Metoprolol succinate sustained release tablet and preparation method thereof

Abstract

The invention discloses a metoprolol succinate sustained-release tablet and a preparation method thereof. The tablet comprises a gastric-soluble film coating, a blank filling auxiliary material and a drug-containing sustained-release pellet, the blank filling auxiliary material comprises the following components in parts by weight: 20-40 parts of microcrystalline cellulose, 0.5-2 parts of magnesium stearate and 0.3-1 part of silicon dioxide; the drug-containing sustained-release pellet is composed of a blank pellet core, a drug layer and a sustained-release coating layer, the blank pellet core comprises 10-25 parts of a microcrystalline cellulose pellet core, and the drug layer comprises 25-100 parts of metoprolol succinate, 5-20 parts of lactose and 1-5 parts of povidone K30; the slow-release coating layer is prepared from 3 to 10 parts of ethyl cellulose; by screening the diameter of the pellet and the viscosity of ethyl cellulose, the preparation can realize slow release of drugs, and is low in content of related substances and total impurities, stable in quality and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a metoprolol succinate sustained-release tablet prepared by a pellet tableting process and a preparation method thereof. Background Art

[0002] Metoprolol succinate is a selective β1 receptor blocker that has a selective blocking effect on β1 receptors and a weaker blocking effect on β2 receptors. It is often used to treat hypertension, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, aortic dissection, arrhythmia, hyperthyroidism, cardiac neurosis and other diseases with good clinical efficacy.

[0003] Metoprolol tartrate has a high solubility of >700 mg / ml in water, which cannot guarantee long-term sustained drug release and is unsuitable for extended-release formulations. Extended-release tablets use metoprolol succinate, which has a lower solubility of approximately 200 mg / ml. Studies have shown that using metoprolol succinate as the primary drug can effectively ensure sustained drug release from polymer films for up to 20 hours.

[0004] Currently, metoprolol succinate preparations are available in a variety of dosage forms on the market. Among them, sustained-release preparations have attracted widespread attention due to their ability to reduce the number of dosing cycles, maintain stable blood drug concentrations, and improve patient compliance. However, existing metoprolol succinate sustained-release preparations suffer from complex processes, high production costs, poor drug release stability, and undesirable control of related substances (impurities) during their preparation. These issues not only affect the quality and efficacy of the preparations but also present certain difficulties for industrialized production.

[0005] The pellet compression process involves mixing pellets with appropriate excipients and then compressing them into tablets. This process combines the advantages of pellets and tablets, offering uniform dosage, stable drug release, and high production efficiency. Therefore, developing a metoprolol succinate sustained-release tablet prepared using a pellet compression process that effectively controls related substances and utilizes a rational process is of great practical significance. Summary of the Invention

[0006] The purpose of the present invention is to overcome the defects of the prior art metoprolol succinate sustained-release preparation, such as complex process, high cost, unstable drug release and poor control of related substances, and to provide a metoprolol succinate sustained-release tablet prepared by a micropellet tableting process and a preparation method thereof.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A metoprolol succinate sustained-release tablet prepared by a pellet tableting process, comprising a gastric-soluble film coating, a blank filling excipient, and drug-containing sustained-release pellets; the blank filling excipients comprise, by weight, 20-40 parts of microcrystalline cellulose, 0.5-2 parts of magnesium stearate, and 0.3-1 parts of silicon dioxide; the drug-containing sustained-release pellets comprise a blank pellet core, a drug layer, and a sustained-release coating layer; the blank pellet core comprises 10-25 parts of microcrystalline cellulose; the drug layer comprises 25-100 parts of metoprolol succinate, 5-20 parts of lactose, and 1-5 parts of povidone K30; and the sustained-release coating layer comprises 3-10 parts of ethyl cellulose.

[0009] The diameter of the drug-containing sustained-release pellets is 0.48-0.52 mm, preferably 0.5 mm.

[0010] The metoprolol succinate sustained-release tablets, in parts by weight, the blank filling excipients include 30 parts of microcrystalline cellulose, 1 part of magnesium stearate, and 0.6 parts of silicon dioxide; the blank pellet cores in the drug-containing sustained-release micropellets are 15 parts of microcrystalline cellulose pellet cores, the drug layer contains: 50 parts of metoprolol succinate, 12 parts of lactose, and 3 parts of povidone K30; and the sustained-release coating layer is 6 parts of ethyl cellulose.

[0011] The viscosity of the ethyl cellulose is 10-20 mPa·s (2% aqueous solution, 25° C.).

[0012] The weight gain of the sustained-release coating layer is 5%-15%.

[0013] The K value of the povidone K30 is 28-32, and the lactose is spray-dried lactose.

[0014] In the drug layer, the weight ratio of metoprolol succinate to lactose is (2.5-6.7):1.

[0015] The weight ratio of ethyl cellulose to drug-containing pellets (blank pellet core + drug layer) in the sustained-release coating layer is (0.1-0.3):1.

[0016] Each sustained-release tablet contains 2000-5000 drug-containing sustained-release micropellets, and the weight of the gastric-soluble film coating accounts for 1%-3% of the total weight of the tablet.

[0017] A method for preparing the metoprolol succinate sustained-release tablets according to any one of claims 1 to 9, characterized in that it comprises the following steps:

[0018] (1) Preparation of drug-containing sustained-release pellets:

[0019] ① Blank pellet processing: Take microcrystalline cellulose pellets with a diameter of 0.3-0.4 mm and sieve them for later use;

[0020] ② Preparation of drug layer: Metoprolol succinate and lactose were passed through an 80-100 mesh sieve and mixed evenly. A 5%-10% aqueous solution of povidone K30 was added to prepare a drug suspension. The drug suspension was coated on blank pellets using a fluidized bed coating method to form a drug layer. The pellets were dried at 40-50°C to a moisture content of 2%-4%. The pellet diameter at this point was controlled to be 0.45-0.47 mm.

[0021] ③ Preparation of sustained-release coating layer: Ethyl cellulose was dissolved in an ethanol-acetone mixed solvent at a volume ratio of 1:1 to prepare a 5%-10% coating solution. The drug-coated pellets were coated using a fluidized bed coating method. The coating weight gain was controlled to be 5%-15% so that the pellet diameter reached approximately 0.5 mm. After coating, the pellets were cured at 40-45°C for 2-4 hours to obtain drug-containing sustained-release pellets.

[0022] (2) Tableting: Mix the drug-containing sustained-release pellets with the microcrystalline cellulose and silicon dioxide in the blank filling excipients, add magnesium stearate and mix for 10-15 minutes, and tablet press to obtain plain tablets;

[0023] (3) Coating: Dissolve the gastric soluble film coating material in purified water to prepare an 8%-12% coating solution, and coat the plain tablets using a fluidized bed coating method, controlling the coating weight gain to 1%-3%.

[0024] The microcrystalline cellulose pellet core, gastric soluble film coating material and the like described in the present invention are commercially available.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] 1. Drug-containing sustained-release micropellets consist of a blank core, a drug layer, and a sustained-release coating layer. By rationally designing the composition and proportions of each layer and controlling parameters such as the micropellet diameter, the drug can be slowly released. This allows the drug to exert its effects continuously in the body, extending its duration of action, reducing the frequency of dosing, avoiding significant fluctuations in blood drug concentrations, and improving therapeutic efficacy.

[0027] 2. Excellent performance in controlling related substances. By rationally selecting the types and parameters of excipients (such as ethylcellulose viscosity) and precisely controlling the preparation process parameters (such as drying temperature and curing time), the generation and growth of impurities during the preparation and storage of the drug can be effectively suppressed. Testing has shown that the impurity content in the metoprolol succinate sustained-release tablets prepared by the present invention can be controlled at a low level, meeting the requirements of relevant quality standards, and ensuring the quality and safety of the drug. DETAILED DESCRIPTION

[0028] Example 1

[0029] prescription:

[0030] Blank filling excipients: microcrystalline cellulose 20g, magnesium stearate 0.5g, silicon dioxide 0.3g.

[0031] Drug-containing sustained-release micropellets: The blank core is a microcrystalline cellulose core 10g; the drug layer contains metoprolol succinate 25g, lactose 5g, and povidone K30 1g (K value 28); the sustained-release coating layer is ethyl cellulose 3g (viscosity 10mPa·s).

[0032] Preparation method:

[0033] (1) Preparation of drug-containing sustained-release pellets:

[0034] ① Blank pellet processing: Take microcrystalline cellulose pellets with a diameter of 0.3-0.4 mm and sieve them for later use.

[0035] ② Preparation of drug layer: Metoprolol succinate and lactose were passed through an 80-mesh sieve and mixed evenly. A 5% povidone K30 aqueous solution was added to prepare a drug suspension. The drug suspension was coated on blank pellet cores using a fluidized bed coating method to form a drug layer. The pellets were dried at 40°C to a moisture content of 2%. The pellet diameter was controlled to be 0.45 mm at this time.

[0036] ③ Preparation of sustained-release coating layer: Ethyl cellulose was dissolved in an ethanol-acetone mixed solvent at a volume ratio of 1:1 to prepare a 5% coating solution. The pellet cores with the drug layer were coated by a fluidized bed coating method. The coating weight gain was controlled to be 5% so that the pellet diameter reached approximately 0.5 mm. After coating, the pellets were cured at 40°C for 2 hours to obtain drug-containing sustained-release pellets.

[0037] (2) Tableting: Mix the drug-containing sustained-release pellets with the microcrystalline cellulose and silicon dioxide in the blank filling excipients, add magnesium stearate and mix for 10 minutes, and tablet press to obtain plain tablets.

[0038] (3) Coating: Dissolve the gastric soluble film coating material in purified water to prepare an 8% coating solution, and coat the plain tablets using a fluidized bed coating method, controlling the coating weight gain to 1%.

[0039] Example 2

[0040] prescription:

[0041] Blank filling excipients: microcrystalline cellulose 30g, magnesium stearate 1g, silicon dioxide 0.6g.

[0042] Drug-containing sustained-release micropellets: The blank core is a 15g microcrystalline cellulose core; the drug layer contains 47.5g metoprolol succinate, 12g lactose, and 3g povidone K30 (K value 30); the sustained-release coating layer is 6g ethyl cellulose (viscosity 15mPa·s).

[0043] Preparation method:

[0044] (1) Preparation of drug-containing sustained-release pellets:

[0045] ① Blank pellet processing: Take microcrystalline cellulose pellets with a diameter of 0.3-0.4 mm and sieve them for later use.

[0046] ② Preparation of drug layer: Metoprolol succinate and lactose were passed through a 90-mesh sieve and mixed evenly. An 8% povidone K30 aqueous solution was added to prepare a drug suspension. The drug suspension was coated on blank pellet cores using a fluidized bed coating method to form a drug layer. The pellets were dried at 45°C to a moisture content of 3%. The pellet diameter was controlled to be 0.45 mm at this time.

[0047] ③ Preparation of sustained-release coating layer: Ethyl cellulose was dissolved in an ethanol-acetone mixed solvent at a volume ratio of 1:1 to prepare an 8% coating solution. The pellet cores with the drug layer were coated by a fluidized bed coating method. The coating weight gain was controlled to be 10% so that the pellet diameter reached approximately 0.5 mm. After coating, the pellets were cured at 42°C for 3 hours to obtain drug-containing sustained-release pellets.

[0048] (2) Tableting: Mix the drug-containing sustained-release pellets with the microcrystalline cellulose and silicon dioxide in the blank filling excipients, add magnesium stearate and mix for 12 minutes, and tablet press to obtain plain tablets.

[0049] (3) Coating: Dissolve the gastric soluble film coating material in purified water to prepare a 10% coating solution, and coat the plain tablets using a fluidized bed coating method, controlling the coating weight gain to 2%.

[0050] Example 3

[0051] prescription:

[0052] Blank filling excipients: microcrystalline cellulose 40g, magnesium stearate 2g, silicon dioxide 1g.

[0053] Drug-containing sustained-release micropellets: The blank core is a 25g microcrystalline cellulose core; the drug layer contains 95g metoprolol succinate, 20g lactose, and 5g povidone K30 (K value 32); the sustained-release coating layer is 10g ethyl cellulose (viscosity 20mPa·s).

[0054] Preparation method:

[0055] (1) Preparation of drug-containing sustained-release pellets:

[0056] ① Blank pellet processing: Take microcrystalline cellulose pellets with a diameter of 0.3-0.4 mm and sieve them for later use.

[0057] ② Preparation of drug layer: Metoprolol succinate and lactose were passed through a 100-mesh sieve and mixed evenly. A 10% povidone K30 aqueous solution was added to prepare a drug suspension. The drug suspension was coated on blank pellet cores using a fluidized bed coating method to form a drug layer. The pellets were dried at 50°C to a moisture content of 4%. The pellet diameter was controlled to be 0.47 mm at this time.

[0058] ③ Preparation of sustained-release coating layer: Ethyl cellulose was dissolved in an ethanol-acetone mixed solvent at a volume ratio of 1:1 to prepare a 10% coating solution. The pellet cores with the drug layer were coated by a fluidized bed coating method. The coating weight gain was controlled to be 15% so that the pellet diameter reached approximately 0.5 mm. After coating, the pellets were cured at 45°C for 4 hours to obtain drug-containing sustained-release pellets.

[0059] (2) Tableting: Mix the drug-containing sustained-release pellets with the microcrystalline cellulose and silicon dioxide in the blank filling excipients, add magnesium stearate and mix for 15 minutes, and tablet press to obtain plain tablets.

[0060] (3) Coating: Dissolve the gastric soluble film coating material in purified water to prepare a 12% coating solution, and coat the plain tablets using a fluidized bed coating method, controlling the coating weight gain to 3%.

[0061] Example 4

[0062] prescription:

[0063] Blank filling excipients: microcrystalline cellulose 25g, magnesium stearate 1g, silicon dioxide 0.5g.

[0064] Drug-containing sustained-release micropellets: The blank core is a microcrystalline cellulose core 18 g; the drug layer contains metoprolol succinate 60 g, lactose 10 g, and povidone K302 g (K value 30); the sustained-release coating layer is ethyl cellulose 5 g (viscosity 12 mPa·s).

[0065] Preparation method:

[0066] (1) Preparation of drug-containing sustained-release pellets:

[0067] ① Blank pellet processing: Take microcrystalline cellulose pellets with a diameter of 0.3-0.4 mm and sieve them for later use.

[0068] ② Preparation of drug layer: Metoprolol succinate and lactose were passed through a 90-mesh sieve and mixed evenly. A 7% povidone K30 aqueous solution was added to prepare a drug suspension. The drug suspension was coated on blank pellet cores using a fluidized bed coating method to form a drug layer. The pellets were dried at 43°C to a moisture content of 3%. The pellet diameter was controlled to be 0.46 mm at this time.

[0069] ③ Preparation of sustained-release coating layer: Ethyl cellulose was dissolved in an ethanol-acetone mixed solvent at a volume ratio of 1:1 to prepare a 7% coating solution. The pellet cores with the drug layer were coated by the fluidized bed coating method. The coating weight gain was controlled to 8% so that the pellet diameter reached approximately 0.5 mm. After coating, the pellets were cured at 41°C for 2.5 hours to obtain drug-containing sustained-release pellets.

[0070] (2) Tableting: The drug-containing sustained-release pellets were mixed evenly with the microcrystalline cellulose and silicon dioxide in the blank filling excipients, magnesium stearate was added, and the mixture was mixed for 13 minutes, and tablets were obtained.

[0071] (3) Coating: Dissolve the gastric soluble film coating material in purified water to prepare a 9% coating solution, and coat the plain tablets using a fluidized bed coating method, controlling the coating weight gain to 1.5%.

[0072] Example 5

[0073] prescription:

[0074] Blank filling excipients: microcrystalline cellulose 35g, magnesium stearate 1.5g, silicon dioxide 0.8g.

[0075] Drug-containing sustained-release micropellets: The blank core is a 22g microcrystalline cellulose core; the drug layer contains 80g metoprolol succinate, 15g lactose, and 4g povidone K30 (K value 31); the sustained-release coating layer is 8g ethyl cellulose (viscosity 18mPa·s).

[0076] Preparation method:

[0077] (1) Preparation of drug-containing sustained-release pellets:

[0078] ① Blank pellet processing: Take microcrystalline cellulose pellets with a diameter of 0.3-0.4 mm and sieve them for later use.

[0079] ② Preparation of drug layer: Metoprolol succinate and lactose were passed through a 90-mesh sieve and mixed evenly. An 8% povidone K30 aqueous solution was added to prepare a drug suspension. The drug suspension was coated on blank pellet cores using a fluidized bed coating method to form a drug layer. The pellets were dried at 47°C to a moisture content of 3%. The pellet diameter was controlled to be 0.46 mm at this time.

[0080] ③ Preparation of sustained-release coating layer: Ethyl cellulose was dissolved in an ethanol-acetone mixed solvent at a volume ratio of 1:1 to prepare a 9% coating solution. The pellet cores with the drug layer were coated by a fluidized bed coating method. The coating weight gain was controlled to be 12% so that the pellet diameter reached approximately 0.5 mm. After coating, the pellets were cured at 43°C for 3.5 hours to obtain drug-containing sustained-release pellets.

[0081] (2) Tableting: The drug-containing sustained-release pellets were mixed evenly with the microcrystalline cellulose and silicon dioxide in the blank filling excipients, magnesium stearate was added, and the mixture was mixed for 14 minutes, and tablets were obtained.

[0082] (3) Coating: Dissolve the gastric soluble film coating material in purified water to prepare an 11% coating solution, and coat the plain tablets using a fluidized bed coating method, controlling the coating weight gain to 2.5%.

[0083] Test Example 1: Ethyl cellulose viscosity screening test

[0084] Comparative Example 1 Prescription: Except for the viscosity of ethyl cellulose, other ingredients and amounts were in accordance with the preferred formula of Example 2, and the diameter of the micropellets was controlled to be 0.5 mm.

[0085] Ethyl cellulose viscosity level setting: 5 different ethyl cellulose viscosity levels are set, namely 8mPa·s, 12mPa·s, 15mPa·s, 18mPa·s, and 22mPa·s (all 2% aqueous solutions, measured at 25°C).

[0086] Preparation method: Prepare according to the preparation method of Example 2.

[0087] Testing indicators and methods:

[0088] Drug Release: Dissolution and Release Determination Method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Rules, Method 2, 0931) was used for the dissolution and release determination of this product. Using 500 ml of phosphate buffer (pH 6.8) as the dissolution medium, the filtration speed was set at 50 rpm. At 1, 4, 8, and 20 hours, 5 ml of the solution was collected and filtered. The solution was immediately replenished with the same volume of dissolution medium at the same temperature. Following the chromatographic conditions under the assay, 40 μl of the filtrate was accurately measured and injected into the liquid chromatograph. The chromatogram was recorded. Separately, accurately weigh the metoprolol succinate reference substance, dissolve it in the dissolution medium, and quantitatively dilute it to a solution containing approximately 50 μg per 1 ml. This solution was used as the reference substance solution and assayed in the same manner. The amount of dissolution per tablet at different time points was calculated using the peak area using the external standard method.

[0089] Table 1 Release data

[0090]

[0091]

[0092] Within the viscosity range of the ethyl cellulose of the present invention, it has better sustained release properties and can effectively ensure that the drug is continuously released from the polymer film for up to 20 hours.

[0093] Test Example 2: Pellets Diameter Screening Test

[0094] Comparative Example 2 Prescription: Except for the diameter of the micropellets, the other prescription ingredients and dosages were according to the preferred formula of Example 2, that is, the blank filling excipients included 30 mg of microcrystalline cellulose, 1 mg of magnesium stearate, and 0.6 mg of silicon dioxide; the blank pellet core in the drug-containing sustained-release micropellets was 15 mg of microcrystalline cellulose pellet core, the drug layer contained 50 mg of metoprolol succinate, 12 mg of lactose, and 3 mg of povidone K30; and the sustained-release coating layer was 6 mg of ethyl cellulose (viscosity 15 mPa·s).

[0095] Pellet diameter level setting: Set 5 different pellet diameter levels, namely 0.46mm, 0.48mm, 0.50mm, 0.52mm, and 0.54mm.

[0096] Preparation method: The preparation was carried out according to the preparation method of Example 2. During the preparation of the sustained-release coating layer, the pellet diameter was adjusted to a set level by controlling the coating weight gain.

[0097] Testing indicators and methods:

[0098] Pellet diameter: Use a microscope (with a micrometer) to randomly measure the diameter of at least 100 pellets and calculate the average value.

[0099] Drug release: same as above

[0100] Table 2 Release data

[0101]

[0102] Although metoprolol succinate has a lower solubility than metoprolol tartrate, the diameter of the drug-containing sustained-release micropellets still affects the release rate of the drug. The drug-containing sustained-release micropellets of the present invention have a diameter within the range of 0.48-0.52 mm, especially 0.5 mm, which have better sustained release properties and can effectively ensure sustained drug release for up to 20 hours.

[0103] The content was determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 edition, Part IV, General Chapter 0512).

[0104] Chromatographic conditions and system suitability test: Octylsilane bonded silica gel was used as the filler; the mobile phase consisted of phosphate buffer (50 ml of 1 mol / L sodium dihydrogen phosphate solution and 8.0 ml of 1 mol / L phosphoric acid solution, diluted to 1000 ml with water, and adjusted to pH 3.0 with 1 mol / L potassium dihydrogen phosphate solution or 1 mol / L phosphoric acid solution)-acetonitrile (75:25); the column temperature was 30°C, the flow rate was 1.0 ml / min, and the detection wavelength was 280 nm. The number of theoretical plates, calculated based on the metoprolol peak, was to be no less than 3000.

[0105] Determination method: Take 10 tablets (47.5 mg) or 20 tablets (23.75 mg) of this product and place them in a 500 ml volumetric flask. Add 50 ml of water and sonicate to completely disperse. Add 150 ml of ethanol and sonicate for 40 minutes. Then add 200 ml of mobile phase and sonicate for 40 minutes to dissolve the metoprolol succinate. Let cool, dilute to the mark with mobile phase, shake well, and centrifuge (15,000 rpm, 5 minutes). Accurately measure 5.0 ml of the supernatant and place it in a 100 ml volumetric flask. Dilute to the mark with mobile phase and shake well to prepare the test solution. Accurately measure 40 μl of the test solution and inject it into the liquid chromatograph, and record the chromatogram. Separately, take an appropriate amount of metoprolol succinate reference substance, accurately weigh it, dissolve it in mobile phase, and prepare a solution containing approximately 0.05 mg of metoprolol succinate per 1 ml. Determine the concentration in the same manner. Calculate the peak area using the external standard method.

[0106] Related substances: Take 10 tablets of this product and place them in a 100ml volumetric flask. Add 5ml of water and sonicate to disperse. Add 15ml of ethanol and sonicate for 40 minutes. Then add 30ml of water and sonicate for 40 minutes to dissolve. Let cool, dilute to the mark with water, shake well, and centrifuge (15000rpm, 5min). The supernatant is used as the test solution. Separately, accurately weigh impurity C and metoprolol succinate reference substance, dissolve them in water, and quantitatively dilute them to a mixed solution containing approximately 9.5μg of each per 1ml. This is used as the reference solution. Separately, accurately measure 2.5ml of the reference solution and place it in a 10ml volumetric flask. Add water to the mark and dilute to the mark. Shake well to use as the sensitivity solution. Test according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0512). Use octadecyl bonded silica gel as the filler (4.6 mm × 250 mm, 5 μm or equivalent performance column); acetate buffer (take 3.9 g of ammonium acetate, add 810 ml of water to dissolve, add 2.0 ml of triethylamine, 10.0 ml of glacial acetic acid, 3.0 ml of phosphoric acid, and shake well) as mobile phase A, methanol-mobile phase A (90:10) as mobile phase B, and the column temperature is 40°C; perform gradient elution according to the table below; the flow rate is 1.0 ml per minute, and the detection wavelength is 280 nm.

[0107] Table 3

[0108]

[0109] Take appropriate amounts of metoprolol succinate, impurity A (1-(ethylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol), impurity B (1-chloro-3-[4-(2-methoxyethyl)phenoxy]-2-propanol), impurity C (4-[2-hydroxy-3-(isopropylamino)-propoxy]benzaldehyde), and impurity D (N,N′-bis{2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propyl}isopropylamine), dissolve them in water, and prepare a mixed solution containing approximately 4.75 mg of metoprolol succinate and 9.5 μg of each impurity per 1 ml. This solution is used as the system suitability solution. 40 μl of the solution is injected into the liquid chromatograph. The peaks are eluted in the order of impurity C, impurity A, metoprolol, impurity B, and impurity D. The resolution between adjacent chromatographic peaks should meet the requirements. Take 40 μl of the sensitivity solution and inject it into the liquid chromatograph. The signal-to-noise ratio of the main component peak height should be greater than 10. Then accurately measure 40 μl of the test solution and the reference solution, respectively, and inject them into the liquid chromatograph and record the chromatogram.

[0110] The sample obtained in Comparative Example 2 was placed at 60°C for stability testing, and the relevant substances were detected at 0, 4, 8, and 24 hours. The results are shown in Table 3.

[0111] Table 4 Prescription stability results of different pellet diameters

[0112]

[0113] From the above results, it can be seen that the drug-containing sustained-release micropellets of the present invention have better stability within the diameter range of 0.48-0.52 mm, especially 0.5 mm.

[0114] Test Example 3: Release Test of Examples 1-5

[0115] Table 5 Release data

[0116]

[0117] Test Example 4: Accelerated stability test of Examples 1-5

[0118] The tablets prepared in Examples 1-5 were placed under high temperature (60°C ± 2°C), high humidity (relative humidity 90% ± 5%, 25°C), and light (4500 lx ± 500 lx) conditions for 5 and 10 days to investigate changes in their contents and related substances.

[0119] Table 6 Stability test results

[0120]

[0121]

[0122] The results showed that the appearance of the tablets of Examples 1-5 did not change significantly, the content decreased by less than 5%, and the increase of related substances did not exceed 0.5%, indicating that the metoprolol succinate sustained-release tablets of the present invention have more excellent stability.

Claims

1. A metoprolol succinate sustained-release tablet, characterized in that: The tablets include a gastric-soluble film coating, blank filling excipients, and drug-containing sustained-release micropellets; the blank filling excipients include 20-40 parts of microcrystalline cellulose, 0.5-2 parts of magnesium stearate, and 0.3-1 parts of silicon dioxide, by weight; the drug-containing sustained-release micropellets consist of a blank pill core, a drug layer, and a sustained-release coating layer; the blank pill core is 10-25 parts of microcrystalline cellulose pill core, the drug layer contains 25-100 parts of metoprolol succinate, 5-20 parts of lactose, and 1-5 parts of povidone K30; and the sustained-release coating layer is 3-10 parts of ethyl cellulose.

2. The metoprolol succinate sustained-release tablet according to claim 1, wherein The diameter of the drug-containing sustained-release pellets is 0.48-0.52 mm, preferably 0.5 mm.

3. The metoprolol succinate sustained-release tablet according to claim 1, wherein In parts by weight, the blank filling excipients include 30 parts of microcrystalline cellulose, 1 part of magnesium stearate, and 0.6 parts of silicon dioxide; the blank pellet core in the drug-containing sustained-release micropellets is 15 parts of microcrystalline cellulose pellet core, the drug layer contains: 50 parts of metoprolol succinate, 12 parts of lactose, and 3 parts of povidone K30; and the sustained-release coating layer is 6 parts of ethyl cellulose.

4. The metoprolol succinate sustained-release tablet according to claim 1, wherein The viscosity of the ethyl cellulose is 10-20 mPa·s (2% aqueous solution, 25° C.).

5. The metoprolol succinate sustained-release tablet according to claim 1, wherein The weight gain of the sustained-release coating layer is 5%-15%.

6. The metoprolol succinate sustained-release tablet according to claim 1, wherein The K value of the povidone K30 is 28-32, and the lactose is spray-dried lactose.

7. The metoprolol succinate sustained-release tablet according to claim 1, wherein In the drug layer, the weight ratio of metoprolol succinate to lactose is (2.5-6.7):

1.

8. The metoprolol succinate sustained-release tablet according to claim 1, wherein The weight ratio of ethyl cellulose to drug-containing pellets (blank pellet core + drug layer) in the sustained-release coating layer is (0.1-0.3):

1.

9. The metoprolol succinate sustained-release tablet according to claim 1, wherein Each sustained-release tablet contains 2000-5000 drug-containing sustained-release micropellets, and the weight of the gastric-soluble film coating accounts for 1%-3% of the total weight of the tablet.

10. A method for preparing the metoprolol succinate sustained-release tablets according to any one of claims 1 to 9, characterized in that: The following steps are involved: (1) Preparation of drug-containing sustained-release pellets: ① Blank pellet processing: Take microcrystalline cellulose pellets with a diameter of 0.3-0.4 mm and sieve them for later use; ② Preparation of drug layer: Metoprolol succinate and lactose were passed through an 80-100 mesh sieve and mixed evenly. A 5%-10% aqueous solution of povidone K30 was added to prepare a drug suspension. The drug suspension was coated on blank pellets using a fluidized bed coating method to form a drug layer. The pellets were dried at 40-50°C to a moisture content of 2%-4%. The pellet diameter at this point was controlled to be 0.45-0.47 mm. ③ Preparation of sustained-release coating layer: Ethyl cellulose was dissolved in an ethanol-acetone mixed solvent at a volume ratio of 1:1 to prepare a 5%-10% coating solution. The drug-coated pellets were coated using a fluidized bed coating method. The coating weight gain was controlled to be 5%-15% so that the pellet diameter reached approximately 0.5 mm. After coating, the pellets were cured at 40-45°C for 2-4 hours to obtain drug-containing sustained-release pellets. (2) Tableting: Mix the drug-containing sustained-release pellets with the microcrystalline cellulose and silicon dioxide in the blank filling excipients, add magnesium stearate and mix for 10-15 minutes, and tablet press to obtain plain tablets; (3) Coating: Dissolve the gastric soluble film coating material in purified water to prepare an 8%-12% coating solution, and coat the plain tablets using a fluidized bed coating method, controlling the coating weight gain to 1%-3%.

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