Bisoprolol amlodipine compound tablet and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically discloses a bisoprolol amlodipine compound tablet and a preparation method thereof. First, bisoprolol fumarate is mixed with a disintegrant, a glidant and a filler, and amlodipine besylate is mixed with a disintegrant, a filler and a lubricant and then dry granulated, wherein the bisoprolol fumarate is controlled to have a larger particle size to improve the mixing uniformity, and amlodipine besylate is controlled to have a smaller particle size for dry granulation, and amlodipine can be wrapped in an auxiliary material, thereby reducing the contact between amlodipine and bisoprolol during the mixing process. More importantly, by using mannitol, a filler with lower hygroscopicity, the moisture content of the tablet can be reduced during production and storage, and the generation of impurities can be reduced. At the same time, the particle size of the filler is controlled, and the physical contact between bisoprolol and amlodipine can also be reduced, and the reaction between the two to form impurity products can be reduced, thereby significantly improving the stability of the drug.

Description

Technical Field

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

[0002] Bisoprolol fumarate is a beta-receptor blocker with the chemical name (±)1-[4-[[2-(1-methylethoxy)ethoxy]methyl]-phenoxy]-3-[(1-methylethyl)amino]-2-propanol fumarate. Amlodipine besylate is a dihydropyridine calcium channel blocker with the chemical name (±)-2-[(2-aminoethoxy)methyl-4-(2-chlorophenyl)-6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid-3-ethyl-5-methyl besylate. Both active ingredients help control high blood pressure.

[0003] Currently, the combination of bisoprolol fumarate and amlodipine besylate is disclosed, but the two will react with each other when in contact in the preparation to generate an added impurity (N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarboxyl)5-(methoxycarboxyl)-6-methyl-1,4-dihydro-2-pyridyl]methoxy}-ethyl)aspartic acid), which is coded as AML-2. According to the import registration standard for bisoprolol amlodipine tablets, the limit of this impurity is ≤1.0%.

[0004]

[0005] CN102164585A discloses a solid pharmaceutical composition, containing amlodipine or a pharmaceutically acceptable salt thereof and bisoprolol fumarate and a pharmaceutically acceptable excipient, wherein the composition is prepared by sieving amlodipine besylate and bisoprolol fumarate together, homogenizing with microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide, then adding magnesium stearate for homogenization, and pressing the homogenate into tablets using a tablet press, wherein the added impurities of the tablets do not exceed 0.5% within 2 years. However, in the production process, amlodipine besylate and bisoprolol fumarate are in contact from the beginning of feeding, and strict moisture control is required during the production process, and an inner packaging material with excellent moisture-proof performance is required, so that production compliance and production cost are improved.

[0006] In CN114668760A, amlodipine and bisoprolol are prepared separately and then combined into SPC medicine by a tablet press. The tablet model described in this process has a core, an isolation layer and a shell layer, and strictly requires the contact ratio of the two medicines, which requires extremely special equipment or strict production operation control, and cannot be realized in industrial production.

[0007] CN116687926A discloses a method for preparing a bisoprolol amlodipine compound tablet, wherein amlodipine is premixed with a glidant, and bisoprolol is premixed with a disintegrant, thereby improving the uniformity of the mixture, and the glidant is adsorbed on the surface of amlodipine, thereby reducing the contact between amlodipine and bisoprolol, and effectively controlling the generation of impurities in both. This process only avoids the contact between the two active substances through a mixing process, and its effect is limited, and the impurity content is still high.

[0008] CN117323331A discloses a bisoprolol amlodipine composition and a preparation method thereof. The two active ingredients of bisoprolol and amlodipine are made into specific micro-pellets respectively, and the micro-pellets are mixed with auxiliary materials and compressed into tablets or filled into capsules after homogenization with auxiliary materials, wherein the bisoprolol coating is arranged on the drug layer on the surface of the micro-pellets, and an isolation layer is further arranged, thereby completely isolating bisoprolol from amlodipine, thereby avoiding mutual contact of active ingredients and generation of impurities, and effectively controlling the impurity IMP-57 to be less than 0.1%. The process is micro-pellet drug loading, and its process steps are complicated, the production time is long, and the process control requirements are extremely high, and it is not easy to achieve industrial production.

[0009] CN118593443A discloses a method for preparing a bisoprolol amlodipine compound tablet, wherein bisoprolol fumarate and microcrystalline cellulose are made into a first material, sodium carboxymethyl starch, silicon dioxide and microcrystalline cellulose are made into a second material, amlodipine besylate and microcrystalline cellulose are made into a third material, sodium carboxymethyl starch, silicon dioxide and microcrystalline cellulose are made into a fourth material, the first material and the second material are made into a bisoprolol mixed material, the third material and the fourth material are made into an amlodipine mixed material, magnesium stearate is added after the mixed materials are mixed, and tableting is performed. This process only avoids the contact of two active substances through a mixing process, and its effect is limited, and the mixing steps are very cumbersome. Summary of the invention

[0010] Aiming at the complexity of the existing production process of bisoprolol amlodipine compound tablets and the problem that impurities generated by the contact between two active ingredients cannot be completely avoided, the present invention provides a bisoprolol amlodipine compound tablet and a preparation method thereof.

[0011] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0012] The present application provides a bisoprolol amlodipine compound tablet composition, which comprises active ingredients bisoprolol fumarate, amlodipine besylate, a filler, and a pharmaceutically acceptable disintegrant, a glidant, and a lubricant, characterized in that the bisoprolol fumarate D90 is ≥70µm, the amlodipine besylate D90 is ≤70µm, and the average particle size of the filler D50 is ≥70µm.

[0013] In some exemplary embodiments, the bisoprolol fumarate D90 is 80-150 µm; the amlodipine besylate D90 is 10-50 µm.

[0014] In some exemplary preferred embodiments, the D90 of bisoprolol fumarate described in the present application is 90~150µm; the D90 of amlodipine besylate is 15~35µm.

[0015] In some exemplary embodiments, the filler described herein is mannitol.

[0016] As a preferred embodiment, the filler described in the present application is mannitol with an average particle size D50 of not less than 90 µm.

[0017] In some exemplary embodiments, the disintegrant described in the present application is sodium starch glycolate, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.

[0018] In some exemplary embodiments, in the composition described in the present application, the mass ratio of bisoprolol fumarate is 1% to 5%, the mass ratio of amlodipine besylate is 1% to 5%, the mass ratio of the filler is 81% to 95%, the mass ratio of the disintegrant is 2% to 5%, the mass ratio of the glidant is 0.5% to 2%, and the mass ratio of the lubricant is 0.5% to 2%.

[0019] Another object of the present application is to provide a method for preparing the composition of the present application, the method comprising the following steps:

[0020] a. Mix bisoprolol fumarate, sodium starch glycolate, colloidal silicon dioxide and microcrystalline cellulose and sieve;

[0021] b. The amlodipine besylate, sodium starch glycolate, microcrystalline cellulose and magnesium stearate are mixed and dry granulated;

[0022] c. The mixture obtained in steps a and b is mixed;

[0023] d. After the mixture in step c is uniformly mixed with the added magnesium stearate, tablets are pressed to obtain bisoprolol amlodipine compound tablets.

[0024] In some exemplary embodiments, the weight percentage of sodium carboxymethyl starch and microcrystalline cellulose in step a described in the present application is 40wt%~60wt%; the sieve mesh aperture in step a described in the present application is 1.0mm, the mixing time is 5~15min, and the mixing speed is 5~15rpm.

[0025] In some exemplary embodiments, the dry granulation pressure in step b described in the present application is 20-40 bar, and the dry granulation screen is 0.8 mm.

[0026] In some exemplary embodiments, the mixing time in step c described in the present application is 5 to 15 minutes, and the mixing speed is 5 to 15 rpm.

[0027] In some exemplary embodiments, the tableting hardness in step d described in the present application is 80~135N.

[0028] Based on the above technical solution, the beneficial effects of this application are:

[0029] 1. Better control of impurities;

[0030] 2. It uses traditional technology and can control impurities, making it suitable for large-scale industrial production and producing high-quality tablets at low cost. DETAILED DESCRIPTION

[0031] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0032] Example 1 Bisoprolol-amlodipine composition

[0033] The prescription composition is shown in Table 1:

[0034] Table 1

[0035]

[0036] Preparation method:

[0037] 1. Bisoprolol Fumarate Mixture:

[0038] Add the prescribed amount of bisoprolol fumarate (particle size D90 is 92µm), sodium carboxymethyl starch, mannitol 100SD (particle size D50 is 100µm), and colloidal silicon dioxide into the mixing hopper at a mixing speed of 10rpm for 10min;

[0039] Add the above materials into the granulator and pass through a 1.0 mm sieve;

[0040] The sieved materials were put into the mixing hopper again, with a mixing speed of 10 rpm and a mixing time of 10 min to obtain a bisoprolol fumarate mixture.

[0041] 2. Amlodipine besylate granulation:

[0042] Add the prescribed amount of amlodipine besylate (particle size D90 is 15µm), sodium carboxymethyl starch, and mannitol 100SD (particle size D50 is 100µm) into the granulator and pass through a 1.0mm sieve;

[0043] Add the above materials into a mixing hopper, and add the prescribed amount of magnesium stearate (internal addition), mix at a speed of 10 rpm, and mix for 10 min to obtain an amlodipine mixture;

[0044] The dry granulator was set at a feeding speed of 10 rpm, a pressure of 30 bar, and a granulation speed of 100 rpm. The amlodipine mixture was granulated using a 0.8 mm granulation screen to obtain amlodipine dry granules.

[0045] 3. Preparation of Bisoprolol Amlodipine Tablets:

[0046] Add the above two materials into the mixing hopper, set the mixing speed to 10 rpm, and mix for 10 minutes;

[0047] Then add the prescribed amount of magnesium stearate (external), set the mixing speed to 10 rpm, and mix for 10 minutes;

[0048] Use a high-speed rotary tablet press and a Φ9.5mm×4.5mm capsule-shaped die to press the tablets, and control the tablet hardness to 80~130N.

[0049] Example 2 Bisoprolol-amlodipine composition

[0050] The prescription composition is shown in Table 2:

[0051] Table 2

[0052]

[0053] Preparation method:

[0054] 1. Bisoprolol Fumarate Mixture:

[0055] Add the prescribed amount of bisoprolol fumarate (particle size D90 is 92µm), sodium starch glycolate, microcrystalline cellulose (vivapur112, average particle size 130µm), and colloidal silicon dioxide into the mixing hopper at a mixing speed of 10rpm for 10min.

[0056] Add the above materials into the granulator and pass through a 1.0 mm sieve;

[0057] The sieved materials were put into the mixing hopper again, with a mixing speed of 10 rpm and a mixing time of 10 min to obtain a bisoprolol fumarate mixture.

[0058] 2. Amlodipine besylate granulation:

[0059] Add the prescribed amount of amlodipine besylate (particle size D90 is 15µm), sodium carboxymethyl starch, and microcrystalline cellulose (vivapur112, average particle size 130µm) into a granulator and pass through a 1.0mm sieve;

[0060] Add the above materials into a mixing hopper, and add the prescribed amount of magnesium stearate (internal addition), mix at a speed of 10 rpm, and mix for 10 min to obtain an amlodipine mixture;

[0061] The dry granulator was set at a feeding speed of 10 rpm, a pressure of 30 bar, and a granulation speed of 100 rpm. The amlodipine mixture was granulated using a 0.8 mm granulation screen to obtain amlodipine dry granules.

[0062] 3. Preparation of Bisoprolol Amlodipine Tablets:

[0063] Add the above two materials into the mixing hopper, set the mixing speed to 10 rpm, and mix for 10 minutes;

[0064] Then add the prescribed amount of magnesium stearate (external), set the mixing speed to 10 rpm, and mix for 10 minutes;

[0065] Use a high-speed rotary tablet press and a Φ9.5mm×4.5mm capsule-shaped die to press the tablets, and control the tablet hardness to 80~130N.

[0066] Example 3 Bisoprolol-amlodipine composition

[0067] This embodiment is the same as Embodiment 2 except for the following differences:

[0068] 1. Bisoprolol Fumarate Mixture:

[0069] Add the prescribed amount of bisoprolol fumarate (particle size D90 is 130µm), sodium carboxymethyl starch, microcrystalline cellulose (vivapur112, average particle size 130µm), and colloidal silicon dioxide into the mixing hopper at a mixing speed of 10rpm for 10min.

[0070] Add the above materials into the granulator and pass through a 1.0 mm sieve;

[0071] The sieved materials were put into the mixing hopper again, with a mixing speed of 10 rpm and a mixing time of 10 min to obtain a bisoprolol fumarate mixture.

[0072] 2. Amlodipine besylate granulation:

[0073] Add the prescribed amount of amlodipine besylate (particle size D90 is 24µm), sodium starch glycolate, and microcrystalline cellulose (vivapur112, average particle size 130µm) into a granulator and pass through a 1.0mm sieve;

[0074] Add the above materials into a mixing hopper, and add the prescribed amount of magnesium stearate (internal addition), mix at a speed of 10 rpm, and mix for 10 min to obtain an amlodipine mixture;

[0075] The dry granulator was set at a feeding speed of 10 rpm, a pressure of 30 bar, and a granulation speed of 100 rpm. The amlodipine mixture was granulated using a 0.8 mm granulation screen to obtain amlodipine dry granules.

[0076] 3. Preparation of Bisoprolol Amlodipine Tablets:

[0077] Add the above two materials into the mixing hopper, set the mixing speed to 10 rpm, and mix for 10 minutes;

[0078] Then add the prescribed amount of magnesium stearate (external), set the mixing speed to 10 rpm, and mix for 10 minutes;

[0079] Use a high-speed rotary tablet press and a Φ9.5mm×4.5mm capsule-shaped die to press the tablets, and control the tablet hardness to 80~130N.

[0080] Example 4 Bisoprolol-amlodipine composition

[0081] This embodiment is the same as Embodiment 2 except for the following differences:

[0082] 1. Bisoprolol Fumarate Mixture:

[0083] Add the prescribed amount of bisoprolol fumarate (particle size D90 is 147µm), sodium starch glycolate, microcrystalline cellulose (vivapur14, average particle size 170µm), and colloidal silicon dioxide into the mixing hopper at a mixing speed of 10rpm for 10min;

[0084] Add the above materials into the granulator and pass through a 1.0 mm sieve;

[0085] The sieved materials were put into the mixing hopper again, with a mixing speed of 10 rpm and a mixing time of 10 min to obtain a bisoprolol fumarate mixture.

[0086] 2. Amlodipine besylate granulation:

[0087] Add the prescribed amount of amlodipine besylate (particle size D90 is 35µm), sodium starch glycolate, and microcrystalline cellulose (vivapur14, average particle size 170µm) into a granulator and pass through a 1.0mm sieve;

[0088] Add the above materials into a mixing hopper, and add the prescribed amount of magnesium stearate (internal addition), mix at a speed of 10 rpm, and mix for 10 min to obtain an amlodipine mixture;

[0089] The dry granulator was set at a feeding speed of 10 rpm, a pressure of 30 bar, and a granulation speed of 100 rpm. The amlodipine mixture was granulated using a 0.8 mm granulation screen to obtain amlodipine dry granules.

[0090] 3. Preparation of Bisoprolol Amlodipine Tablets:

[0091] Add the above two materials into the mixing hopper, set the mixing speed to 10 rpm, and mix for 10 minutes;

[0092] Then add the prescribed amount of magnesium stearate (external), set the mixing speed to 10 rpm, and mix for 10 minutes;

[0093] Use a high-speed rotary tablet press and a Φ9.5mm×4.5mm capsule-shaped die to press the tablets, and control the tablet hardness to 80~130N.

[0094] Example 5 Bisoprolol-amlodipine composition

[0095] This embodiment is the same as Embodiment 2 except for the following differences:

[0096] 1. Bisoprolol Fumarate Mixture:

[0097] Add the prescribed amount of bisoprolol fumarate (particle size D90 is 92µm), sodium starch glycolate, microcrystalline cellulose (vivapur14, average particle size 170µm), and colloidal silicon dioxide into the mixing hopper at a mixing speed of 10rpm for 10min.

[0098] Add the above materials into the granulator and pass through a 1.0 mm sieve;

[0099] The sieved materials were put into the mixing hopper again, with a mixing speed of 10 rpm and a mixing time of 10 min to obtain a bisoprolol fumarate mixture.

[0100] 2. Amlodipine besylate granulation:

[0101] Add the prescribed amount of amlodipine besylate (particle size D90 is 35µm), sodium starch glycolate, and microcrystalline cellulose (vivapur14, average particle size 170µm) into a granulator and pass through a 1.0mm sieve;

[0102] Add the above materials into a mixing hopper, and add the prescribed amount of magnesium stearate (internal addition), mix at a speed of 10 rpm, and mix for 10 min to obtain an amlodipine mixture;

[0103] The dry granulator was set at a feeding speed of 10 rpm, a pressure of 30 bar, and a granulation speed of 100 rpm. The amlodipine mixture was granulated using a 0.8 mm granulation screen to obtain amlodipine dry granules.

[0104] 3. Preparation of Bisoprolol Amlodipine Tablets:

[0105] Add the above two materials into the mixing hopper, set the mixing speed to 10 rpm, and mix for 10 minutes;

[0106] Then add the prescribed amount of magnesium stearate (external), set the mixing speed to 10 rpm, and mix for 10 minutes;

[0107] Use a high-speed rotary tablet press and a Φ9.5mm×4.5mm capsule-shaped die to press the tablets, and control the tablet hardness to 80~130N.

[0108] Comparative Example 1 Bisoprolol-amlodipine composition

[0109] The prescription, dosage and preparation method of this comparative example are exactly the same as those of Example 1, but the particle size D90 of the bisoprolol fumarate raw material is 43 µm.

[0110] Comparative Example 2 Bisoprolol-amlodipine composition

[0111] The prescription, dosage and preparation method of this comparative example are exactly the same as those of Example 1, but the particle size D90 of the amlodipine besylate raw material is 89 µm.

[0112] Comparative Example 3 Bisoprolol-amlodipine composition

[0113] The prescription, dosage and preparation method of this comparative example are exactly the same as those of Example 1, but the filler is microcrystalline cellulose vivapur103 with an average particle size of 65 μm.

[0114] Reference preparation: Bisoprolol Amlodipine Tablets, the licensee is Merck Kft, batch number is 5543C0421.

[0115] Experimental Example 1 Content Uniformity Test

[0116] The compositions prepared in Examples 1-5 and the compositions prepared in Comparative Examples 1-3 were sampled at different locations for content detection by full transfer to examine the uniformity of the mixed particle content. The test results are shown in Table 3.

[0117] Table 3

[0118] / Average content of bisoprolol fumarate (mg / mg) RSD% Average content of amlodipine (mg / mg) RSD% Example 1 0.033 1.4 0.033 0.8 Example 2 0.033 1.2 0.033 0.6 Example 3 0.033 0.9 0.033 0.5 Example 4 0.033 1.1 0.033 0.6 Example 5 0.033 2.1 0.033 2.3 Comparative Example 1 0.033 4.6 0.033 3.4 Comparative Example 2 0.033 1.1 0.033 1.2 Comparative Example 3 0.033 1.8 0.033 2.5 .

[0119] From the above data, it can be seen that selecting bisoprolol fumarate with a larger particle size for mixing can significantly improve the mixing uniformity of amlodipine besylate and bisoprolol fumarate.

[0120] Experimental Example 2 Dissolution Test

[0121] Using 900 ml of 0.005 mol / L hydrochloric acid solution as the medium, the rotation speed was 50 revolutions per minute, and sampling was performed after 30 minutes. The dissolution test was performed on the compositions prepared in Examples 1-5 and the reference preparation (batch number: 5543C0421). The test results are shown in Table 4.

[0122] Table 4

[0123] Sample No. Bisoprolol Fumarate Dissolution Amlodipine dissolution 5543C0421 (reference preparation) 99% 98% Example 1 100% 98% Example 2 99% 97% Example 3 99% 98% Example 4 100% 98% Example 5 100% 99% .

[0124] Experimental Example 3 Stability Test

[0125] In order to investigate the stability of the composition prepared in the present application, the composition prepared in Examples 1-5 and the reference preparation and the composition prepared in Comparative Examples 2-3 were placed under high temperature (60°C) for 30 days, and samples were taken after 30 days to detect the content of the comparative impurity AML-2, and compared with the results of 0 days. The results are shown in Table 5;

[0126] Table 5

[0127] Sample No. Day 0 High temperature 60℃-30 days 5543C0421 (reference preparation) 0.05% 11.98% Example 1 Not detected 3.26% Example 2 Not detected 4.03% Example 3 Not detected 4.21% Example 4 Not detected 3.98% Example 5 Not detected 3.86% Comparative Example 2 Not detected 8.63% Comparative Example 3 Not detected 8.54% .

[0128] It can be seen from the data in Table 5 that the bisoprolol amlodipine compound tablets prepared by the embodiment of the present invention can reduce the physical contact between bisoprolol fumarate and amlodipine besylate, thereby reducing the generation of added impurities between the two. Compared with the reference preparation, the stability is higher, the storage stability of the drug is improved, and the safety of its medication is further improved.

[0129] In summary, the bisoprolol amlodipine compound tablets prepared in the embodiment of the present invention have a lower content of impurity AML-2 than the reference preparation (original research) and better drug stability. At the same time, the preparation preparation process adopted in the present invention is simple, and all of them are commonly used equipment for large-scale production, which is easy to realize industrial large-scale production.

Claims

1. A bisoprolol amlodipine compound tablet composition, comprising active ingredients bisoprolol fumarate and amlodipine besylate, a filler, and a pharmaceutically acceptable disintegrant, a glidant, and a lubricant, wherein the disintegrant is sodium carboxymethyl starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate. In the composition, the mass ratio of bisoprolol fumarate is 1% to 5%, the mass ratio of amlodipine besylate is 1% to 5%, the mass ratio of the filler is 81% to 95%, the mass ratio of the disintegrant is 2% to 5%, the mass ratio of the glidant is 0.5% to 2%, and the mass ratio of the lubricant is 0.5% to 2%, characterized in that: The D90 of the bisoprolol fumarate is 80-150µm; the D90 of the amlodipine besylate is 10-50µm and the average particle size D50 of the filler is not less than 90µm; the filler is mannitol or microcrystalline cellulose.

2. The composition according to claim 1, characterized in that: The filler is mannitol.

3. The composition according to claim 1, characterized in that: The prescription of the composition is: 。 4. A method for preparing the composition as claimed in claim 3, characterized in that: The method comprises the following steps: a. Mix bisoprolol fumarate, sodium starch glycolate, colloidal silicon dioxide and microcrystalline cellulose and sieve; b. The amlodipine besylate, sodium starch glycolate, microcrystalline cellulose and magnesium stearate are mixed and dry granulated; c. The mixture obtained in steps a and b is mixed; d. After the mixture in step c is uniformly mixed with the added magnesium stearate, tablets are pressed to obtain bisoprolol amlodipine compound tablets.

5. The method according to claim 4, characterized in that In the step a, the sieve mesh aperture is 1.0 mm, the mixing time is 5 to 15 min, and the mixing speed is 5 to 15 rpm.

6. The method according to claim 4, characterized in that In the step b, the dry granulation pressure is 20-40 bar, and the dry granulation screen is 0.8 mm.

7. The method according to claim 4, characterized in that In the step c, the mixing time is 5 to 15 minutes and the mixing speed is 5 to 15 rpm.

8. The method according to claim 4, characterized in that The tableting hardness in step d is 80-135N.

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