CN102357087B - Metoprolol fumarate sustained-release tablet and preparation method thereof - Google Patents
Metoprolol fumarate sustained-release tablet and preparation method thereof Download PDFInfo
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- CN102357087B CN102357087B CN 201110328696 CN201110328696A CN102357087B CN 102357087 B CN102357087 B CN 102357087B CN 201110328696 CN201110328696 CN 201110328696 CN 201110328696 A CN201110328696 A CN 201110328696A CN 102357087 B CN102357087 B CN 102357087B
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Images
Abstract
A metoprolol fumarate sustained-release tablet and a preparation method thereof. The sustained-release tablet with a total amount of 1000 tablets and an administration interval of 24 h is prepared by the following components: 95 g of metoprolol fumarate used as a main drug; 100-300 g of hydroxypropyl methyl cellulose used as a skeletal material; 30-50 g of ethyl cellulose or low-permeability acrylic resin used as a retarding agent; 100-300 g of 85% ethanol used as a wetting agent; 2.68 g-4.02 g of magnesium stearate used as a lubricant, and 5.025-8.375 g of talcum powder used as a flow aid. The main drug is well mixed firstly with the retarding agent and then with the skeletal material; a soft material and granules are prepared by he wetting agent; the granules are dried and sized; the lubricant and the flow aid are added for tabletting; when the tablet is qualified after examination, the metoprolol fumarate sustained-release tablet is obtained. After administration, the drug is released slowly; not only the everyday administration frequency is decreased, which is convenient for drug administration of clinical doctors and patients, but also the blood concentration of the drug is stable; no peak-valley phenomenon is generated; the toxic and side effect is decreased to a lowest level; and the patient compliance is good.
Description
Technical field
The present invention relates to metoprolol fumarate sustained-release tablet and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Metoprolol fumarate sustained-release tablet, English name Metoprolol Fumarate Sustained Release tablets; P-(2-the methoxyethyl)-phenoxy group of chemical name (±) 1-(isopropylamine base)-3-[]-2-propanol fumarate.
Along with the aging of population, cardiovascular diseases's sickness rate sharply increases, and is perplexing for a long time people.Hypertension, angina pectoris, arrhythmia and heart failure (heart failure) are modal cardiovascular disease clinically, and sickness rate is high.
Classical theory is thought, its contractility reduction of the heart of exhaustion, and the increase myocardial contraction is useful to Patients with Cardiac Failure, therefore positive inotropic medicament is regarded as effective treatment of Patients with Cardiac Failure always.Positive inotropic medicament is still disputable to the curative effect of acute and chronic heart failure at present, and when thinking chronic heart failure, the sympathetic nervous system excessive activation can cause cardiac damage, makes the further down-regulation of beta receptor density, thereby reduces cardiac muscle to the sensitivity of positive inotropic medicament.Beta-blocker is except being usually used in resisting hypertension, myocardial infarction and antiarrhythmic effect, and anti-heart failure treatment in recent years receives publicity day by day.
Metoprolol is a kind of novel, the safe and effective adrenergic beta receptor blockaders of Sweden Astra company development, to heart β
1Receptor has high selectivity, and peripheral vessels and bronchus are had no significant effect, and membrane stabilizing action is also very weak.Metoprolol fumarate be at present American-European clinical in beta-blocker commonly used.
1, to hypertensive effect: in the U.S. to 1609 routine patients with hypertension Metoprolol in Posts, 1652 examples compare with thiazide diuretic, result proves that the former is starkly lower than the latter by mortality rate, 24 h ABP detect 201 routine hyperpietics, metoprolol and nitrendipine, mepindolol and enalapril are relatively, metoprolol reduces systolic pressure and the diastolic pressure amplitude is maximum, and the most effective aspect the frequency that makes systolic pressure depreciation＞24kPa (180mmHg).Total effective rate to hypertension therapeutic is 91.4%.
2, to the effect of acute myocardial infarction: generally adopt first intravenously administrable then to carry out again oral medication, as angular vein administration in several hours after the acute myocardial infarction outbreak, can ease the pain, reduce myocardial oxygen consumption, dwindle infarct size, and reduce the generation of ventricular fibrillation, prevent sudden death.Sum up 27, whole world random experiments, 27000 routine patients' data proves, at the early stage metoprolol of using of morbidity, in 2 weeks mortality rates reduce the sudden death that reduces after 35%, 3 month in 36%, 42 day and again the infraction rate all significantly reduce.
3, antiarrhythmic effect: metoprolol has unique effect to arrhythmia, belongs to II class anti-arrhythmic, and is all effective to chamber property and supraventricular arrhythmia.Chamber property and supraventricular tachycardia are reduced 50%, and the chamber of obviously reducing the while in hospital incidence rate of quivering.To the paroxysmal supraventricular tachycardia patient, use the 5-10mg Metoprolol in Post, cardiac cycle obviously extends as a result, and the average rhythm of the heart descends 10.9%, all obviously extends after atrioventricular node effective refractory period and the medication of function refractory stage.Use Metoprolol in Post after myocardial infarction occurs, the ventricular arrhythmia incidence rate reduces 75%.
4, the effect of anti-heart failure: the report such as Hjalmarson in recent years
[1,2]Long-acting controlled release preparation 100mg/d and the each 50mg of spectinomycin hydrochloride with metroprolol succinate administration once a day, twice administration every day, mortality rate, hospital stays, symptom, quality of life and hematodinamics to 3991 Patients with Cardiac Failures have carried out reaching the randomized, double-blind contrast test of 1 year, result of study proves, produce significant function with these two kinds of preparation long-term treatments and improve, hemodynamic parameter there was no significant difference both.Recently the controlled release ditch slotted vane of a kind of new 25mg goes on the market in the U.S., 25mg once-a-day to the initial dose of secondary Patients with Cardiac Failure, serious Patients with Cardiac Failure initial dose is 12.5mg once-a-day, reaches patient's maximum tolerated dose or reach 200mg if dosage can tolerate to double in every two weeks.
Domestic and international present Research: metoprolol is the specificity receptor blocking agent of Sweden Astra company exploitation, to heart β
1-adrenoreceptor has high selectivity
[1]But this product is decreased heart rate not only, reduces cardiac output, reduces systolic pressure, and vertical position and clinostatism all can reduce blood pressure, and the Atrioventricular Conduction that can slow down slows down sinus rate, deeply is subjected to clinical welcome, statistics in 2000, and 100 kinds of situation of selling well medicine metas occupy the 24th at home.The initial product of releasing of Astra company is the tartrate of metoprolol, because this salt has bad hemodynamics response in vivo, and fumarate and the succinate of the present multiplex metoprolol of European ﹠ American Market, its crude drug records in American Pharmacopeia
[3]And European Pharmacopoeia
[4]
Metoprolol fumarate clinical commonly used be 95mg/ sheet, 190mg/ sheet, three kinds of specifications of 285mg/ sheet, China there is no crude drug and the preparation production of Metoprolol fumarate.According to domestic conditions and with reference to external clinical application specification, we have developed the slow releasing preparation of 95mg/ sheet.
Summary of the invention
The application's goal of the invention is to develop to take medicine to be spaced apart the metoprolol fumarate sustained-release tablet of 24h.
The application's goal of the invention is implemented by following technical solution:
Develop a kind of metoprolol fumarate sustained-release tablet, it is characterized in that it is the slow releasing tablet of 1000 that raw material by following proportioning prepares total amount:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 100～300g: 30～50g: 100～300g: 2.68g～4.02g: 5.025～8.375g;
Described principal agent is Metoprolol fumarate;
It is K that described framework material is set to the viscosity specification
15～100MHydroxypropyl emthylcellulose;
Described blocker is set to ethyl cellulose or the hyposmosis type acrylic resin that viscosity is 30～60mPas;
Described wetting agent is set to 85% alcoholic solution;
Described lubricant is set to magnesium stearate;
Described fluidizer is set to Pulvis Talci;
Described metoprolol fumarate sustained-release tablet is characterized in that being set to take medicine and is spaced apart the slow releasing tablet of 24h.
Another kind of metoprolol fumarate sustained-release tablet is that to prepare total amount be the slow releasing tablet of 1000 for raw material by following proportioning:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 200g: 40g: 200g: 3.35g: 6.70g;
Described principal agent is Metoprolol fumarate;
It is K that described framework material is set to the viscosity specification
100MHydroxypropyl emthylcellulose;
Described blocker is set to the ethyl cellulose that viscosity is 40～50mPas;
Described wetting agent is set to 85% alcoholic solution;
Described lubricant is set to magnesium stearate;
Described fluidizer is set to Pulvis Talci;
Described metoprolol fumarate sustained-release tablet is characterized in that being set to take medicine and is spaced apart the slow releasing tablet of 24h.
The preparation method of above-mentioned a kind of metoprolol fumarate sustained-release tablet is characterized in that method for making is divided into several steps:
(1) take principal agent by required weight respectively, framework material, blocker, wetting agent, lubricant and fluidizer;
(2) with principal agent and blocker mix homogeneously, standby;
(3) with (2) step mixing material again with the framework material mix homogeneously, the alcoholic solution with 85% prepares the tablet and powder soft material;
(4) with (3) step granule soft material, cross 20 mesh sieves and prepare granule, 55～60 ℃ of dryings are crossed 18 mesh sieve granulate;
(5) (4) step is made granule, add magnesium stearate lubricant, fluidizer Pulvis Talci mix homogeneously is standby;
(6) selecting as requested diameter is 10mm scrobicula shape punch die tabletting;
(7) be up to the standards by medicinal requirements, namely obtain metoprolol fumarate sustained-release tablet.
Advantage of the present invention
Kinetic character according to patient's needs, clinical application situation and this medicine, the metoprolol fumarate sustained-release tablet of development pastille 95mg, medication in 24 hours 1 time, after taking, sustained release, not only reduce medicining times every day, facilitate clinician and patient's medication, and blood drug level is steady, can produce " peak valley " phenomenon, make toxic and side effects be down to floor level, patient compliance is good.
Description of drawings
Fig. 1 is process flow diagram of the present invention;
Fig. 2 is three batches of metoprolol fumarate sustained-release tablet release curve synoptic diagrams.
In Fig. 1, the digitized representation operation sequence, wherein: 1 weighing; 2 sieve respectively; 3 batch mixings; 4 guiding humid mediums; 5 preparation soft materials; 6 soft materials sieve; 7 granulate; 8 dryings; 9 granulate; 10 add lubricant and fluidizer; 11 mix again; 12 survey granule content; 13 tablettings; 14 quality inspections; 15 qualified rear packings; 16 finished product warehouse-ins.
Letter represents principal agent and other adjuvant, wherein, and the A principal agent; The B framework material; The C blocker; The D wetting agent; The E lubricant; The F fluidizer.
Show in Fig. 2, ordinate is rate of releasing drug (%), and abscissa is drug release time (h), and three rate of releasing drug curves of three batch samples are respectively:
Curve with diamond block is the rate of releasing drug curve of lot number 020103;
Curve with rectangular block is the rate of releasing drug curve of lot number 020104;
Curve with gore is the rate of releasing drug curve of lot number 020105.
Result shows: three batch samples discharge repeatability and each batch sample release homogeneity is all good, and three curves almost completely overlap.Metoprolol fumarate sustained-release tablet stable preparation process of the present invention is described, the requirement up to specification of the release of three main time points (discharged 10%～30% in 1 hour; Discharged 50%～70% in 6 hours; Discharged more than 75% in 16 hours).
The specific embodiment
One, preparing total amount by the raw material of following proportioning is 1000, and taking medicine is spaced apart the slow releasing tablet of 24h:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 300g: 50g: 300g: 4.02g: 8.375g;
* except principal agent, other raw materials are referred to as " adjuvant ", and are lower same.
Described principal agent is Metoprolol fumarate, and Qidu Pharmaceutical Co., Ltd., Shandong Prov. provides.
Described framework material specification is viscosity K
15～100MHydroxypropyl emthylcellulose (English: Hydroxypropyl Methyl Cellulose is called for short: HPMC), the commercial goods, Dow Chemical company makes (viscosity K
15～100M, after being converted into legal dosage unit, viscosity K
15MBe equivalent to the legal unit of measurement 13～18mPas; Viscosity K
100MBe equivalent to the legal unit of measurement 80～120mPas.)
Described blocker is that viscosity is the ethyl cellulose (English name Ethyl cellulose ethoce, be called for short EC) of 40～50mPas, the commercial goods, and Dow Chemical company makes;
Described wetting agent is 85% alcoholic solution, the dehydrated alcohol commercial goods, and Solution on Chemical Reagents in Shanghai factory makes, and the alcoholic solution that is made into 85% (v/v) uses;
Described lubricant is the magnesium stearate commercial goods, and Shandong Province A Hua pharmaceutical Co. Ltd makes;
Described fluidizer is the Pulvis Talci commercial goods, and Shandong Province A Hua pharmaceutical Co. Ltd makes;
In principal agent and adjuvant, medicine or manufacturer are the pharmaceutical factory, and the specification of quality meets 2010 editions Chinese Pharmacopoeias or external corresponding pharmacopeia; All the other quality of chemical products specifications meet the specification of synchronization chemical product.
Two, its preparation method is divided into following a few step:
(1) take principal agent and other raw materials by required weight respectively; Metoprolol fumarate is crossed 100 mesh sieves, and HPMC crosses 120 mesh sieves, and EC crosses 80 mesh sieves, and is standby;
(2) with principal agent and blocker mix homogeneously, standby;
(3) with (2) step mixing material again with the framework material mix homogeneously, the alcoholic solution with 85% prepares the tablet and powder soft material, and is standby;
(4) with (3) step granule soft material, cross 20 mesh sieves and prepare granule, 5560 ℃ of dryings are crossed 18 mesh sieve granulate;
(5) (4) step is made granule, add magnesium stearate lubricant, fluidizer Pulvis Talci mix homogeneously is standby;
(6) selecting as requested diameter is 10mm scrobicula shape punch die tabletting;
(7) be up to the standards by medicinal requirements, namely obtain metoprolol fumarate sustained-release tablet.
Three, detect
Drug release determination
With reference to " Chinese pharmacopoeia adopts to turn blue laws, and release medium is that 900ml distilled water, temperature are that 37 ℃ ± 0.5 ℃, rotating speed are 100r/min, and the detection wavelength is 274nm.Respectively at 1,6, the 16h 5ml (adding simultaneously synthermal distilled water 5ml) that takes a sample, with 0.8 μ m filtering with microporous membrane, get subsequent filtrate as need testing solution, another precision takes through 60 ℃ of drying under reduced pressure appropriate to the reference substance of constant weight, accurately weighed, the solution of making about 100 μ g/ml with distilled water is liquid in contrast.Get above-mentioned two kinds of solution, measure trap according to ultraviolet spectrophotometry in 274nm wavelength place, try to achieve content with By Absorbance Ratio Method, calculate the cumulative release percentage rate of each time point.
Investigate index
With reference to two appendix of Chinese Pharmacopoeia version in 2000, slow, controlled release preparation guideline, to the 1h of metoprolol fumarate sustained-release tablet, 6 and the composite request of 16h release for investigating index, establish X
1, X
2, X
3Be respectively the cumulative release percentage rate of three time points, its release scope and best point of release are as follows:
Select many Index Orthogonal Tests comprehensive scoring method, be about to many index analysis and be converted into to test to such an extent that be divided into the single index analysis of index.
Date processing
The drug release determination result:
The drug release determination result
Adopt the intuitive analysis method, the cumulative release percentage rate of three time points of high spot reviews:
Cumulative release percentage rate (the X of (1) 1 hour
1) take 20% as standard
Cumulative release percentage rate (the X of (2) 6 hours
2) take 60% as standard
The cumulative release amount percentage rate (X of (3) 16 hours
3) take 80% as standard
Usually we adopt " method of weighting scores ", namely determine " power " of corresponding index according to the significance level of each index.Then, calculate the total points of each result of the test.
Power+------of the power of score=1st desired value * the 1st index+the 2nd desired value * 2nd index
Power determine it is the key of comprehensive grading, the power that the power that we are decided to be 1, the second index with the power of first index is decided to be 1, the three index is decided to be 0.5.Score is lower, shows with selected standard more approachingly, and result of calculation sees the following form:
Orthogonal experiments is analyzed
Extreme difference R reacts each factor to the degree of Index Influence, and extreme difference R is larger, and influence degree is larger.
* A, B, C, the D in upper table refers to respectively hydroxypropyl emthylcellulose, ethyl cellulose, 85% alcoholic solution, magnesium stearate.
Metoprolol fumarate sustained-release tablet repeatability of the present invention and homogeneity are investigated
Best prescription with Orthogonal Experiment and Design optimization, by above-mentioned preparation technology, prepare respectively three batches of metoprolol fumarate sustained-release tablets, press the operation of drug release determination method for 6 every batch, inspection repeatability between batches reaches the homogeneity with each sampling time point of batch sample, investigates preparation technology's stability.The release percentage data of three batches of metoprolol fumarate sustained-release tablets sees the following form and accompanying drawing 2 release profiles.
The release percentage data (n=6) of three batches of metoprolol fumarate sustained-release tablets
After testing, the release percentage rate of three batches of metoprolol fumarate sustained-release tablets produces a desired effect.
Preparing total amount by the raw material of following proportioning is 1000, and taking medicine is spaced apart the slow releasing tablet of 24h:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 100g: 30g: 100g: 2.68g: 5.025g;
Except dosage changes, raw material, adjuvant, preparation method and testing result all are equal to embodiment 1 or approach.
Embodiment 3
Preparing total amount by the raw material of following proportioning is 1000, and taking medicine is spaced apart the slow releasing tablet of 24h:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 200g: 40g: 200g: 3.35g: 6.70g;
It is K that framework material is set to the viscosity specification
100MHydroxypropyl emthylcellulose;
All the other except dosage changes, raw material, adjuvant, preparation method and testing result all are equal to embodiment 1 or are approaching.
Embodiment 4
Preparing total amount by the raw material of following proportioning is 1000, and taking medicine is spaced apart the slow releasing tablet of 24h:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 150g: 35g: 150g: 3.02g: 5.86g;
It is K that framework material is set to the viscosity specification
100MHydroxypropyl emthylcellulose;
All the other except dosage changes, raw material, adjuvant, preparation method and testing result all are equal to embodiment 1 or are approaching.
Embodiment 5
Preparing total amount by the raw material of following proportioning is 1000, and taking medicine is spaced apart the slow releasing tablet of 24h:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 250g: 45g: 250g: 3.7g: 7.5g;
It is K that framework material is set to the viscosity specification
100MHydroxypropyl emthylcellulose;
All the other except dosage changes, raw material, adjuvant, preparation method and testing result all are equal to embodiment 1 or are approaching.
List of references
[1]Hjalmarson?A.et?al：JAMA?20008(10)：1295～1302
[2]Kukin?ML.et?al：J?Am?Coll?Cardiol?200035(1)：45～50
[3]United?States?Pharmacopoeia，24，2000，1100～1101
[4]European?Pharmacopoeia?Supplement?2000，952～954
Claims (1)
1. the preparation method of a metoprolol fumarate sustained-release tablet is characterized in that it is the slow releasing tablet of 1000 that raw material by following proportioning prepares total amount:
Principal agent: framework material: blocker: wetting agent: lubricant: fluidizer=95g: 200g: 40g: 200g: 3.35g: 6.70g;
Described principal agent is Metoprolol fumarate;
It is K that described framework material is set to the viscosity specification
100MHydroxypropyl emthylcellulose;
Described blocker is set to the ethyl cellulose that viscosity is 40～50mPas;
Described wetting agent is set to 85% alcoholic solution;
Described lubricant is set to magnesium stearate;
Described fluidizer is set to Pulvis Talci;
Described metoprolol fumarate sustained-release tablet is characterized in that being set to take medicine and is spaced apart the slow releasing tablet of 24h;
Its method for making is divided into several steps:
⑴ take principal agent by required weight respectively, framework material, blocker, wetting agent, lubricant and fluidizer;
⑵ with principal agent and blocker mix homogeneously, standby;
With ⑵ go on foot the mixing material again with the framework material mix homogeneously, the alcoholic solution with 85% prepares the tablet and powder soft material;
⑷ go on foot the granule soft material with ⑶, crosses 20 mesh sieves and prepare granule, and 55～60 ℃ of dryings are crossed 18 mesh sieve granulate;
⑸ make granule with the ⑷ step, adds magnesium stearate lubricant, and fluidizer Pulvis Talci mix homogeneously is standby;
⑹ select as requested diameter is 10mm scrobicula shape punch die tabletting;
⑺ be up to the standards by medicinal requirements, namely obtains metoprolol fumarate sustained-release tablet.
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| CN101904828A (en) * | 2010-07-27 | 2010-12-08 | 广州汉方现代中药研究开发有限公司 | Metoprolol controlled release mixed matrix tablet and preparation method thereof |
| CN102008456A (en) * | 2009-09-04 | 2011-04-13 | 鲁南制药集团股份有限公司 | Novel skeleton sustained release tablet containing metoprolol succinate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008456A (en) * | 2009-09-04 | 2011-04-13 | 鲁南制药集团股份有限公司 | Novel skeleton sustained release tablet containing metoprolol succinate |
| CN101904828A (en) * | 2010-07-27 | 2010-12-08 | 广州汉方现代中药研究开发有限公司 | Metoprolol controlled release mixed matrix tablet and preparation method thereof |
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| 黄桂华 等.琥珀酸美托洛尔HPMC骨架片释放影响因素研究.《生物医学工程学杂志》.2006,第23卷(第3期),587～591. |
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