Metoprolol succinate sustained release tablet and preparation method thereof

Abstract

The invention discloses a metoprolol succinate sustained-release tablet and a preparation method thereof, and belongs to the field of pharmaceutical preparations, the metoprolol succinate sustained-release tablet comprises a tablet and a coating layer coated on the surface of the tablet, and the tablet is obtained by tabletting sustained-release pellets and auxiliary materials; the sustained-release pellet comprises a drug-containing pellet core and a sustained-release layer wrapping the drug-containing pellet core; the medicine-containing pill core contains a metoprolol succinate main medicine; the sustained-release layer is formed by coating the drug-containing pellet core with a sustained-release coating material; the medicine-containing pellet core is prepared by the following steps: preparing a soft material from metoprolol succinate, pellet core auxiliary materials and water by using a wet method, and then extruding, rolling and drying to obtain the medicine-containing pellet core. The sustained-release tablet adopts a multi-unit pellet sustained-release technology, so that the medicine is continuously and uniformly released within 24 hours, the blood concentration is more stable, and the heart rate and blood pressure fluctuation are reduced.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparation, and relates to a metoprolol succinate sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] Metoprolol succinate, the chemical name of which is 1-isopropylamino-3-[p-(2-methoxyethyl) phenoxy]-2-propanol L(+)-succinate, has the following structural formula:

[0003]

[0004] Metoprolol was successfully developed in the 1970s, and is the first high-selectivity beta receptor blocker in the world. The affinity of metoprolol to β1 receptor is as high as 20 times that of β2 receptor. This property significantly reduces the risk of bronchial asthma or other obvious obstructive pulmonary diseases, weakens the effect of catecholamines related to physiological and psychological load, reduces heart rate, cardiac output and blood pressure, and becomes a drug cornerstone for treating hypertension, angina pectoris and stable chronic heart failure with left ventricular systolic dysfunction.

[0005] The early dosage form of metoprolol is metoprolol tartrate. However, the ordinary metoprolol tartrate tablet (short-acting preparation) has a short half-life (3-5 hours), and needs to be taken multiple times a day, which leads to large fluctuations in blood drug concentration, and may affect the efficacy and increase the risk of adverse reactions. Therefore, the development of sustained-release preparations to prolong the action time of the drug and reduce peak-trough fluctuations has become a clinical need.

[0006] Compared with tartrate, the solubility of metoprolol succinate in water at 37℃ (270 mg / mL) is significantly lower than that of metoprolol tartrate (>700 mg / mL), which makes it more suitable for sustained-release preparations, can slow down the release rate of the drug, and achieve more lasting therapeutic effect. In addition, the stability of succinate is better, and it is more suitable for long-term storage.

[0007] Metoprolol succinate sustained-release tablets were launched in the United States in 1992, and the original research manufacturer was AstraZeneca. The product name is Toprol-Xl. In April 2007, metoprolol succinate sustained-release tablets were imported and marketed in China, and the product name is Metoprolol Succinate Sustained-Release Tablets. The specifications are 23.75 mg, 47.5 mg, 95 mg and 190 mg, which are equivalent to 25 mg, 50 mg, 100 mg and 200 mg of metoprolol tartrate, respectively.

[0008] US4927640A discloses a preparation method of metoprolol succinate controlled release tablets, which is to dissolve metoprolol succinate in dichloroethane-ethanol mixed solvent, then spray on inert core to form drug-loaded core, and then coat a sustained-release layer on the core to form sustained-release pellets, and then mix with additional excipients and press into tablets. The above-mentioned preparation method uses blank core to spray medicine, which has the disadvantage that during the spraying process or the initial drying stage, drug molecules may migrate to the inside or surface of the core with the solvent, resulting in uneven content, and the drug migrated to the surface may cause burst release, increasing the safety hazard of the drug.

[0009] Chinese patent CN106109431A discloses a sustained-release micro-pellet tablet and a preparation method, which is to prepare metoprolol succinate core, then spray a sustained-release coating liquid on the drug-containing core to form micro-pellets, and then mix the drug-containing sustained-release micro-pellets with additional excipients to press into tablets. The sustained-release tablets are prepared by breaking the sustained-release micro-pellets during tabletting to prepare tablets with required release rate. However, the degree of micro-pellet breakage is difficult to accurately control, and batch differences may occur due to parameter fluctuations during production. Excessive breakage of micro-pellets may cause drug burst release, and insufficient breakage may not achieve the expected release effect.

[0010] Chinese patent application CN113143877A discloses a preparation method of metoprolol succinate micro-pellet sustained-release tablets, which comprises the following steps: (1) preparing drug-containing cores by high-speed centrifugal atomization of metoprolol succinate and sucrose, with an inlet temperature of 80-120℃ and an outlet temperature of 60-80℃; (2) dissolving metoprolol succinate in purified water, and spraying on the drug-containing cores prepared in step (1) under fluidized state to coat a drug layer and prepare drug-loaded micro-pellets; (3) coating the drug-loaded micro-pellets prepared in step (2) with sustained-release coating material to prepare sustained-release coated micro-pellets; (4) mixing the sustained-release coated micro-pellets prepared in step (3) with fillers, disintegrants, glidants and lubricants, then pressing into tablets, and then coating a layer of wax material on the surface to prepare metoprolol succinate micro-pellet sustained-release tablets. The high-speed centrifugal atomization method used in the method needs to be accurately coordinated in terms of speed, feeding rate and temperature, and small deviations may lead to uneven particle size distribution of the pellets, micro-pellet breakage and uneven drug distribution, which is difficult to control in batch production. Rapid drying may form a porous structure, affecting drug release. SUMMARY

[0011] Problems to be solved by the present application

[0012] The existing metoprolol succinate sustained-release tablets are prepared by multi-unit pellet sustained-release technology or common technology, and the sustained-release tablets prepared by common technology are prone to cause large batch difference and increase the risk of drug burst release. Some sustained-release tablets prepared by multi-unit pellet technology adopt the process of coating medicine on blank pellet cores, and this method is prone to cause the medicine to migrate to the inside or surface of the pellet cores along with the solvent in the sustained-release coating process, thereby causing uneven content and increasing the risk of drug burst release. The existing technology also has a method for preparing drug-loaded pellets, but the method uses high-speed centrifugal atomization, and has the defects of being difficult to control and uneven particle size distribution. Therefore, the application provides a new multi-unit pellet system technology, which mixes metoprolol succinate raw materials with excipients to prepare drug-containing pellet cores, and then forms thousands of independent pellet systems through sustained-release coating, and through further optimization of the types and proportions of buffer excipients, reduces the pressure sensitivity and the breakage rate of the pellets, and ensures the long-acting and stable release of the drug.

[0013] To achieve the object of the application, the application adopts the following technical solutions:

[0014] A metoprolol succinate sustained-release tablet comprises a blank tablet and a coating layer coated on the surface of the blank tablet, and the blank tablet is obtained by compressing sustained-release pellets and excipients;

[0015] The sustained-release pellets comprise a drug-containing pellet core and a sustained-release layer wrapped around the drug-containing pellet core;

[0016] The drug-containing pellet core contains metoprolol succinate as the main drug;

[0017] The sustained-release layer is formed by coating the drug-containing pellet core with a sustained-release coating material;

[0018] The drug-containing pellet core is prepared by first preparing a soft material from metoprolol succinate, pellet excipients and water by a wet method, and then extruding, rounding and drying;

[0019] The particle size of the drug-containing pellet core ranges from 20 to 60 mesh;

[0020] The particle size of the sustained-release pellets ranges from 18 to 80 mesh.

[0021] In the metoprolol succinate sustained-release tablet prepared by the application, the pellet core is prepared by mixing metoprolol succinate as the main drug with excipients, which can uniformly disperse the drug in the pellet core, reduce the influence of the coating process on the content uniformity, and control the size of the drug-containing pellet core and the sustained-release pellets. The sustained-release tablet prepared by this method contains a large number of independent and coated pellets, and each pellet is an independent drug delivery unit. Therefore, the tablet has a significant advantage in breaking, and when the tablet is broken, the broken parts are uniformly distributed, achieving relatively accurate dose segmentation, and the broken parts can still maintain stable release characteristics.

[0022] In this invention, the drug-containing pellet core includes a filler and a binder. The filler includes at least one selected from lactose, corn starch, pregelatinized starch, microcrystalline cellulose, and mannitol, preferably lactose and microcrystalline cellulose. The binder includes at least one selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose. Based on the total weight of the drug-containing pellet core, the proportions of each component are: filler 25%–35%, binder 2%–4%.

[0023] This invention further reduces tableting sensitivity by optimizing the types and proportions of sustained-release excipients and added excipients. This results in a synergistic effect between the microcapsules and excipients, reducing stratification between the sustained-release microcapsules and excipients, as well as breakage during tableting, and minimizing the impact of material stratification on content uniformity. Simultaneously, the reduced tableting sensitivity results in sustained-release tablets with ideal drug release behavior, reducing burst release and ensuring clinical drug safety. The sustained-release layer of the sustained-release microcapsules includes sustained-release excipients, plasticizers, and anti-adhesion agents. The sustained-release excipient is at least one of ethyl cellulose, cellulose acetate, and polymethyl methacrylate, preferably ethyl cellulose. Ethyl cellulose is a water-insoluble polymer, and its core advantage as a sustained-release excipient lies in its excellent hydrophobicity and film-forming properties. The strong hydrophobicity of ethyl cellulose allows it to form a dense barrier film on the surface of the capsule core. This coating film resists mechanical stress during tableting, reducing microcapsule breakage or peeling. Ethyl cellulose grades include 10cp, 20cp, and 45cp, among which 45cp ethyl cellulose has superior compressive strength and sustained-release properties, making it more suitable for microcapsule tableting. Plasticizers include at least one of polyethylene glycol, triethyl citrate, and glyceryl triacetate, preferably triethyl citrate. The addition of triethyl citrate improves the compressive strength of the coating and regulates drug release. Anti-adhesion agents include silica, titanium dioxide, and talc, preferably talc. The addition of talc reduces adhesion between microcapsules, protecting their integrity. Based on the total weight of the sustained-release microcapsules, the proportion of sustained-release excipients is 10-20%, plasticizers are 1-3%, and anti-adhesion agents are 2-4%.

[0024] The tablets comprise a filler, a disintegrant, and a lubricant. The filler comprises at least one of microcrystalline cellulose, starch, and spray-dried lactose, preferably spray-dried lactose and microcrystalline cellulose. Microcrystalline cellulose has a hydrogen bond network between its molecules, which associates under pressure, giving it excellent compressibility. This high compressibility allows it to quickly form a continuous matrix, encapsulating the microspheres to form a "buffer layer" and preventing damage to the microspheres under high pressure. Spray-dried lactose particles have high sphericity and good flowability, ensuring uniform dosage during high-speed tableting. When used with microcrystalline cellulose, it is less prone to static electricity, reducing powder adhesion problems. The disintegrant comprises at least one of sodium hydroxypropyl methylcellulose, croscarmellose sodium, polyoxyethylene, sodium carboxymethyl starch, and croscarmellose, preferably croscarmellose sodium or polyoxyethylene. The advantage of croscarmellose sodium as a disintegrant is that it can expand directionally without damaging the microspheres, and its smooth fiber surface reduces friction between microspheres, preventing coating wear during tableting. Polyoxyethylene molecules have long chains (molecular weight 100,000-7,000,000), allowing them to form a strong, adhesive network through molecular entanglement even under low pressure, reducing damage to the microcapsules under high pressure. The lubricant includes at least one of sodium stearate fumarate, talc, magnesium stearate, and stearic acid, preferably sodium stearate and stearic acid. Sodium stearate fumarate and stearic acid effectively reduce friction between the powder and the mold, reducing the tableting force by 10%-15% while maintaining tablet hardness. They are gentler than traditional magnesium stearate and provide better protection for the microcapsule coating than talc and magnesium stearate. Based on the total weight of the uncoated tablets, the components are distributed as follows: filler 42%–70%, disintegrant 2%–6%, and lubricant 0.5%–3%.

[0025] The coating material of the coated tablets is a gastrointestinal soluble film coating premix, composed of polyvinyl alcohol, titanium dioxide, talc, and lecithin (soybean). The coating material accounts for 2% to 6% of the total weight of the coated tablets.

[0026] The present invention provides a method for preparing metoprolol succinate sustained-release tablets, comprising:

[0027] (1) Prepare a drug-containing pellet core by mixing metoprolol succinate, filler, binder and purified water;

[0028] (2) Dissolve the sustained-release coating material in an alcohol solvent to prepare a sustained-release coating solution, and spray it onto the drug-containing pellet core to prepare sustained-release micro pellets;

[0029] (3) The sustained-release microcapsules are mixed with fillers, disintegrants and lubricants and compressed into tablets to prepare plain tablets;

[0030] (4) Dissolve the gastric-soluble film coating premix in water to make a coating solution, and spray it onto the uncoated tablets to make coated tablets.

[0031] In this invention, the formation of the drug-containing pellet core includes: mixing metoprolol succinate and a filler in a granulator, adding a binder and purified water to prepare a wet soft material, and drying the wet soft material by extrusion spheroidization, fluidized bed drying, or oven drying to form the drug-containing pellet core. The weight ratio of all raw materials and excipients to purified water in the drug-containing pellet core is 3–5:1. The aperture of the extrusion mesh is preferably 0.3–0.7 mm. The drug-containing pellet core has a mesh size of 20–60 mesh.

[0032] In this invention, the formation of the sustained-release microspheres includes: dissolving sustained-release excipients, triethyl citrate, and talc in an alcoholic solvent to prepare a sustained-release coating solution; and spraying the sustained-release coating solution onto a drug-containing pellet core using a fluidized bed bottom spraying process to form sustained-release microspheres. The weight ratio of all raw materials and excipients to the alcoholic solvent in the sustained-release microspheres is 1:2 to 4; the solvent is at least one of methanol, ethanol, and isopropanol, preferably ethanol. The weight gain of the sustained-release microsphere coating is preferably 12 to 20%. The sustained-release microspheres have a mesh size of 18 to 80 mesh.

[0033] In this invention, the formation of the unprocessed tablets includes: mixing sustained-release microspheres with added excipients and compressing them into unprocessed tablets.

[0034] In this invention, the formation of the coated tablets includes: dissolving a gastrointestinal film coating premix in a solvent and stirring until homogeneous; and then coating the uncoated tablets using a coating machine to obtain the coated tablets. The solvent is at least one of ethanol, isopropanol, and purified water, preferably purified water; the weight ratio of all raw materials and excipients in the coated tablets to purified water is 4–6:1.

[0035] The metoprolol succinate sustained-release tablets prepared by this invention have better content uniformity, and their dissolution in different dissolution media is similar to that of the original formulation, with a similarity factor f2 value greater than 50.

[0036] In this invention, each unit of metoprolol succinate extended-release tablet is composed of the following components:

[0037]

[0038]

[0039] The positive effects of this invention are as follows:

[0040] (1) The metoprolol succinate sustained-release microcapsules prepared by the present invention are prepared into drug-containing capsule cores by mixing the main drug and excipients. This method can make the drug evenly dispersed inside the capsule core and reduce the impact of the coating process on the content uniformity.

[0041] (2) The metoprolol succinate sustained-release tablets prepared by the present invention reduce the impact of material stratification on content uniformity by optimizing the sustained-release coating material and the types and proportions of excipients.

[0042] (3) The method for preparing metoprolol succinate sustained-release tablets of the present invention achieves ideal drug release behavior and can obtain a drug release curve similar to that of the original drug.

[0043] (4) The metoprolol succinate sustained-release tablets prepared by the present invention have significant advantages in terms of tablet breaking. When the tablet is broken, the broken part is evenly distributed, achieving relatively accurate dose division, and the broken part can still maintain stable release characteristics. Attached Figure Description

[0044] Figure 1 Comparison of dissolution curves of metoprolol succinate sustained-release tablets prepared in Example 1 and control Example 1 (using pH 6.8 phosphate buffer as the dissolution medium).

[0045] Figure 2 Comparison of dissolution curves of metoprolol succinate sustained-release tablets prepared in Example 2 and control Example 2 (using pH 6.8 phosphate buffer as the dissolution medium).

[0046] Figure 3 Comparison of dissolution curves of metoprolol succinate sustained-release tablets prepared in Example 3 and control Example 3 (using pH 6.8 phosphate buffer as the dissolution medium).

[0047] Figure 4 Comparison of dissolution curves of metoprolol succinate sustained-release tablets prepared in Example 4 and control Example 4 (using pH 6.8 phosphate buffer as the dissolution medium).

[0048] Figure 5 Comparison of dissolution curves of metoprolol succinate sustained-release tablets prepared in Examples 5-12 and control example 2 (using pH 6.8 phosphate buffer as the dissolution medium). Detailed Implementation

[0049] The following examples further illustrate the metoprolol succinate sustained-release tablets and their preparation method of the present invention. Obviously, the examples are only for the purpose of helping to understand the content of the present invention and should not be construed as limiting the subject matter and scope of protection of the present invention.

[0050] Release rate determination method

[0051] Methods: The release rate was determined according to Method 1 (Second Method, Paddle Method, 50 rpm, 500 mL, pH 6.8 phosphate buffer) of metoprolol succinate sustained-release tablets in USP.

[0052] Calculation of similarity factor (f2):

[0053] The similarity factor (f2) is a parameter that measures the similarity between two dissolution curves. The calculation formula is as follows:

[0054] f2=50log[[1+1 / nΣ(Rt-Tt)2]-0.5×100]

[0055] In the formula, Rt represents the cumulative drug release percentage of the reference formulation at time t; Tt represents the cumulative drug release percentage of the test formulation at time t; and n represents the number of sampling points. When the two drug release curves perfectly match, f2 is 100; as the difference between the two curves increases, the f2 value decreases. Generally, an f2 value between 50 and 100 indicates that the drug release of the two formulations under the same release conditions is considered to be indistinguishable.

[0056] The formulations of metoprolol succinate sustained-release tablets in Examples 1-4 are 23.75 mg, 47.5 mg, 95 mg, and 190 mg, respectively.

[0057] Prescription composition in Examples 1-4

[0058] Table 1

[0059]

[0060] Preparation methods of Examples 1-4:

[0061] (1) Preparation of drug-containing pellet cores: Hydroxypropyl methylcellulose was dispersed in a portion of hot water and stirred until evenly dispersed. Then, the remaining cold water was added and stirred until completely dissolved. Metoprolol succinate and filler were added and placed in a wet granulator. The stirring speed was set to 75-100 rpm and the cutting speed to 800-900 rpm for premixing. Then, the dissolved binder solution was sprayed in to prepare a soft material. The prepared soft material was then placed in an extrusion spheroidizer for extrusion and spheroidizing. A screen aperture of 0.5 mm was selected, the extrusion speed was 35-40 rpm, the spheroidizing speed was 800-900 rpm, and the spheroidizing time was 2-4 min. The formed pellet cores were placed in a fluidized bed for drying. The inlet air temperature was 50-65℃. The dried pellet cores were then sieved through a 20-60 mesh sieve.

[0062] (2) Microsphere coating: Ethyl cellulose, triethyl citrate and talc are added to an ethanol solution and stirred evenly to prepare a slow-release coating solution. The pellet core is placed in a fluidized bed for slow-release coating. The inlet air temperature is set to 50-65℃, the inlet air volume is 20-24Hz, the atomization pressure is 1-2 bar, the material temperature is controlled to 28-32℃, and the coating weight gain is 14-19%. After the microsphere coating is completed, it is dried, and then the dried microspheres are passed through an 18-60 mesh sieve.

[0063] (3) Total mixing and tableting: Weigh the prescribed amount of coated pellets and other excipients except stearic acid and sodium stearate, and add them to a mixer for total mixing at a total speed of 150-200 rpm; weigh the prescribed amount of stearic acid and sodium stearate, add them to the mixer and continue mixing at a total speed of 30 rpm. Compress the total mixed powder into tablets on a tableting machine. The tableting die is a 17.0*8.5mm elliptical die, the turntable speed is 15-20 rpm, the feeding speed is 5-10 rpm, and the tablet hardness is controlled at 10-22 kg.

[0064] (4) Coating: Dissolve the film coating premix (the coating material consists of 43% polyvinyl alcohol, 27% titanium dioxide, 25% talc, and 5% lecithin (soybean)) in water to prepare an aqueous coating solution. Place the compressed tablets into a coating pan, set the air inlet frequency to 40-45Hz, the coating pan speed to 5-10rpm, the peristaltic pump speed to 5-10rpm, and the air inlet temperature to 70-75℃ for coating, and control the coating weight gain to 2-6%.

[0065] The prescriptions for Examples 5-10 are as follows:

[0066] Table 2

[0067]

[0068]

[0069] The preparation method is the same as in Examples 1-4.

[0070] Example 11-12 Prescription Composition

[0071] Table 3

[0072]

[0073] According to the metoprolol succinate extended-release tablet formulation of Example 11, it was prepared using the following method:

[0074] (1) Preparation of drug-containing pellet cores: Hydroxypropyl methylcellulose was dispersed in a portion of hot water and stirred until evenly dispersed. Then, the remaining cold water was added and stirred until completely dissolved. Metoprolol succinate and filler were added and placed in a wet granulator. The stirring speed was set to 75-100 rpm and the cutting speed to 800-900 rpm for premixing. Then, the dissolved binder solution was sprayed in to prepare a soft material. The prepared soft material was then placed in an extrusion spheroidizer for extrusion and spheroidizing. The screen aperture was 0.8 mm, the extrusion speed was 45-50 rpm, the spheroidizing speed was 1000-1200 rpm, and the spheroidizing time was 2-6 min. The formed pellet cores were placed in a fluidized bed for drying. The inlet air temperature was 40-65℃. The dried pellet cores were then sieved through a 16-40 mesh sieve.

[0075] (2) Microsphere coating: Polymethyl methacrylate, triethyl citrate and titanium dioxide are added to an ethanol solution and stirred evenly to prepare a slow-release coating solution. The pellet cores are placed in a fluidized bed for slow-release coating. The inlet air temperature is set to 50-65℃, the inlet air volume is 20-24Hz, the atomization pressure is 1-2 bar, the material temperature is controlled to 28-32℃, and the coating weight gain is 14-19%. After the microsphere coating is completed, it is dried, and then the dried microspheres are passed through a 14-45 mesh sieve.

[0076] (3) Total mixing and tableting: Weigh the prescribed amount of coated pellets and other excipients except stearic acid and sodium stearate, and add them to a mixer for total mixing at a total speed of 150-200 rpm; weigh the prescribed amount of stearic acid and sodium stearate, add them to the mixer and continue mixing at a total speed of 30 rpm. Compress the total mixed powder into tablets on a tableting machine. The tableting die is a 17.0*8.5mm elliptical die, the turntable speed is 15-20 rpm, the feeding speed is 5-10 rpm, and the tablet hardness is controlled at 10-22 kg.

[0077] (4) Coating: Dissolve the film coating premix (the coating material consists of 43% polyvinyl alcohol, 27% titanium dioxide, 25% talc, and 5% lecithin (soybean)) in water to prepare an aqueous coating solution. Place the compressed tablets into a coating pan, set the air inlet frequency to 40-50Hz, the coating pan speed to 5-20rpm, the peristaltic pump speed to 5-10rpm, and the air inlet temperature to 70-75℃ for coating, and control the coating weight gain to 2-5%.

[0078] According to the metoprolol succinate extended-release tablet formulation of Example 12, it was prepared using the following method:

[0079] (1) Preparation of drug-containing pellet cores: Hydroxypropyl methylcellulose was dispersed in a portion of hot water and stirred until evenly dispersed. Then, the remaining cold water was added and stirred until completely dissolved. Metoprolol succinate and filler were added and placed in a wet granulator. The stirring speed was set to 75-100 rpm and the cutting speed to 800-900 rpm for premixing. Then, the dissolved binder solution was sprayed in to prepare a soft material. The prepared soft material was then placed in an extrusion spheroidizer for extrusion and spheroidizing. The screen aperture was 0.8 mm, the extrusion speed was 45-50 rpm, the spheroidizing speed was 1000-1200 rpm, and the spheroidizing time was 2-6 min. The formed pellet cores were placed in a fluidized bed for drying. The inlet air temperature was 50-65℃. The dried pellet cores were then sieved through a 16-40 mesh sieve.

[0080] (2) Microsphere coating: Ethyl cellulose, triethyl citrate and talc are added to an ethanol solution and stirred evenly to prepare a slow-release coating solution. The pellet core is placed in a fluidized bed for slow-release coating. The inlet air temperature is set to 50-65℃, the inlet air volume is 20-24Hz, the atomization pressure is 1-2 bar, the material temperature is controlled to 28-32℃, and the coating weight gain is 14-19%. After the microsphere coating is completed, it is dried, and then the dried microspheres are passed through a 14-45 mesh sieve.

[0081] (3) Total mixing and tableting: Weigh the prescribed amount of coated pellets and other excipients except stearic acid and sodium stearate, and add them to a mixer for total mixing at a total speed of 150-200 rpm; weigh the prescribed amount of stearic acid and sodium stearate, add them to the mixer and continue mixing at a total speed of 30 rpm. Compress the total mixed powder into tablets on a tableting machine. The tableting die is a 17.0*8.5mm elliptical die, the turntable speed is 15-20 rpm, the feeding speed is 5-10 rpm, and the tablet hardness is controlled at 10-22 kg.

[0082] (4) Coating: Dissolve the film coating premix (the coating material consists of 43% polyvinyl alcohol, 27% titanium dioxide, 25% talc, and 5% lecithin (soybean)) in water to prepare an aqueous coating solution. Place the compressed tablets into a coating pan, set the air inlet frequency to 40-50Hz, the coating pan speed to 5-10rpm, the peristaltic pump speed to 5-10rpm, and the air inlet temperature to 70-75℃ for coating, and control the coating weight gain to 2-5%.

[0083] Comparative Example 1: Metoprolol succinate extended-release tablets original formulation, manufactured by AstraZeneca, trade name TOPRPL-XL, specification 25mg, batch number LH0290.

[0084] Comparative Example 2: Metoprolol succinate extended-release tablets original formulation, manufactured by AstraZeneca, trade name TOPRPL-XL, specification 50mg, batch number JN0123.

[0085] Comparative Example 3: Metoprolol succinate extended-release tablets original formulation, manufactured by AstraZeneca, trade name TOPRPL-XL, specification 50mg, batch number JN0033.

[0086] Control Example 4: Metoprolol succinate extended-release tablets, original formulation, manufactured by AstraZeneca, trade name TOPRPL-XL, specification 50mg, batch number JN1800. Experimental Example 1: Dissolution comparison test.

[0087] The release rate was determined according to Method 1 (Second Method, Paddle Method, 50 rpm, 500 mL, pH 6.8 phosphate buffer) of metoprolol succinate extended-release tablets in USP. The release rate was measured at 1 hour, 4 hours, 8 hours, 20 hours, and 24 hours, and the eluent was analyzed by HPLC (the same applies below). Comparison of release rates between the test reagents and reference formulations in Examples 1-4.

[0088] Table 3

[0089]

[0090]

[0091] Comparison of release rates between test reagents and reference formulations in Examples 5–11

[0092] Table 4

[0093]

[0094] The results above show that Examples 5-10 have similar dissolution to Control Example 2, while Examples 11 and 12 have dissolution that is not similar to Control Example 2. This indicates that using ethyl cellulose, triethyl citrate, and talc as sustained-release coating materials and using croscarmellose sodium as a disintegrant can effectively improve product dissolution. By optimizing the sustained-release coating liquid materials and the types of excipients, an ideal drug release effect was achieved.

[0095] Metoprolol succinate extended-release tablets prepared according to the formulation and process of Example 2 were tested for dissolution before and after being broken along the score line. The dissolution rate before and after breaking the tablets is compared as follows:

[0096] Table 5

[0097]

[0098]

[0099] The metoprolol succinate sustained-release tablets prepared according to the present invention have a similarity factor f2 greater than 50 before and after breaking the tablets, indicating that the dissolution is similar before and after breaking the tablets.

[0100] Test Example 2: Stability Test

[0101] Samples from Examples 1-4 of this invention and control samples 1, 2, 3, and 4 were placed in a stability test chamber at a temperature of 40℃±2℃ and a humidity of 75%RH±5%RH for accelerated stability testing. Samples were taken at 0, 1, 2, 3, and 6 months to test the properties, content, related substances, and dissolution rate. The results are shown in the table below.

[0102] Table 6

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] As can be seen from the data in the table above, the metoprolol succinate sustained-release tablets prepared in the embodiments of the present invention did not show significant changes in appearance, content, related substances, and dissolution rate during the accelerated testing period of 6 months, and had a similar dissolution curve to the original control tablets. This indicates that the metoprolol succinate sustained-release tablets prepared in this invention have stable product quality.

[0109] Experimental Example 3: Study on Content Uniformity

[0110] In Examples 1-4 of this invention, samples were taken during the tableting stage to test the content uniformity. The results of the content uniformity are shown in the table below.

[0111]

Claims

1. A metoprolol succinate sustained-release tablet, comprising a plain tablet and a coating layer covering the surface of the plain tablet, characterized in that, The tablets are obtained by compressing sustained-release microcapsules and excipients; The sustained-release microspheres include a drug-containing core and a sustained-release layer encapsulating the drug-containing core; The drug-containing pill core contains metoprolol succinate as the main drug. The sustained-release layer is formed by coating the drug-containing pellet core with a sustained-release coating material. The drug-containing pellet core is prepared by first using a wet process to prepare a soft material from metoprolol succinate, pellet core excipients, and water, and then extruding, spheroidizing, and drying it. The particle size range of the pill core is 20-60 mesh; The particle size range of the sustained-release microspheres is 18–80 mesh.

2. The metoprolol succinate sustained-release tablet according to claim 1, characterized in that: The excipients for the medicated pellet core include fillers and binders; The filler includes at least one of lactose, corn starch, pregelatinized starch, microcrystalline cellulose, and mannitol, preferably lactose and microcrystalline cellulose; The adhesive includes at least one of polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose; Based on the total weight of the pill core, the proportions of each component are as follows: metoprolol succinate 54%–70%, filler 25%–35%, and binder 2%–4%.

3. The metoprolol succinate sustained-release tablet according to claim 1, characterized in that: The sustained-release coating material of the sustained-release microspheres includes sustained-release excipients, plasticizers, and anti-sticking agents; The sustained-release excipient is at least one of ethyl cellulose, cellulose acetate, and polymethacrylate, preferably ethyl cellulose; The plasticizer includes at least one of polyethylene glycol, triethyl citrate, and glyceryl triacetate, preferably triethyl citrate; the anti-sticking agent includes at least one of silica, titanium dioxide, and talc, preferably talc. Based on the total weight of the sustained-release microcapsules, the proportion of sustained-release excipients is 10-20%, the proportion of plasticizers is 1-3%, and the proportion of anti-sticking agents is 2-4%.

4. The metoprolol succinate sustained-release tablet according to claim 1, characterized in that: The excipients of the raw tablets include fillers, disintegrants, and lubricants; The filler includes at least one of microcrystalline cellulose, starch, and spray-dried lactose, preferably spray-dried lactose and microcrystalline cellulose; The disintegrant includes at least one of sodium hydroxypropyl methylcellulose, sodium croscarmellose, polyoxyethylene, sodium carboxymethyl starch, and croscarmellose, preferably sodium croscarmellose and polyoxyethylene; The lubricant includes at least one of sodium stearate fumarate, talc, magnesium stearate, and stearic acid, preferably sodium stearate fumarate and stearic acid; Based on the total weight of the unflakes, the proportions of each component are as follows: filler 42%–70%, disintegrant 2%–6%, and lubricant 0.5%–3%.

5. The metoprolol succinate sustained-release tablet according to claim 1, characterized in that: The coating material of the uncoated tablet is a gastrointestinal soluble film coating premix, which is composed of polyvinyl alcohol, titanium dioxide, talc, and lecithin (soybean); The coating material accounts for 2% to 6% of the total weight of the sustained-release tablets.

6. A method for preparing metoprolol succinate sustained-release tablets according to any one of claims 1-5, characterized in that, include: (1) Prepare a drug-containing pellet core by mixing metoprolol succinate, filler, binder and purified water; (2) Dissolve the sustained-release coating material in an alcohol solvent to prepare a sustained-release coating solution, and spray it onto the drug-containing pellet core to prepare sustained-release micro pellets; (3) The sustained-release microcapsules are mixed with fillers, disintegrants and lubricants and compressed into tablets; (4) Dissolve the gastrointestinal film coating premix in water to make a coating solution, and spray it onto the uncoated tablets to make coated tablets.

7. The method for preparing metoprolol succinate sustained-release tablets according to claim 6, characterized in that: In step (1), the weight ratio of raw materials and excipients to purified water in the drug-containing pill core is 3 to 5:1; In step (2), the weight ratio of raw materials and excipients to alcohol solvent in the sustained-release microspheres is 1:2 to 4; In step (4), the weight ratio of raw materials and excipients to purified water in the coated tablets is 4 to 6:

1.

8. The method for preparing metoprolol succinate sustained-release tablets according to claim 7, characterized in that: In step (2), the alcohol solvent is at least one of methanol, ethanol, and isopropanol, preferably ethanol.

9. The method for preparing metoprolol succinate sustained-release tablets according to any one of claims 6 to 8, characterized in that, In step (1), a wet granulation machine is used to prepare soft material. The soft material is then extruded and spheroidized by an extrusion spheroidizer, dried in a fluidized bed or oven to form a drug-containing pellet core, and passed through a 20-60 mesh sieve. In step (2), the sustained-release coating material is prepared into sustained-release microspheres by bottom spray coating of the drug-containing pellet core and then passed through an 18-80 mesh sieve.

10. The method for preparing metoprolol succinate sustained-release tablets according to claim 9, characterized in that, The perforated plate of the soft material extrusion has a pore size of 0.3–0.7 mm, and the weight gain of the sustained-release microsphere coating is 12–20%.

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