Metoprolol succinate sustained-release capsule and preparation method thereof

Abstract

The invention provides a metoprolol succinate sustained-release capsule and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The metoprolol succinate sustained-release capsule is prepared from the following components in percentage by mass: 40 percent to 45 percent of metoprolol succinate, 10 percent to 30 percent of microcrystalline cellulose, 10 percent to 25 percent of cane sugar, 10 percent to 30 percent of lactose, 0.4 percent to 0.9 percent of hydroxypropyl cellulose, 4 percent to 9 percent of ethyl cellulose, 0.4 percent to 0.9 percent of triethyl citrate and 3 percent to 5 percent of talcum powder. According to the metoprolol succinate sustained-release capsule disclosed by the invention, by adjusting the component dosage and the preparation method of the metoprolol succinate sustained-release capsule, the raw material components and the particle size of the pellet are controlled, and the content uniformity and the in-vivo bioavailability of the medicine are improved; meanwhile, the metoprolol succinate sustained-release capsule slowly and lastingly releases drugs, a large blood concentration fluctuation range cannot be generated, safety is high, tabletting is not carried out, and the problems of dissolution acceleration and the like caused by breakage of a pellet sustained-release layer are solved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a metoprolol succinate sustained-release capsule and a preparation method thereof. Background Art

[0002] Angina pectoris is a clinical syndrome mainly caused by insufficient blood supply to the coronary arteries, temporary myocardial ischemia and hypoxia. The common cause is coronary artery disease caused by atherosclerosis. Angina pectoris is divided into stable, unstable and variant types, and the duration, inducing factors and severity of pain caused by the reduction of coronary blood flow are different. The main group of patients are middle-aged and elderly people, and the prevalence of angina pectoris increases significantly with age. Hypertension and angina pectoris are becoming more and more serious threats to human health, and for this reason, they are attracting more and more attention. Improving lifestyle and drug therapy are the most commonly used treatments.

[0003] Metoprolol is used to treat various types of hypertension (can be used in combination with diuretics and vasodilators) and angina pectoris. Intravenous injection is also effective for arrhythmias, especially supraventricular arrhythmias. It is a selective β1 receptor blocker, and the dose required to act on cardiac β1 receptors is lower than the dose required to act on β2 receptors on peripheral blood vessels and bronchi.

[0004] Metoprolol succinate is an organic substance with the chemical formula C34H56N2O10. It is easily soluble in water, soluble in methanol, slightly soluble in ethanol, and difficult to dissolve in ethyl acetate. The selectivity of metoprolol succinate is dose-dependent. Since the peak blood drug concentration of the sustained-release tablet is significantly lower than that of the ordinary tablet of the same dose, this dosage form has a relatively higher β1 receptor selectivity.

[0005] There are many metoprolol sustained-release preparations on the market, such as Kapspargo Sprinkle, metoprolol tartrate sustained-release tablets, metoprolol controlled-release tablets, etc. These preparations mainly use coating, dispersion technology, osmotic pumps, etc. to control the drug release rate, but there are still some shortcomings. The blood drug concentration of these preparations fluctuates greatly after taking them, which may affect the therapeutic effect and safety.

[0006] US Patent US04927640 introduces the preparation method of Betaloc sustained-release tablets, which is a multi-unit controlled-release pellet system, each tablet containing many pellets. The pellets are small glass beads or silica cores. The drug is coated on the surface of the core by coating to form a pill core, and then a sustained-release coating layer is coated on the outside of the drug core. The sustained-release pellets are then mixed with other excipients and compressed into tablets. The sustained-release layer is easily broken during the tableting process, which speeds up the release rate.

[0007] Chinese patents CN101055579A and CN101055580A disclose two metoprolol sustained-release tablets and their preparation methods. Both patents use dispersion technology to directly disperse the drug in a skeleton formed by a polymer material. The drug dosage of the skeleton tablet is relatively concentrated and is easily affected by factors such as the human gastrointestinal tract and food, resulting in large differences.

[0008] Chinese patent CN 101190180 B provides a metoprolol sustained-release pharmaceutical composition and a preparation method thereof produced by Beijing Liling Hengtai Pharmaceutical Co., Ltd. The metoprolol tartrate sustained-release composition is prepared by coating blank pill cores with drugs, and then coating the pill cores with Eudragit NE30D to control drug release. The micro-pellet technology uses a method of coating blank pill cores with drugs, and the process is complicated.

[0009] Chinese patent CN 102274205 B provides a metoprolol succinate sustained-release capsule and preparation method disclosed by Foshan Longxin Pharmaceutical Technology Co., Ltd., which adopts an extrusion spheronization method or a pan-pill method to prepare a pill core containing a drug, and coats the pill core containing a drug with a methacrylic resin polymer or ethyl cellulose as a sustained-release coating layer. Both the extrusion spheronization method and the pan-pill method require the use of a blank pill core as a carrier, which increases raw material consumption and cost; the coating technology requires the use of a large amount of polymer materials and solvents, which increases cost and environmental burden, and it is difficult to control uniformity during the coating process.

[0010] Chinese patent CN 116687881 A provides a metoprolol succinate sustained-release capsule disclosed by Guilin Huaxin Pharmaceutical Co., Ltd. and a preparation method thereof, comprising a pill core including metoprolol succinate, microcrystalline cellulose and polyethylene glycol-polylysine block copolymer, and a sustained-release coating layer including ethyl cellulose, triethyl citrate and polylactic acid-alanine copolymer, wherein the polyethylene glycol-polylysine block copolymer and the polylactic acid-alanine copolymer have a narrow source and a high cost.

[0011] The above-mentioned prior arts for preparing metoprolol succinate sustained-release capsules all have preparation process defects and content uniformity risks. Summary of the invention

[0012] In view of this, the object of the present invention is to provide a metoprolol succinate sustained-release capsule and a preparation method thereof, so as to solve the problems of poor content uniformity, low bioavailability, large fluctuation range of blood drug concentration after taking and high production cost of the existing metoprolol succinate sustained-release capsule.

[0013] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0014] The invention provides a metoprolol succinate sustained-release capsule, comprising the following components in mass fraction: 40% to 45% of metoprolol succinate, 10% to 30% of microcrystalline cellulose, 10% to 25% of sucrose, 10% to 30% of lactose, 0.4% to 0.9% of hydroxypropyl cellulose, 4% to 9% of ethyl cellulose, 0.4% to 0.9% of triethyl citrate and 3% to 5% of talc.

[0015] The present invention also provides a method for preparing the metoprolol succinate sustained-release capsules, comprising the following steps:

[0016] 1) dissolving hydroxypropyl cellulose in water to obtain a binder solution, mixing metoprolol succinate, microcrystalline cellulose, lactose and sucrose, and then adding the binder solution to prepare a soft material;

[0017] 2) Extruding and spheronizing the soft material to obtain pellet cores;

[0018] 3) dissolving ethyl cellulose, sucrose and triethyl citrate in an ethanol solution to obtain a coating solution, mixing the coating solution with talcum powder to obtain a sustained-release coating solution, and coating the pellet cores with the sustained-release coating solution to obtain sustained-release pellets;

[0019] 4) Mixing the sustained-release pellets and talcum powder to obtain metoprolol succinate sustained-release pellets, and filling the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0020] Preferably, in step 1), the concentration of the binder is 10% to 20%, and the particle size of the sucrose is 0.4 mm to 0.7 mm;

[0021] The stirring speed of the mixing is 100 rpm to 500 rpm, the chopping speed of the mixing is 500 rpm to 1000 rpm, and the mixing time is 3 min to 8 min.

[0022] Preferably, in step 1), the stirring speed after adding the binder solution is 200 rpm to 800 rpm, the chopping speed is 1000 rpm to 2000 rpm, and the time for preparing the soft material is 1 min to 3 min.

[0023] Preferably, the extrusion conditions in step 2) are: the thickness of the extrusion orifice plate is 0.4 mm to 1.0 mm, and the extrusion speed is 30 rpm to 50 rpm;

[0024] The rotation speed of the tumbling is 50 rpm to 600 rpm, and the tumbling time is 1 min to 10 min;

[0025] The particle size of the pellet core is 10 meshes to 60 meshes.

[0026] Preferably, the volume fraction of the ethanol solution in step 3) is 50% to 70%, and the coating conditions are: air inlet temperature 50°C to 60°C, fan speed 1000rpm to 2500rpm, material temperature 30°C to 40°C, air volume 15m 3 / min~30m 3 / min, atomization pressure 0.1MPa~0.4MPa, spray needle pressure ≥0.4MPa.

[0027] Preferably, the coating is dried, and the drying conditions are: air inlet temperature 50°C to 60°C, fan speed 1000rpm to 1500rpm, material temperature 30°C to 40°C, air volume 15m 3 / min~30m 3 / min, atomizing pressure 0.1MPa~0.4MPa, spray needle pressure 0.1MPa~0.4MPa; drying to moisture content of 1.5%~4.5%.

[0028] Preferably, in step 4), the mixing method is stirring, the stirring speed is 50 rpm to 70 rpm, and the stirring time is 5 min to 10 min.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The invention improves the uniformity of drug content by adjusting the dosage of ingredients and the preparation method of the metoprolol succinate sustained-release capsule, controlling the raw material ingredients and the particle size of the micro-pills, and each particle is wrapped with a polymer film to form independent storage units, thereby achieving the effects of controlling the release rate of the drug, improving the in vivo bioavailability, and reducing the frequency of drug administration; at the same time, the metoprolol succinate sustained-release capsule releases the drug slowly and persistently, does not produce a large fluctuation range of blood drug concentration, has high safety, and does not require tableting to reduce the problem of accelerated dissolution caused by rupture of the sustained-release layer of the micro-pills.

[0031] The metoprolol succinate sustained-release capsules of the present invention have low production cost and can be produced in a closed manner. Compared with processes such as pellet tableting, the losses of blank pellet cores and raw materials are reduced, and the raw material granulation is directly used to participate in the preparation of pellets, thereby reducing production costs and facilitating commercial production. DETAILED DESCRIPTION

[0032] The invention provides a metoprolol succinate sustained-release capsule, comprising the following components in mass fraction: 40% to 45% of metoprolol succinate, 10% to 30% of microcrystalline cellulose, 10% to 25% of sucrose, 10% to 30% of lactose, 0.4% to 0.9% of hydroxypropyl cellulose, 4% to 9% of ethyl cellulose, 0.4% to 0.9% of triethyl citrate and 3% to 5% of talc.

[0033] In the present invention, the dosage of metoprolol succinate is preferably 41% to 44%; the dosage of microcrystalline cellulose is preferably 15% to 25%; the dosage of sucrose is preferably 15% to 20%; the dosage of lactose is preferably 15% to 25%; the dosage of hydroxypropyl cellulose is preferably 0.5% to 0.8%; the dosage of ethyl cellulose is preferably 5% to 8%; the dosage of triethyl citrate is preferably 0.5% to 0.8%; and the dosage of talc is preferably 3.5% to 4.5%.

[0034] The present invention also provides a method for preparing the metoprolol succinate sustained-release capsules, comprising the following steps:

[0035] 1) dissolving hydroxypropyl cellulose in water to obtain a binder solution, dry-mixing metoprolol succinate, microcrystalline cellulose, lactose and sucrose, and then adding the binder solution to prepare a soft material;

[0036] 2) Extruding and spheronizing the soft material to obtain pellet cores;

[0037] 3) dissolving ethyl cellulose, sucrose and triethyl citrate in an ethanol solution to obtain a coating solution, mixing the coating solution with talcum powder to obtain a sustained-release coating solution, and coating the pellet cores with the sustained-release coating solution to obtain sustained-release pellets;

[0038] 4) Mixing the sustained-release pellets and talcum powder to obtain metoprolol succinate sustained-release pellets, and filling the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0039] In the present invention, hydroxypropylcellulose is dissolved in water to obtain a binder solution, metoprolol succinate, microcrystalline cellulose, lactose and sucrose are dry-mixed, and then the binder solution is added to prepare a soft material. The concentration of the adhesive is preferably 10% to 20%, and more preferably 12% to 18%; the particle size of the sucrose is preferably 0.4mm to 0.7mm, and more preferably 0.5mm to 0.6mm; the stirring speed of the mixing is preferably 100rpm to 500rpm, and more preferably 200rpm to 400rpm; the chopping speed of the mixing is preferably 500rpm to 1000rpm, and more preferably 600rpm to 900rpm; the mixing time is 3min to 8min, and more preferably 4min to 7min; the stirring speed after adding the adhesive solution is preferably 200rpm to 800rpm, and more preferably 300rpm to 700rpm; the chopping speed is preferably 1000rpm to 2000rpm, and more preferably 1200rpm to 1800rpm; the time for preparing the soft material is preferably 1min to 3min, and more preferably 1.5min to 2.5min; after adding the adhesive solution, 10g to 20g of water is added according to the state, and the amount of water is preferably 12g to 18g.

[0040] In the present invention, the soft material is subjected to an extrusion spheronization method to obtain a pellet core. The extrusion conditions are as follows: the thickness of the extrusion orifice is preferably 0.4 mm to 1.0 mm, more preferably 0.6 mm to 0.8 mm; the extrusion speed is preferably 30 rpm to 50 rpm, more preferably 35 rpm to 45 rpm; the spheronization speed is preferably 50 rpm to 600 rpm, more preferably 100 rpm to 500 rpm; the spheronization time is preferably 1 min to 10 min, more preferably 3 min to 8 min; the particle size of the pellet core is preferably 10 mesh to 60 mesh, more preferably 20 to 50 mesh. During the spheronization process, 10g to 20g of purified water is added according to the conditions, and the amount of water is preferably 12g to 18g; then dried to a moisture content of 1.5% to 4.5%, and further dried to a moisture content of 2% to 4%; the drying conditions are preferably: the air inlet temperature is preferably 60 to 80°C, the fan speed is preferably 1000rpm to 1500rpm, and more preferably 1100rpm to 1400rpm; the material temperature is preferably 35°C to 60°C, and more preferably 40°C to 55°C; the air volume is preferably 15m 3 / min~30m 3 / min, more preferably 20m 3 / min~25m 3 / min.

[0041] In the present invention, ethyl cellulose, sucrose, and triethyl citrate are dissolved in an ethanol solution to obtain a coating solution, the coating solution and talcum powder are mixed to obtain a sustained-release coating solution, and the pellet core and the sustained-release coating solution are mixed and coated to obtain sustained-release micropills. The volume fraction of the ethanol solution is preferably 50% to 70%, and more preferably 55% to 65%; the coating conditions are: the air inlet temperature is preferably 50°C to 60°C, and more preferably 52°C to 58°C; the fan speed is preferably 1000rpm to 2500rpm, and more preferably 1500rpm to 2000rpm; the material temperature is preferably 30°C to 40°C, and more preferably 32°C to 38°C; the air volume is preferably 15m 3 / min~30m 3 / min, more preferably 20m 3 / min~25m 3 / min; the atomization pressure is preferably 0.1MPa~0.4MPa, more preferably 0.2MPa~0.3MPa; the needle pressure is ≥0.4MPa. The drying after coating, the drying conditions are: the air inlet temperature is preferably 50℃~60℃, more preferably 52℃~58℃; the fan speed is preferably 1000rpm~1500rpm, more preferably 1100rpm~1400rpm; the material temperature is preferably 30℃~40℃, more preferably 32℃~38℃; the air volume is preferably 15m 3 / min~30m 3 / min, more preferably 20m 3 / min~25m 3 / min; the atomization pressure is preferably 0.1MPa~0.4MPa, and more preferably 0.2MPa~0.3MPa; the needle pressure is preferably 0.1MPa~0.4MPa, and more preferably 0.2MPa~0.3MPa; dried to a moisture content of 1.5%~4.5%, and further dried to a moisture content of 2%~4%; the particle size of the sustained-release microcapsules is preferably 10 mesh~60 mesh, and more preferably 20 mesh~50 mesh.

[0042] In the present invention, the sustained-release pellets and talcum powder are mixed to obtain metoprolol succinate sustained-release pellets, and the metoprolol succinate sustained-release pellets are loaded into capsule shells to obtain metoprolol succinate sustained-release capsules. The mixing method is stirring, and the stirring speed is preferably 50 rpm to 70 rpm, more preferably 55 rpm to 65 rpm; the stirring time is preferably 5 min to 10 min, more preferably 6 min to 9 min.

[0043] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0044] Example 1

[0045] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, 30g of sucrose (0.4mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 1.5g of triethyl citrate, and 9g of talc. The preparation method thereof is as follows:

[0046] 1. Preparation of soft material: Weigh 1.5g of hydroxypropyl cellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, and 20g of crushed sucrose (0.4mm) and mix them. Stir at 100rpm and chop at 500rpm for 5min. Then add the adhesive solution. After adding the adhesive, increase the stirring speed to 200rpm and chop at 1000rpm. Prepare the soft material for 2min. Add 10g of purified water according to the state, prepare the soft material for 1min, and discharge.

[0047] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the raw pellets through a 30-mesh screen. Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0048] 3. Sustained-release coating: Weigh 15 g of ethyl cellulose, 10 g of sucrose, and 1.5 g of triethyl citrate, dissolve in 292.5 g of ethanol solution (60%) to obtain a coating solution, then add 6 g of talcum powder and stir evenly, mix the pellet cores and the coating solution, and coat them to obtain sustained-release micropellets.

[0049] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0050] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m 3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 30 mesh.

[0051] 4. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0052] Example 2

[0053] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, 30g of sucrose (0.7mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 1.5g of triethyl citrate, and 9g of talc. The preparation method thereof is as follows:

[0054] 1. Preparation of soft material: Weigh 1.5g of hydroxypropyl cellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, and 20g of crushed sucrose (0.7mm) and mix them. When dry mixing, stir at a speed of 100rpm and chop at a speed of 500rpm for 5min. Then add the adhesive solution. After adding the adhesive solution, increase the stirring speed by 200rpm and chop at a speed of 1000rpm. Prepare the soft material for 2min. Add 10g of purified water according to the state, prepare the soft material for 1min, and discharge.

[0055] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the pellets through a 30-mesh screen. . Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0056] 3. Sustained-release coating: Weigh 15g ethyl cellulose, 10g sucrose, 1.5g triethyl citrate, dissolve in 292.5g ethanol solution (60%) to obtain coating solution, then add 6g talcum powder and stir evenly. Mix the pellet core and coating solution to obtain sustained-release micropellets.

[0057] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0058] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m 3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 30 mesh.

[0059] 4. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0060] Example 3

[0061] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 45g of lactose, 10g of sucrose (0.4mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 1.5g of triethyl citrate, and 9g of talc. The preparation method thereof is as follows:

[0062] 1. Preparation of soft material: Weigh 1.5g of hydroxypropyl cellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, and 45g of lactose, and mix them. When dry mixing, the stirring speed is 100rpm, and the chopping speed is 500rpm for 5min. After adding the adhesive, the stirring speed is increased by 200rpm, the chopping speed is 1000rpm, and the soft material is prepared for 2min. According to the state, add 10g of purified water, prepare the soft material for 1min, and discharge.

[0063] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the pellets through a 30-mesh screen. . Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0064] 4. Sustained-release coating: Weigh 15g of ethyl cellulose, 10g of sucrose, and 1.5g of triethyl citrate, dissolve in 292.5g of ethanol solution (60%) to obtain a coating solution, and then add 6g of talcum powder and stir evenly. Mix the pellet core and the coating solution and coat them to obtain sustained-release micropellets.

[0065] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0066] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m 3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 30 mesh.

[0067] 5. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0068] Example 4

[0069] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 35g of microcrystalline cellulose, 30g of lactose, 35g of sucrose (0.4mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 1.5g of triethyl citrate, and 9g of talc. The preparation method thereof is as follows:

[0070] 1. Preparation of soft material: Weigh 1.5g of hydroxypropyl cellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 35g of microcrystalline cellulose, 30g of lactose, and 25g of crushed sucrose (0.4mm) and mix them. When dry mixing, stir at a speed of 100rpm and chop at a speed of 500rpm for 5min. Then add the adhesive solution. After adding the adhesive solution, increase the stirring speed by 200rpm and chop at a speed of 1000rpm. Prepare the soft material for 2min. Add 10g of purified water according to the state, prepare the soft material for 1min, and discharge.

[0071] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the pellets through a 30-mesh screen. . Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0072] 3. Sustained-release coating: Weigh 15g ethyl cellulose, 10g sucrose, 1.5g triethyl citrate, dissolve in 292.5g ethanol solution (60%) to obtain coating solution, then add 6g talcum powder and stir evenly. Mix the pellet core and coating solution to obtain sustained-release micropellets.

[0073] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0074] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m 3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 30 mesh.

[0075] 4. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0076] Example 5

[0077] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 35g of lactose, 20g of sucrose (0.4mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 3.0g of triethyl citrate, and 9g of talc. The preparation method thereof is as follows:

[0078] 1. Preparation of soft material: Weigh 1.5g of hydroxypropyl cellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, and 20g of crushed sucrose (0.4mm) and mix them. Stir at a speed of 100rpm and chop at a speed of 500rpm for 5min. After adding the adhesive, increase the stirring speed by 200rpm, chop at a speed of 1000rpm, and prepare the soft material for 2min. Add 10g of purified water according to the state, prepare the soft material for 1min, and discharge.

[0079] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the pellets through a 30-mesh screen. . Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0080] 3. Sustained-release coating: Weigh 15g ethyl cellulose, 10g lactose, 3.0g triethyl citrate, dissolve in 292.5g ethanol solution (60%) to obtain coating solution, then add 6g talcum powder and stir evenly. Mix the pellet core and coating solution to obtain sustained-release micropellets.

[0081] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0082] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 30 mesh.

[0083] 4. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0084] Example 6

[0085] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, 21.5g of sucrose (0.4mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 1.5g of triethyl citrate, and 9g of talc. The preparation method thereof is as follows:

[0086] 1. Preparation of soft material: Weigh 1.5g of hydroxypropylcellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, and 20g of crushed sucrose (0.4mm) and mix them. When dry mixing, stir at a speed of 100rpm and chop at a speed of 500rpm for 5min. Then add the adhesive solution. After adding the adhesive, increase the stirring speed by 200rpm and chop at a speed of 1000rpm. Prepare the soft material for 2min. Add 10g of purified water according to the state, prepare the soft material for 1min, and discharge.

[0087] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the raw pellets through a 40-mesh screen. . Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0088] 3. Sustained-release coating: Weigh 15g ethyl cellulose, 1.5g sucrose, and 1.5g triethyl citrate, dissolve in 292.5g ethanol solution (60%) to obtain a coating solution, and then add 6g talcum powder and stir evenly. Mix the pellet core and the coating solution and coat them to obtain sustained-release micropellets.

[0089] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0090] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m 3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 40 mesh.

[0091] 4. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0092] Example 7

[0093] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, 21.5g of sucrose (0.4mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 1.5g of triethyl citrate and 11g of talc.

[0094] 1. Preparation of soft material: Weigh 1.5g of hydroxypropylcellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, and 20g of crushed sucrose (0.4mm) and mix them. When dry mixing, stir at a speed of 100rpm and chop at a speed of 500rpm for 5min. Then add the adhesive. After adding the adhesive, increase the stirring speed by 200rpm and chop at a speed of 1000rpm. Prepare the soft material for 2min. Add 10g of purified water according to the state, prepare the soft material for 1min, and discharge.

[0095] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the raw pellets through a 30-mesh screen. Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0096] 3. Sustained-release coating: Weigh 15g ethyl cellulose, 1.5g sucrose, and 1.5g triethyl citrate, dissolve in 292.5g ethanol solution (75%) to obtain a coating solution, and then add 8g talcum powder and stir evenly. Mix the pellet core and the coating solution and coat them to obtain sustained-release micropellets.

[0097] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0098] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m 3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 30 mesh.

[0099] 4. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0100] Example 8

[0101] A metoprolol succinate sustained-release capsule is composed of the following ingredients: 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, 21.5g of sucrose (0.4mm), 1.5g of hydroxypropyl cellulose, 15g of ethyl cellulose, 1.5g of triethyl citrate, and 11g of talc. The preparation method thereof is as follows:

[0102] 1. Preparation of soft material: Weigh 1.5g of hydroxypropyl cellulose and dissolve it in 13.5g of purified water to prepare a 10% adhesive solution. Weigh 95g of metoprolol succinate raw material, 45g of microcrystalline cellulose, 25g of lactose, and 20g of crushed sucrose (0.4mm) and mix them. Stir at a speed of 100rpm and chop at a speed of 500rpm for 5min. After adding the adhesive, increase the stirring speed by 200rpm, chop at a speed of 1000rpm, and prepare the soft material for 2min. Add 10g of purified water according to the state, prepare the soft material for 1min, and discharge.

[0103] 2. Pellet making: The soft material is extruded and spheronized to obtain the pellet core. Set the extrusion process parameters: extrusion orifice 0.4mm, extrusion speed 30rpm; spheronization process parameters: speed 50rpm, spheronization time 5min, 10g purified water can be added during the spheronization process according to the state. Dry to 3.0% moisture, and dry the raw pellets through a 30-mesh screen. Parameter settings for drying: inlet air temperature 70℃, fan 1300rpm, material temperature 45℃, air volume 20m 3 / min.

[0104] 3. Sustained-release coating: Weigh 15g ethyl cellulose, 1.5g sucrose, and 1.5g triethyl citrate, dissolve in 292.5g ethanol solution (75%) to obtain a coating solution, and then add 8g talcum powder and stir evenly. Mix the pellet core and the coating solution and coat them to obtain sustained-release micropellets.

[0105] Coating parameters: inlet air temperature 55°C, fan 1500rpm, material temperature 35°C, air volume 20m 3 / min, atomization pressure 0.2MPa, spray needle pressure ≥0.4MPa.

[0106] Drying parameters: inlet air temperature 55°C, fan 1300rpm, material temperature 35°C, air volume 20m 3 / min, atomizing pressure 0.2MPa, spray needle pressure 0.2MPa. Dry to 3% moisture. Sieve to 30 mesh.

[0107] 4. Total mixing: Mix the sustained-release pellets and 3 g of talcum powder at 60 rpm for 10 min to obtain metoprolol succinate sustained-release pellets, and put the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

[0108] Experimental Example 1

[0109] The cumulative release of metoprolol succinate sustained-release capsules of Examples 1 to 8 was detected by the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia. The dissolution test meets the sink condition. Take 5 ml of sample at 60, 240, 480, 720, and 1200 min, and add 5 ml of fresh dissolution medium. After the sample is filtered through a 0.22 μm microporous membrane, 10 μl of the filtrate is taken into the HPLC instrument for analysis, and the cumulative release is calculated.

[0110] Experimental results: as shown in Table 1.

[0111] Table 1 Cumulative release of metoprolol succinate sustained-release capsules prepared in Examples 1 to 8

[0112]

[0113]

[0114] As shown in Table 1, by comparing the dissolution with the reference preparation, the metoprolol succinate sustained-release capsules prepared in Example 6 are closest to the reference preparation in terms of dissolution, and the composition ratio of the pellet core and the sustained-release coating is the most appropriate.

[0115] Experimental Example 2

[0116] Taking Example 6 as an example, under the condition that the preparation method remains unchanged, different coating weight gain treatments are performed on the pill cores containing the drug (coating weight gain is 6%, 8%, 10% and 12%, respectively), and the cumulative release of each group of sustained-release micropellets under different coating weight gain conditions is determined. The detection method of the cumulative release is shown in Experimental Example 1.

[0117] Experimental results: as shown in Table 2.

[0118] Table 2 Cumulative release of different coating weight gain

[0119]

[0120] By comparing the release rates of samples with different weight gain, it can be seen that the 12% weight gain is closest to the reference preparation.

[0121] Experimental Example 3

[0122] Content uniformity test: Content uniformity Take the contents of one tablet of this product, place it in a 50ml volumetric flask, add 15ml of ethanol and ultrasonicate for 20min, add 25ml of 0.1N hydrochloric acid, ultrasonicate for 10min, cool, dilute to scale with 0.1N hydrochloric acid, and shake well. Centrifuge or filter, accurately measure 3ml of supernatant or filtrate, place it in a 25ml volumetric flask, dilute to scale with mobile phase, shake well, and use it as the test solution. Determine the content according to the method under the content determination item, which should comply with the regulations (General Rule 0941), and the others should comply with the relevant regulations under the capsule item (General Rule 0103).

[0123] Experimental results: as shown in Table 3.

[0124] Table 3 Content uniformity test data of metoprolol succinate sustained-release capsules prepared in Examples 1 to 8

[0125]

[0126] It can be seen from Table 3 that by comparing the content uniformity of samples under different embodiments, the formulation composition and parameter control will have different degrees of influence on the uniformity of the particle size of the micropellets. The particle size control of the micropellets in Example 6 is beneficial to the content uniformity, and the result is better than that of other embodiments.

[0127] Experimental Example 4

[0128] Effect of sustained-release pellets on bioavailability

[0129] Test method: 6 beagle dogs (weighing about 8kg) were randomly divided into two groups, 3 in each group. Fasting for 12h before the test, a single dose test was conducted. Group 1: Oral administration of metoprolol succinate sustained-release capsules prepared in Example 6; the dosage was 47.5mg / dog; Group 2: Oral administration of reference preparation metoprolol succinate sustained-release capsules, the dosage was 47.5mg / dog. 3ml of venous blood was collected from the hind limbs at 1, 4, 6, 8, 10, 12, 14, and 24h after administration, and the blood was centrifuged (3000r / min) for 10min, and the upper yellow serum was collected.

[0130] Blood sample processing: add 0.2 ml of 4 mol / L NaOH solution and 5 ml of acetaldehyde to 1 ml of serum, vortex for 1 min, centrifuge to obtain the organic phase, add 120 μl of 0.01 mol / L H2SO4 solution, vortex for 1 min, centrifuge to obtain the aqueous phase, and use HPLC-UV method to determine the content.

[0131] Experimental results: as shown in Table 4.

[0132] Table 4 Bioavailability of Metoprolol Succinate Sustained Release Capsules Prepared in Examples 1 to 8

[0133]

[0134]

[0135] As shown in Table 4, the bioavailability of the metoprolol succinate sustained-release capsules prepared in Example 6 is basically consistent with that of the reference preparation, and the drug release rate is stable.

[0136] It can be seen from the above embodiments and experimental examples that the present invention improves the uniformity of drug content and in vivo bioavailability by adjusting the dosage of ingredients and the preparation method of metoprolol succinate sustained-release capsules, controlling the particle size of raw materials and pellets; at the same time, the metoprolol succinate sustained-release capsules release the drug slowly and persistently, will not produce a large fluctuation range of blood drug concentration, have high safety, and do not perform tableting to reduce the problem of accelerated dissolution caused by rupture of the sustained-release layer of the pellets.

[0137] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A metoprolol succinate sustained-release capsule, characterized in that: The invention comprises the following ingredients in mass fraction: 40% to 45% metoprolol succinate, 10% to 30% microcrystalline cellulose, 10% to 25% sucrose, 10% to 30% lactose, 0.4% to 0.9% hydroxypropyl cellulose, 4% to 9% ethyl cellulose, 0.4% to 0.9% triethyl citrate and 3% to 5% talc.

2. The method for preparing the metoprolol succinate sustained-release capsules according to claim 1, characterized in that: The following steps are involved: 1) dissolving hydroxypropyl cellulose in water to obtain a binder solution, mixing metoprolol succinate, microcrystalline cellulose, lactose and sucrose, and then adding the binder solution to prepare a soft material; 2) Extruding and spheronizing the soft material to obtain pellet cores; 3) dissolving ethyl cellulose, sucrose and triethyl citrate in an ethanol solution to obtain a coating solution, mixing the coating solution with talcum powder to obtain a sustained-release coating solution, and coating the pellet cores with the sustained-release coating solution to obtain sustained-release pellets; 4) Mixing the sustained-release pellets and talcum powder to obtain metoprolol succinate sustained-release pellets, and filling the metoprolol succinate sustained-release pellets into capsule shells to obtain metoprolol succinate sustained-release capsules.

3. The preparation method according to claim 2, characterized in that: Step 1) The concentration of the binder is 10% to 20%, and the particle size of the sucrose is 0.4 mm to 0.7 mm; The stirring speed of the mixing is 100 rpm to 500 rpm, the chopping speed of the mixing is 500 rpm to 1000 rpm, and the mixing time is 3 min to 8 min.

4. The preparation method according to claim 2, characterized in that: In step 1), after adding the binder solution, the stirring speed is 200 rpm to 800 rpm, the chopping speed is 1000 rpm to 2000 rpm, and the time for preparing the soft material is 1 min to 3 min.

5. The preparation method according to claim 2, characterized in that: Step 2) The extrusion conditions are: the thickness of the extrusion orifice is 0.4 mm to 1.0 mm, and the extrusion speed is 30 rpm to 50 rpm; The rotation speed of the tumbling is 50 rpm to 600 rpm, and the tumbling time is 1 min to 10 min; The particle size of the pellet core is 10 meshes to 60 meshes.

6. The preparation method according to claim 2, characterized in that: Step 3) The volume fraction of the ethanol solution is 50% to 70%, and the coating conditions are: air inlet temperature 50°C to 60°C, fan speed 1000rpm to 2500rpm, material temperature 30°C to 40°C, air volume 15m 3 / min~30m 3 / min, atomization pressure 0.1MPa~0.4MPa, spray needle pressure ≥0.4MPa.

7. The preparation method according to claim 6, characterized in that: The drying after coating is carried out under the following conditions: air inlet temperature 50°C to 60°C, fan speed 1000rpm to 1500rpm, material temperature 30°C to 40°C, air volume 15m 3 / min~30m 3 / min, atomizing pressure 0.1MPa~0.4MPa, spray needle pressure 0.1MPa~0.4MPa; drying to moisture content of 1.5%~4.5%.

8. The preparation method according to claim 2, characterized in that: Step 4) The mixing method is stirring, the stirring speed is 50 rpm to 70 rpm, and the stirring time is 5 min to 10 min.

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