Bisoprolol fumarate microtableted capsules, process for their preparation and use

Abstract

The application provides a bisoprolol fumarate microtablet type capsule, each capsule containing 1-8 microtablets, each microtablet comprising: 0.625 mg of bisoprolol fumarate, and a filler, a disintegrant, a glidant, a lubricant and a binder. The filler is selected from microcrystalline cellulose, the disintegrant is selected from corn starch, the glidant is selected from silicon dioxide, the lubricant is selected from magnesium stearate, and the binder is selected from corn starch, povidone or hypromellose. Compared with the common tablet of the prior art, the dose segmentation can be more accurately realized, the clinical advantages are that the use is convenient, the dose control is more accurate, and the stability of the preparation is better.

Description

Technical Field

[0001] This invention relates to bisoprolol fumarate microcapsules, their preparation method and uses, which involve filling bisoprolol fumarate microcapsules into capsules, and belongs to the field of pharmaceutical preparations. Background Technology

[0002] Bisoprolol fumarate is a third-generation beta-blocker. Its mechanism of action is as follows: it inhibits the effect of adrenergic nerves on myocardial beta receptors, blocks the agonistic effect of catecholamines on beta receptors, slows down the depolarization rate of myocardial action potential during the diastolic phase 4, thereby reducing automaticity, slows down the cardiac conduction system by reducing the rise rate of action potential during phase 0, and lowers blood pressure and myocardial metabolism.

[0003] Advantages compared to similar drugs include: (1) high affinity and selectivity for β1 receptors. (2) good pharmacokinetic properties: it combines the characteristics of two β-receptor antagonists (lipophilic and hydrophilic), and can be administered from both effective receptors in equal doses (half the dose is inactivated by the liver and half the dose is cleared by the kidneys). (3) good safety: bisoprolol has no endogenous sympathomimetic activity, no membrane stability, and no effect on human glucose metabolism or lipid metabolism.

[0004] According to the "Reference Preparations Catalog" published by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration, the original manufacturer of bisoprolol fumarate tablets is Merck. The original formulation was first marketed in Germany in 1986 and approved for marketing in China in 1995. Imported strengths include 2.5mg and 5mg, and domestic generic versions also include 2.5mg and 5mg. When using this product to treat chronic stable heart failure, a dose titration phase is necessary, starting with a low dose and gradually increasing according to the following regimen:

[0005] 1.25 mg once daily for one week. If well tolerated, the dose can be increased to [presumably a dose of a specific dosage].

[0006] 2.5 mg once daily for one week. If well tolerated, increase to [previous dose].

[0007] 3.75 mg once daily for one week. If well tolerated, the dose may be increased to [presumably a dose].

[0008] 5 mg once daily for 4 weeks. If well tolerated, increase to [previous dose].

[0009] 7.5 mg once daily for one week. If well tolerated, increase to [previous dose].

[0010] 10 mg once daily as maintenance therapy.

[0011] The maximum recommended dose is 10 mg once daily.

[0012] Bisoprolol is a cornerstone of heart failure treatment, but it needs to be titrated starting from a low dose of 0.625 mg (Japan) or 1.25 mg (China, Europe and the United States). Currently, only 2.5 mg and 5 mg scored tablets are available in China. In order to meet the clinical requirement of starting dose of 0.625-1.25 mg, the existing 2.5 mg tablets can only be manually split, either into two or four pieces. Due to manual splitting, the dosage is inaccurate and cannot meet the requirements of patients with heart failure for precise drug administration. Summary of the Invention

[0013] The primary objective of this invention is to address the shortcomings of existing bisoprolol tablets, which suffer from inaccurate dosage fractionation and thus fail to meet the precise dosing requirements for patients with heart failure. This invention innovatively provides a new technical solution that overcomes these deficiencies: bisoprolol fumarate microcapsules. These capsules contain 0.625 mg of bisoprolol fumarate in microcapsules, with each microcapsule containing 1-8 microcapsules, covering all clinically applicable strengths from 0.625 mg to 5 mg, such as 2.5 mg (4 microcapsules) and 5 mg (8 microcapsules). This is completely equivalent to existing 2.5 mg and 5 mg tablets, but because it contains multiple independent microcapsules, patients can select the appropriate microcapsule for precise dosing according to their individual needs. This technique covers all dose titration stages and offers advantages over existing products, including: meeting clinical needs and providing patients with more choices; reducing dosage inaccuracies caused by fractionation and achieving precise dose control.

[0014] Mini-tablets (or simply microtablets) are typically less than 3 mm in diameter and are generally multi-unit formulations. Microtablets offer advantages such as easy swallowing, accurate dosing, and flexible dosage adjustment, making them suitable for children and patients with swallowing difficulties. Currently, there are no reports of using microtablet technology to treat heart failure drugs, especially not in bisoprolol fumarate formulations requiring titration. Existing methods generally involve manually breaking or cutting commercially available 2.5 mg tablets. For a 1.25 mg dosage requirement, this is manageable, although the dosage error after splitting is relatively large, it is still acceptable. However, for a 0.625 mg dosage requirement, it is difficult to perform this manually, whether breaking or cutting, and it is impossible to guarantee that the dosage error after splitting is within an acceptable range. The microcapsules of this invention contain 0.625mg of microcapsules, and each capsule contains 1-8 microcapsules. The appropriate number of microcapsules can be taken directly according to the dosage requirements, which unexpectedly and effectively solves the problems of convenient dosage division and dosage accuracy.

[0015] The second objective of this invention is to provide a novel formulation and process for bisoprolol fumarate microplates.

[0016] During the research on bisoprolol fumarate microcapsules, we found that if the original tablet formulation and process were used, the resulting microcapsules would have insufficient stability, requiring improvements to the formulation and process. Therefore, the second objective of this invention is to provide a new formulation and process for bisoprolol fumarate microcapsules. The bisoprolol fumarate microcapsules prepared according to the improved formulation and process exhibit better stability than the original tablets.

[0017] The third objective of this invention is to provide the application of bisoprolol fumarate microcapsules in the clinical treatment of chronic stable heart failure, and in particular, to provide the use of bisoprolol fumarate microcapsules in the preparation of medicaments for treating chronic stable heart failure requiring dose titration.

[0018] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0019] This invention provides bisoprolol fumarate microcapsules, their preparation method, and uses. The resulting microcapsules are filled into capsules for clinical application in the form of bisoprolol fumarate capsules.

[0020] First, the present invention provides a bisoprolol fumarate microcapsule, each capsule containing 1-8 microcapsules, each microcapsule containing: 0.625 mg of bisoprolol fumarate, as well as fillers, disintegrants, glidants, lubricants and binders.

[0021] As a preferred technical solution, the filler is selected from microcrystalline cellulose, the disintegrant is selected from corn starch, the flow aid is selected from silica, the lubricant is selected from magnesium stearate, and the binder is selected from corn starch, povidone, or hydroxypropyl methylcellulose.

[0022] As a further preferred technical solution, each microplate contains: 0.625 mg of bisoprolol fumarate, 15-25 mg of microcrystalline cellulose as filler, 0.5-5 mg of corn starch as disintegrant, 0.2-1.0 mg of silica as flow aid, 0.2-1.0 mg of magnesium stearate as lubricant, and a binder selected from corn starch (0.5-1.5 mg), or from povidone (0.5-1.5 mg), or from hydroxypropyl methylcellulose (0.5-2.5 mg).

[0023] The preferred polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the preferred hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5.

[0024] As a preferred technical solution, each microplate contains: 0.625 mg of bisoprolol fumarate, 20-23.5 mg of microcrystalline cellulose as filler, 0.5-4 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 1 mg of corn starch as binder; the solution is further preferred to contain each microplate containing: 0.625 mg of bisoprolol fumarate, 22 mg of microcrystalline cellulose as filler, 2 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 1 mg of corn starch as binder.

[0025] As another preferred technical solution, each microplate contains: 0.625 mg of bisoprolol fumarate, 22 mg of microcrystalline cellulose as filler, 2 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 1 mg of povidone K30 as binder.

[0026] As another preferred technical solution, each microplate contains: 0.625 mg of bisoprolol fumarate, 22 mg of microcrystalline cellulose as filler, 2 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 2 mg of hydroxypropyl methylcellulose E5 as binder.

[0027] The microfilms are preferably further coated with a film coating solution selected from common gastric-soluble film coating materials, preferably a suspension of hydroxypropyl methylcellulose and titanium dioxide, preferably with a solid content ratio of 8%, wherein hydroxypropyl methylcellulose accounts for 6% of the coating solution, titanium dioxide accounts for 2% of the coating solution, and the coating weight gain is 1-3%.

[0028] Secondly, the present invention provides a method for preparing the above-mentioned bisoprolol fumarate capsules, as follows:

[0029] ① Adhesive preparation: Take the amount of corn starch in the above adhesive formula, add water to prepare a 5-10% starch paste, and use it as an adhesive; or take the amount of povidone K30 in the above formula, add water to prepare an 8% povidone K30 aqueous solution as an adhesive; or take the amount of hydroxypropyl methylcellulose E5 in the above formula, add water to prepare a 5% hydroxypropyl methylcellulose E5 aqueous solution as an adhesive; choose one of the three.

[0030] ②Wet granulation: Weigh out the amount of corn starch (part of the disintegrant prescription), microcrystalline cellulose (filler), and bisoprolol fumarate and place them in a wet granulator. Turn on the stirring and shearing mixing for 5-10 minutes. Then add the binder obtained in step ① to prepare wet granules.

[0031] ③ Drying: Transfer the medium-moisture particles from step ② to a fluidized bed for drying, controlling the moisture content to ≤5.0%;

[0032] ④ Granulation: The dried wet granules are passed through a 20-40 mesh sieve using a vibrating pellet mill or a high-speed granulator;

[0033] ⑤ General mixing: After granulation, the granules are mixed with external flow aids (such as silica) and lubricants (such as magnesium stearate) in a lifting mixer for 5-10 minutes;

[0034] ⑥ Tableting: Tableting is performed using a 3mm circular die, controlling the tablet weight difference to ±7.5%, and the hardness to be 20~60N;

[0035] ⑦ Coating: The tablet core is coated with a film using a high-efficiency coating machine. The coating material is a common gastric-soluble film coating material, selected from hydroxypropyl methylcellulose and titanium dioxide, with hydroxypropyl methylcellulose E15 being the preferred model. The weight gain of the coating is controlled to be 1-3%.

[0036] ⑧ Capsule filling: Depending on the requirements, each capsule is filled with 1-8 microtablets, equivalent to 0.625mg-5mg. Specifically, filling 2 microtablets into an empty capsule yields a 1.25mg bisoprolol fumarate capsule; filling 4 microtablets into an empty capsule yields a 2.5mg bisoprolol fumarate capsule; filling 6 microtablets into an empty capsule yields a 3.75mg bisoprolol fumarate capsule; and filling 8 microtablets into an empty capsule yields a 5mg bisoprolol fumarate capsule.

[0037] Third, the present invention provides the application of the above-mentioned bisoprolol fumarate microcapsules in the clinical treatment of chronic stable heart failure: in particular, it provides the use of bisoprolol fumarate microcapsules in the preparation of drugs for treating chronic stable heart failure requiring dose titration.

[0038] This product is a multi-unit release formulation, with dosage control based on each microtablet. This provides greater flexibility in clinical use when treating chronic stable heart failure requiring dose titration: ① Different specifications of bisoprolol fumarate capsules can be directly selected, each containing 1-8 microtablets, with strengths ranging from 0.625mg to 5mg. Taking 1-2 capsules in combination covers the entire dosage requirement from a starting dose of 0.625mg to a maximum dose titration of 10mg. ② Even when using capsules containing 4 or 8 0.625mg microtablets, the capsule shell can be opened, and the number of microtablets calculated according to the required dose can be determined before administration, facilitating dosage titration. Because the production process controls the content uniformity, weight variation, and hardness of each microtablet as a unit, the dosage accuracy between each microtablet is higher, reducing the risks associated with clinical fractionation.

[0039] The technical advantages of this invention are as follows:

[0040] Bisoprolol fumarate microcapsules are an improvement on bisoprolol fumarate tablets, which can better achieve dose fractionation. Clinical advantages include ease of use, more precise dose control, and better product stability.

[0041] 1. More accurate dose segmentation

[0042] Oral solid dosage forms typically employ scoring to achieve flexible dosage control in clinical practice. Single-score aliquots are the most common in the market, and bisoprolol fumarate tablets marketed in China also use this method for dosage fractionation. With advancements in formulation technology, multi-particle delivery systems offer significant advantages, including predictable and reproducible gastric residence time; lower inter- and intra-individual variability; and greater flexibility in dosage design. Based on market research on bisoprolol fumarate tablets, the feasibility of applying a multi-particle system to this product was assessed, ultimately leading to the development of bisoprolol fumarate capsules. Using 0.625 mg / microplate unit, the dosage of the finished product can be flexibly controlled by adjusting the number of microplates filled into the capsule, meeting the requirements of clinical dose titration. Therefore, scoring is no longer necessary, simplifying patient use and avoiding dosage control deviations that may arise from unprofessional fractionation.

[0043] 2. The product of this invention has better stability.

[0044] The original drug's formulation, as found on the European Medicines Agency (EMA) website, consists of anhydrous dicalcium phosphate, corn starch, silica, crospovidone, microcrystalline cellulose, yellow iron oxide, polyethylene glycol, hydroxypropyl methylcellulose, and titanium dioxide. The components of the original drug were separated and individually mixed with bisoprolol fumarate active pharmaceutical ingredient (API) in specific proportions. Compatibility studies were conducted, using changes in properties, weight gain / loss, and related substances as evaluation indicators to screen the excipients. Specific results are shown in Appendix Table 2. The screening demonstrated that crospovidone and anhydrous dicalcium phosphate in the original drug's formulation underwent significant changes in related substances after mixing with the API. Analysis of their properties revealed that crospovidone may introduce peroxides and other substances, providing conditions for oxidative degradation of the API, thus accelerating impurity degradation. Furthermore, anhydrous dicalcium phosphate from different sources and processed using different methods has different pH values, which directly correlates with the pH of the API's microenvironment, thereby accelerating impurity degradation. Through multiple comparative studies, the self-made formulation eliminated unfavorable factors and optimized dosages. The final inactive ingredients included corn starch, silica, microcrystalline cellulose, yellow iron oxide, hydroxypropyl methylcellulose, and titanium dioxide. The optimized formulation obtained through screening was used for process transfer to a commercial production line. Comprehensive quality comparisons demonstrated the feasibility and reproducibility of the self-made formulation and process, enabling future commercial production.

[0045] According to the original drug's instructions for bisoprolol fumarate tablets, the storage conditions are: store below 25°C, with a shelf life of 24 months. The original drug uses double aluminum packaging, which is a packaging material with good water and oxygen barrier properties for oral solid dosage forms. Stability studies of the original drug showed that, under the influencing factors of the stability study, related substances underwent significant changes, and some related substances exceeded their limits. In contrast, the self-made bisoprolol fumarate microcapsules, through control and optimization of the formulation and process, showed significantly better stability under the influencing factors compared to the original drug. Under long-term stability study conditions, no significant changes were observed in key quality attributes. Attached Figure Description

[0046] Figure 1 Comparison of dissolution curves between Sample 1 and the original sample

[0047] Figure 2 Comparison of dissolution curves between Sample 3 and the original sample

[0048] Figure 3 Comparison of dissolution curves of samples 4 and 5 with the original sample

[0049] Figure 4 Comparison of dissolution curves of samples 6 and 7 with the original sample Detailed Implementation

[0050] Example 1: Compatibility test of raw materials and excipients based on the formulation information of the original product.

[0051] Based on the formulation of the original product, bisoprolol fumarate active pharmaceutical ingredient (API) was mixed with excipients, and the effects of various excipients on the stability of bisoprolol fumarate API were investigated in accordance with the requirements of API compatibility testing.

[0052] 1. The composition and proportions of raw and auxiliary materials are shown in Table 1 below:

[0053] Table 1: Composition and Proportioning of Raw and Auxiliary Materials

[0054]

[0055] 2. Processing method: Weigh the above materials according to the material ratio, sieve and mix them evenly, then release them for sampling. Sampling conditions: 40℃ / 75%RH, sampling time: 15 days. Take samples at 0 days and 15 days respectively to investigate the related substances of each sample.

[0056] 3. Testing Method: The related substances were detected according to the method in the European Pharmacopoeia EP9.0 standard for bisoprolol fumarate (the same as the related substances detection method in the BP2018 standard for bisoprolol fumarate tablets), using high performance liquid chromatography.

[0057] 4. Results of the investigation: The results of the relevant substance tests are shown in Table 2:

[0058] Table 2: Summary of Related Substance Detection Results of Raw Material Compatibility Tests

[0059]

[0060] Note: / indicates not detected.

[0061] Example 2: Preparation of bisoprolol fumarate microcapsules Sample 1

[0062] 1. Prescription: See Table 3

[0063] Table 3: Prescription Composition

[0064]

[0065] 2. Preparation process:

[0066] The preparation method of the above-mentioned bisoprolol fumarate capsules is as follows:

[0067] ① Preparation of adhesive starch paste: Take an appropriate amount of corn starch and prepare a 5% starch paste to be used as an adhesive.

[0068] ②Wet granulation: Weigh the prescribed amounts of corn starch, microcrystalline cellulose, and bisoprolol fumarate as disintegrants and place them in a wet granulator. Turn on the stirring and shearing mixing for 5-10 minutes; then add 5% corn starch slurry to prepare wet granules.

[0069] ③ Drying: The wet particles from step ② are transferred to a fluidized bed for drying, and the moisture content is controlled to be ≤5.0%;

[0070] ④ Granulation: The dried wet granules are passed through a 20-40 mesh sieve using a vibrating pellet mill or a high-speed granulator;

[0071] ⑤ General mixing: After granulation, the granules are mixed with externally mixed silica and magnesium stearate in a lifting mixer for 5-10 minutes;

[0072] ⑥ Tableting: Tableting is performed using a 3mm circular die, with the weight difference controlled at ±7.5% and the hardness at 20~50N;

[0073] ⑦ Coating: The tablet cores are coated with a high-efficiency coating machine. The coating solution is an 8% suspension of hydroxypropyl methylcellulose E15 and titanium dioxide, and the weight gain of the coating is controlled at 1-3%.

[0074] ⑧ Capsule filling: Four microplates were filled into each gelatin capsule to obtain 2.5mg bisoprolol fumarate capsules, named Sample 1.

[0075] Related tests:

[0076] ① Dissolution curve detection: Following the dissolution test method in the imported registration quality standard of the original bisoprolol fumarate tablets, the paddle method at 75 rpm was used. The dissolution medium was degassed purified water with a volume of 900 ml. The sampling points for the dissolution curve were 5 min, 10 min, 15 min, and 20 min. The detection method was HPLC. Dissolution tests were performed on a self-made bisoprolol fumarate microcapsule sample 1 and commercially available original bisoprolol fumarate tablets. The results are shown in Table 4 below.

[0077] Table 4: Dissolution curve of self-made bisoprolol fumarate microcapsules, sample 1

[0078]

[0079] The dissolution curves of Sample 1 and the commercially available original bisoprolol fumarate tablets (2.5 mg, batch number G01TCU, manufactured by Merck Healthcare Germany GmbH) are shown in the attached figure. Figure 1 .

[0080] ②Stability test

[0081] Experimental method: The experimental conditions were investigated according to the influencing factors, and the sampling period was 30 days. Samples were taken at 0, 10, and 30 days to investigate the changes in related substances in each sample.

[0082] Methods of Investigation: Related Substances Detection: The method is the same as in Example 1. HPLC was used to detect related substances in Sample 1 and the commercially available original product, and the results are compared in Table 5 below:

[0083] Table 5: Stability Study of Self-made Bisoprolol Fumarate Microcapsules Sample 1

[0084]

[0085] Compared with the original product, this product has the following advantages: the self-made product has better stability than the original product.

[0086] Example 2: Preparation of bisoprolol fumarate tablets sample 2 based on the original formulation.

[0087] Prescription: See Table 6, and compare with Sample 1.

[0088] Table 6: Prescription Composition

[0089]

[0090] Preparation process:

[0091] Sample 2 was prepared using a direct powder compression process, completely following the original formulation. The detailed process is as follows:

[0092] ① Weighing: Weigh anhydrous dicalcium phosphate, microcrystalline cellulose, crospovidone, corn starch, silicon dioxide, magnesium stearate, and bisoprolol fumarate according to the prescription composition.

[0093] ② Premix: Add anhydrous dicalcium phosphate, bisoprolol fumarate, microcrystalline cellulose, crospovidone, corn starch and silica into a hopper mixer in sequence and mix for 10-20 minutes.

[0094] ③ General mixing: Add the weighed magnesium stearate to the premixed powder and continue mixing in the hopper mixer for 5 minutes.

[0095] ④ Tableting: Referring to the original tablet shape, heart-shaped notch punches are used for tableting, and the tablet core hardness is controlled at 40-80N.

[0096] ⑤ Coating: The tablet cores are coated with a high-efficiency coating machine to control the weight gain of the coating by 1-3%.

[0097] Test results

[0098] ① Changes in matter

[0099] As can be seen from Examples 1 and 2, the preliminary stability and raw material compatibility studies of the original bisoprolol fumarate tablets showed poor stability, characterized by rapid growth of related substances. Therefore, we compared the trends of related substances in Sample 1 and Sample 2 under influencing factors. According to conventional research practices in the pharmaceutical field, changing the dosage form from tablets to microcapsules increases the risk of impurity degradation due to the increased exposure area. Based on the study of bisoprolol fumarate tablets, by adjusting the formulation and dosage, the prepared bisoprolol fumarate microcapsules showed better impurity degradation during the stability period than not only the original product but also the ordinary tablets (Sample 2) prepared with the same components as the original product. Detailed research data are shown in Table 7 below:

[0100] Table 7: Changes in related substances between Sample 1 and Sample 2

[0101]

[0102]

[0103] ② Examine the weight difference after segmentation:

[0104] Bisoprolol fumarate tablets involve dose fractionation in clinical applications. The original drug only has a central notch, therefore the 2.5mg strength was divided into two equal parts. The testing methods and limits are as follows:

[0105] Segmentation methods: Both manual and mechanical segmentation are used.

[0106] Measurement method: Randomly select 30 whole slices, break them apart, weigh one part of each slice after it has been split, discard the other parts, and calculate the average weight.

[0107] Limitation requirement: No more than one portion of the weight after division shall exceed the average weight by 85% to 115%. If more than one portion of the weight after division exceeds the average weight by 85% to 115%, or if one portion of the weight after division exceeds the average weight by 75% to 125%, it shall be deemed unqualified.

[0108] Results of the study: Sample 2 met the requirements for different segmentation methods, but the overall deviation was large. The weight difference after manual segmentation was -12% to +16%, and the weight difference after batch-by-batch segmentation was -12% to +10%, both of which were greater than the control range of ±7.5% for the weight difference of micro-tablet compression.

[0109] The experimental results are shown in Tables 8 and 9.

[0110] Table 8: Statistical Table of Weight Differences After Sample 2 Division

[0111]

[0112]

[0113] For microtablets, there is no need to manually break or cut them using a tablet divider during dosage titration; the tablets can be counted directly before consumption. Therefore, the weight variation during the microtablet compression process represents the accuracy of the dosage; the higher the dosage, the more accurate the dose. The designed weight variation range for microtablets is -4.8% to 3.8%, which shows a significant advantage compared to the traditional splitting method for bisoprolol fumarate tablets.

[0114] Table 9: Statistical Table of Tablet Weight Differences During Tableting Process of Sample 1

[0115]

[0116] Example 3: Preparation of 5mg bisoprolol fumarate microcapsule sample 3

[0117] Prescription: See Table 10 below:

[0118] Table 10: Prescription Composition

[0119]

[0120] Brief description of the preparation process:

[0121] The preparation method of the above 5mg bisoprolol fumarate microcapsules is as follows:

[0122] ① Preparation of adhesive starch paste: Take an appropriate amount of corn starch and prepare a 10% starch paste to be used as an adhesive.

[0123] ②Wet granulation: Weigh the disintegrant portion of corn starch, microcrystalline cellulose, and bisoprolol fumarate and place them in a wet granulator. Turn on the stirring and shearing mixing for 5-10 minutes; then add corn starch slurry to prepare wet granules.

[0124] ③ Drying: Transfer the medium-moisture particles from step ② to a fluidized bed for drying, controlling the moisture content to ≤5.0%;

[0125] ④ Granulation: The dried wet granules are passed through a 20-40 mesh sieve using a vibrating pellet mill or a high-speed granulator;

[0126] ⑤ General mixing: After granulation, the granules are mixed with externally mixed silica and magnesium stearate in a lifting mixer for 5-10 minutes;

[0127] ⑥ Tableting: Tableting is performed using a 3mm circular die, with the weight difference controlled at ±7.5% and the hardness at 20~50N;

[0128] ⑦ Coating: The tablet cores are coated with a film using a high-efficiency coating machine, with the aim of controlling the weight gain of the coating to 1-3%.

[0129] ⑧ Capsule filling: 8 microplates were filled into each gelatin capsule to obtain 5mg bisoprolol fumarate capsules, named Sample 3.

[0130] Related tests:

[0131] ① Dissolution curve detection: Based on the import drug registration standards for the original bisoprolol fumarate tablets, the dissolution method was performed at 75 rpm using a paddle method. The dissolution medium was degassed purified water with a volume of 900 ml. Sampling points for the dissolution curve were 5 min, 10 min, 15 min, and 20 min. The dissolution curve detection results are shown in Table 11 below:

[0132] Table 11: Dissolution curve data of self-made bisoprolol fumarate capsules, sample 3

[0133]

[0134] A comparison of the dissolution curves of Sample 3 and the original sample is attached. Figure 2 .

[0135] Example 4: Preparation of samples 4 and 5 using 0.625 mg bisoprolol fumarate micro-tablets to investigate the amount of corn starch used.

[0136] Due to their small diameter, micro-tablets require good compressibility. This product is a coated tablet, and the requirements for uncoated tablets are even higher. The amount of corn starch in the formulation may directly affect the compressibility of the total mixed particles. The amount of corn starch used in 0.625 mg bisoprolol fumarate micro-tablets was investigated, and samples 4 and 5 were prepared. The formulation and process are as follows:

[0137] (1) The prescriptions of samples 4 and 5 are compared with the prescription of sample 3, as shown in Table 12 below:

[0138] Table 12: Prescription Composition

[0139]

[0140] (2) Brief description of the preparation process:

[0141] The preparation method of the above-mentioned bisoprolol fumarate capsules is as follows:

[0142] ① Starch slurry preparation: Take an appropriate amount of corn starch and prepare a 5% starch slurry, which will be used as an adhesive.

[0143] ②Wet granulation: Weigh out the corn starch, anhydrous dicalcium phosphate, microcrystalline cellulose, and bisoprolol fumarate and place them in a wet granulator. Turn on the stirring and shearing mixing for 5-10 minutes; then add corn starch slurry to prepare wet granules.

[0144] ③ Drying: Transfer the medium-moisture particles from step ② to a fluidized bed for drying, controlling the moisture content to ≤5.0%;

[0145] ④ Granulation: The dried wet granules are passed through a 20-40 mesh sieve using a vibrating pellet mill or a high-speed granulator;

[0146] ⑤ General mixing: After granulation, the granules are mixed with externally mixed silica and magnesium stearate in a lifting mixer for 5-10 minutes;

[0147] ⑥ Tableting: Use a 3mm circular die for tableting, control the tablet weight difference to ±7.5%, and control the hardness to 20~50N;

[0148] When the amount of powder used changes, the compressibility of the particles changes significantly.

[0149] Table 13: Hardness of Samples 3-5 after compression

[0150]

[0151] ⑦ Coating: The tablet cores are coated with a film using a high-efficiency coating machine. For samples 4 and 5, the weight gain from coating is to be controlled at 1-3%.

[0152] ⑧ Capsule filling: Fill each gelatin capsule with 8 microplates to obtain 5mg bisoprolol fumarate capsules.

[0153] Related tests:

[0154] ① Dissolution curve detection: Referring to the original production standard of bisoprolol fumarate tablets, the paddle method at 75 rpm was used. The dissolution medium was degassed purified water with a volume of 900 ml. The sampling points for the dissolution curve were 5 min, 10 min, 15 min, and 20 min.

[0155] The dissolution curve test results are as follows:

[0156] Table 14: Dissolution curves of self-made bisoprolol fumarate capsules

[0157]

[0158] The dissolution curves of samples 4 and 5 are compared with those of the original sample. (See attached figure) Figure 3 .

[0159] Results Analysis: In the formulation of this product, corn starch serves as both a disintegrant and a binder. Variations in its dosage may affect the compressibility of the material and the dissolution profile of the tablets. Comparison of the dissolution profiles and tablet hardness monitoring ranges of samples 3, 4, and 5 demonstrates that when the dosage of the disintegrant corn starch is within the range of 0.5 mg to 4 mg and the dosage of the binder corn starch is within the range of 0.5 mg to 1.5 mg, the material exhibits good compressibility, and the dissolution profiles of the formulation all meet the requirements for rapid dissolution.

[0160] Example 5: Selection of Adhesive Type

[0161] The adhesive was replaced with either 5% starch paste or 8% povidone K30 aqueous solution or 5% hydroxypropyl methylcellulose E5 aqueous solution to prepare samples 6 and 7, and the effect of adhesive type was investigated.

[0162] (1) The prescription composition is shown in Table 15 below:

[0163] Table 15: Prescription Composition

[0164]

[0165] (2) Brief description of the preparation process:

[0166] The preparation method of the above-mentioned bisoprolol fumarate capsules is as follows:

[0167] ① Adhesive preparation: Take an appropriate amount of povidone K30 and prepare an 8% povidone K30 aqueous solution to be used as an adhesive, and prepare sample 6. Take an appropriate amount of hydroxypropyl methylcellulose E5 and prepare a 5% hydroxypropyl methylcellulose E5 aqueous solution to be used as an adhesive, and prepare sample 7.

[0168] The procedures ② to ⑧ for Sample 6 are the same as those for Sample 7, as detailed below:

[0169] ②Wet granulation: Weigh the disintegrant corn starch, microcrystalline cellulose, and bisoprolol fumarate and place them in a wet granulator. Turn on the stirring and shearing mixing for 5-10 minutes. Then add the binder 8% povidone K30 aqueous solution or 5% hydroxypropyl methylcellulose E5 aqueous solution to prepare wet granules.

[0170] ③ Drying: Transfer the medium-moisture particles from step ② to a fluidized bed for drying, controlling the moisture content to ≤5.0%;

[0171] ④ Granulation: The dried wet granules are passed through a 20-40 mesh sieve using a vibrating pellet mill or a high-speed granulator;

[0172] Table 16 Powder properties of particles

[0173] Sample Name Angle of repose ° Bulk density g / ml Tap density (g / ml) Carr index Sample 3 32.6 0.51 0.67 23.9 Sample 6 31.7 0.49 0.65 24.6 Sample 7 38.2 0.53 0.69 23.2

[0174] Note: Carr index = (tap density - bulk density) / tap density × 100.

[0175] ⑤ General mixing: After granulation, the granules are mixed with externally mixed silica and magnesium stearate in a lifting mixer for 5-10 minutes;

[0176] ⑥ Tableting: Tableting is performed using a 3mm circular die, with the weight difference controlled at ±7.5% and the hardness at 20~50N;

[0177] ⑦ Coating: The tablet cores are coated with a film using a high-efficiency coating machine, with the aim of controlling the weight gain of the coating to 1-3%.

[0178] ⑧ Capsule filling: Fill each gelatin capsule with 8 microplates to obtain 5mg bisoprolol fumarate capsules.

[0179] Related tests:

[0180] ① Dissolution curve detection: Referring to the imported registration quality standard of the original drug bisoprolol fumarate tablets, the dissolution method was adopted at 75 rpm using a paddle method. The dissolution medium was degassed purified water with a volume of 900 ml. The sampling points for the dissolution curve were 5 min, 10 min, 15 min, and 20 min. The detection method was HPLC. The detection results are shown in Table 17 below:

[0181] Table 17: Dissolution curves of self-made bisoprolol fumarate capsules, samples 7 and 8

[0182]

[0183] A comparison of the dissolution curves of samples 6 and 7 with the original sample is attached. Figure 4 .

[0184] Results Analysis: Povidone and hydroxypropyl methylcellulose are commonly used binders in solid oral dosage forms. The type and amount of binder affect the flowability and compressibility of the granules, and also influence the dissolution profile of the formulation. The Karl Fischer index of samples 6 and 7 is between 20 and 25, demonstrating that the prepared granules exhibit good flowability and compressibility, while the formulation disintegrates and dissolves rapidly; all samples meet the requirements for rapid dissolution. The preferred binders for this product are corn starch, povidone K30, and hydroxypropyl methylcellulose E5, with preferred concentrations of 5% corn starch slurry, 8% povidone K30 aqueous solution, and 5% hydroxypropyl methylcellulose E5 aqueous solution.

Claims

1. A bisoprolol fumarate microcapsule, characterized in that, Each capsule contains 1-8 microcapsules, each microcapsule containing: 0.625 mg of bisoprolol fumarate, as well as fillers, disintegrants, glidants, lubricants, and binders.

2. The bisoprolol fumarate microcapsule as described in claim 1, characterized in that, The filler is selected from microcrystalline cellulose, the disintegrant is selected from corn starch, the flow aid is selected from silica, the lubricant is selected from magnesium stearate, and the binder is selected from one or more of corn starch, povidone, or hydroxypropyl methylcellulose.

3. The bisoprolol fumarate microcapsule as described in claim 1, characterized in that, Each microplate contains: 0.625 mg of bisoprolol fumarate, 15–25 mg of microcrystalline cellulose as filler, 0.5–5 mg of corn starch as disintegrant, 0.2–1.0 mg of silica as a flow aid, 0.2–1.0 mg of magnesium stearate as a lubricant, and a binder selected from corn starch (0.5–1.5 mg), povidone (0.5–1.5 mg), or hydroxypropyl methylcellulose (0.5–2.5 mg).

4. The bisoprolol fumarate microcapsule as described in claim 3, characterized in that, The povidone is povidone K30, and the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5.

5. The bisoprolol fumarate microcapsule as described in claim 1, characterized in that, Each microplate contains: 0.625 mg of bisoprolol fumarate, 20-23.5 mg of microcrystalline cellulose as filler, 0.5-4 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 1 mg of corn starch as binder; more preferably, each microplate contains: 0.625 mg of bisoprolol fumarate, 22 mg of microcrystalline cellulose as filler, 2 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 1 mg of corn starch as binder.

6. The bisoprolol fumarate microcapsule as described in claim 1, characterized in that, Each microplate contains: 0.625 mg of bisoprolol fumarate, 22 mg of microcrystalline cellulose as filler, 2 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 1 mg of povidone K30 as binder.

7. The bisoprolol fumarate microcapsule as described in claim 1, characterized in that, Each microplate contains: 0.625 mg of bisoprolol fumarate, 22 mg of microcrystalline cellulose as filler, 2 mg of corn starch as disintegrant, 0.4 mg of silica as flow aid, 0.4 mg of magnesium stearate as lubricant, and 2 mg of hydroxypropyl methylcellulose E5 as binder.

8. The bisoprolol fumarate microcapsule as described in claims 1-7, characterized in that, The microplates are further coated with a film coating material, which is a common gastric-soluble film coating material, resulting in a weight gain of 1-3%.

9. The method for preparing bisoprolol fumarate microcapsules as described in claims 1-8, characterized in that, Includes the following steps: ① Adhesive preparation: Take an appropriate amount of corn starch, add water to prepare a 5-10% starch paste, and use it as an adhesive; or take an appropriate amount of povidone K30, add water to prepare an 8% povidone K30 aqueous solution as an adhesive; or take an appropriate amount of hydroxypropyl methylcellulose E5, add water to prepare a 5% hydroxypropyl methylcellulose E5 aqueous solution as an adhesive; choose one of the three. ②Wet granulation: Weigh corn starch (as a disintegrant), microcrystalline cellulose (as a filler), and bisoprolol fumarate and place them in a wet granulator. Turn on the stirring and shearing mixing for 5-10 minutes. Then add the binder obtained in step ① to prepare wet granules. ③ Drying: Transfer the medium-moisture particles from step ② to a fluidized bed for drying, controlling the moisture content to ≤5.0%; ④ Granulation: The dried wet granules are passed through a 20-40 mesh sieve using a vibrating pellet mill or a high-speed granulator; ⑤ General mixing: After granulation, the granules are mixed with external flow aids and lubricants in a lift mixer for 5-10 minutes; ⑥ Tableting: Use a 2-3mm circular die for tableting, control the tablet weight difference to ±7.5%, and the hardness to be 20-60N; ⑦ Coating: The tablet core is coated with a film using a high-efficiency coating machine. The coating material is a common gastric-soluble film coating material, and the weight gain of the coating is controlled at 1-3%. ⑧ Capsule filling: Depending on the requirements, each capsule is filled with 1-8 microtablets to obtain bisoprolol fumarate microtablet capsules; specifically, filling 2 microtablets into an empty capsule yields 1.25mg bisoprolol fumarate capsules; filling 4 microtablets into an empty capsule yields 2.5mg bisoprolol fumarate capsules; filling 6 microtablets into an empty capsule yields 3.75mg bisoprolol fumarate capsules; and filling 8 microtablets into an empty capsule yields 5mg bisoprolol fumarate capsules.

10. The use of the bisoprolol fumarate microcapsules as described in claims 1-8 in the preparation of a medicament for treating chronic stable heart failure requiring dose titration.

Images