CN107149597A - A kind of preparation method of metroprolol succinate sustained-release compaction of pellet - Google Patents
A kind of preparation method of metroprolol succinate sustained-release compaction of pellet Download PDFInfo
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- CN107149597A CN107149597A CN201710189390.5A CN201710189390A CN107149597A CN 107149597 A CN107149597 A CN 107149597A CN 201710189390 A CN201710189390 A CN 201710189390A CN 107149597 A CN107149597 A CN 107149597A
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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
- A61K9/5015—Organic compounds, e.g. fats, sugars
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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
- A61K9/5036—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
- 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
- A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Abstract
The present invention relates to a kind of preparation method of metroprolol succinate sustained-release compaction of pellet, belong to pharmaceutical technology field.Metoprolol salt and adhesive are dissolved in suitable solvent, prepare medicine layer coating solution, then sustained release resistance to compression layer Sustained release coating materials, plasticizer, pore-foaming agent are dissolved in coating solution solvent, prepared slow release layer coating solution, add appropriate auxiliary materials and mixing, tabletting, coating.Product of the present invention, which has the advantages that to break into two with one's hands to take, still keeps active component rate of release constant, and can continue slow release in 24 hours.
Description
Technical field
The present invention relates to a kind of preparation method of metroprolol succinate sustained-release compaction of pellet, belong to pharmaceutical technology field.
Background technology
Heart disease is the relatively common circulation system disease of a class.Metoprolol is a kind of selective β1receptor retardance
Agent, dosage acts institute less than the beta 2 receptor on its human peripheral blood pipe and bronchus needed for it is acted to heart β1receptor
Need dosage.The selectivity of metroprolol succinate is dose-dependent, because the peak value of sustained release tablets blood concentration is significantly lower than same
The common plain film of dosage, makes the formulation have relatively higher β1receptor selectivity.Metoprolol is without beta receptor agonism, almost
Without film activation.Beta-blocker has negative inotropic and chronotropic action.The treatment of metoprolol can weaken and physiology and psychology
The effect of the relevant catecholamine of load, reduction heart rate, heart discharge and blood pressure.Under stress situation, the kidney of acth secretion
Upper parathyrine increase, metoprolol will not hinder physiological blood vessel dilatation.In therapeutic dose, metoprolol is to bronchial smooth muscle
Contraction is weaker than non-selective beta-blocker, and the characteristic makes it to share with β 2 receptor agonist, and treatment is associated with branch
The patient of san bronchial asthma or other obvious obstructive lung diseases.Influence of the metoprolol to insulin releasing and glycometabolism is less than non-
Selective beta-blocker, thus available for diabetic.Compared with non-selective beta-blocker, metoprolol is to low
For example tachycardic influence of the cardiovascular response of blood glucose is smaller, and blood glucose gos up to the speed of normal level.For hypertension
Patient, metroprolol succinate can obviously reduce blood pressure when orthostatic position, horizontal position and motion, effect lasts more than 24 hours.
The increase of peripheral vascular resistance can be observed when Metoprolol in Post starts, however, the drop in blood pressure that long-term treatment is obtained may
Be due to peripheral vascular resistance decline and heart discharge is constant.For in male/severe hypertension patient, metoprolol can reduce
The danger of cardiovascular death.Metoprolol will not cause electrolyte disturbance.Effect to chronic heart failure：It is related at one
The research for the heart failure patient that 3991 II-IV grade of heart function NYHA, LVEFs decline (≤0.40) (is referred to as MERIT-
HF in), metroprolol succinate can increase survival rate, reduce number of times of being hospitalized for treatment.Total Signs of long-term patient receiving treatment
Shape improves (the association's classification of New York Heart disease and overall therapeutic point value of evaluation).In addition, metroprolol succinate, which can increase, penetrates blood system
Number, reduces the capacity of left ventricular contraction latter stage and diastasis.To the patient of tachyarrhythmia, this product can block sympathetic god
Through the increased effect of activity, make decreased heart rate.This is mainly by reducing the self-disciplining of pacemaker cells, and the supraventricular conduction of extension
Time.After myocardial infarction in patient, metoprolol can reduce the danger of myocardial infarction again, reduce cardiac death and be particularly
The danger died suddenly after myocardial infarction.
The sour metoprolol sustained-release piece preparation method of most amber is to prepare butanedioic acid U.S. support by direct compression method at present
Luo Er sustained release tablets, are optimized using orthogonal test to its formulation and technology, high effective liquid chromatography for measuring vitro release, to place
The repeatability of square technique is investigated, and the SD values of its F2 similar factors sample point release are most of all below 2%.And it is existing
The sour metoprolol sustained-release piece technology of preparing Production Time longer cost of amber it is higher.
The content of the invention
In order to solve problems of the prior art, the invention provides a kind of metroprolol succinate sustained-release micropill pressure
The preparation method of piece, fluidized bed coating equipment is used in preparation technique, butanedioic acid is prepared by carrier of microcrystalline cellulose pellets
Metoprolol sustained-release micropill, plasticizer coating material is dissolved in coating solution solvent, is prepared resistance to compression layer coating solution, is prepared micro-
Ball, compaction of pellet, active ingredient is quality controllable, and drug effect release behavior can produce a desired effect in water, acid, aqueous slkali, with
The similar factors f2 of reference reagent Betaloc is all higher than that 50 therapeutic effects are good, using the present invention prepare the tablet of tablet forming technique into
This is relatively low.
A kind of preparation method of metroprolol succinate sustained-release compaction of pellet：
A. metoprolol salt and adhesive are dissolved in suitable solvent, prepare medicine layer coating solution:
Metroprolol succinate is taken, 50~60 DEG C of purified waters is added, is stirred to dissolve, adds hydroxypropylcellulose EF, stir
Mixing makes dissolving, obtains the coating solution that solid content is 10.30%~27.8%.Microcrystalline cellulose pellets capsule core CP203 is added and fluidized
In bed, 38 DEG C ± 5 DEG C of temperature of charge of regulation, material relative humidity 20%~60% and other appropriate coating parameters spray into bag
Drug solns, are coated by medicine layer twice, and it is 83.0%~93.4% to make dose on medicine layer；
B. sustained release resistance to compression layer Sustained release coating materials, plasticizer, pore-foaming agent are dissolved in coating solution solvent again, prepare slow release layer
Coating solution:
Take ethyl cellulose, acrylic resin, lemon triethylenetetraminehexaacetic acid liposoluble solution or leach in isopropanol, it is 3 to obtain solid content
~6% coating solution.Medicine layer micropill is added in fluid bed, 26 DEG C ± 3 DEG C of temperature of charge of regulation, material relative humidity 30%
~70% and other appropriate coating parameters, spraying into slow release layer Coating Solution makes slow release layer weightening be 16~22%, obtains slow release layer
Micropill.
C. appropriate auxiliary materials and mixing, tabletting, coating are added:
It is standby that silica or magnesium stearate cross 60 mesh sieves；It is standby that microcrystalline cellulose or lactose add appropriate amount of ethanol to be prepared into particle
With；Metroprolol succinate sustained-release micropill and microcrystalline cellulose crude granule or lactose granule are first added into mixing (mixing in mixer
Equipment can select V-Mixer or three-dimensional mixer), set and be adapted to rotating speed, mix 20 minutes, add silica or tristearin
Sour magnesium, continues to mix 5 minutes, and with the circular shallow concave punch tablettings of diameter 9mm, 7~10kg/cm2 of hardness takes film coating agent (stomach
Molten type) it is dispersed in water, the coating suspensions that solid content is 10% are made.Plain piece is added in film coater, regulation is appropriate
Coating parameter, preheating, be then sprayed into coating suspensions coating, make coating weight gain be 3.5% ± 0.5%.
Release is tested
This product is taken, (annex X the first methods of D are filled using dissolution method (methods of annex XC second) according to drug release determination method
Put, using pH6.8 phosphate buffers 500ml as dissolution medium, rotating speed is 50 turns per minute, is operated in accordance with the law, 1 hour, it is 4 small
When, take solution 5ml respectively within 8 hours, 20 hours, filter, and supplement mutually synthermal, same volume dissolution medium in time, take continuous
Filtrate is used as need testing solution；It is another to take metroprolol succinate reference substance appropriate, it is accurately weighed, plus dissolution medium dissolves and quantifies
Dilution is made the solution containing 0.1mg in every 1ml and, as reference substance solution, determined according to the method under assay.Calculate every
In the burst size of different time.This product every should be not surpassing for labelled amount in the burst size of 1 hour, 4 hours, 8 hours, 20 hours
25%, 20%~40%, 40%~60%, more than 80% is crossed, regulation all should be met.
| Accumulation dissolution (%) | 0.5h | 1h | 2h | 4h | 6h | 8h | 12h | 16h | 20h | 24h | f2Similar factors |
| Original is ground | 5.47 | 9.86 | 16.77 | 26.32 | 37.13 | 48.17 | 68.22 | 83.30 | 91.62 | 96.15 | 100 |
| 20110901 | 5.17 | 9.00 | 16.51 | 26.11 | 36.05 | 47.21 | 66.08 | 81.21 | 91.21 | 96.08 | 91 |
The pH6.8 medium release profiles correction datas of table 1
Contrast effect refers to Fig. 1 in brief description of the drawings and Figure of description.
By release experiment it is recognised that the present invention and the similar factors f2 of reference reagent Betaloc are all higher than 50,
Therapeutic effect is good.
The beneficial effects of the present invention are：A kind of new technology is provided, sustained release pellet is made in metoprolol salt, is sustained micro-
Ball has slow release characteristics, and by sustained release pellet and tablet filler mixed pressuring plate, the release characteristics of tabletting latter two composition are protected
Hold constant, i.e. the release profiles of two kinds of compositions of micropill and tablet do not have significant change.Product of the present invention have can break into two with one's hands take according to
The constant advantage of active component rate of release is so kept, and slow release can be continued in 24 hours.
Brief description of the drawings
Fig. 1 is the former burst size curve comparison for grinding medicine and this product in identical release time.This product is scale up test lot number
For 20110901 Metoprolol succinate sustained-release tablets.
Embodiment
Inventive embodiments 1
(1) prescription：
(2) tablet of every 47.5mg metroprolol succinate is made according to (1) prescription, the piece preparation method is as follows：
This product micropill is divided into three layers, is followed successively by microcrystalline cellulose pellets capsule core from the inside to the outside, medicine layer, sustained release resistance to compression layer,
Its drug layer due to the limitation of capacity of equipment and Coating times, can in two times or three times completion.(coating equipment in sugar production line is many kinetic energy streams
Change bed seed-coating machine)
Medicine layer is coated：Metroprolol succinate is taken, 50~60 DEG C of purified waters is added, is stirred to dissolve, adds hydroxypropyl
Cellulose EF, is stirred to dissolve, and obtains the coating solution that solid content is 10.30%~27.8%.By microcrystalline cellulose pellets capsule core
CP203 is added in fluid bed, 38 DEG C ± 5 DEG C of temperature of charge of regulation, material relative humidity 20%~60% and other appropriate bags
Clothing parameter, sprays into bag drug solns, is coated by medicine layer twice, and it is 83.0%~93.4% to make dose on medicine layer.
Resistance to compression layer is sustained to be coated：Take ethyl cellulose, acrylic resin, lemon triethylenetetraminehexaacetic acid liposoluble solution or leach in isopropanol
In, obtain the coating solution that solid content is 3~6%.Medicine layer micropill is added in fluid bed, 26 DEG C ± 3 DEG C of temperature of charge of regulation, thing
Expect relative humidity 30%~70% and other appropriate coating parameters, spray into slow release layer Coating Solution make slow release layer weightening for 16~
22%, obtain slow release layer micropill.
(3) total mixed pressure piece：
It is standby that silica or magnesium stearate cross 60 mesh sieves；It is standby that microcrystalline cellulose or lactose add appropriate amount of ethanol to be prepared into particle
With；Metroprolol succinate sustained-release micropill and microcrystalline cellulose crude granule or lactose granule are first added into mixing (mixing in mixer
Equipment can select V-Mixer or three-dimensional mixer), set and be adapted to rotating speed, mix 20 minutes, add silica or tristearin
Sour magnesium, continues to mix 5 minutes, with the circular shallow concave punch tablettings of diameter 9mm, 7~10kg/cm2 of hardness.
(4) film coating：
Take film coating agent (stomach dissolution type) to be dispersed in water, the coating suspensions that solid content is 10% are made.By plain piece plus
Enter in film coater, adjust appropriate coating parameter, preheating is then sprayed into coating suspensions coating, make the coating weight gain be
3.5% ± 0.5%.
Claims (1)
1. a kind of preparation method of metroprolol succinate sustained-release compaction of pellet, it is characterised in that：
A. metoprolol salt and adhesive are dissolved in suitable solvent, prepare medicine layer coating solution:
Metroprolol succinate is taken, 50~60 DEG C of purified waters is added, is stirred to dissolve, adds hydroxypropylcellulose EF, stirring makes
Dissolving, obtains the coating solution that solid content is 10.30%~27.8%, microcrystalline cellulose pellets capsule core CP203 is added in fluid bed, adjust
38 DEG C ± 5 DEG C of temperature of charge, material relative humidity 20%~60% and other appropriate coating parameters are saved, bag drug solns, warp are sprayed into
It is coated after medicine layer twice, it is 83.0%~93.4% to make dose on medicine layer；
B. sustained release resistance to compression layer Sustained release coating materials, plasticizer, pore-foaming agent are dissolved in coating solution solvent again, prepare slow release layer bag
Clothing liquid:
Take ethyl cellulose, acrylic resin, lemon triethylenetetraminehexaacetic acid liposoluble solution or leach in isopropanol, it is 3~6% to obtain solid content
Coating solution, by medicine layer micropill add fluid bed in, adjust 26 DEG C ± 3 DEG C of temperature of charge, material relative humidity 30%~70%
With other appropriate coating parameters, spraying into slow release layer Coating Solution makes slow release layer weightening be 16~22%, obtains slow release layer micropill；
C. appropriate auxiliary materials and mixing, tabletting, coating are added:
It is standby that silica or magnesium stearate cross 60 mesh sieves, and it is standby that microcrystalline cellulose or lactose add appropriate amount of ethanol to be prepared into particle,
First metroprolol succinate sustained-release micropill and microcrystalline cellulose crude granule or lactose granule are added in mixer and mixed（Mixing apparatus
V-Mixer or three-dimensional mixer can be selected）, set and be adapted to rotating speed, mix 20 minutes, add silica or stearic acid
Magnesium, continues to mix 5 minutes, and with the circular shallow concave punch tablettings of diameter 9mm, 7 ~ 10kg/cm2 of hardness takes film coating agent（It is soluble in the stomach
Type）It is dispersed in water, the coating suspensions that solid content is 10% is made, plain piece is added in film coater, appropriate bag is adjusted
Clothing parameter, preheating is then sprayed into coating suspensions coating, and it is 3.5% ± 0.5% to make coating weight gain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710189390.5A CN107149597A (en) | 2017-03-27 | 2017-03-27 | A kind of preparation method of metroprolol succinate sustained-release compaction of pellet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710189390.5A CN107149597A (en) | 2017-03-27 | 2017-03-27 | A kind of preparation method of metroprolol succinate sustained-release compaction of pellet |
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| CN107149597A true CN107149597A (en) | 2017-09-12 |
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| CN201710189390.5A Pending CN107149597A (en) | 2017-03-27 | 2017-03-27 | A kind of preparation method of metroprolol succinate sustained-release compaction of pellet |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110585154A (en) * | 2019-10-17 | 2019-12-20 | 武汉光谷亚太医药研究院有限公司 | Method for tabletting metoprolol succinate pellets |
| CN112691086A (en) * | 2019-10-22 | 2021-04-23 | 翰宇药业（武汉）有限公司 | Microporous metoprolol succinate sustained-release tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104173312A (en) * | 2014-05-30 | 2014-12-03 | 广西博科药业有限公司 | Sustained-release tablet containing felodipine and metoprolol salt and preparation method of sustained-release tablet containing felodipine and metoprolol salt |
| CN104758937A (en) * | 2014-01-02 | 2015-07-08 | 石药集团中奇制药技术（石家庄）有限公司 | Metoprolol sustained-release pellet preparation |
-
2017
- 2017-03-27 CN CN201710189390.5A patent/CN107149597A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758937A (en) * | 2014-01-02 | 2015-07-08 | 石药集团中奇制药技术（石家庄）有限公司 | Metoprolol sustained-release pellet preparation |
| CN104173312A (en) * | 2014-05-30 | 2014-12-03 | 广西博科药业有限公司 | Sustained-release tablet containing felodipine and metoprolol salt and preparation method of sustained-release tablet containing felodipine and metoprolol salt |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110585154A (en) * | 2019-10-17 | 2019-12-20 | 武汉光谷亚太医药研究院有限公司 | Method for tabletting metoprolol succinate pellets |
| CN110585154B (en) * | 2019-10-17 | 2021-07-02 | 武汉光谷亚太医药研究院有限公司 | Method for tabletting metoprolol succinate pellets |
| CN112691086A (en) * | 2019-10-22 | 2021-04-23 | 翰宇药业（武汉）有限公司 | Microporous metoprolol succinate sustained-release tablet and preparation method thereof |
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Application publication date: 20170912 |
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