, 20-30:1 and 3-8:1, respectively. Specifically, the mass ratios are 5:35, 5:1, 25:1 and 5:1, respectively.

[0019] That is, the mass ratio of bisoprolol or its pharmaceutically acceptable salt to magnesium stearate is 5:30-40; the mass ratio of microcrystalline cellulose to magnesium stearate is 3-8:1; the mass ratio of sodium starch glycolate to magnesium stearate is 20-30:1; and the mass ratio of colloidal silicon dioxide to magnesium stearate is 3-8:1.

[0020] Preferably, before dry granulation of bisoprolol, bisoprolol or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate are mixed at a mixing speed of 10-20 rpm and a mixing time of 20-50 min.

[0021] In some embodiments, in the amlodipine granules, the mass ratios of amlodipine or its pharmaceutically acceptable salt, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and anhydrous citric acid are 5:30-40, 3-8:2, 20-30:1, 40-60:1, and 3-5:1, respectively. Specifically, 5:35, 5:2, 25:1, 50:1, and 4:1.

[0022] That is, the mass ratio of amlodipine or its pharmaceutically acceptable salt to anhydrous citric acid is 5:30-40; the mass ratio of microcrystalline cellulose to anhydrous citric acid is 3-8:2; the mass ratio of sodium starch glycolate to anhydrous citric acid is 20-30:1; the mass ratio of colloidal silicon dioxide to anhydrous citric acid is 40-60:1; and the mass ratio of magnesium stearate to anhydrous citric acid is 3-5:1.

[0023] Preferably, before amlodipine is granulated, amlodipine or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and anhydrous citric acid are mixed at a mixing speed of 10-20 rpm for a mixing time of 20-50 min.

[0024] In some embodiments, the mass ratio of bisoprolol particles, amlodipine particles and lubricant is 0.8-1.2:0.8-1.2:0.01-0.03; specifically 1:1:0.02.

[0025] Preferably, the mixing speed of the bisoprolol granules, amlodipine granules and lubricant is 10-20 rpm, and the mixing time is 3-15 min.

[0026] In some embodiments, the particle size of the bisoprolol granules and the amlodipine granules on the granulation screen is 0.8-1.5 mm, and the particle size of the granulation screen is 20-30 mesh.

[0027] In some embodiments, in the tableting process, the hardness of the compressed compound tablet is 30-120 N. The tableting equipment can be any type of tablet press to directly tablet the mixed material S3 to obtain the compound tablet, and the process parameters of the tableting can be adjusted conventionally.

[0028] In some embodiments, the prepared bisoprolol amlodipine compound tablets are composed of the following components in parts by mass:

[0029] 1-7 parts of bisoprolol or a pharmaceutically acceptable salt thereof, 1-7 parts of amlodipine or a pharmaceutically acceptable salt thereof, 0.2-1.0 parts of anhydrous citric acid, 30-90 parts of microcrystalline cellulose, 1-10 parts of sodium starch glycolate, 0.1-4 parts of colloidal silicon dioxide, and 0.2-3 parts of magnesium stearate.

[0030] In some embodiments, the packaging form of the bisoprolol amlodipine combination tablets is aluminum-plastic packaging, an external silica gel desiccant and a composite film bag.

[0031] Preferably, the packaging specifically comprises: polyvinyl chloride solid pharmaceutical hard sheet (a hard sheet made of polyvinyl chloride (PVC) resin as the main raw material), pharmaceutical aluminum foil (aluminum as the main raw material, and coated with a protective layer and an adhesive layer), bagged silica gel desiccant (a fine-porous spherical silica gel desiccant packaged in a solid pharmaceutical paper bag), polyester / aluminum / polyethylene pharmaceutical composite film bag (a pharmaceutical packaging composite film made of polyester / aluminum / polyethylene). The polyvinyl chloride solid pharmaceutical hard sheet and pharmaceutical aluminum foil are used as the inner packaging that directly contacts the drug, and the bagged silica gel desiccant and polyester / aluminum / polyethylene pharmaceutical composite film bag are used as the outer packaging, and the bagged silica gel desiccant is placed between the inner packaging and the outer packaging.

[0032] This packaging form can not only absorb the water vapor that enters the package through the composite film bag, but also absorb the water vapor that passes through the aluminum-plastic packaging to the outside, thereby improving the stability of the product.

[0033] In a second aspect, the present invention provides a bisoprolol-amlodipine compound tablet prepared by the preparation method.

[0034] The beneficial effects achieved by one or more embodiments of the present invention are as follows:

[0035] In order to solve the problem of excessive impurities during product stability caused by the interaction between bisoprolol and amlodipine, the present invention, under the premise of simple and easy preparation process and easy to scale up production, separates two active ingredients by dry granulation of two raw materials respectively, effectively separates two active ingredients by protection of auxiliary materials, improves the combination of raw materials and auxiliary materials, reduces the contact area of ​​two raw materials, and uses anhydrous citric acid as pH regulator in the preparation process of amlodipine besylate granules to further improve the stability of the product. The process does not adopt a relatively complex double-layer tablet process, but can substantially separate the two active ingredients, can effectively simplify the operation, and improve the stability of the product.

[0036] The product does not require special control of environmental humidity during its preparation. Adding a desiccant during the packaging process and packaging with a composite film bag further improves the stability of the drug. From the influencing factors, accelerated tests, and stability results of long-term tests of this product, the combined impurity AML-2 of bisoprolol and amlodipine in this product can be stabilized at a very low level, and the product has good stability.

[0037] The compound tablet prepared by the present invention and the reference preparation are sampled and tested for dissolution in a paddle method at 50 rpm, 900 ml dissolution medium (37±0.5° C.), 0.005 mol / L hydrochloric acid solution, pH 4.5 acetate buffer solution, and pH 6.8 phosphate buffer solution. The dissolution curves of the homemade preparation and the reference preparation in different dissolution media are similar. The dissolution and absorption in the body are ensured, thereby achieving the same clinical efficacy as the reference preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0039] Figure 1 : Dissolution curve of bisoprolol fumarate in 0.005 mol / L hydrochloric acid medium;

[0040] Figure 2 : Dissolution curve of bisoprolol fumarate in pH 4.5 acetate buffer;

[0041] Figure 3 : Dissolution curve of bisoprolol fumarate in pH 6.8 phosphate buffer;

[0042] Figure 4 : Dissolution curve of amlodipine besylate in 0.005 mol / L hydrochloric acid medium;

[0043] Figure 5 : Dissolution curve of amlodipine besylate in pH 4.5 acetate buffer;

[0044] Figure 6 : Dissolution curve of amlodipine besylate in pH 6.8 phosphate buffer. DETAILED DESCRIPTION

[0045] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0046] The present invention will be further described below in conjunction with the embodiments.

[0047] Example 1

[0048] A composition of 1000 tablets, wherein % is the mass percentage, and the following mass percentages are the mass percentages of each component to the total mass of the tablets:

[0049] Bisoprolol granules:

[0050]

[0051] Amlodipine granules:

[0052]

[0053]

[0054] Additional lubricant:

[0055] Magnesium stearate 0.62%.

[0056] Preparation process:

[0057] S1, sequentially placing microcrystalline cellulose, colloidal silicon dioxide, bisoprolol fumarate and sodium starch glycolate in a mixer for mixing, the mixing speed is 10 rpm, and the mixing time is 40 min. Then mixing with a lubricant, the mixing speed is 20 rpm, and the mixing time is 10 min. The mixture is put into a dry granulator. Appropriate granulation parameters are set, the dry granulation screen is 1 mm, and the whole granulation screen is 20 meshes, to obtain bisoprolol fumarate granules.

[0058] S2, sequentially placing microcrystalline cellulose, anhydrous citric acid, colloidal silicon dioxide, amlodipine besylate, and sodium starch glycolate in a mixer for mixing, the mixing speed is 10 rpm, and the mixing time is 40 min. Then mixing with an additional lubricant, the mixing speed is 20 rpm, and the mixing time is 10 min. The mixture is put into a dry granulator. Appropriate granulation parameters are set, the dry granulation screen is 1 mm, and the whole granulation screen is 20 meshes, to obtain amlodipine besylate granules.

[0059] S3, placing bisoprolol fumarate granules and amlodipine besylate granules in a mixer for mixing. The mixing speed is 20 rpm and the mixing time is 40 min. Then a lubricant is added, and the mixing speed is 20 rpm and the mixing time is 10 min to obtain a total mixed material.

[0060] S4, the hardness of the compressed compound tablet is controlled to be about 90 N. The tablet pressing equipment can be any type of tablet press to directly compress the mixed materials to obtain the compound tablet.

[0061] Example 2

[0062] A composition of 1000 tablets, wherein % is the mass percentage, and the following mass percentages are the mass percentages of each component to the total mass of the tablets:

[0063] Bisoprolol granules:

[0064]

[0065] Amlodipine granules:

[0066]

[0067] Additional lubricant:

[0068] Magnesium stearate 0.60%.

[0069] Preparation process: Same as Example 1.

[0070] Comparative Example 1

[0071] The difference from Example 1 is that anhydrous citric acid is omitted and the disintegrant is cross-linked carboxymethyl cellulose sodium. The rest is the same as Example 1.

[0072] A composition of 1000 tablets, wherein % is the mass percentage, and the following mass percentages are the mass percentages of each component to the total mass of the tablets:

[0073] Bisoprolol granules:

[0074]

[0075] Amlodipine granules:

[0076]

[0077] Additional lubricant:

[0078] Magnesium stearate 0.62%.

[0079] Preparation process:

[0080] S1, sequentially placing microcrystalline cellulose, colloidal silicon dioxide, bisoprolol fumarate and croscarmellose sodium in a mixer for mixing, the mixing speed is 10 rpm, and the mixing time is 40 min. Then mixing with a lubricant, the mixing speed is 20 rpm, and the mixing time is 10 min. The mixture is put into a dry granulator. Appropriate granulation parameters are set, the dry granulation screen is 1 mm, and the whole granulation screen is 20 meshes, to obtain bisoprolol fumarate granules.

[0081] S2, sequentially placing microcrystalline cellulose, colloidal silicon dioxide, amlodipine besylate, and croscarmellose sodium in a mixer for mixing, the mixing speed is 10 rpm, and the mixing time is 40 min. Then mixing with a lubricant, the mixing speed is 20 rpm, and the mixing time is 10 min. The mixture is put into a dry granulator. Appropriate granulation parameters are set, the dry granulation screen is 1 mm, and the whole granulation screen is 20 meshes, to obtain amlodipine besylate granules.

[0082] S3, placing bisoprolol fumarate granules and amlodipine besylate granules in a mixer for mixing. The mixing speed is 20 rpm and the mixing time is 40 min. Then a lubricant is added, and the mixing speed is 20 rpm and the mixing time is 10 min to obtain a total mixed material.

[0083] S4, the hardness of the compressed compound tablet is controlled to be about 90 N. The tablet pressing equipment can be any type of tablet press to directly compress the mixed materials to obtain the compound tablet.

[0084] Comparative Example 2

[0085] A composition of 1000 tablets, wherein % is the mass percentage, and the following mass percentages are the mass percentages of each component to the total mass of the tablets:

[0086] Bisoprolol granules:

[0087]

[0088] Amlodipine granules:

[0089]

[0090]

[0091] Additional lubricant:

[0092] Magnesium stearate 0.84%.

[0093] Preparation process: same as Comparative Example 1.

[0094] Comparative Example 3

[0095] Composition of 1000 tablets (the disintegrants in the two granules are different), wherein % is the mass percentage, and the following mass percentages are the mass percentages of each component to the total mass of the tablet:

[0096] Bisoprolol granules:

[0097]

[0098] Amlodipine granules:

[0099]

[0100] Lubricant:

[0101] Magnesium stearate 0.62%.

[0102] Preparation process: same as Comparative Example 1.

[0103] Comparative Example 4

[0104] This comparative example provides a bisoprolol amlodipine compound tablet, the prescription of which is exactly the same as that of Example 1, except that the preparation method is different. The specific process steps are as follows:

[0105] S1, placing microcrystalline cellulose (1 / 2 of the prescription amount), colloidal silicon dioxide, bisoprolol fumarate, amlodipine besylate, and sodium starch glycolate in a mixer and mixing them at a mixing speed of 10 rpm for 40 min. Then mixing with a lubricant at a mixing speed of 10-20 rpm for 3-15 min to obtain a mixed material 1.

[0106] S2, then mixing material 1 and microcrystalline cellulose (1 / 2 of the prescription amount) in a mixer for mixing at a mixing speed of 10 rpm for 40 min to obtain material 2.

[0107] S3, mixing material 2 and lubricant, placing in a mixer, mixing at a speed of 20 rpm, mixing for 10 min, to obtain a total mixed material.

[0108] S4, the hardness of the compressed compound tablet is controlled to be about 90 N. The tablet pressing equipment can be any type of tablet press to directly compress the mixed materials to obtain the compound tablet.

[0109] Comparative Example 5

[0110] This comparative example provides a bisoprolol amlodipine compound tablet, the prescription of which is exactly the same as that of Example 1, except that the preparation method is different. The specific process steps are as follows:

[0111] S1, placing microcrystalline cellulose (1 / 2 of the prescription amount), colloidal silicon dioxide, bisoprolol fumarate, amlodipine besylate, and sodium starch glycolate in a mixer and mixing them in sequence, the mixing speed is 10 rpm, and the mixing time is 40 min. Then mixing with a lubricant, the mixing speed is 20 rpm, and the mixing time is 10 min, to obtain mixed material 1.

[0112] S2, then mixing material 1 and microcrystalline cellulose (1 / 2 of the prescription amount) in a mixer for mixing at a mixing speed of 10 rpm for 40 min to obtain material 2.

[0113] S3, placing the mixed material 2 and the lubricant in a mixer, mixing at a speed of 20 rpm for 10 min to obtain the mixed material 3.

[0114] S4, put the mixed material 3 into the dry granulator, set appropriate granulation parameters, the dry granulation screen is 1mm, the whole granulation screen is 20 mesh, and the dry granulation particles are obtained. Then mix with an appropriate amount of lubricant, place in the mixer, mix at a speed of 20rpm, and mix for 15min to obtain the total mixed material.

[0115] S5, the hardness of the compressed compound tablet is controlled to be about 90 N. The tablet pressing equipment can be any type of tablet pressing machine to directly compress the mixed materials to obtain the compound tablet.

[0116] Table 1: Content uniformity test results

[0117]

[0118] The above results indicate that the mixing uniformity of bisoprolol fumarate and amlodipine besylate can be improved by granulating them separately and then mixing and tableting them.

[0119] Table 2: Self-made formulation stability investigation data - influencing factors test results (Example 2)

[0120]

[0121]

[0122] Table 3: Self-made formulation stability investigation data - accelerated test results (Example 2)

[0123]

[0124] Table 4: Self-made formulation stability investigation data - long-term test results (Example 2)

[0125]

[0126]

[0127] The above stability test results show that: this product adopts the packaging form of aluminum plastic packaging + external silica gel desiccant and composite film bag. During the product's 30-day, accelerated 6-month and long-term 6-month stability period, amlodipine and fumaric acid added impurity AML-2 have good stability and do not exceed the limit of 0.2%. In addition, other impurities, other maximum single impurities and total impurities of bisoprolol and amlodipine all meet the limit requirements, proving that the packaging form used by this product can well improve the stability of the product.

[0128] Table 5-1: Data on stability of self-developed preparations - Experiments on influencing factors

[0129]

[0130]

[0131] The above stability test results show that: in the preparation process of amlodipine besylate granules of this product, by adding anhydrous citric acid as a pH adjuster in an amount within the range of 0.2% to 1.0%, the stability of the product at a high temperature of 60°C can be further improved. The impurity test results of the self-developed preparation at a high temperature of 60°C all meet the requirements, and the stability of impurity AML-2 is good, which proves that the stability of this product at a high temperature of 60°C can be further improved by adding a pH adjuster to the amlodipine besylate granules.

[0132] In the attached drawings, the self-developed preparations 2022110111, 2022110211, and 2022110311 are all three batches of samples prepared in Example 2. The reference preparations 5543C0421, 5544A0421, and 6286A0721 are all original research drugs listed in China, the original research manufacturer is Merck Kft, and the trade name is:

[0133] Figure 1 : Dissolution curve of bisoprolol fumarate in 0.005 mol / L hydrochloric acid medium;

[0134] Figure 2 : Dissolution curve of bisoprolol fumarate in pH 4.5 acetate buffer;

[0135] Figure 3 : Dissolution curve of bisoprolol fumarate in pH 6.8 phosphate buffer;

[0136] Figure 4 : Dissolution curve of amlodipine besylate in 0.005 mol / L hydrochloric acid medium;

[0137] Figure 5 : Dissolution curve of amlodipine besylate in pH 4.5 acetate buffer;

[0138] Figure 6 : Dissolution curve of amlodipine besylate in pH 6.8 phosphate buffer.

[0139] From the dissolution curves of the self-developed preparation and the reference preparation in 0.005 mol / L hydrochloric acid medium, pH 4.5 acetate buffer and pH 6.8 phosphate buffer, it can be seen that the dissolution curves of bisoprolol fumarate and amlodipine of the self-developed preparation and the reference preparation in the three media are consistent, and the three batches of samples of the self-developed preparation and the three batches of samples of the reference preparation have good batch reproducibility. The preparation process of the self-developed preparation can prepare stable and reliable products to ensure dissolution and absorption in the body, thereby achieving the same clinical efficacy as the reference preparation.

[0140] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a bisoprolol-amlodipine compound tablet, characterized in that: The steps include: Mixing bisoprolol or a pharmaceutically acceptable salt thereof with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate in a certain proportion for dry granulation to obtain bisoprolol granules; Dry granulating amlodipine or a pharmaceutically acceptable salt thereof with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and anhydrous citric acid in proportion to obtain amlodipine granules; After the bisoprolol granules and the amlodipine granules are uniformly mixed, the bisoprolol granules and the amlodipine granules are uniformly mixed with an external lubricant to obtain a total mixed granule; The total mixed granules are tableted to obtain bisoprolol-amlodipine compound tablets.

2. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, wherein: In the bisoprolol granules, the mass ratios of bisoprolol or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate are 5:30-40; 3-8:1; 20-30:1; 3-8:1, respectively. Preferably, before dry granulation of bisoprolol, bisoprolol or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate are mixed at a mixing speed of 10-20 rpm and a mixing time of 20-50 min.

3. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, wherein: In the amlodipine granules, the mass ratios of amlodipine or its pharmaceutically acceptable salt, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and anhydrous citric acid are 5:30-40; 3-8:2; 20-30:1; 40-60:1; 3-5:1, respectively; Preferably, before amlodipine is granulated, amlodipine or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and anhydrous citric acid are mixed at a mixing speed of 10-20 rpm for a mixing time of 20-50 min.

4. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, wherein: The mass ratio of bisoprolol granules, amlodipine granules and lubricant is 0.8-1.2:0.8-1.2:0.01-0.03; Preferably, the mixing speed of the bisoprolol granules, amlodipine granules and lubricant is 10-20 rpm, and the mixing time is 3-15 min.

5. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, wherein: The particle size of the granulation screen of bisoprolol granules and amlodipine granules is 0.8-1.5 mm, and the particle size of the granulation screen is 20-30 mesh.

6. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, wherein: In the tableting process, the hardness of the compressed compound tablets is 30-120N.

7. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, characterized in that: The prepared bisoprolol amlodipine compound tablets are composed of the following components in parts by mass: 1-7 parts of bisoprolol or a pharmaceutically acceptable salt thereof, 1-7 parts of amlodipine or a pharmaceutically acceptable salt thereof, 0.2-1.0 parts of anhydrous citric acid, 30-90 parts of microcrystalline cellulose, 1-10 parts of sodium starch glycolate, 0.1-4 parts of colloidal silicon dioxide, and 0.2-3 parts of magnesium stearate.

8. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, characterized in that: The packaging form of the bisoprolol amlodipine compound tablets is aluminum-plastic packaging, an external silica gel desiccant and a composite film bag.

9. The method for preparing the bisoprolol-amlodipine compound tablet according to claim 1, wherein: The specific packaging composition is: polyvinyl chloride solid medicinal hard tablets and medicinal aluminum foil as the inner packaging that directly contacts the medicine, and bagged silica gel desiccant and polyester / aluminum / polyethylene medicinal composite film bags as the outer packaging, with bagged silica gel desiccant placed between the inner packaging and the outer packaging.

10. A bisoprolol-amlodipine compound tablet, characterized in that: Prepared by the preparation method described in any one of claims 1 to 9.

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