CN101773482B - Three-stage pulsed release controlled release tablet and preparation method thereof - Google Patents
Three-stage pulsed release controlled release tablet and preparation method thereof Download PDFInfo
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- CN101773482B CN101773482B CN2009102476740A CN200910247674A CN101773482B CN 101773482 B CN101773482 B CN 101773482B CN 2009102476740 A CN2009102476740 A CN 2009102476740A CN 200910247674 A CN200910247674 A CN 200910247674A CN 101773482 B CN101773482 B CN 101773482B
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Abstract
The invention provides a metoprolol pulse osmotic pump controlled release tablet and a preparation method thereof. The controlled release tablet comprises a tablet core, a time lag coating layer and a controlled release coating layer with a release orifice from inside to outside, wherein the tablet core consists of a drug containing layer and a boosting layer, based on the gross weight of the drug containing layer, the drug containing layer comprises 5-65 wt% of metoprolol as active material and 35-95 wt% of pharmaceutically acceptable carrier; based on the gross weight of the boosting layer, the boosting layer comprises 30-85 wt% of swelling agent and 15-70 wt% of osmotic pressure promoting agent; the weight gain of the time lag coating layer is 5-50 wt% of the tablet core; and the weight gain of the controlled release coating layer is 3-30 wt% of the tablet core. The metoprolol pulse osmotic pump controlled release tablet has three-stage release behavior, and is characterized in that the tablet has 2-5 hours time lag at the initial period after being taken orally, increased release is showed at the intermediate period, and release at constant speed is showed at the later period.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly, the present invention relates to a kind of metoprolol pulse osmotic pump controlled release tablet and preparation method thereof.
Background technology
In recent years, along with China's living standards of the people improve constantly and the continuous increase of aging population, the sickness rate of cardiovascular and cerebrovascular diseases such as hypertension, angina pectoris increases just year by year.According to the mortality statistics of The World Health Organization (WHO) to global various diseases; With hypertension, angina pectoris etc. is the ratio that the cardiovascular and cerebrovascular disease death toll of representative accounts for total death toll; By 1997 28.8% rise to 2002 36.0%, cardiovascular and cerebrovascular disease is just becoming the killer of serious harm human health.
Nearest result of study shows, the high mortality of cardiovascular and cerebrovascular disease is because people do not recognize the chronobiology that it is hidden behind to a certain extent; Especially the daily rhythmicity of such disease; The viewpoint in past it has been generally acknowledged that, the incidence rate of cardiovascular disease be randomly Stationary Distribution in 24 hours periods, but there are some researches show; Sickness rate between 6 o'clock to 12 o'clock early morning is higher by 30%～40% than other times; And the ambulatory blood pressure monitoring result finds that blood pressure is lower at night, and can raise 10%～25% after waking up in the morning; Heart rate is at a low ebb at night, begins to accelerate about 10%～20% before reviving.The reason that causes above-mentioned difference possibly be since during this period of time the intravital catecholamine levels of patient increase, cause blood pressure and heart rate to peak, thereby cause patient's at this moment mortality rate higher.
Research shows that one attack times is minimum when finding from 12pm to 6am in the research that totally 33999 times are shown effect of 1022 routine patients with stable angina, and 6am increases later on, reaches the outbreak peak during 10～11am, and this rhythm and pace of moving things is remarkable especially at angina of effort.This shows that no matter hypertension or angina pectoris, its onset peak all in the morning to 12 points, then is in the physiology low ebb night.So such treatment of diseases then needs medicine night hardly, and the certain timely drug level of a needs in early morning to 12 is supplied with, and therefore designing a kind of can be very significant by the transmission system that preset time discharges required medicine.
Pulsatile drug delivery system (Pulsed Release System) is these biorhythies variation characteristics according to human body, a kind of novel drug-supplying system of timing, quantitative medicament release according to the needs of physiology and treatment.The main pattern of pulsatile administration system is 2 subpulse controlled release preparations, and studying more at present is the pulsatile drug delivery system of the 1st dosage deletion form, claims the delayed release preparation again, release preparation when selecting.Seldom release or the not release within a certain period of time of such preparation then discharges needed dosage in the given time.The representative product that utilizes such technology to be developed has: 1999, and the verapamil pulse preparation that is used to treat essential hypertension (trade name:
) of the Elan company development of FDA approval; 2003, the trust pharmacy of drugs approved by FDA (Reliant Pharmaceuticals) company propranolol hydrochloride pulse controlled release capsule (trade name:
) etc.
Metoprolol (Metoprolol) belongs to the second filial generation heart is had the high selectivity β1Shou Tizuzhiji.1975, develop successfully by ASTRA company, be one of the world's ten big situation of selling well medicines, be treatment hypertension, anginal choice drug.Metoprolol is mainly through retardance human body β
1Receptor (maximum in the myocardial cell), thus myocardial contraction is descended, decreased heart rate, total cardiac output reduces, and finally reaches the purpose that makes blood pressure drops.Because metoprolol is for β
1Receptor has the selectivity of height (promptly for β
1Effect greatly more than β
2Receptor), therefore, it seldom has the normal side effect such as bringing out asthma that exists of other non-selective beta-blockers.Metoprolol not only has hypotensive activity, plays an important role at aspects such as treatment angina pectoris, myocardial infarction, arrhythmia, heart failure simultaneously, and be " a many-side people " of Cardioprotective.
At present, the metoprolol dosage form of listing mainly comprises: conventional tablet, injection, capsule and slow releasing tablet etc.Traditional tablet, the blood concentration fluctuation of capsule are bigger, are easy to have side effects; Though common slow releasing preparation can provide comparatively mild blood drug level, do not consider the division of day and night rhythmicity of cardiovascular disease, can not come control drug release targetedly to the characteristics of cardiovascular disease, and be easy to generate shortcoming such as drug resistance.Therefore; Design a kind of can (9～10pm) take medicine before sleeping; Begin release morning next day, reach stable effective blood drug concentration morning, make drug effect consistent with occurrence regularity; Make patient safety spend the cardiovascular and cerebrovascular disease pulse preparation in period occurred frequently, significant for the cardiovascular and cerebrovascular disease patient that China is increasing.
United States Patent (USP) 5681584 has been introduced a kind of segmented intestine targeted drug-supplying system that postpones to discharge, and said preparation is made up of monolayer label and three layers of coating, and three layers of clothing film are respectively the time lag clothing, have the semipermeable membrane and the enteric coating of drug release hole.Said preparation has solved ordinary preparation to a certain extent the patient has been complied with poor problem; Certain time lag is also arranged; But be subject to the influence of gastrointestinal tract pH value, if edible for patients meta-alkalescence food, the release behavior of medicine will be had a strong impact on; Be difficult to reach predetermined release behavior, and preparation technology is comparatively complicated.
United States Patent (USP) 4871549 has been introduced a kind of explosion type controlled release system that contains metoprolol; This system makes extender with low-substituted hydroxypropyl cellulose, starch, manna sodium alkoxide and sodium carboxymethyl cellulose; With water-insoluble coating material coating, behind certain hour, provide the film explosion to discharge medicine.This system has successfully realized delay pulse release, can be taken at bed time with and reach therapeutic effect morning.But; Regrettably this system is rapid at drug release after a period of time; Drug release finishes in very short time, and blood concentration fluctuation is relatively large, and for cardiovascular system diseases in the afternoon another onset peak of 3 o'clock to 6 o'clock can not play effective preventive effect.
Chinese patent 200710056948.9 discloses a kind of metoprolol salt impulse pellet preparation and preparation method thereof, and said preparation is the multiple coatings micropill, and basic structure is followed successively by 20～100mg principal agent rapid release ball core, alkaline layer, sluggish layer from inside to outside.Wherein, sluggish layer contains polyacrylic resin III, and its weightening finish is 100～240% of rapid release ball core, and alkaline layer is medicinal inorganic alkaline adjuvant, and weight is 10～30% of rapid release ball core.Said preparation also can reach administration after the rapid release of beginning that lags behind 3～4 hours the time reaches the effect that pulsatile once discharges.But because the cause that its structure is formed, still there is the influence of factors such as being subject to pH value, food in said preparation, and blood concentration fluctuation is bigger, short, the shortcomings such as dosage is wayward, complex process of holding time.
For the ordinary tablet of metoprolol, the dosage regimen of recommendation is to take medicine every day 2～3 times, and blood drug level is unstable in this scheme body, and paddy peak concentration difference is bigger, and the treatment compliance is low.
The metoprolol sustained-release sheet has improved the bigger problem of ordinary preparation blood concentration fluctuation, and lower Cmax and higher Cmin can be provided, and can reduce administration number of times, increases the compliance of patient's medication.But because the metoprolol sustained-release sheet is failed the characteristics according to the daily rhythmicity of cardiovascular disease; Provide the division of day and night pharmacology desired release curve; Promptly can not be provided at the blood drug level of the needed high concentration in cardiovascular disease incidence peak, be prone to produce toleration, lessen the curative effect.
Therefore, need to study a kind of have long-acting controlled release drug release behavior, steady, the good patient compliance of blood drug level, meet the characteristics of the morbidity daily rhythmicity of cardiovascular disease simultaneously, make medicine give full play to the novel controlled release preparation of therapeutic effect.
Summary of the invention
The present invention has overcome the deficiency of the existing preparation of metoprolol; A kind of convenient drug administration, good patient compliance are provided; Can be according to morbidity rhythmicity characteristics pulsed release, blood drug level is steady, and the metoprolol pulse osmotic pump controlled release tablet of lasting medicine and preparation method thereof.
An object of the present invention is to provide a kind of metoprolol pulse osmotic pump controlled release tablet, this controlled release tablet comprises from the inside to the outside:
The label of forming by medicated layer and boosting layer;
Time lag clothing layer; With
The controlled release clothing layer of band drug release hole;
Wherein, based on the gross weight of medicated layer, medicated layer comprises 5～65 weight %, preferred 10～60 weight %, the more preferably metoprolol as active substance of 20～50 weight %; With 35～95 weight %, preferred 40～90 weight %, the more preferably pharmaceutically acceptable carrier of 50～80 weight %;
Based on the gross weight of boosting layer, said boosting layer comprises 30～85 weight %, preferred 40～80 weight %, the more preferably extender of 45～75 weight %; With 15～70 weight %, preferred 20～60 weight %, more preferably the osmotic pressure promoter of 25～55 weight %;
Said time lag clothing layer weightening finish is 5～50 weight % of label, preferred 10～40 weight %, more preferably 15～35 weight %;
Said controlled release clothing layer weightening finish is 3～30 weight % of label, preferred 5～20 weight %, more preferably 5～15 weight %.
Said active substance with pharmacological action is metoprolol or its physiologically acceptable salt, and said physiologically acceptable salt is fumarate, tartrate and/or succinate.
Said pharmaceutically acceptable carrier is a hydrophilic high molecular material.The selection of hydrophilic high molecular material is crucial in the medicated layer, and its kind and consumption are often bigger to the release rate of drugs influence.Described hydrophilic high molecular material can be selected from one or more in hypromellose, polyoxyethylene, polyvidone, copolyvidone, sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, arabic gum and the chitin, and preferred molecular weight is one or more in 300,000 to 2,000,000 hypromellose, polyoxyethylene, polyvidone and the carbomer.
Said medicated layer can further comprise and is selected from diluent, lubricant and the coloring agent one or more.Diluent in the said medicated layer is to be selected from starch, dextrin, lactose, sucrose, sodium chloride, microcrystalline Cellulose and the mannitol one or more, and consumption is 0～20 weight % of medicated layer.Lubricant in the said medicated layer is one or more in magnesium stearate, micropowder silica gel and the Pulvis Talci, and consumption is 0～5 weight % of medicated layer, is preferably 0.1～2 weight %.Coloring agent in the said medicated layer is to be selected from iron oxide red, iron oxide yellow, iron oxide purple and the iron oxide black one or more, and its consumption is 0～5 weight % of medicated layer, is preferably 0.05～2 weight %.
The boosting layer is the required power resources of osmotic pumps drug release, and extender and osmotic pressure promoter are crucial in the said label boosting layer, the different release behaviors that change medicine of its kind and consumption.The adding of extender expands after can making boosting layer aquation, promotes the release of medicated layer medicine; Extender is to be selected from polyoxyethylene, hypromellose, hydroxypropyl cellulose, hydroxyethyl-cellulose, carbomer, sodium carboxymethyl cellulose and the sodium alginate one or more in the boosting layer of the present invention, is preferably to be selected from polyoxyethylene and the hypromellose one or both.Osmotic pressure promoter is the source of osmotic pump tablet in-core exosmosis pressure reduction, and osmotic pressure promoter being is selected from one or more in sodium chloride, potassium chloride, mannitol, sorbitol, lactose and the sucrose, is preferably sodium chloride.Said boosting layer can further comprise and is selected from lubricant and the coloring agent one or both, and based on the gross weight of boosting layer, the content of lubricant is 0～5 weight %, is preferably 0.1～2 weight %; The content of coloring agent is 0～5 weight %, is preferably 0.05～2 weight %.Identical in the optional kind of lubricant and the medicated layer.Identical in the optional kind of coloring agent and the medicated layer.
The weight ratio of said medicated layer and boosting layer is preferably between 4: 1～1: 4.
Said time lag clothing layer is wrapped in outside the label, and it is processed by one or more aqueous polymers.Said aqueous polymer is to be selected from hypromellose, hydroxypropyl cellulose, hydroxyethyl-cellulose, polyvidone, copolyvidone, polyoxyethylene and the Polyethylene Glycol one or more, is preferably to be selected from hypromellose and the polyvidone one or both.The consumption of time lag clothing layer will directly influence the length of time lag, but less to the influence of rate of release.The solvent that dissolves said aqueous high molecular material is selected from one or more of acetone, water, ethanol, isopropyl alcohol, dichloromethane, methanol and ethyl acetate.
The composition of the controlled release clothing layer of said band drug release hole comprises: filmogen and nonessential plasticizer or porogen, said drug release hole are arranged on the controlled release clothing layer that adjoins label medicated layer one side.
The filmogen that said controlled release clothing layer is comprised is to be selected from cellulose acetate, ethyl cellulose, hypromellose and the acrylic resin one or more.The solvent of being dissolved into membrane material is selected from one or more of acetone, water, ethanol, isopropyl alcohol, dichloromethane, methanol and ethyl acetate.For increasing the permeability of controlled release clothing layer to moisture; Can add porogen regulates; Described porogen is to be selected from Polyethylene Glycol, polyvidone, copolyvidone and the hydroxypropyl cellulose one or more, and its consumption is 0～50 weight % of controlled release clothing layer, is preferably 1～20 weight %; On the contrary; For reducing the permeability of controlled release clothing layer to moisture; Can add plasticizer regulates; Described plasticizer is to be selected from diethyl phthalate, triethyl citrate, dibutyl sebacate and the citroflex A-4 one or more, and its consumption is 0～20 weight % of controlled release clothing layer, is preferably 1～10 weight %.
Drug release hole on the controlled release clothing layer of said metoprolol osmotic pump controlled release tablet can adopt laser boring method or mechanical punching method to form, and its pore size is 0.2mm～1mm, preferred 0.5～0.9mm.The number of said drug release hole is preferably 1～4.
Another object of the present invention provides a kind of method for preparing of above-mentioned metoprolol pulse osmotic pump controlled release tablet, and this method may further comprise the steps:
(1) medicated layer is granulated
With medicated layer each component uniform mixing except that lubricant, add in the fluid bed and carry out wet granulation, after the intensive drying, add lubricant, mixing is as the medicated layer granule;
(2) the boosting layer is granulated
With boosting layer each component uniform mixing except that lubricant, add in the fluid bed and carry out wet granulation, after the intensive drying, add lubricant, mixing is as boosting layer granule;
(3) compacting of double-deck label
Medicated layer granule and boosting layer granule are pressed into double-deck label according to the prescription ratio; The preferred bi-layer tablet press that adopts is suppressed double-deck label.
(4) bag time lag clothing layer
Preparation time lag clothing layer coating solution carries out coating with the atomizing coating method to double-deck label, to predetermined coating weightening finish;
(5) bag controlled release clothing layer
Preparation controlled release clothing layer coating solution is being enclosed with the double-layer tablet outsourcing controlled release clothing layer of time lag clothing with the atomizing coating method, to predetermined coating weightening finish; With
(6) punching
Drilling on the controlled release clothing layer of coated tablet is preferably made 1～4 hole adjoining on the controlled release clothing layer of medicated layer one side, and more preferably this hole is in the central authorities of controlled release clothing layer; Preferred machine drilling method or the laser drilling method of adopting.
It should be appreciated by those skilled in the art; The term that uses among the present invention " medicated layer ", " boosting layer ", " time lag clothing layer ", " controlled release clothing layer " both can represent to prepare the mixture of controlled release tablet each respective components before; Also can represent to process the afterwards corresponding each several part of controlled release tablet, generally adopting above term only is for the convenience on describing.
The present invention is based on the basis of chronopharmacology principle, fully uses osmotic pump controlled-releasing technology and pulsed release technology to be prepared from.This preparation is a release power with the permeable pressure head inside and outside the controlled release clothing layer, can in the certain hour scope, discharge active constituents of medicine with predetermined rate of releasing drug, takes once in one day, can satisfy patient's medication demand, realizes long-acting controlled release; Adjusting through to these article contagion gown film prescription and consumption has realized the commutator pulse release, and the release medicine of promptly under the minimum sleep state of blood pressure, trying one's best few makes blood pressure be unlikely to low, and a spot of blood drug level can prevent anginal outbreak of late night to morning; And when early morning WA blood drug level reach the peak, effectively control the rising of back blood pressure of waking up early morning, thereby let blood drug level and blood pressure keep synchronous; Simultaneously, these article blood drug level in the morning reach the angina pectoris attacks peak that 6am～12am in morning can also be effectively controlled at the peak, thereby reach the optimization curative effect, reduce the purpose of side effect.Particularly; Metoprolol pulse osmotic pump controlled release tablet of the present invention has unique syllogic drug release behavior, and these article release initial stage has 2～5 hours time lag; Appear mid-term and increase progressively release (2～4 hours), the later stage has the characteristics (6～12 hours) of constant speed release medicine.The characteristic of this drug release of described metoprolol pulsatile release tablets can make the curative effect of active medicine metoprolol fully played; The usefulness thereby the assurance patient can be taken at bed time evening; Through 2～5 hours (time demurrage), before m seq paradoxical sleep phase angina pectoris was prone to the outbreak dangerous periods and arrives, beginning discharged effective dose of medicine thing (accelerated period) with the rate of release that increases progressively; Thereby guarantee that medicine can reach effective treatment concentration, quick acting; After reaching effective treatment concentration, can keep in a long time and discharge medicine (constant speed phase) reposefully; The drug release behavior of these article can make the occurrence regularity of drug treating time and disease be consistent; Make angina pectoris and hyperpietic's degree of safety spend the stage occurred frequently of cardiovascular disease; Not only can reduce since night the cardiovascular and cerebrovascular diseases such as apoplexy that hypopiesia causes incidence rate, and can effectively prevent the seizure of disease of morning 6～12 and afternoon 3～6 again.Based on the unique release behavior of these article, remedied the shortcoming of ordinary preparation and conventional sustained-release, realized timing, pulsed release, more accurately satisfy the clinical needs of patients with coronary heart disease treatment, improve patient's compliance.Therefore, these article of general overview have the advantage of following several respects:
(1) the drug release behavior of special syllogic realizes the division of day and night therapeutic characteristics of these article.Characteristics of incidence according to cardiovascular disease such as hypertension, angina pectoriss; The usefulness that is taken at bed time, the time lag after date through certain hour presents the rate of releasing drug that increases progressively mid-term; Can make the medicine quick acting; Thereby sleeping back paradoxical sleep phase angina pectoris is prone to the outbreak dangerous periods timely treatment is provided, the persistent period of effective blood drug concentration covers patients with coronary heart disease and is prone to the outbreak period, thereby improves the curative effect of metoprolol more accurately, effectively.
(2) few, the lasting medicine of administration number of times.Be administered once just before going to bed every night, can satisfy patient's medication demand, reduced administration number of times, improved patient's compliance.
(3) blood drug level is steady, untoward reaction is few.The drug release behavior that these article are special can obviously reduce untoward reaction such as dizziness that blood medicine fluctuation causes greatly, vomiting, is suitable for hypertension, patient with angina pectoris life-time service.
(4) good inside and outside dependency.The release of these article medicine does not receive the influence of factors such as media environment pH value, gastrointestinal peristalsis and food, has inside and outside dependency preferably.
Description of drawings
Fig. 1 metoprolol pulse of the present invention osmotic pump controlled release tablet cumulative release curve chart;
Fig. 2 is according to the rate of release block diagram of the metoprolol pulse osmotic pump controlled release tablet of the embodiment of the invention 4 preparations;
The average rate of release block diagram of the commercially available metoprolol sustained-release sheet of Fig. 3 (metoprolol);
Fig. 4 is according to the cumulative release curve chart of metoprolol pulse osmotic pump controlled release tablet in four kinds of different mediums of the embodiment of the invention 4 preparations;
Fig. 5 according to the metoprolol pulse osmotic pump controlled release tablet of the embodiment of the invention 4 preparation on the feed with the empty stomach situation under the cumulative release curve.
The specific embodiment
Below illustrate metoprolol osmotic pump controlled release tablet of the present invention and preparation method thereof through concrete embodiment, but be not limited only to following examples.
Prescription: (1000 amounts)
Medicated layer:
The boosting layer:
Time lag clothing layer:
Controlled release clothing layer:
Method for preparing:
(1) pretreatment is crossed 80 mesh sieves respectively with each component of raw material, and is subsequent use;
(2) the medicated layer preparation of granules is according to embodiment 1 prescription, and each component of medicated layer (except that magnesium stearate) is adopted the equivalent method mix homogeneously that progressively increases, and adds fluid bed, sprays into 95% ethanol water granulation; After the intensive drying, cross 20 mesh sieves, granulate then, adds the magnesium stearate mixing, and is as the medicated layer granule, subsequent use;
(3) boosting layer preparation of granules according to the recipe quantity mix homogeneously, adds fluid bed with each component of boosting layer (except that magnesium stearate) according to embodiment 1 prescription, sprays into 95% ethanol water granulation; After the intensive drying, cross 20 mesh sieves, granulate; Add the magnesium stearate mixing, as boosting layer granule, subsequent use;
(4) double-deck label preparation is adopted bi-layer tablet press with the medicated layer granule for preparing, boosting layer granule, is pressed into double-deck label, and is subsequent use;
(5) preparation of time lag clothing layer adopts the high-efficiency coating pot to double-deck label bag time lag clothing according to prescription preparation time lag clothing coating solution, the label behind the coating under 45 ℃ of conditions, dry 2h, subsequent use;
(6) preparation of controlled release clothing layer adopts the high-efficiency coating pot being enclosed with the double-layer tablet outsourcing controlled release clothing of time lag clothing according to prescription preparation controlled release clothing coating solution, the label behind the coating under 45 ℃ of conditions, dry 2h, subsequent use;
(7) machine drilling method or laser drilling method are adopted in the punching of coated tablet, 1 drug release hole that the aperture is 0.8mm of preparation on the semipermeable membrane of medicated layer one side of coated tablet.
Drug release determination: get these article,, adopt dissolution method (two appendix XC second methods of Chinese Pharmacopoeia version in 2005) device according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2005); Release medium is the phosphate buffer 500ml of pH6.8; Rotating speed 50rpm, 37 ± 0.5 ℃ of temperature, operation in accordance with the law; Respectively at getting solution 8ml in 1,2,3,4,5,6,7,8,10,12,14,16,18,20 hour; It is centrifugal that (8000rpm 15min), replenishes the release medium of uniform temp, equal volume simultaneously.It is an amount of that other gets the spectinomycin hydrochloride reference substance, with the phosphate buffer of pH6.8, is mixed with the solution that contains spectinomycin hydrochloride 60mg in every ml soln, as reference substance solution; It is an amount of to get above-mentioned reference substance and need testing solution respectively, adopts ultraviolet visible spectrophotometry, measures absorbance respectively in the 278nm wavelength; Calculate every cumulative release amount by external standard method at different time.
The result sees Fig. 1, and drug release has 2.5 hours time lag, and increasing progressively drug release time is 2 hours, nearly 7.5 hours of the persistent period of constant speed release medicine.
Prescription: (1000 amounts)
Medicated layer:
The boosting layer:
Time lag clothing layer:
Controlled release clothing layer:
Method for preparing: except time lag clothing layer and controlled release clothing layer according to embodiment 2 prescriptions, method for preparing is with embodiment 1.
Drug release determination method: with embodiment 1.
The result sees Fig. 1, and drug release has about 4 hours time lag, increases progressively drug release time and is about 3 hours, and the constant speed release medicine persistent period is 9 hours.
Prescription: (1000 amounts)
Medicated layer:
The boosting layer:
Time lag clothing layer:
Controlled release clothing layer:
Drug release determination method: with embodiment 1.
The result sees Fig. 1, and drug release has 2 hours time lag, and increasing progressively drug release time is 2 hours, and the constant speed release medicine persistent period is 8 hours.
Prescription: (1000 amounts)
Medicated layer:
The boosting layer:
Time lag clothing layer:
Controlled release clothing layer:
Method for preparing: except prescription was formed difference, method for preparing was with embodiment 1.
Drug release determination method: with embodiment 1.
The result sees Fig. 1, and drug release has 3 hours time lag, and increasing progressively drug release time is 2.5 hours, and the constant speed release medicine persistent period is 9.5 hours.
Prescription: (1000 amounts)
Medicated layer:
The boosting layer:
Time lag clothing layer:
Controlled release clothing layer:
Method for preparing: except prescription was formed difference, method for preparing was with embodiment 1.
Drug release determination method: with embodiment 1.
The result sees Fig. 1, and drug release has about 4 hours time lag, and increasing progressively drug release time is about 3 hours, and the constant speed release medicine persistent period is about 9 hours.
Prescription: (1000 amounts)
Medicated layer:
The boosting layer:
Time lag clothing layer:
Controlled release clothing layer:
Method for preparing: except prescription was formed difference, method for preparing was with embodiment 1.
Drug release determination method: with embodiment 1.
The result sees Fig. 1, and drug release has about 5 hours time lag, and increasing progressively drug release time is 2 hours, and the constant speed release medicine persistent period is 10 hours.
EXPERIMENTAL EXAMPLE 1:
Measure preparation of the present invention and commercially available metoprolol sustained-release sheet (metoprolol) release degree according to the drug release determination method of embodiment 1 at each time point; Through calculating; Average rate of release and time with metoprolol map, and the average rate of release block diagram of embodiment 4 and commercially available metoprolol sustained-release sheet (metoprolol) is seen Fig. 2,3 respectively.The medicine average release profiles figure of comparison diagram 2, Fig. 3; Be surprised to find; Metoprolol pulse osmotic pump controlled release tablet according to the present invention is with respect to commercially available metoprolol sustained-release sheet, has comparatively significantly syllogic drug release behavior: patient's usefulness that can be taken at bed time evening, through 2～5 hours (time demurrage); Before m seq paradoxical sleep phase angina pectoris is prone to the arrival of outbreak dangerous periods; Beginning discharges effective dose of medicine thing (accelerated period) with the rate of release that increases progressively, thereby guarantees that medicine can reach effective treatment concentration, quick acting; After reaching effective treatment concentration, can keep in a long time and discharge medicine (constant speed phase) reposefully, the medicine average rate of release is more steady, can reduce the fluctuation of blood drug level, reduces the incidence rate of adverse effect.The special release behavior of these article has been realized regularly, pulsed release, can more accurately satisfy the clinical needs of patients with coronary heart disease treatment, has improved safety, finiteness and compliance that the patient uses.
In the present invention, (Radio Factory of Tianjin Univ. makes, model: the drug release characteristics (except that release medium, assay method is with embodiment 1) of RCZ-8B) measuring preparation of the present invention to adopt the drug release determination device.Selecting the release medium of 4 kinds of different pH value to simulate intravital gastrointestinal tract environment, is the situation that influences (result sees Fig. 4) that drug release characteristics that example is estimated this preparation receives release medium with the preparation of embodiment 4.By visible among Fig. 4, the preparation of embodiment 4 discharges medicine according to predetermined rate of release in the release medium of four kinds of different pH value, and release characteristic receives the influence of medium very little.
Simultaneously, being the further drug release situation difference of these article of research under empty stomach and feed condition, is example with the preparation of embodiment 4, according to following release medium the food effect situation of these article has been carried out estimating (except that release medium, assay method is with embodiment 1).
Visible by Fig. 5; The preparation of embodiment 4 is in simulated intestinal fluid, and evident difference is not all seen in the release of medicine under empty stomach and the feed condition, can predict these article in clinical use; Also can discharge medicine, for the patient provides more steady, persistent curative effect according to predetermined release characteristic.
Claims (8)
1. metoprolol pulse osmotic pump controlled release tablet, this controlled release tablet comprises from the inside to the outside:
By the double-deck label that medicated layer and boosting layer are formed, the weight ratio of wherein said medicated layer and boosting layer is between 4: 1～1: 4;
Time lag clothing layer; With
The controlled release clothing layer of band drug release hole;
Wherein,
Based on the gross weight of medicated layer, said medicated layer comprise 5～65 weight % as the metoprolol of active substance and the pharmaceutically acceptable carrier of 35～95 weight %;
Based on the gross weight of boosting layer, said boosting layer comprises the osmotic pressure promoter of extender and 15～70 weight % of 30～85 weight %;
Said time lag clothing layer weightening finish is 5～50 weight % of label;
Said controlled release clothing layer weightening finish is 3～30 weight % of label;
Wherein, Said metoprolol as active substance is metoprolol or its physiologically acceptable salt, and said pharmaceutically acceptable carrier is one or more hydrophilic high molecular materials that are selected from hypromellose, polyoxyethylene, polyvidone, copolyvidone, sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, arabic gum and the chitin;
Said extender is to be selected from polyoxyethylene, hypromellose, hydroxypropyl cellulose, hydroxyethyl-cellulose, carbomer, sodium carboxymethyl cellulose and the sodium alginate one or more, and said osmotic pressure promoter being is selected from one or more in sodium chloride, potassium chloride, mannitol, sorbitol, lactose and the sucrose;
Said time lag clothing layer is processed by one or more aqueous polymers that are selected from hypromellose, hydroxypropyl cellulose, hydroxyethyl-cellulose, polyvidone, copolyvidone, polyoxyethylene and the Polyethylene Glycol;
Said controlled release clothing layer comprises filmogen, and said filmogen is to be selected from cellulose acetate, ethyl cellulose, hypromellose and the acrylic resin one or more.
2. metoprolol pulse osmotic pump controlled release tablet according to claim 1, wherein,
The physiologically acceptable salt of said metoprolol is fumarate, tartrate or succinate, and said pharmaceutically acceptable carrier is that to be selected from molecular weight be in 300,000 to 2,000,000 hypromellose, polyoxyethylene, polyvidone and the carbomer one or more;
Said extender is selected from one or both in polyoxyethylene and the hypromellose, and said osmotic pressure promoter is sodium chloride;
Said time lag clothing layer is processed by one or both aqueous polymers that are selected from hypromellose and the polyvidone.
3. metoprolol pulse osmotic pump controlled release tablet according to claim 1 and 2, wherein, said medicated layer further comprises and is selected from diluent, lubricant and the coloring agent one or more,
Said diluent is to be selected from starch, dextrin, lactose, sucrose, sodium chloride, microcrystalline Cellulose and the mannitol one or more;
Said lubricant is to be selected from magnesium stearate, micropowder silica gel and the Pulvis Talci one or more;
Said coloring agent is to be selected from iron oxide red, iron oxide yellow, iron oxide purple and the iron oxide black one or more.
4. metoprolol pulse osmotic pump controlled release tablet according to claim 1 and 2, wherein, said boosting layer further comprises and is selected from lubricant and the coloring agent one or both,
Said lubricant is to be selected from magnesium stearate, micropowder silica gel and the Pulvis Talci one or more;
Said coloring agent is to be selected from iron oxide red, iron oxide yellow, iron oxide purple and the iron oxide black one or more.
5. metoprolol pulse osmotic pump controlled release tablet according to claim 1, wherein, said controlled release clothing layer further comprises plasticizer or porogen,
Said plasticizer is to be selected from diethyl phthalate, triethyl citrate, dibutyl sebacate and the citroflex A-4 one or more;
Said porogen is to be selected from Polyethylene Glycol, polyvidone, copolyvidone and the hydroxypropyl cellulose one or more.
6. metoprolol pulse osmotic pump controlled release tablet according to claim 5, wherein, said plasticizer dosage is 0～20 weight % of controlled release clothing layer; The consumption of said porogen is 0～50 weight % of controlled release clothing layer.
7. metoprolol pulse osmotic pump controlled release tablet according to claim 1 and 2, wherein, the drug release hole on the said controlled release clothing layer is being adjoined on the controlled release clothing layer of medicated layer one side, and its number is 1～4, and the aperture is 0.2mm～1mm.
8. method for preparing each described metoprolol pulse osmotic pump controlled release tablet in the claim 1～7, this method comprises the steps:
(1) medicated layer is granulated;
(2) the boosting layer is granulated;
(3) compacting of double-deck label;
(4) bag time lag clothing layer;
(5) bag controlled release clothing layer; With
(6) punching.
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| CN102144987B (en) * | 2011-04-19 | 2013-01-16 | 暨南大学 | Metoprolol oral pulsatile tablet and preparation method and application of metoprolol oral pulsatile tablet |
| CN102525986A (en) * | 2012-02-01 | 2012-07-04 | 齐齐哈尔医学院 | Osmotic pump controlled release tablet |
| CN114053237A (en) * | 2020-07-30 | 2022-02-18 | 上海汉都医药科技有限公司 | Controlled release tablet and preparation method thereof |
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| CN101269056A (en) * | 2007-03-19 | 2008-09-24 | 天津药物研究院 | Metoprolol salt oral administration impulse pellet preparation |
| CN101516356A (en) * | 2006-02-24 | 2009-08-26 | 特瓦制药工业有限公司 | Metoprolol succinate e.r. tablets and methods for their preparation |
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| CN101516356A (en) * | 2006-02-24 | 2009-08-26 | 特瓦制药工业有限公司 | Metoprolol succinate e.r. tablets and methods for their preparation |
| CN101269056A (en) * | 2007-03-19 | 2008-09-24 | 天津药物研究院 | Metoprolol salt oral administration impulse pellet preparation |
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