A bisoprolol fumarate tablet

Abstract

This invention belongs to the field of pharmaceutical formulation technology, and particularly relates to a bisoprolol fumarate tablet. The tablet comprises: bisoprolol fumarate, anhydrous dicalcium phosphate, hydrogenated castor oil, and other excipients; the particle size of bisoprolol fumarate meets the following requirements: D90≤150μm, D50≤50μm; the bulk density of anhydrous dicalcium phosphate is not greater than 0.8g / mL; the preparation process involves first mixing hydrogenated castor oil and anhydrous dicalcium phosphate, then adding bisoprolol fumarate and other excipients, mixing, and then tableting. Firstly, the lubricity and hydrophobicity of hydrogenated castor oil are used to coat and fill the microscopic surface structure of anhydrous dicalcium phosphate, forming a protective film, effectively solving the problem of gray flakes and black spots caused by friction with the metal surfaces of equipment during high-speed tableting in large-scale production; the uniformity of the product is improved by controlling the particle size of bisoprolol fumarate and anhydrous dicalcium phosphate. The bisoprolol fumarate tablet prepared by this invention has good stability, and the preparation process is simple and efficient.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to a bisoprolol fumarate tablet. Background Technology

[0002] Bisoprolol fumarate is a beta-blocker with a high affinity for β1-receptors in bronchial and vascular smooth muscle, thereby causing vasodilation and lowering blood pressure. It is indicated for hypertension, coronary heart disease, and moderate to severe chronic stable heart failure.

[0003] Anhydrous dicalcium phosphate is a commonly used filler in bisoprolol fumarate tablets. However, due to the significant density difference between bisoprolol fumarate tablets and anhydrous dicalcium phosphate, their mixing uniformity is poor. During the tableting process, the material is prone to stratification, causing the tablet content to exceed the limit range of 95%~105%. During the tableting process, gray tablets, black spots, and other defects are very likely to occur, resulting in a high rate of non-compliance. Furthermore, the wet granulation process and storage process also have many problems, such as rapid increase in impurities, poor stability, low production efficiency, and difficulty in large-scale production. Summary of the Invention

[0004] To address the aforementioned problems in the existing technology, the present invention provides a bisoprolol fumarate tablet with high uniformity, good stability, and a high pass rate in the preparation process.

[0005] To achieve the above objectives, the technical solution provided by the present invention is as follows: This application provides a bisoprolol fumarate tablet comprising: bisoprolol fumarate, anhydrous calcium hydrogen phosphate, hydrogenated castor oil, and other excipients; The particle size of the bisoprolol fumarate meets the following requirements: D90≤150μm, D50≤50μm; The bulk density of the anhydrous dicalcium phosphate is not greater than 0.8 g / mL; The preparation method of the bisoprolol fumarate tablets includes: first, mixing hydrogenated castor oil and anhydrous calcium hydrogen phosphate evenly, then adding bisoprolol fumarate and other excipients, mixing, and compressing into tablets.

[0006] Optionally, the mass fraction of each component in the tablet is: bisoprolol fumarate 1%~10%, anhydrous dicalcium phosphate 50%~80%, and hydrogenated castor oil 1%~5%.

[0007] Optionally, the other additives include one or more of the following: fillers, disintegrants, and gliding agents.

[0008] Optionally, the mass fraction of the filler in the tablet is 5% to 50%.

[0009] Optionally, the mass fraction of the disintegrant in the tablet is 1% to 5%.

[0010] Optionally, the mass fraction of the glidant in the tablet is 0.5% to 1%.

[0011] Optionally, the filler is selected from one or more of microcrystalline cellulose and corn starch.

[0012] Optionally, the disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0013] Optionally, the flow aid is selected from one or more of silica, colloidal silica, talc, and magnesium aluminum metasilicate.

[0014] Compared with the prior art, the present invention has at least the following beneficial effects: In this invention, anhydrous dicalcium phosphate is first mixed with hydrogenated castor oil. This process utilizes the lubricity and hydrophobicity of hydrogenated castor oil to coat and fill the microscopic surface structure of the anhydrous dicalcium phosphate, forming a protective film that effectively solves the problem of gray flakes and black spots caused by friction with the metal surfaces of equipment during high-speed tableting in large-scale production. Furthermore, by specifically controlling the particle size of bisoprolol fumarate and anhydrous dicalcium phosphate, the product can achieve better content uniformity.

[0015] The bisoprolol fumarate tablets prepared by this invention have good stability. According to the stability test results, the increase in related substances (referring to the active ingredient: bisoprolol fumarate) and the decrease in bisoprolol fumarate content of the tablets of this invention are significantly better than those of commercially available formulations.

[0016] The preparation method of this invention does not require cumbersome granulation and drying processes, and the preparation process is quick, making it more suitable for large-scale industrial production and improving production efficiency. Detailed Implementation

[0017] The present invention will now be described in further detail: Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0018] All reagents and materials used in this example can be purchased routinely. The quantitative experiments involved in the examples were all repeated at least three times, and the results were averaged.

[0019] Source of commercially available formulations: Commercially available formulation 2.5mg: Trade name: concor cor, Source: Merck HealthcareGernany GmbH, Batch number: G02W13.

[0020] Commercially available formulation 5mg: Trade name: concor, Source: Merck HealthcareGernany GmbH, Approval number: 25046A.

[0021] Methods for detecting bisoprolol fumarate content: Determine by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512). Operate in the dark.

[0022] Solvent: 0.05 mol / L diammonium hydrogen phosphate solution (adjust the pH to 4.5 with phosphoric acid).

[0023] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; mobile phase A was 0.05 mol / L diammonium hydrogen phosphate solution (pH adjusted to 4.5 with phosphoric acid) - acetonitrile (81:19); mobile phase B was 0.05 mol / L diammonium hydrogen phosphate solution (pH adjusted to 4.5 with phosphoric acid) - acetonitrile (30:70); linear gradient elution was performed according to Table 1; flow rate was 1.2 mL / min; column temperature was 30 °C; detection wavelength was 225 nm; injection volume was 20 μL.

[0024] Table 1: Elution Procedure for Content Detection 0 100 0 20 100 0 25 0 100 25.1 100 0 35 100 0 Methods for detecting related substances (impurities): Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512).

[0025] Solvent: Acetonitrile-water (20:80).

[0026] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Welch Ultimate LP-C18 4.6mm×250mm, 5μm or equivalent column, with trapping column); phosphoric acid-water (5:1000) was used as mobile phase A, and phosphoric acid-acetonitrile (5:1000) was used as mobile phase B, with linear gradient elution according to Table 2; flow rate was 1.0 mL / min; column temperature was 20℃; detection wavelength was 225 nm; injection volume was 10 μL.

[0027] Table 2: Impurity Detection and Elution Process 0 95 5 5 95 5 15 85 15 20 80 20 35 65 35 50 20 80 60 20 80 61 95 5 70 95 5 The present invention includes Examples 1 to 3 and Comparative Examples 1 to 3 to investigate the effects of tablet components and preparation methods on tablet performance.

[0028] Example 1

[0029] A bisoprolol fumarate tablet, taking a 5mg bisoprolol fumarate formulation as an example, comprises the following ingredients: 5mg bisoprolol fumarate, 131.8mg anhydrous dicalcium phosphate, 1.7mg hydrogenated castor oil, and other excipients (14.5mg corn starch, 1.5mg colloidal silica, 10mg microcrystalline cellulose, 5.5mg crospovidone); it also includes 4mg of film-coating premix. Among them, the D90 of bisoprolol fumarate is 68 μm, the D50 is 42 μm, and the D10 is 14 μm; Anhydrous dicalcium phosphate has a D90 of 180 μm, a D50 of 94 μm, a D10 of 49 μm, and a bulk density of 0.53 g / mL. The preparation method is as follows: hydrogenated castor oil and anhydrous dicalcium phosphate are thoroughly mixed, and then mixed evenly with bisoprolol fumarate and other excipients before tableting and coating.

[0030] Example 2

[0031] The difference between this embodiment and Embodiment 1 is that the amount of hydrogenated castor oil used is 5 mg, and the amount of anhydrous dicalcium phosphate used is 128.5 mg.

[0032] Example 3

[0033] The difference between this embodiment and Embodiment 1 is that the amount of hydrogenated castor oil used is 8.5 mg, and the amount of anhydrous dicalcium phosphate used is 125 mg.

[0034] Comparative Example 1 The difference between this comparative example and Example 1 is that hydrogenated castor oil was not used; instead, 1.7 mg of magnesium stearate was used in place of hydrogenated castor oil.

[0035] Comparative Example 2 The difference between this comparative example and Example 1 is that, in terms of preparation method, anhydrous dicalcium phosphate, bisoprolol fumarate, and other excipients are first mixed evenly, and then hydrogenated castor oil is added and mixed evenly before tableting and coating.

[0036] Comparative Example 3 The difference between this comparative example and Example 3 is that, in terms of preparation method, anhydrous dicalcium phosphate, bisoprolol fumarate, and other excipients are first mixed evenly, and then hydrogenated castor oil is added and mixed evenly before tableting and coating.

[0037] Table 3: Performance of tablets obtained in Examples 1-3 and Comparative Examples 1-3

[0038] Table 3 shows the relevant performance results of bisoprolol fumarate tablets in Examples 1-3 and Comparative Examples 1-3. It can be seen that Examples 1-3 of the present invention have higher production speed, qualified tablet properties, and better stability, while Comparative Examples 1-3 have unqualified tablet properties (gray tablets and black spots). Iron content, as an accurate quantitative indicator, directly reflects that the friction between Comparative Examples 1-3 and the production equipment led to unqualified tablet properties and a significant increase in impurities during the stability period.

[0039] The differences between the results of Comparative Examples 1-3 and Examples 1-3 demonstrate that the type of lubricant and the mixing method selected in this invention effectively solve problems such as gray flakes, black spots, low production speed, and poor stability in the production process.

[0040] The present invention includes Examples 4 to 6 and Comparative Examples 4 to 8, designed to investigate the effects of dry and wet granulation, anhydrous dicalcium phosphate powder parameters, and bisoprolol fumarate powder parameters.

[0041] Example 4

[0042] The difference between this embodiment and Embodiment 2 is that: The D90 of bisoprolol fumarate is 12 μm, the D50 is 6.5 μm, and the D10 is 1.9 μm. The anhydrous dicalcium phosphate has a D90 of 135 μm, a D50 of 74 μm, a D10 of 28 μm, and a bulk density of 0.74 g / mL.

[0043] Example 5

[0044] The difference between this embodiment and Embodiment 2 is that: The D90 of bisoprolol fumarate is 150 μm, the D50 is 50 μm, and the D10 is 18 μm. The anhydrous dicalcium phosphate has a D90 of 119 μm, a D50 of 58 μm, a D10 of 25 μm, and a bulk density of 0.81 g / mL.

[0045] Example 6

[0046] This embodiment is exactly the same as Embodiment 2.

[0047] Comparative Example 4 The difference between this comparative example and Example 6 is that the anhydrous dicalcium phosphate has a D90 of 135 μm, a D50 of 74 μm, a D10 of 28 μm, and a bulk density of 0.74 g / mL. The preparation method uses wet granulation: anhydrous dicalcium phosphate, bisoprolol fumarate and other additives are mixed evenly, and wet granulation is performed with purified water. The moisture content of the fluidized bed drying is ≤2.0%. Then hydrogenated castor oil is added, mixed evenly, tableted, and coated.

[0048] Comparative Example 5 The difference between this comparative example and Example 6 is that the anhydrous dicalcium phosphate has a D90 of 78 μm, a D50 of 56 μm, a D10 of 29 μm, and a bulk density of 1.29 g / mL.

[0049] Comparative Example 6 The difference between this comparative example and Example 6 is that the anhydrous dicalcium phosphate has a D90 of 67 μm, a D50 of 45 μm, a D10 of 28 μm, and a bulk density of 0.95 g / mL.

[0050] Comparative Example 7 The difference between this comparative example and Example 6 is that the anhydrous dicalcium phosphate has a D90 of 115 μm, a D50 of 83 μm, a D10 of 50 μm, and a bulk density of 1.11 g / mL.

[0051] Comparative Example 8 The difference between this comparative example and Example 4 is that the D90 of bisoprolol fumarate is 194 μm, the D50 is 75 μm, and the D10 is 21 μm.

[0052] Table 4: Performance of tablets obtained in Examples 4-6 and Comparative Examples 4-8

[0053] Table 4 shows the relevant performance results of the bisoprolol fumarate tablets in Examples 4-6 and Comparative Examples 4-8. It can be seen that, compared with Comparative Examples 4-8, Examples 4-6 of the present invention have higher production speed, better mixing uniformity, no significant change in the content of the active ingredient bisoprolol throughout the production process, and better tablet stability.

[0054] The results of Comparative Example 4 show that the wet granulation process results in a higher initial impurity level and poorer stability in the product, further illustrating the advantages of the present invention.

[0055] The results of Comparative Examples 5 to 7 show that anhydrous dicalcium phosphate has a significant impact on the production process and product stability when it exceeds the powder property requirements of this invention. The mixing uniformity and content uniformity are both unqualified, and the content fluctuates greatly during the tableting process, exceeding the standard requirement of 95% to 105%.

[0056] The results of Comparative Example 8 show that when the particle size of the bisoprolol fumarate of the present invention exceeds the particle size requirement range of the present invention, it has a huge impact on the stability of the production process and the product. The mixing uniformity and content uniformity are both unqualified, and the content fluctuates greatly during the tableting process, exceeding the standard requirement of 95%~105%.

[0057] The present invention includes Examples 7 to 10 to illustrate that, within the scope of protection of the present invention, the stability of bisoprolol fumarate tablets in 2.5 mg and 5 mg specifications is superior to that of the reference preparation, and the results are shown in Table 5.

[0058] Example 7

[0059] The difference between this embodiment and Embodiment 1 is that: The dosage of bisoprolol fumarate was 2.5 mg, the dosage of anhydrous dicalcium phosphate was 131 mg, and the dosage of hydrogenated castor oil was 5 mg.

[0060] Example 8

[0061] The difference between this embodiment and embodiment 7 is that: Anhydrous dicalcium phosphate 200mg, corn starch 18.5mg, microcrystalline cellulose 17mg.

[0062] Example 9

[0063] The difference between this embodiment and Embodiment 2 is that: Anhydrous calcium hydrogen phosphate 136mg, corn starch 14.5mg, microcrystalline cellulose 5mg.

[0064] Example 10

[0065] The difference between this embodiment and Embodiment 2 is that: 85mg anhydrous dicalcium phosphate, 32.5mg corn starch, 35.5mg microcrystalline cellulose.

[0066] Table 5: Performance comparison of tablets obtained in Examples 7-10 with commercially available formulations

[0067] The above embodiments illustrate the technical solution of the bisoprolol fumarate tablets of the present invention, which improves production efficiency and tablet stability, and the product has better content uniformity.

[0068] While specific terms and methods have been used to describe embodiments of the invention above, such descriptions are for illustrative purposes only. The vocabulary used is descriptive and not limiting. It should be understood that variations and modifications can be made by those skilled in the art without departing from the spirit and scope of this disclosure as set forth in the appended claims. Furthermore, it should be understood that aspects of the various embodiments may be interchanged in whole or in part. The spirit and scope of the appended claims should not be limited to the descriptions of the preferred forms contained therein.

Claims

1. A bisoprolol fumarate tablet, characterized in that, include: Bisoprolol fumarate, anhydrous dicalcium phosphate, hydrogenated castor oil, and other adjuvants; The particle size of the bisoprolol fumarate meets the following requirements: D90≤150μm, D50≤50μm; The bulk density of the anhydrous dicalcium phosphate is not greater than 0.8 g / mL; The preparation method of the bisoprolol fumarate tablets includes: first, mixing hydrogenated castor oil and anhydrous calcium hydrogen phosphate evenly, then adding bisoprolol fumarate and other excipients, mixing, and compressing into tablets.

2. The bisoprolol fumarate tablets according to claim 1, characterized in that, The mass fractions of each component in the tablet are: bisoprolol fumarate 1%~10%, anhydrous dicalcium phosphate 50%~80%, and hydrogenated castor oil 1%~5%.

3. The bisoprolol fumarate tablets according to claim 1, characterized in that, The other additives include one or more of the following: fillers, disintegrants, and flow aids.

4. The bisoprolol fumarate tablets according to claim 3, characterized in that, The mass fraction of filler in the tablet is 5% to 50%.

5. The bisoprolol fumarate tablets according to claim 3, characterized in that, The mass fraction of disintegrant in the tablets is 1% to 5%.

6. The bisoprolol fumarate tablets according to claim 3, characterized in that, The mass fraction of the glidant in the tablet is 0.5% to 1%.

7. The bisoprolol fumarate tablets according to claim 3, characterized in that, The filler is selected from one or more of microcrystalline cellulose and corn starch.

8. The bisoprolol fumarate tablets according to claim 3, characterized in that, The disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

9. The bisoprolol fumarate tablets according to claim 3, characterized in that, The flow aid is selected from one or more of silica, colloidal silica, talc, and magnesium aluminum metasilicate.

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