A bisoprolol fumarate tablet with long-term storage stability and its preparation method

Abstract

This invention belongs to the field of pharmaceutical formulation technology and relates to a bisoprolol fumarate tablet with long-term storage stability and its preparation method. The formulation of the bisoprolol fumarate tablet of this invention includes bisoprolol fumarate, filler, disintegrant, lubricant, binder, composite stabilizer, and appropriate amount of water; the preparation method includes steps such as raw material pretreatment, composite stabilizer pretreatment, binder preparation, granulation, total mixing, tableting, and coating. This invention significantly improves the long-term storage stability of bisoprolol fumarate tablets through the synergistic effect of the three components in the composite stabilizer, combined with an optimized preparation process, effectively reducing problems such as drug content decline, increase of related substances, and abnormal physical properties of tablets, ensuring the efficacy and safety of the drug.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a bisoprolol fumarate tablet with long-term storage stability and its preparation method. Background Technology

[0002] Bisoprolol fumarate, a highly selective β1 receptor blocker, is widely used in clinical practice to treat cardiovascular diseases such as hypertension, coronary heart disease (angina pectoris), and chronic stable heart failure. It has definite efficacy and high safety, and is one of the important drugs in the field of cardiovascular disease treatment.

[0003] As the primary oral formulation of this drug, bisoprolol fumarate tablets' quality stability directly impacts the efficacy and safety of clinical use. However, during long-term storage, bisoprolol fumarate tablets are susceptible to environmental factors (such as temperature and humidity), leading to problems such as decreased drug content, increased related substances (such as degradation products), changes in tablet appearance (such as discoloration, deliquescence, and cracking), and abnormal dissolution. These changes not only reduce the drug's efficacy but may also increase the risk of adverse reactions, posing a potential threat to patients' treatment outcomes and health.

[0004] Currently, to improve the storage stability of bisoprolol fumarate tablets, existing technologies typically employ methods such as optimizing the formulation (e.g., selecting appropriate fillers, binders, lubricants, and other excipients), improving the production process (e.g., controlling granulation humidity, drying temperature, and time), and improving packaging materials (e.g., using aluminum-plastic blister packaging or moisture-proof packaging).

[0005] However, these methods still have certain limitations in practical applications. For example, Chinese patent CN101467985A discloses a bisoprolol fumarate dispersible tablet and its preparation method. The formulation contains 55% dicalcium phosphate. However, if the proportion of dicalcium phosphate is too high, the tablets will turn black during compression, and the tablets will have poor stability during storage, especially under high temperature and high humidity conditions, making it difficult to effectively prevent changes in the quality of the drug.

[0006] Therefore, developing a composition and its preparation method that can significantly improve the long-term storage stability of bisoprolol fumarate tablets, in order to solve the problem of insufficient stability of existing formulations during long-term storage, is of great practical significance for ensuring drug quality, improving clinical treatment effects, and ensuring patient medication safety. Summary of the Invention

[0007] To address the issue of insufficient stability of existing bisoprolol fumarate tablets during long-term storage, this invention provides bisoprolol fumarate tablets with long-term storage stability and its preparation method. By optimizing the formulation and preparation process, the chemical and physical stability of the formulation are significantly improved, ensuring that the drug maintains good efficacy and safety even after long-term storage.

[0008] The core of the bisoprolol fumarate tablets of this invention lies in the synergistic effect of a specific ratio of composite stabilizer and other excipients, as detailed in the following formula: Active ingredient: Bisoprolol fumarate 2.5-5 parts by weight, as an effective ingredient for treating cardiovascular diseases, exerts its therapeutic effect by selectively blocking β1 receptors. Filler: 60-120 parts by weight, selected from at least one of microcrystalline cellulose, lactose monohydrate, and mannitol, used to increase tablet volume and improve powder flowability and compressibility. Disintegrant: 4-9 parts by weight, selected from at least one of croscarmellose sodium, croscarmellose, and sodium carboxymethyl starch, promotes rapid disintegration of tablets in vivo, releasing the drug. Lubricant: 0.5-1.4 parts by weight, selected from at least one of magnesium stearate, sodium stearate fumarate, and talc, reduces friction between materials and equipment, improving tableting efficiency. Binder: 1-5 parts by weight (based on solids), selected from at least one of hydroxypropyl methylcellulose, povidone K30, and starch paste, binds the powder into granules, ensuring granule strength. Composite stabilizer: Composed of 0.05-0.3 parts by weight of disodium edetate, 5-15 parts by weight of erythritol, and 0.8-2.5 parts by weight of low-substituted carboxymethyl chitosan. These three components work synergistically to improve formulation stability. Solvent: Water, in appropriate amount, used to adjust material moisture during granulation.

[0009] This invention solves the stability problem of bisoprolol fumarate tablets by using a composite stabilizer with a specific ratio. Its core advantage lies in the synergistic effect of the three components: (1) Synergistic effect of antioxidation and hydrolysis: Disodium edetate, as a metal ion chelating agent, can chelate metal ions such as iron and copper that may be present in the environment, inhibiting the metal ion-catalyzed oxidative degradation reaction of bisoprolol fumarate; low-substituted carboxymethyl chitosan has good film-forming properties and barrier function, and can form a protective film inside the tablet to reduce water intrusion and inhibit the hydrolytic degradation of the drug; erythritol, as a polyol, can bind to drug molecules through hydrogen bonds, enhance its structural stability, and at the same time regulate the osmotic pressure of the tablet microenvironment, further reducing the impact of moisture on the drug. The three work together to block drug deterioration from the two main degradation pathways of oxidation and hydrolysis, and significantly reduce the decline in drug content during long-term storage.

[0010] (2) Synergistic regulation of microenvironment: Erythritol has low hygroscopicity and good hygroscopic balance ability, which can maintain a relatively stable low humidity environment inside the tablet; the film-forming property of low-substituted carboxymethyl chitosan further enhances this effect, reduces the decrease in the chelation efficiency of disodium edetate caused by fluctuations in environmental humidity, and ensures that the three stabilizers play a stable role in the long term, maintaining the stability of the tablet's physical structure (such as hardness and brittleness) and disintegration performance.

[0011] To maximize the synergistic effect of the composite stabilizer, the preparation process is specifically optimized in this invention, and the specific steps are as follows: (1) Pretreatment of raw materials and auxiliary materials: Bisoprolol fumarate, fillers and disintegrants are passed through an 80-mesh sieve, and lubricants are passed through a 60-mesh sieve to ensure uniform particle size and improve mixing uniformity.

[0012] (2) Pretreatment of composite stabilizer: Disodium edetate, erythritol and low-substituted carboxymethyl chitosan are dry-mixed and then water is added to make a soft material. After vacuum drying (60℃±5℃, vacuum degree -0.08MPa) and air jet pulverization (passing through 120 mesh sieve), the three components are formed into uniformly dispersed composite particles, which enhances their dispersibility and synergistic effect in the formulation.

[0013] (3) Granulation and mixing: Wet granulation is adopted. Bisoprolol fumarate, filler, internal disintegrant (70%) and pretreated composite stabilizer are mixed. 2%-5% binder aqueous solution is added for granulation. After drying, it is mixed with external disintegrant (30%) and lubricant to ensure that the content uniformity RSD≤3%.

[0014] (4) Tableting and Coating: After the total mixture is compressed into tablets, it is coated with a film to further isolate the tablets from the influence of the external environment.

[0015] By combining the above-mentioned formulation and process, the bisoprolol fumarate tablets prepared by this invention exhibit a significantly lower decrease in drug content during long-term storage (12 months at 30℃±2℃ and 65%±5% relative humidity) compared to existing technologies and commercially available products. Furthermore, they maintain good physical stability (hardness and brittleness) and disintegration performance, effectively solving the stability defects of existing formulations. Attached Figure Description

[0016] Figure 1 Long-term stability test of bisoprolol fumarate tablets. Detailed Implementation

[0017] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0018] Examples 1-2: Bisoprolol Fumarate Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Bisoprolol fumarate, filler and disintegrant are passed through an 80-mesh sieve, and lubricant is passed through a 60-mesh sieve for later use; (2) Pretreatment of composite stabilizers: Weigh disodium edetate, erythritol, and low-substituted carboxymethyl chitosan, place them in a mixing pulverizer, dry mix for 10 minutes (300 rpm) to initially mix the three materials, add purified water equivalent to 30% of the total weight to make a soft material, continue mixing and pulverizing for 10 minutes (400 rpm) to form uniform suspended particles; place the suspended particles in a vacuum drying oven and dry for 6 hours at 60℃±5℃ and vacuum degree -0.08MPa, turning them over every 2 hours to ensure uniform drying; the dried composite stabilizer particles are treated by air jet pulverization (pulverization pressure 0.5-0.7MPa), pulverized and passed through a 120-mesh sieve, and placed in a desiccator for later use; (3) Adhesive preparation: Prepare an aqueous solution of adhesive with purified water to a mass fraction of 3% for later use; (4) Granulation: Take bisoprolol fumarate, filler, internal disintegrant (70%), and pretreated composite stabilizer, place them in a wet granulator, dry mix for 15 minutes (150-200 rpm), add binder aqueous solution, granulate at 200-300 rpm, make soft material, granulate through an 18-mesh sieve, dry in a fluidized bed (inlet air temperature 50-60℃) until the moisture content is 1.0%-2.0%, and granulate through a 16-mesh sieve.

[0019] (5) Total mixing: Add external disintegrant (30%) and lubricant, and mix in three dimensions for 5-8 minutes (10-15 rpm) to ensure that the content uniformity RSD ≤ 3%.

[0020] (6) Tableting, Opadry II film coating.

[0021] Examples 3-7: Bisoprolol Fumarate Tablets Preparation methods of Examples 3, 5, and 6: (1) Pretreatment of raw materials and auxiliary materials: Bisoprolol fumarate, filler and disintegrant are passed through an 80-mesh sieve, and lubricant is passed through a 60-mesh sieve for later use; (2) Pretreatment of composite stabilizers: Weigh disodium edetate, erythritol, and low-substituted carboxymethyl chitosan, place them in a mixing pulverizer, dry mix for 10 minutes (300 rpm) to initially mix the three materials, add purified water equivalent to 30% of the total weight to make a soft material, continue mixing and pulverizing for 10 minutes (400 rpm) to form uniform suspended particles; place the suspended particles in a vacuum drying oven and dry for 6 hours at 60℃±5℃ and vacuum degree -0.08MPa, turning them over every 2 hours to ensure uniform drying; the dried composite stabilizer particles are treated by air jet pulverization (pulverization pressure 0.5-0.7MPa), pulverized and passed through a 120-mesh sieve, and placed in a desiccator for later use; (3) Adhesive preparation: Prepare an aqueous solution of 2% by mass with purified water for later use; (4) Granulation: Take bisoprolol fumarate, filler, internal disintegrant (70%), and pretreated composite stabilizer, place them in a wet granulator, dry mix for 15 minutes (150-200 rpm), add binder aqueous solution, granulate at 200-300 rpm, make soft material, granulate through an 18-mesh sieve, dry in a fluidized bed (inlet air temperature 50-60℃) until the moisture content is 1.0%-2.0%, and granulate through a 16-mesh sieve.

[0022] (5) Total mixing: Add external disintegrant (30%) and lubricant, and mix in three dimensions for 5-8 minutes (10-15 rpm) to ensure that the content uniformity RSD ≤ 3%.

[0023] (6) Tableting, Opadry II film coating.

[0024] Preparation methods for Examples 4 and 7: (1) Pretreatment of raw materials and auxiliary materials: Bisoprolol fumarate, filler and disintegrant are passed through an 80-mesh sieve, and lubricant is passed through a 60-mesh sieve for later use; (2) Pretreatment of composite stabilizers: Weigh disodium edetate, erythritol, and low-substituted carboxymethyl chitosan, place them in a mixing pulverizer, dry mix for 10 minutes (300 rpm) to initially mix the three materials, add purified water equivalent to 30% of the total weight to make a soft material, continue mixing and pulverizing for 10 minutes (400 rpm) to form uniform suspended particles; place the suspended particles in a vacuum drying oven and dry for 6 hours at 60℃±5℃ and vacuum degree -0.08MPa, turning them over every 2 hours to ensure uniform drying; the dried composite stabilizer particles are treated by air jet pulverization (pulverization pressure 0.5-0.7MPa), pulverized and passed through a 120-mesh sieve, and placed in a desiccator for later use; (3) Adhesive preparation: Prepare an aqueous solution of adhesive with purified water to a mass fraction of 5% for later use; (4) Granulation: Take bisoprolol fumarate, filler, internal disintegrant (70%), and pretreated composite stabilizer, place them in a wet granulator, dry mix for 15 minutes (150-200 rpm), add binder aqueous solution, granulate at 200-300 rpm, make soft material, granulate through an 18-mesh sieve, dry in a fluidized bed (inlet air temperature 50-60℃) until the moisture content is 1.0%-2.0%, and granulate through a 16-mesh sieve.

[0025] (5) Total mixing: Add external disintegrant (30%) and lubricant, and mix in three dimensions for 5-8 minutes (10-15 rpm) to ensure that the content uniformity RSD ≤ 3%.

[0026] (6) Tableting, Opadry II film coating.

[0027] Comparative Examples 1-5: Bisoprolol Fumarate Tablets formula: The active ingredients and excipients in the formula, as well as the preparation method, are the same as in Example 1.

[0028] Comparative Example 5: Bisoprolol Fumarate Tablets In the formulation and preparation method, (1) and (3)-(6) are the same as in Example 1. In the preparation method, (2) pretreatment with composite stabilizers: weigh disodium edetate, erythritol, and low-substituted carboxymethyl chitosan, place them in a mixing pulverizer, dry mix for 10 minutes, treat with air jet pulverization (pulverization pressure 0.5-0.7MPa), pulverize and pass through a 120-mesh sieve, and place in a desiccator for later use.

[0029] Comparative Example 6: Commercially available bisoprolol fumarate tablets: National Drug Approval Number H20205007.

[0030] Stability of bisoprolol fumarate tablets Each group of bisoprolol fumarate tablets, packaged according to commercial specifications, was subjected to a long-term test at 30℃±2℃ and 65%±5% relative humidity for 12 months. The bisoprolol fumarate content was determined according to the high-performance liquid chromatography method (General Chapter 0512) in the Chinese Pharmacopoeia. Test solution: Accurately weigh 20 tablets, grind them finely, and accurately weigh an appropriate amount (approximately equivalent to 5 mg of bisoprolol fumarate). Place the powder in a 50 ml volumetric flask, add an appropriate amount of water to dissolve the bisoprolol fumarate, and dilute to the mark. Shake well, filter, and collect the filtrate. Reference solution: Accurately weigh an appropriate amount of bisoprolol fumarate reference standard, dissolve it in water, and quantitatively dilute to prepare a solution containing approximately 0.1 mg per ml. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.05 mol / L diammonium hydrogen phosphate solution (pH adjusted to 4.5 with phosphoric acid) - acetonitrile (70:30) was used as the mobile phase; the detection wavelength was 225 nm; the injection volume was 20 μl. System suitability requirements: The retention time of the bisoprolol peak was approximately 6–8 minutes; the theoretical plate number calculated based on the bisoprolol peak was not less than 1000; the resolution between the bisoprolol peak and adjacent impurity peaks should meet the requirements. Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the bisoprolol peak area using the external standard method.

[0031] Table 1. Stability of bisoprolol fumarate tablets in long-term tests Table 1 shows that the drug content of bisoprolol fumarate tablets in Examples 1-7 of this invention decreased significantly less than that in comparative examples 1-5 and commercially available products during long-term testing, indicating that the long-term storage stability of the formulation can be effectively improved through a specific composite stabilizer formulation and pretreatment process. The three stabilizers in the formulation significantly improved the long-term storage stability of the tablets through the following synergistic effects: (1) Synergistic effect of antioxidation and hydrolysis: Disodium edetate chelates metal ions to inhibit oxidation, the protective film of low-substituted carboxymethyl chitosan reduces water intrusion, and the hydrogen bonding effect of erythritol further enhances the stability of drug molecules. The three together block the two main degradation pathways of oxidation and hydrolysis. (2) Synergistic effect of microenvironment regulation: The hygroscopic balance ability of erythritol combined with the film-forming properties of low-substituted carboxymethyl chitosan can maintain a low humidity environment inside the tablet, reduce the decrease in chelation efficiency of disodium edetate due to humidity fluctuations, and ensure long-term stable function.

[0032] Long-term stability study of physicochemical properties of bisoprolol fumarate tablets After each group of bisoprolol fumarate tablets was packaged according to commercial specifications, a long-term test was conducted for 12 months at a temperature of 30℃±2℃ and a relative humidity of 65%±5%. The hardness, friability, and disintegration time of the tablets were measured at 0 months, 3 months, 6 months, 9 months, and 12 months.

[0033] Hardness was measured using a tablet hardness tester. Ten tablets were tested, and the average value was calculated.

[0034] Table 2 Hardness of Bisoprolol Fumarate Tablets in Each Group Table 2 shows that the bisoprolol fumarate tablets of Examples 1-7 of the present invention exhibited a significantly smaller decrease in hardness compared to Comparative Examples 1-6 and commercially available products during a 12-month long-term test. This indicates that the present invention, through specific composite stabilizers and pretreatment processes, can effectively maintain the structural integrity of tablets, reduce hardness decay during long-term storage, and ensure the physical stability of tablets.

[0035] Friability was determined according to General Chapter 0923 of the Chinese Pharmacopoeia. Take 20 tablets, weigh them accurately, place them in a friability tester, rotate them 100 times, remove them, sift out the powder, weigh them accurately, and calculate the weight loss rate.

[0036] Table 3. Friability of Bisoprolol Fumarate Tablets in Each Group The analysis in Table 3 shows that the fumarate bisoprolol tablets of Examples 1-7 maintained a low level of friability during 12 months of storage, indicating that the tablets had stable abrasion resistance.

[0037] The disintegration time was determined according to General Chapter 0921 (Tablet Disintegration Time Test Method) of the Chinese Pharmacopoeia, using water as the medium, taking 6 tablets for testing, and recording the time for complete disintegration.

[0038] Table 4. Disintegration time of bisoprolol fumarate tablets in each group Table 4 shows that the bisoprolol fumarate tablets of Examples 1-7 maintained good disintegration properties after 12 months of storage, which can avoid the problem of slow disintegration caused by long-term storage and ensure the dissolution efficiency and bioavailability of the drug.

Claims

1. A tablet of bisoprolol fumarate, characterized in that, The formula of the bisoprolen fumarate tablet is: bisoprolen fumarate 2.5-5 parts by weight, filler 60-120 parts by weight, disintegrant 4-9 parts by weight, lubricant 0.5-1.4 parts by weight, binder 1-5 parts by weight, stabilizer, water; the stabilizer is 0.05-0.3 parts by weight of edetate disodium and 5-15 parts by weight of erythritol and 0.8-2.5 parts by weight of low-substituted carboxymethyl chitosan.

2. The bisoprolol fumarate tablet according to claim 1, wherein The filler is selected from at least one of microcrystalline cellulose, lactose monohydrate, mannitol.

3. The bisoprolol fumarate tablet according to claim 1, wherein the tablet is a tablet having a weight of 2.5 mg. The disintegrant is selected from at least one of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, sodium carboxymethyl starch.

4. The bisoprolol fumarate tablet according to claim 1, wherein The lubricant is selected from at least one of magnesium stearate, sodium stearyl fumarate, talc.

5. The bisoprolol fumarate tablet according to claim 1, wherein the tablet is a tablet having a weight of 2.5 mg. The binder is selected from at least one of hypromellose, povidone K30, starch paste.

6. The bisoprolol fumarate tablet according to any one of claims 1 to 5, wherein The formula of the bisoprolen fumarate tablet is: bisoprolen fumarate 2.5 parts by weight, microcrystalline cellulose 45 parts by weight, lactose monohydrate 30 parts by weight, cross-linked sodium carboxymethyl cellulose 3 parts by weight, cross-linked povidone 1.5 parts by weight, magnesium stearate 0.4 parts by weight, sodium stearyl fumarate 0.25 parts by weight, hypromellose 1.5 parts by weight, edetate disodium 0.1 parts by weight, erythritol 8 parts by weight, low-substituted carboxymethyl chitosan 1.2 parts by weight, water in proper amount.

7. The bisoprolol fumarate tablet according to any one of claims 1 to 5, wherein The formula of the bisoprolen fumarate tablet is: bisoprolen fumarate 2.5 parts by weight, microcrystalline cellulose 45 parts by weight, lactose monohydrate 30 parts by weight, cross-linked sodium carboxymethyl cellulose 3 parts by weight, cross-linked povidone 1.5 parts by weight, magnesium stearate 0.4 parts by weight, sodium stearyl fumarate 0.25 parts by weight, hypromellose 1.5 parts by weight, edetate disodium 0.1 parts by weight, erythritol 8 parts by weigh, low-substituted carboxymethyl chitosan 1.2 parts by weight and water in proper amount.

8. A process for the preparation of bisoprolol fumarate tablet according to claim 1, characterized in that, The preparation method of the bisoprolen fumarate tablet comprises the following steps: (1) Pre-treatment of raw and auxiliary materials: bisoprolen fumarate, filler, disintegrant and lubricant are sieved respectively and prepared for use; (2) Pre-treatment of composite stabilizer: edetate disodium, erythritol and low-substituted carboxymethyl chitosan are dry-mixed, water is added to prepare soft material, mixed, dried, airflow pulverized, sieved and prepared for use; (3) Preparation of binder solution: a binder solution is prepared and prepared for use; (4) Granulation: bisoprolen fumarate, filler, additional disintegrant (70%), pre-treated composite stabilizer and binder solution are wet granulated to prepare soft material, dried and granulated; (5) Total mixing: additional disintegrant (30%) and lubricant are added and mixed; (6) Tabletting and film coating.

9. The process for preparing bisoprolol fumarate tablet according to claim 8, wherein the process is carried out at a temperature of 20 to 30°C. The mass fraction of the binder solution is 2%-5%.

10. The process for preparing bisoprolol fumarate tablet as claimed in claim 8, wherein, ###00003### The pre-treatment of the composite stabilizer is: edetate disodium, erythritol and low-substituted carboxymethy chitosan are placed in a mixing pulverizer, dry-mixed, 30% of purified water of the total weight is added to prepare soft material, and uniform suspension particles are formed; the suspension particles are placed in a vacuum drying oven, dried under the condition of 60℃±5℃ and vacuum degree-0.08MPa for 6 hours, the dried composite stabilizer particles are treated by airflow pulverization, sieved through a 120 mesh sieve after pulverization and prepared for use.

Images