CN113143877A - Preparation method of metoprolol succinate pellet sustained-release tablet - Google Patents
Preparation method of metoprolol succinate pellet sustained-release tablet Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention discloses a preparation method of metoprolol succinate pellet sustained-release tablets. Based on the solubility of metoprolol succinate, the metoprolol succinate drug-containing pellet core is prepared by spraying part of metoprolol succinate and sucrose in a dissolved state, and a drug layer coating is carried out on the surface of the metoprolol succinate drug-containing pellet core to prepare a drug-loaded pellet; then coating the drug-loaded pellet core with a slow-release material to prepare a slow-release coated pellet; and the materials are mixed and tabletted to prepare the pellet tablet, and the surface of the pellet tablet is sealed by wax to isolate influence factors such as water, oxygen and the like. The metoprolol succinate pellet sustained-release tablet prepared by the invention has stable process, can well play a sustained-release role, is stable in release within 24 hours, has no phenomena of burst release and difficult dissolution, and can achieve dissolution behavior consistent with the original preparation in vitro.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of metoprolol succinate pellet sustained-release tablets.
Background
Hypertension is the first killer causing death and disability of the old in cardiovascular diseases, and the world health organization indicates that the number of deaths caused by cardiovascular diseases such as hypertension accounts for 79% of the total number of deaths in the country, and the hypertension and induced symptoms thereof seriously threaten the life health of human beings.
Metoprolol Succinate (Metoprolol Succinate) with chemical name of 1-isopropylamino-3- [ p- (2-methoxyethyl) phenoxy]-2-propanol succinate of formula C34H56N2O10Molecular weight of 652.82, and structural formula as follows:
the metoprolol succinate is a dose-dependent beta 1 receptor blocker, the peak value of the blood concentration of a sustained-release preparation is lower than that of a common preparation with the same dose, and the metoprolol tartrate which is a selective beta 1 receptor blocker widely used for treating hypertension, coronary heart disease, chronic heart failure and arrhythmia at home at present is a metoprolol tablet, has short elimination half-life period of about 3-4 hours, so that the plasma drug concentration fluctuates greatly and needs to be taken 2-4 times per day. In order to overcome the defects, the metoprolol succinate sustained-release tablet recently introduced by the company of Aslican is a brand-new metoprolol long-acting preparation, can ensure the constant metoprolol blood concentration and the beta 1 receptor blocking effect within 24 hours by only taking the tablet 1 time every day, and has a plurality of advantages in pharmacology and clinical therapeutics. The traditional Chinese medicine composition is mainly used for treating hypertension, angina pectoris and chronic heart failure with stable symptoms accompanied by left ventricular contraction chemical book dysfunction in clinic. Orally administered once a day, preferably in the morning, in an unbroken form, but not chewed or crushed, and administered in at least half a glass of liquid. And the bioavailability of the food is not influenced by the intake of the food. The dose should be individualized to avoid bradycardia. The following are effective medication guidelines: hypertension: 47.5-95 mg, once a day. Patients who are ineffectual upon taking 95mg of metoprolol succinate sustained release tablets may be co-administered with other antihypertensive agents, preferably diuretics and dihydropyridine calcium antagonists, or at increased doses. Angina pectoris: 95-190 mg, once a day. If necessary, nitrate ester medicines can be used together or dosage can be increased.
The currently marketed sustained release tablet is betamethasone. The original manufacturer of metoprolol succinate sustained release tablets is AstraZeneca AB, which is first marketed in Sweden 12 months and 12 days in 1986, and the specifications are as follows: 190mg (equivalent to metoprolol tartrate 200mg), 95mg (equivalent to metoprolol tartrate 100mg), 47.5mg (equivalent to metoprolol tartrate 50mg) and 23.75mg (equivalent to metoprolol tartrate 25 mg). Under the trade name Betaloc ZOK.
There is no product available in the united states and japanese former companies, in russia and argentina, where prescription information is available in the russian specification.
Compared with the common tablet, the pellet coating product has the following advantages: 1) the micro-pill has small granularity (generally less than 1mm), the gastrointestinal tract transportation is not limited by the closing of the pylorus of the stomach, is not extruded by the stomach and the intestine, the transportation speed is stable, the influence of food is small, and the individual difference of pharmacokinetics is small; 2) the specific surface area is large, so that the irritation can be reduced, and the bioavailability can be improved; 3) the multi-unit release is adopted, hundreds of micro-pills can be filled in each capsule, each micro-pill is an independent drug release unit, the overall release effect of the drug cannot be influenced by sudden release or non-release of the individual micro-pills, the slow release effect is constant, and the multi-unit release is safer and more effective; 4) the pellets with different release rates can be mixed and then put in the same capsule to adjust the overall release speed of the drug, so that the pharmacokinetics is more reasonable; 5) the micro-pills can be taken separately or mixed with diet, not only can solve the problem of swallowing disorder, but also can greatly improve the compliance of patients, and the advantage is very obvious for children, old people and mental patient groups.
Disclosure of Invention
Aiming at the prior art, the invention aims to provide a preparation method of metoprolol succinate pellet sustained-release tablets. The metoprolol succinate pellet sustained-release tablet prepared by the invention has stable process, can well play a sustained-release role, is stable in release within 24 hours, has no phenomena of burst release and difficult dissolution, and can achieve dissolution behavior consistent with the original preparation in vitro.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of metoprolol succinate pellet sustained-release tablets, which comprises the following steps:
(1) manufacturing a drug-containing pill core by adopting a high-speed centrifugal atomization mode on metoprolol succinate and sucrose, wherein the air inlet temperature is 80-120 ℃, and the air outlet temperature is 60-80 ℃;
(2) dissolving metoprolol succinate in purified water, spraying the solution on the surface of the drug-containing pellet prepared in the step (1) in a fluidized state, and coating a drug layer to prepare a drug-loaded pellet;
(3) carrying out slow release coating on the drug-loaded pellets prepared in the step (2) by adopting a slow release coating material to prepare slow release coated pellets;
(4) and (3) mixing the sustained-release coated pellets prepared in the step (3) with a filler, a disintegrant, a glidant and a lubricant, tabletting after mixing, and coating a layer of waxy material on the surface after tabletting forming to prepare the metoprolol succinate pellet sustained-release tablet.
Preferably, in the step (1), the metoprolol succinate and the sucrose are added in a weight ratio of (20-32): (8-12).
Preferably, in the step (1), the particle size of the prepared pill-containing core is 0.056-0.155 mm.
Preferably, the weight ratio of the metoprolol succinate in the step (1) to the metoprolol succinate in the step (2) is (35-68): (65-32).
Preferably, in the step (2), the spraying conditions are as follows: under the condition that the atomization pressure is kept at 1.5bar, the air inlet speed is 10-20 m3/h, the air inlet temperature is controlled at 60-80 ℃, the material temperature is 38-45 ℃, the size of fog drops is controlled at 20-40 mu m, and the rotation speed of a liquid supply peristaltic pump is controlled at 10-25 rpm.
Preferably, in the step (2), the prepared drug-loaded pellets have a particle size of 0.153-0.286 mm.
Preferably, in the step (3), the slow release coating material comprises a slow release material and a plasticizer; the slow release material is selected from one or more of ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, Cellulose Acetate Phthalate (CAP), polyvinyl alcohol phthalate (PVAP), methacrylic acid copolymer, Cellulose Acetate Trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin; the plasticizer is selected from one or more of polyethylene glycol 400, polyvinyl alcohol and polyvinylpyrrolidone.
Preferably, in the step (3), the particle size of the prepared sustained-release coated pellet is 0.232-0.319 mm.
Preferably, in step (4), the waxy material is selected from one or more of paraffin wax, vegetable wax, animal wax, mineral wax and synthetic wax.
In a second aspect of the invention, a metoprolol succinate pellet sustained-release tablet prepared by the method is provided. The specifications of the metoprolol succinate pellet sustained-release tablet prepared by the invention comprise: 190mg, 95mg, 47.5mg and 23.75 mg.
The invention has the beneficial effects that:
the metoprolol succinate pellet sustained-release tablet prepared by the method has stable process, can well play a sustained-release role, is stable in release within 24 hours, has no phenomena of burst release and difficult dissolution, and can achieve the dissolution behavior consistent with the original preparation in vitro.
Drawings
FIG. 1: spray pill core D with four specifications10、D50、D90Compare the figures.
FIG. 2: four-specification drug-loaded pellet D10、D50、D90Compare the figures.
FIG. 3: four-specification coated pellet D10、D50、D90Compare the figures.
FIG. 4: dissolution comparison of four size coated pellets in pH1.0 medium.
FIG. 5: dissolution comparison of four size coated pellets in pH4.5 medium.
FIG. 6: dissolution comparison of four size coated pellets in pH6.8 medium.
FIG. 7: the dissolution contrast of the four specifications of coated pellets in an aqueous medium.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As introduced in the background section, the stable control of the blood concentration of metoprolol succinate has important significance for improving the curative effect and lightening the adverse reaction.
In order to develop the metoprolol succinate pellet sustained-release tablet, the design concept of the invention is as follows: based on the solubility of metoprolol succinate, spraying part of metoprolol succinate and sucrose in a dissolved state to prepare a metoprolol succinate drug-containing pellet core, and coating a drug layer on the surface of the metoprolol succinate drug-containing pellet core to prepare a drug-loaded pellet; then coating the drug-loaded pellet core with a slow-release material to prepare a slow-release coated pellet; and the materials are mixed and tabletted to prepare the pellet tablet, and the surface of the pellet tablet is sealed by wax to isolate influence factors such as water, oxygen and the like.
The metoprolol succinate pellet sustained-release tablet prepared by the preparation method has stable process, can well play a sustained-release role, is stable in release within 24 hours, has no phenomena of burst release and difficult dissolution, and can achieve dissolution behavior consistent with the original preparation in vitro.
The specifications of the metoprolol succinate pellet sustained-release tablet prepared by the invention comprise: 190mg, 95mg, 47.5mg and 23.75 mg. The prescription and process are designed, optimized and improved, and are finally shown as follows:
the specific process comprises the following steps:
1. part of metoprolol succinate in Mobile MinorTMSpray drying in an experimental spray dryer, manufacturing a pill-containing core by adopting a high-speed centrifugal atomization mode, wherein the air inlet temperature is 80-120 ℃, the air outlet temperature is 60-80 ℃, and the particle size (D90) of the pill-containing core is controlled to be 0.056-0.155 mm;
2. the remaining prescribed amount of metoprolol succinate is dissolved in purified water inSpraying on the surface of the pill core under fluidization condition by bottom spraying technique, keeping the atomization pressure at 1.5bar, and controlling the air inlet speed at 10-20 m3The air inlet temperature is controlled to be 60-80 ℃, the material temperature is 38-45 ℃, the droplet size is controlled to be 20-40 mu m, the rotation speed of the liquid supply peristaltic pump is controlled to be 10-25 rpm, and the particle size (D90) of the prepared drug-loaded pellets is 0.153-0.286 mm;
3. the surfaces of the drug-loaded pellets are coated in a sustained-release manner, 95 percent of medicinal ethanol is used for dissolving ethyl cellulose and polyethylene glycol 400, the air inlet temperature is selected to be 35-48 ℃, and the air inlet speed is 10-20 m3H is used as the reference value. Under the condition of keeping the atomization pressure at 1.5bar, controlling the size of fog drops at 20-40 mu m, controlling the rotating speed of a liquid supply peristaltic pump at 10-25 rpm, controlling the liquid inlet flow rate at 0.3-1.8 g/min, and controlling the particle size (D90) of the prepared sustained-release coated pellets at 0.232-0.319 mm.
4. Mixing the sustained-release coated pellet with microcrystalline cellulose, silicon dioxide and croscarmellose sodium in three-dimensional mixing equipment for 10min, adding sodium stearyl fumarate, and mixing for 3 min.
5. After mixing, tabletting according to the weight of the tablet, controlling the hardness range to be 5-10 kgf, and forming a middle notch on one side of the tablet;
6. in the coating equipment, wax sealing is carried out on the pressed tablets by liquid paraffin, wherein the coating temperature is 40-50 ℃, the air inlet temperature is 50-80 ℃, and the air outlet temperature is 35-45 ℃.
The metoprolol succinate tablet obtained by the process can generate sustained release within 24h, and compared with the original preparation, the metoprolol succinate tablet can be dissolved out in vitro and keep good consistency
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention, which were not specifically described, were all those conventional in the art and commercially available.
Example 1: preparation of metoprolol succinate pellet sustained-release tablet with specification of 190mg
1. Prescription information is as follows:
2. the preparation method comprises the following steps:
(1) preparing a drug-containing pill core by taking 60% of the prescription amount of metoprolol succinate and sucrose and adopting a high-speed centrifugal atomization mode, wherein the air inlet temperature is 100 ℃, the air outlet temperature is 75 ℃, and the particle size (D90) of the drug-containing pill core is 0.079 mm;
(2) dissolving the residual metoprolol succinate with purified water, spraying the solution on the surface of the pill core containing the medicine by adopting a bottom spraying technology in a fluidized state, and keeping the atomizing pressure at 1.5bar and the air inlet speed at 10-20 m3The air inlet temperature is controlled to be 60-80 ℃, the material temperature is 38-45 ℃, the droplet size is controlled to be 20-40 mu m, the rotation speed of a liquid supply peristaltic pump is controlled to be 10-25 rpm, and the particle size (D90) of the prepared drug-loaded pellets is 0.178 mm;
(3) and carrying out slow release coating on the surface of the drug-loaded pellet, dissolving ethyl cellulose and Eudragit RS30D by using 95% medicinal ethanol, dissolving HPC by using purified water, mixing the ethyl cellulose and the Eudragit RS30D, and carrying out spray coating, wherein the air inlet temperature is 35-48 ℃, and the air inlet speed is 10-20 m 3/h. Under the condition that the atomization pressure is kept at 1.5bar, the rotating speed of a liquid supply peristaltic pump is controlled to be 10-25 rpm, the liquid inlet flow rate is 0.9-1.4 g/min, and the particle size (D90) of the prepared sustained-release coated pellets is 0.251 mm.
(4) Mixing the sustained-release coated pellet with microcrystalline cellulose, silicon dioxide and croscarmellose sodium in three-dimensional mixing equipment for 10min, adding sodium stearyl fumarate, and mixing for 3 min.
(5) After mixing, tabletting according to the weight of the tablet, controlling the hardness range to be 5-10 kgf, and forming a middle notch on one side of the tablet;
(6) in the coating equipment, wax sealing is carried out on the pressed tablets by liquid paraffin, wherein the coating temperature is 40-50 ℃, the air inlet temperature is 50-80 ℃, and the air outlet temperature is 35-45 ℃.
Example 2: preparation of metoprolol succinate pellet sustained-release tablet with specification of 95mg
1. Prescription information is as follows:
2. the preparation method comprises the following steps:
(1) preparing a drug-containing pill core by taking 60% of the prescription amount of metoprolol succinate and sucrose and adopting a high-speed centrifugal atomization mode, wherein the air inlet temperature is 120 ℃, the air outlet temperature is 75 ℃, and the particle size (D90) of the drug-containing pill core is 0.111 mm;
(2) dissolving the residual metoprolol succinate with purified water, spraying the solution on the surface of the pill core containing the medicine by adopting a bottom spraying technology in a fluidized state, and keeping the atomizing pressure at 2.3bar and the air inlet speed at 15-25 m3The air inlet temperature is controlled to be 60-80 ℃, the material temperature is 38-45 ℃, the droplet size is controlled to be 20-40 mu m, the rotation speed of a liquid supply peristaltic pump is controlled to be 10-25 rpm, and the particle size (D90) of the prepared drug-loaded pellets is 0.245 mm;
(3) carrying out slow release coating on the surface of the drug-loaded pellet, dissolving ethyl cellulose by using 95% medicinal ethanol, dissolving PEG2000 by using purified water, mixing the ethyl cellulose and the purified water, and then carrying out spray coating, wherein the air inlet temperature is 35-48 ℃, and the air inlet speed is 10-20 m3H is used as the reference value. Under the condition that the atomization pressure is kept at 1.5bar, the rotating speed of a liquid supply peristaltic pump is controlled to be 10-25 rpm, the liquid inlet flow rate is 0.5-1.1 g/min, and the particle size (D90) of the prepared sustained-release coated pellets is 0.319 mm.
(4) Mixing the sustained-release coated pellet with microcrystalline cellulose, silicon dioxide and croscarmellose sodium in three-dimensional mixing equipment for 10min, adding sodium stearyl fumarate, and mixing for 3 min.
(5) After mixing, tabletting according to the weight of the tablet, controlling the hardness range to be 5-10 kgf, and forming a middle notch on one side of the tablet;
(6) in the coating equipment, wax sealing is carried out on the pressed tablets by liquid paraffin, wherein the coating temperature is 40-50 ℃, the air inlet temperature is 50-80 ℃, and the air outlet temperature is 35-45 ℃.
Example 3: preparation of metoprolol succinate pellet sustained-release tablet with 47.5mg specification
1. Prescription information is as follows:
2. the preparation method comprises the following steps:
(1) preparing a drug-containing pill core by taking 60% of metoprolol succinate and sucrose according to a prescription amount and adopting a high-speed centrifugal atomization mode, wherein the air inlet temperature is 120 ℃, the air outlet temperature is 75 ℃, and the particle size (D90) of the drug-containing pill core is 0.094 mm;
(2) dissolving the residual metoprolol succinate with 50% methanol water, spraying on the surface of the pill core under a fluidized state by adopting a bottom spraying technology, and keeping the atomizing pressure at 1.8bar and the air inlet speed at 15-20 m3The air inlet temperature is controlled to be 60-80 ℃, the material temperature is 38-45 ℃, the droplet size is controlled to be 20-40 mu m, the rotation speed of a liquid supply peristaltic pump is controlled to be 10-20 rpm, and the particle size (D90) of the prepared drug-loaded pellets is 0.200 mm;
(3) carrying out slow release coating on the surface of the drug-loaded pellet, dissolving ethyl cellulose by using 95% medicinal ethanol, dissolving polyvinylpyrrolidone K30 by purified water, mixing the two, and carrying out spray coating, wherein the air inlet temperature is 35-48 ℃, and the air inlet speed is 10-30 m3H is used as the reference value. Under the condition of keeping the atomization pressure at 25bar, the rotating speed of a liquid supply peristaltic pump is controlled to be 10-35 rpm, the liquid inlet flow rate is 0.9-1.8 g/min, and the particle size (D90) of the prepared sustained-release coated pellets is 0.275 mm.
(4) Mixing the sustained-release coated pellet with silicified microcrystalline cellulose, lactose, colloidal silicon dioxide, and sodium carboxymethyl starch in three-dimensional mixing equipment for 10min, adding magnesium stearate, and mixing for 3 min.
(5) After mixing, tabletting according to the weight of the tablet, controlling the hardness range to be 5-10 kgf, and forming a middle notch on one side of the tablet;
(6) in the coating equipment, wax sealing is carried out on the pressed tablets by liquid paraffin, wherein the coating temperature is 40-50 ℃, the air inlet temperature is 50-80 ℃, and the air outlet temperature is 35-45 ℃.
Example 4: preparation of 23.75mg metoprolol succinate pellet sustained-release tablet
1. Prescription information is as follows:
2. the preparation method comprises the following steps:
(1) preparing a drug-containing pill core by taking 35% of metoprolol succinate and sucrose according to a prescription amount and adopting a high-speed centrifugal atomization mode, wherein the air inlet temperature is 120 ℃, the air outlet temperature is 75 ℃, and the particle size (D90) of the drug-containing pill core is 0.056 mm;
(2) dissolving the residual metoprolol succinate with 50% ethanol water, spraying on the surface of the pill core containing the medicine by adopting a bottom spraying technology in a fluidized state, and keeping the atomizing pressure at 1.5bar and the air inlet speed at 15-20 m3The air inlet temperature is controlled to be 60-80 ℃, the material temperature is 38-45 ℃, the droplet size is controlled to be 20-40 mu m, the rotation speed of a liquid supply peristaltic pump is controlled to be 10-20 rpm, and the particle size (D90) of the prepared drug-loaded pellets is 0.168 mm;
(3) carrying out slow release coating on the surface of the drug-loaded pellet, dissolving ethyl cellulose by using 95% medicinal ethanol, dissolving polyethylene glycol 4000 by using purified water, mixing the ethyl cellulose and the purified water, and then carrying out spray coating, wherein the air inlet temperature is 35-48 ℃, and the air inlet speed is 10-30 m3H is used as the reference value. Under the condition of keeping the atomization pressure at 25bar, the rotating speed of a liquid supply peristaltic pump is controlled to be 10-30 rpm, the liquid inlet flow rate is 0.6-1.5 g/min, and the particle size (D90) of the prepared sustained-release coated pellets is 0.237 mm.
(4) Mixing the sustained-release coated pellet with microcrystalline cellulose, compressible starch, pulvis Talci, and croscarmellose sodium in three-dimensional mixing equipment for 10min, adding sodium fumarate stearate, and mixing for 3 min.
(5) After mixing, tabletting according to the weight of the tablet, controlling the hardness range to be 5-10 kgf, and forming a middle notch on one side of the tablet;
(6) in the coating equipment, wax sealing is carried out on the pressed tablets by liquid paraffin, wherein the coating temperature is 40-50 ℃, the air inlet temperature is 50-80 ℃, and the air outlet temperature is 35-45 ℃.
Test example: dissolution test
The dissolution medium is specified in detail in the technical guide principle of dissolution test of common oral solid preparations issued by the nation: the volume is generally 500, 900 or 1000mL, the volume of the dissolving medium can best meet the condition of a leak tank, and the aqueous medium with the pH value of 1.2-6.8 is generally adopted. The enzyme-free dissolution medium with pH 1.2 and 6.8 can be used as artificial gastric juice and artificial intestinal juice. In particular cases, dissolution media of high pH may be used, but should generally not exceed pH 8.0. The sustained-release coated pellets prepared in examples 1 to 4 of the present invention were subjected to dissolution test with reference to FDA regulations, and the media selected in the present invention were: pH1.0, pH4.5, pH6.8, water, stirring: paddle method, the rotational speed is: 50rpm, medium volume: 900ml, sample points set to: 1h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, 20h and 24 h.
The results are shown in FIGS. 4 to 7. The result shows that the sustained-release coated pellet prepared by the invention has stable process, can well play a sustained-release role, has stable release within 24 hours, and has no phenomena of burst release and difficult dissolution.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. A preparation method of metoprolol succinate pellet sustained-release tablets is characterized by comprising the following steps:
(1) manufacturing a drug-containing pill core by adopting a high-speed centrifugal atomization mode on metoprolol succinate and sucrose, wherein the air inlet temperature is 80-120 ℃, and the air outlet temperature is 60-80 ℃;
(2) dissolving metoprolol succinate in purified water, spraying the solution on the surface of the drug-containing pellet prepared in the step (1) in a fluidized state, and coating a drug layer to prepare a drug-loaded pellet;
(3) carrying out slow release coating on the drug-loaded pellets prepared in the step (2) by adopting a slow release coating material to prepare slow release coated pellets;
(4) and (3) mixing the sustained-release coated pellets prepared in the step (3) with a filler, a disintegrant, a glidant and a lubricant, tabletting after mixing, and coating a layer of waxy material on the surface after tabletting forming to prepare the metoprolol succinate pellet sustained-release tablet.
2. The preparation method according to claim 1, wherein in the step (1), the metoprolol succinate and the sucrose are added in a weight ratio of (20-32): (8-12).
3. The preparation method according to claim 1, wherein in the step (1), the prepared drug-containing pellet core has a particle size of 0.056 to 0.155 mm.
4. The method according to claim 1, wherein the weight ratio of metoprolol succinate in step (1) to metoprolol succinate in step (2) is (35-68): (65-32).
5. The production method according to claim 1, wherein in the step (2), the spraying conditions are: the atomization pressure is kept at 1.5bar, and the air inlet speed is 10-20 m3The air inlet temperature is controlled to be 60-80 ℃, the material temperature is controlled to be 38-45 ℃, the size of fog drops is controlled to be 20-40 mu m, and the rotating speed of the liquid supply peristaltic pump is controlled to be 10-25 rpm.
6. The preparation method of claim 1, wherein in the step (2), the prepared drug-loaded pellets have a particle size of 0.153-0.286 mm.
7. The preparation method according to claim 1, wherein in the step (3), the sustained-release coating material comprises a sustained-release material and a plasticizer; the slow release material is selected from one or more of ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, polypropylene alcohol phthalate, methacrylic acid copolymer, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate and acrylic resin; the plasticizer is selected from one or more of polyethylene glycol 400, polyvinyl alcohol and polyvinylpyrrolidone.
8. The preparation method according to claim 1, wherein in the step (3), the particle size of the prepared sustained-release coated pellet is 0.232-0.319 mm.
9. The method according to claim 1, wherein in the step (4), the waxy material is selected from one or more of paraffin wax, vegetable wax, animal wax, mineral wax and synthetic wax.
10. Metoprolol succinate pellet sustained release tablets prepared by the method of any one of claims 1 to 9.
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