CN102614130B - Carvedilol sulfate sustained release preparation - Google Patents
Carvedilol sulfate sustained release preparation Download PDFInfo
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- CN102614130B CN102614130B CN201110033149.6A CN201110033149A CN102614130B CN 102614130 B CN102614130 B CN 102614130B CN 201110033149 A CN201110033149 A CN 201110033149A CN 102614130 B CN102614130 B CN 102614130B
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Abstract
The invention relates to a carvedilol sulfate sustained-release preparation, especially relates to carvedilol sulfate sustained-release pellets and a controlled-release preparation containing the sustained-release pellets. The preparation contains the sustained-release pellets and quick-release pellets, and can contain enteric pellets. The sustained-release pellets start the release of medicine in a solution environment with the pH of 1.0 or above, and the release effect is good.
Description
Technical field
The present invention relates to a kind of controlled release preparation of carvedilol sulfate, especially contain the capsule of the micropill composition that active component disengaged by control, be used for the treatment of cardiovascular disease, comprise hypertension, congestive heart failure, atherosclerosis and angina pectoris.
Background technology
Carvedilol (Carvedilol, Car) is a kind of to β
1aryl ethanolamines (arylethanolamine) B-adrenergic receptor (hereinafter to be referred as beta-receptor) antagonist optionally a little less than-adrenoreceptor has.It is disclosed in the US Patent No. 4503067 of Wiedemann etc., chemistry (±) 1-(9H-carbazole-4-base oxygen base)-3-[[2-(2-methoxyphenoxy) ethyl by name] amino]-2-propanol, structural formula is
It also has α 1 receptor retardation concurrently, without intrinsic sympathomimetic acitivity.This double pharmacological action can make carvedilol there is no to expand merely blood vessel or beta-receptor to block the side reaction (as reflex tachycardia and peripheral vascular resistance) bringing.Generally the impact of the heart rate on healthy volunteer or cardiac index is seldom or not impact for it, be the 3rd generation beta-receptor blockader a kind of new product, developed by Smithkline Beecham company of the U.S., become at present the highest beta-blocker of chronic heart failure evaluation both at home and abroad.Compared with similar drugs metoprolol, this product total effective rate is high and occur that heart failure increases the weight of and atrioventricular block number of cases (AVB) is low.When this product treatment exercise induced hypertension, cardiac output can reduce.Compare with metoprolol with propranolol, this product seldom has impact to tranquillization or exercise induced hypertension patient's heart rate.
Carvedilol contains Alpha-hydroxy secondary amine functional groups, pKa value is 7.8, dissolubility relatively low (< 1 μ g/ml), when pH value reduces, carvedilol dissolubility improves, near pH=5, reach stationary value, at room temperature saturation solubility is about 23 μ g/ml in the time of pH=7, is about 100 μ g/ml at pH=5.Some salt and/or the novel crystal forms of carvedilol have larger water solublity, chemical stability etc., can absorb the whole body system levels of drugs that has obtained expection or extended by maintaining gastrointestinal, the pH value that particularly maintains drug solubility minimum obtains the absorption of neutral region.The free radical form of carvedilol is the racemic mixture of R (+) and R (-) enantiomer, wherein R (-) mapping body surface shape is located non-selective β-adrenoreceptor retardance, and R (+) and R (-) enantiomer all show α-adrenoreceptor and can obtain blocking activity.The abnormal feature that these are relevant with raceme carvedilol mixture or characteristic are because two kinds of supplementary pharmacological actions: the non-heart selectivity β-adrenoreceptor of mixed venous and arteries expansion can block.Therefore, develop the carvedilol salt that a kind of result of use is good, it is also significant making it have higher water solublity, chemical stability/maintain or prolong drug level or absorption level (as in gastrointestinal pH neutral region etc.) with respect to carvedilol base.Phosphate, the mesylate of having reported at present carvedilol, for example International Application No. WO 2004002419 specifically discloses the phosphate of carvedilol.
International Application No. WO 2005051322 discloses the slow releasing preparation of carvedilol and salt thereof, said preparation contains three kinds of micropills, be respectively fast release micropill and two kinds of controlled release micro pills, fast release micropill discharges medicine by time-dependent, just entering after gastrointestinal tract can rapid delivery of pharmaceuticals, two kinds of controlled release micro pills are relied on and are discharged medicine by pH, and wherein the first controlled release micro pill starts to discharge medicine in pH5.5 medium, and the second controlled release micro pill starts to discharge medicine in pH6.4 medium.Compared with the conventional tablet of carvedilol free radical form, sustained-release pellet preparation has reduced medicining times, has improved patient's compliance.GSK company listing medicine Coreg CR (Carvedilol PhosphateExtended-release Capsules, phosphoric acid carvedilol slow releasing capsule) be on the basis of International Application No. WO 2005051322 disclosed slow release methods, the concrete pharmaceutical preparation of the carvedilol phosphate salts of implementing, this medicine has obtained U.S. FDA approval at present, for the treatment of three kinds of cardiovascular disease: left ventricular insufficiency and mild to moderate heart failure after hypertension, myocardial infarction, be mainly used in the treatment of essential hypertension and congestive heart failure at present.
Summary of the invention
Develop a kind of novel carvedilol slow releasing preparation, it is significant controlling medicine continuous release from sour environment to neutral environment in gastrointestinal tract.The present invention is directed to carvedilol sulfate analog a kind of reasonable slow releasing preparation is provided.
Alleged " the carvedilol sulfate analog " of the present invention all refers to one or more in carvedilol sulfate or its hydrate.
The Carbediolo controlled release formulation that International Application No. WO 2005051322 provides comprises three parts, is respectively fast release micropill part, the first controlled release micro pill part and the second controlled release micro pill part, and its medicament contg ratio is 1: 3: 4.Fast release micropill discharges medicine by time-dependent, just entering after gastrointestinal tract can rapid delivery of pharmaceuticals, two kinds of controlled release micro pills discharge medicine by relying on by pH completely, in the time that preparation is transported to environment pH value and is 5.5 in gastrointestinal tract, the first controlled release micro pill starts to discharge medicine, in the time that preparation is transported to environment pH value and is 6.4 in gastrointestinal tract, the second controlled release micro pill starts to discharge medicine, therefore the drug release characteristics of this controlled release preparation is equivalent to three kinds of micropills different time points pulse release cumulative in the time that gastrointestinal tract is transported, when this drug release characteristics has also caused medicine, curve presents a diphasic curve model, there are two peak concentrations, there is first peak concentration at 1～3 hour, there is second peak concentration at 5～10 hours.And after utilizing this patented method to prepare the slow releasing preparation of carvedilol sulfate, find, the method is bad to the controlled-release effect of carvedilol sulfate, and release in vitro exists obvious difference, is difficult to meet the demands.
Research worker has been carried out a large amount of experiments to carvedilol slow releasing preparation, surprisingly find that the micropill in a kind of and International Application No. WO 2005051322 has the slow-release micro-pill of diverse release in vitro feature, described slow-release micro-pill just starts to discharge under the condition of gastrointestinal tract pH 1.0.Slow releasing preparation Chinese medicine provided by the invention is distributed in rapid release and two kinds of micropills of slow release, control the medicament contg ratio 1 of fast release micropill part and slow-release micro-pill part: 5-9, preferably 1: 5.5-8.5, preferably 1: 7, wherein fast release micropill discharges medicine by time-dependent, ensures to enter gastrointestinal tract rapid delivery of pharmaceuticals; Slow-release micro-pill relies on release medicine jointly by time and pH, starts to delay Slow release in the environment of gastrointestinal tract pH1.0.By the Overlay containing drug ratios and slow releasing pharmaceutical micropill and fast release micropill of two kinds of micropills, reach the effect that good control discharges, the slow releasing preparation consisting of these two kinds of micropills has obvious prescription, the simple advantage of technique than three kinds of micropills in International Application No. WO 2005051322, save production cost, solve the defect of two peak concentrations of WO2005051322 slow releasing preparation, and can reach the good result of controlling sustained release completely.
In slow releasing preparation of the present invention, also can add a small amount of enteric coated micropill more optimizes the effect in whole release later stage.Therefore, the slow releasing preparation relating in this patent can also be controlled by the micropill of three kinds of different release characteristics, respectively fast release micropill, enteric coated micropill and slow-release micro-pill, control fast release micropill part: slow-release micro-pill part: the medicament contg ratio 0.9-1.1 of enteric coated micropill part: 6-10: 0.9-1.1, preferably 1: 6-8: 1, preferably 1: 8: 1.After drug administration, first fast release micropill discharges medicine by time-dependent, enters gastrointestinal tract rapid delivery of pharmaceuticals; Meanwhile, slow-release micro-pill relies on release medicine jointly by time and pH, and slow Slow release in the surrounding medium of gastrointestinal tract pH1.0, with the releasing effect of fast release micropill co-controlling medicine; Enteric coated micropill is relied on and is discharged medicine by pH, in gastrointestinal tract pH5.5 medium, starts to discharge medicine, optimizes later stage releasing effect.The drug release characteristic of slow releasing preparation involved in the present invention depends primarily on the drug release behavior after slow-release micro-pill and fast release micropill combination, enteric coated micropill just plays certain micro adjusting effect to the drug release feature of this slow releasing preparation, but enteric coated micropill can more be optimized the later stage releasing effect of medicine.
In slow releasing preparation, only contain fast release micropill and slow-release micro-pill and when the enteric coated micropill, the content of dispersion of fast release micropill part is accumulated dose 10%～20%, and it is accumulated dose 80%～90% that slow release is released the content of dispersion of micropill part.When slow releasing preparation contains fast release micropill, slow-release micro-pill and three kinds of micropills of enteric coated micropill, wherein the content of dispersion of fast release micropill part is accumulated dose 10%～15%, the content of dispersion of enteric coated micropill part is 10%～15% of accumulated dose, and it is accumulated dose 70%～80% that slow release is released the content of dispersion of micropill part; The medicament contg of fast release micropill part, enteric coated micropill part and slow-release micro-pill part is 0.9-7.2mg: 0.9-7.2mg: 7-58mg.
Slow-release micro-pill in slow releasing preparation involved in the present invention just starts slow Slow release in the surrounding medium of gastrointestinal tract pH1.0, wherein first 2 hours drug mains only discharge a small amount of medicine under one's belt time, mainly discharge medicine by fast release micropill part during this period of time, in the time that medicine enters intestinal, slow-release micro-pill continues to discharge medicine, reaches the releasing effect of controlling whole slow releasing preparation.If contain enteric coated micropill, enteric coated micropill reaches at 5.5 o'clock at environment pH and starts to discharge medicine, finely tunes.Micropill combination of the present invention makes this carvedilol sulfate slow releasing preparation can make blood drug level maintain a higher level at the release initial stage, along with slow-release micro-pill continues to transport in intestinal, the release medicine that this slow-release micro-pill continues too, thereby ensure that carvedilol sulfate slow releasing preparation of the present invention can discharge medicine all the time between whole gastrointestinal tract transit period, and the steady release that relatively keeps medicine, thereby make carvedilol sulfate slow releasing preparation involved in the present invention extend blood drug level level in body than quick releasing formulation, curve while presenting in vivo a level and smooth medicine, reach peak concentration at 2～7h, and after taking medicine, 24h blood drug level level and conventional carvedilol are taken once every 12h, 2 times on the one, after taking medicine, after 24h, blood drug level is on close level, area under the drug-time curve (AUC) is taken once every 12h with conventional carvedilol, the area under the drug-time curve (AUC) of 2 times on the one is suitable.And the difference of carvedilol sulfate slow releasing preparation involved in the present invention curve while having caused medicine due to the difference of micropill release characteristic only occurred a peak concentration at 2～7 hours, when medicine, curve is more steady, has more embodied the advantage of slow releasing preparation.
Slow-release micro-pill
Core of the present invention is just that research obtains a kind of slow-release micro-pill that meets certain release request, and by using this slow-release micro-pill and fast release micropill combination to obtain the slow releasing preparation that releasing effect is good.
Slow-release micro-pill of the present invention comprises the ball heart, medicated layer and slow release layer three parts, optionally contains sealing coat.Drug-loaded layer is wrapped in outside the ball heart, and slow release layer is wrapped in outside drug-loaded layer, between drug-loaded layer and the ball heart, optionally contain sealing coat between drug-loaded layer and slow release layer.Drug-loaded layer contains carvedilol sulfate anhydride or solvate, optionally contains acceptable adjuvant on binding agent, solubilizing agent, sweller or other preparations, and the main purpose of this one deck is to meet carrying medicament.
Concrete slow-release micro-pill of the present invention contains drug-loaded layer and slow release layer, and described drug-loaded layer contains carvedilol sulfate analog, and carvedilol sulfate analog is selected from one or more in carvedilol sulfate or carvedilol sulfate hydrate.Specifically can be carvedilol sulfate monohydrate.Carvedilol sulfate analog is in carvedilol sulfate, and its content is 7-72mg.
Described slow release layer makes this slow-release micro-pill discharge 0-30% carvedilol sulfate 1 hour time in pH1.0 medium, discharges 25%～90% carvedilol sulfate in the time of 8 hours, in the time of 24 hours, discharges and is greater than 75% carvedilol sulfate; Preferably this slow-release micro-pill discharges 0-10% carvedilol sulfate 1 hour time in pH1.0 medium, discharges 35%～70% carvedilol sulfate in the time of 8 hours, in the time of 24 hours, discharges and is greater than 85% carvedilol sulfate.Those skilled in the art can select the conventional film forming macromolecular material that uses, and need only and finally ensure that medicine meets above-mentioned releasing effect and can reach the effect that whole slow releasing preparation control discharges, more accurate in order to control releasing trend.In slow release layer, contain two class film property polymer, first kind polymer has been the molten polymer dissolving at pH5-6 and under the condition higher than this pH, Equations of The Second Kind polymer has been that molten point is pH6.5-7.5 and the polymer dissolving under the condition higher than this pH or water-insoluble polymer, with the total weight of first kind polymer and Equations of The Second Kind polymer, first kind polymer proportion is greater than Equations of The Second Kind polymer proportion.
First kind polymer is selected from one or more: acrylic resin base polymer or cellulose derivative, be preferably selected from Eudragit L100-55, Eudragit L100, Acrycoat L100D, CAP (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS, L-type or M type); Described Equations of The Second Kind polymer is selected from one or more: acrylic resin base polymer or cellulose derivative, be preferably selected from Eudragit S100, Eudragit RL, Eudragit RS, Acrycoa S100, hydroxypropyl methylcellulose acetate succinate (HPMCAS, H type), carboxymethylethylcellulose (CMEC) or ethyl cellulose (EC).
Found through experiments, if select suitable plasticizers can make the releasing effect of slow-release micro-pill better, therefore good embodiment as a comparison, contains one or more plasticizers in slow release layer.Find by more multiple plasticizer, Oleum Ricini is particularly suitable for the present invention, and effect is best; In addition find that triethyl citrate, diethyl phthalate also can be used for the present invention.The weight ratio of plasticizer in slow release layer is 25-50%, preferably 30～50%, most preferably 35～40%.
With first and second base polymer and the total restatement of plasticizer, it is 20～50% that described first kind polymer accounts for three's gross weight ratio, is preferably 30～40%; It is 10～30% that Equations of The Second Kind polymer accounts for three's gross weight ratio, preferably 20～35%.
Two class film property polymer in the slow release layer of slow-release micro-pill can be all acrylic resin base polymers, preferably contain methacrylic acid copolymer C type (Eudragit L100-55) and methacrylic acid copolymer Type B (Eudragit S100), most preferably film forming polymer is two kinds of methacrylic acid copolymer C type (Eudragit L100-55) and methacrylic acid copolymer Type Bs (Eudragit S100), , the weight ratio of wherein said methacrylic acid copolymer C type (Eudragit L100-55) in slow release layer is 30～45%, the weight ratio of methacrylic acid copolymer Type B (Eudragit S100) in slow release layer is 20～30%.
As preferred forms, in slow release layer, contain methacrylic acid copolymer C type (EudragitL100-55), methacrylic acid copolymer Type B (Eudragit S100) and Oleum Ricini, with their total restatement, methacrylic acid copolymer C type (Eudragit L100-55) is 30～40%, methacrylic acid copolymer Type B (Eudragit S100) is 20～30%, and Oleum Ricini is 30～40%.
Drug-loaded layer can be implemented according to conventional embodiment, and one or more that for example use binding agent, sweller, solubilizing agent make drug loading at ball in the heart, and the reasonable detailed description of the invention of effect is that binding agent is polyvidon; Or/and sweller is cross-linked pvp; Or/and solubilizing agent is selected from as one or more in PLURONICS F87 (Lutrol F 68), polyoxyethylene hydrogenated Oleum Ricini (CremophorRH 40) or Solutol HS15 (Solutol HS 15).
Fast release micropill
Fast release micropill of the present invention comprises the ball heart, drug-loaded layer, optionally contains sealing coat, and drug-loaded layer is wrapped in outside the ball heart, between drug-loaded layer and the ball heart or outside drug-loaded layer, can also increase by a sealing coat.Drug-loaded layer contains carvedilol sulfate anhydride or solvate.Drug-loaded layer can have one or more in binding agent, sweller, solubilizing agent, preferably contains three kinds of compositions simultaneously.Reasonable embodiment is that binding agent is polyvidon (PVP), sweller is cross-linked pvp (CPVP), and solubilizing agent is selected from one or more in PLURONICS F87 (Lutrol F68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40) or Solutol HS15 (Solutol HS 15).
Enteric coated micropill
Although slow releasing preparation of the present invention is as long as just can reach by fast release micropill and two kinds of micropill combinations of slow-release micro-pill the effect that good control discharges.If but the releasing effect in order more to optimize can add enteric coated micropill again the later stage of its release is carried out to small adjustment
Enteric coated micropill comprises the ball heart, medicated layer and enteric layer three parts, optionally contains sealing coat.Drug-loaded layer is wrapped in outside the ball heart, and enteric layer is wrapped in outside drug-loaded layer, between drug-loaded layer and the ball heart, optionally contain sealing coat between drug-loaded layer and enteric layer.Drug-loaded layer contains carvedilol sulfate anhydride or solvate.Can contain one or more in binding agent, sweller, solubilizing agent.Preferred adhesive is polyvidon (PVP), sweller is cross-linked pvp (CPVP), and solubilizing agent is selected from one or more in PLURONICS F87 (Lutrol F 68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40) or Solutol HS15 (Solutol HS 15).
In enteric layer, at least contain a kind of enteric solubility film property polymer, preferably enteric layer contains plasticizer.Wherein film property high molecular polymer is the conventional enteric macromolecular material using in this area, and this enteric macromolecular material ensures that micropill starts to discharge medicine in intestinal.Enteric solubility film property polymer is selected from the enteric material of this area routine, for example, in Eudragit L100-55, EudragitL100, Eudragit S100, Acrycoat L100D, Acrycoa S100, CAP (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC) or Lac one or more.Plasticizer is selected from one or more in triethyl citrate, Oleum Ricini, Polyethylene Glycol or diethyl phthalate.Specifically can adopt methacrylic acid copolymer C type (Eudragit L100-55) as enteric filmogen polymer, triethyl citrate and/or Oleum Ricini are as plasticizer.
Slow releasing preparation
Slow releasing preparation can be made up of fast release micropill and two kinds of micropills of slow-release micro-pill, and the content of dispersion of fast release micropill part is accumulated dose 10%～20%, and it is accumulated dose 80%～90% that slow release is released the content of dispersion of micropill part.
In the time that slow releasing preparation is made up of fast release micropill, enteric coated micropill and three kinds of micropills of slow-release micro-pill, the content of dispersion of fast release micropill part is 10%～15% of accumulated dose, the content of dispersion of enteric coated micropill part is 10%～15% of accumulated dose, and it is accumulated dose 70%～80% that slow release is released the content of dispersion of micropill part.
When carvedilol sulfate slow releasing preparation of the present invention only contains fast release micropill and two kinds of micropills of slow-release micro-pill, it is that 1.1mg is to 9mg that fast release micropill part contains carvedilol sulfate; It is that 7.8mg is to 63mg that slow-release micro-pill contains carvedilol sulfate.
When carvedilol sulfate slow releasing preparation of the present invention is made up of fast release micropill, enteric coated micropill and slow-release micro-pill, it is that 0.9mg is to 7.2mg that fast release micropill part contains carvedilol sulfate; It is that 0.9mg is to 7.2mg that enteric coated micropill part contains carvedilol sulfate; It is that 7.2mg is to 57.6mg that slow-release micro-pill part contains carvedilol sulfate.
Binding agent in carvedilol sulfate slow releasing preparation of the present invention in the drug-loaded layer of fast release micropill, enteric coated micropill and slow-release micro-pill can be acceptable adjuvant on polyvidon (PVP), polyoxyethylene (PEO), hydroxypropyl cellulose (HPC), hypromellose (HPMC) and other preparations.Wherein preferably polyethylene pyrrolidone (PVP).
Sweller in carvedilol sulfate slow releasing preparation of the present invention in the drug-loaded layer of fast release micropill, enteric coated micropill and slow-release micro-pill can be cross-linked pvp (CPVP), cross-linked carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose.Wherein preferred cross-linked pvp (CPVP).
Solubilizing agent in carvedilol sulfate slow releasing preparation of the present invention in the drug-loaded layer of fast release micropill, enteric coated micropill and slow-release micro-pill can be poloxamer, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, tween, polyglycol distearate.Wherein preferred PLURONICS F87 (LutrolF 68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40), Solutol HS15 (Solutol HS 15).
In carvedilol sulfate slow releasing preparation of the present invention, micropill also can contain antiplastering aid, for example, one or more mixture in Pulvis Talci, magnesium stearate, glyceryl behenate, enuatrol.Preferably talc powder, magnesium stearate.
Micropill in carvedilol sulfate slow releasing preparation of the present invention can contain sealing coat, and it at least contains a kind of thin film coating material, and thin film coating material can be HPMC, HPC, PVP, Polyethylene Glycol, Opadry, Kollicoat IR etc.Wherein preferred HPMC, HPC.
By the micropill combined effect of two or three different drug release characteristics in carvedilol sulfate slow releasing preparation of the present invention, thereby make carvedilol sulfate slow releasing preparation involved in the present invention extend blood drug level level in body than quick releasing formulation, curve while presenting in vivo a level and smooth medicine, reach peak concentration at 2～7h, and after taking medicine, 24h blood drug level level and conventional carvedilol are taken once every 12h, 2 times on the one, after taking medicine, after 24h, blood drug level is on close level, area under the drug-time curve (AUC) is taken once every 12h with conventional carvedilol, the area under the drug-time curve (AUC) of 2 times on the one is suitable.
Brief description of the drawings
The release profiles contrast of Fig. 1, embodiment 2 and embodiment 7.
Curve when Fig. 2, the interior medicine of embodiment 7 carvedilol sulfate slow releasing capsule bodies.
Curve when Fig. 3, the interior medicine of embodiment 18 carvedilol sulfate slow releasing capsule bodies.
Curve when medicine in the body of Fig. 4, the Coreg CR of GSK company.
Detailed description of the invention
Slow releasing preparation drug release determination method
The present invention, in the time measuring slow releasing preparation release, according to 2005 editions two annex XD first methods of Chinese Pharmacopoeia, adopts the device of dissolution method the second method, release medium 900ml, rotating speed is 100rpm, temperature is 37 DEG C, respectively through Isosorbide-5-Nitrae, 8,12,18,24 hours, get solution 6ml, carry out HPLC mensuration as test liquid, calculate the burst size of every capsules at different time.The release medium using is 0.1mol/L hydrochloric acid solution.
The preparation of embodiment 1 sulphuric acid carvedilol monohydrate
For exemplary illustration preparation effect of the present invention, the application's embodiment compares content and the effect of explanation invention as an example of carvedilol sulfate monohydrate example.
The embodiment 25 of International Application No. WO 2005051322 has provided the preparation method of sulphuric acid carvedilol.Those skilled in the art can prepare pharmaceutical raw material according to the record of above-mentioned document.The carvedilol sulfate monohydrate that the embodiment of the present application is used is the carvedilol sulfate monohydrate preparing in accordance with the following methods.
In 50L reactor, drop into carvedilol 2.7kg, acetone 26.3kg, 35 DEG C are stirred 20 minutes, dissolve, slowly add the aqueous solution 4.1kg containing 98% sulphuric acid 182ml, stir 1 hour, being cooled to 0-10 DEG C stirs 2 hours, centrifugal rejection filter, the washing of acetone/water for filter cake (1: 1, V/V) 1.5L × 2, put into hot air circulation drying oven, 50 DEG C dry is no less than 12 hours.Obtain sulphuric acid carvedilol monohydrate 2.68kg～2.9kg, yield 87%～94%, purity >=99%.This product is about 101 DEG C of incipient meltings, and then sample becomes similar dope, until approximately 184 DEG C, become supernatant liquid.
The carvedilol slow releasing preparation of embodiment 2 International Application No. WO 2005051322
Prepare carvedilol sulfate slow releasing preparation according to the embodiment of International Application No. WO 2005051322.
Fast release micropill prescription
| Carvedilol sulfate monohydrate | 9g |
| PVP | 2g |
The carvedilol sulfate that adds soluble in water PVP is made to drug suspension, use Glatt fluid bed that drug suspension is sprayed on to ball in the heart.
Delayed release micropill I prescription
| Carvedilol sulfate monohydrate | 27g |
| Cross-linked pvp | 30g |
| PVP | 30g |
| Cremophor RH 40 | 2g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Cremophor RH 40 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, hydrogenated vegetable oil (Lubritab) are prepared to coating solution in ratio and the appropriate magnesium stearate of 75: 25 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart delayed release micropill I.
Delayed release micropill II prescription
| Carvedilol sulfate monohydrate | 36g |
| Cross-linked pvp | 12g |
| PVP | 12g |
| Cremophor RH 40 | 3g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Cremophor RH 40 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, EudragitS100 hydrogenated vegetable oil (Lubritab) are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 25: 35: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.Fast release micropill, delayed release micropill I and tri-kinds of micropills of delayed release micropill II are prepared final slow releasing capsule in the drug loading ratio fill capsule of 1: 3: 4.Measure its release in 0.1mol/LHCl, the results are shown in Table 3 and Fig. 1.
Can find out from release result, the sample of preparing according to the enforcement of International Application No. WO 2005051322, within 1 hour, be mainly that fast release micropill releases after medicine, delayed release micropill I and delayed release micropill II substantially no longer discharge medicine, confirmed delayed release micropill I in International Application No. WO 2005051322 and in the time of pH5.5, started to discharge, and delayed release micropill II starts to discharge in the time of pH6.4.But the final release of medicine is incomplete.
Embodiment 3
Prepare carvedilol sulfate slow-release micro-pill.
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, Eudragit S100, Oleum Ricini are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 35: 25: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.Measure its release.The results are shown in Figure 1.
Can find out that from this release profiles slow-release micro-pill of the present invention has obvious 24 hours sustained releasing character 0.1mol/L hydrochloric acid.Slow-release micro-pill initial stage drug release of the present invention is slower, just starts slow Slow release after 1h.By increasing after fast release micropill part, this product also can discharge rapidly medicine effectively at the release initial stage, after making to take medicine, can reach rapidly effective blood drug concentration.
Embodiment 4
Prepare carvedilol sulfate fast release micropill.
Rapid release ball prescription
| Carvedilol sulfate monohydrate | 9g |
| Cross-linked pvp | 2.7g |
| PVP | 2.7g |
| Lutrol F 68 | 0.675g |
Carvedilol sulfate, cross-linked pvp and the Lutrol F 68 of adding soluble in water PVP made to drug suspension, use Glatt fluid bed that drug suspension is sprayed on to ball in the heart.
Embodiment 5
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 4 in fast release micropill and slow release, the results are shown in Table 3.
Embodiment 6
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 5.5 in fast release micropill and slow release, the results are shown in Table 3.
Embodiment 7
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 3.Fig. 1 is shown in the release profiles contrast of the slow releasing capsule of preparing with embodiment 2.
Embodiment 8
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 8.5 in fast release micropill and slow release, the results are shown in Table 3.
Embodiment 9
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 10 in fast release micropill and slow release, the results are shown in Table 3.
Embodiment 10
Prepare carvedilol sulfate slow-release micro-pill.
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, Eudragit S100, Oleum Ricini are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 25: 35: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.Measure its release.The results are shown in Figure 1.
Conclusion: can find out the increase along with fast release micropill part content of dispersion, the initial stage burst size of this product obviously increases, and the rate of release at initial stage is too fast, easily causes the prominent phenomenon of releasing of medicine to increase drug risk; Along with the minimizing of fast release micropill part content of dispersion, the initial stage burst size of this product obviously reduces, and the rate of release at initial stage is excessively slow, is difficult to onset rapidly.This product fast release micropill and slow-release micro-pill part content of dispersion are 1: 4 or 1: although also can use for 10 o'clock, if in order to be effective better, preferably the two proportion control is 1: between 5.5-8.5, by relatively finding that optimization ratio is 1: 7.
Reach good releasing effect, the ratio of the polymer using in the slow release layer of slow-release micro-pill must be controlled.Can be found out by experimental result, the consumption of first kind polymer need be higher than the consumption of Equations of The Second Kind polymer, just can reach the releasing effect of slow-release micro-pill of the present invention.If the consumption of Equations of The Second Kind polymer is higher than first kind polymer, the releasing effect of slow-release micro-pill is poor, and the slow releasing preparation that contains slow-release micro-pill is difficult to reach the release request of expection.
Embodiment 11
The slow releasing preparation of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill
Fast release micropill prescription:
| Carvedilol sulfate monohydrate | 9g |
| PVP | 2.7g |
The carvedilol sulfate that adds soluble in water PVP is made to drug suspension, use Glatt fluid bed that drug suspension is sprayed on to ball in the heart.
Slow-release micro-pill prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Cremophor RH 40 | 5g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Cremophor RH 40 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, EudragitS100, triethyl citrate are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 40: 25: 35 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.Prepare in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, measure release, the results are shown in Table 3.
Table 3 release result
Embodiment 12
The slow releasing preparation of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, Eudragit S100, diethyl phthalate are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 35: 25: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.
Fast release micropill prepared by the slow-release micro-pill of preparation and embodiment 4,, and measures it and discharges in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 4.
Embodiment 13
The slow releasing preparation slow release ball of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill is write out a prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again by hydroxypropyl methyl cellulose phthalate (HPMCP, HP-55), Eudragit S100, Oleum Ricini prepare slow release layer coating solution in ratio and the appropriate magnesium stearate of 35: 25: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.
Fast release micropill prepared by the slow-release micro-pill of preparation and embodiment 4,, and measures it and discharges in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 4.
Embodiment 14
The slow releasing preparation of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again by hydroxypropyl methylcellulose acetate succinate (HPMCAS, L-type), hydroxypropyl methylcellulose acetate succinate (HPMCAS, H type), Oleum Ricini prepares slow release layer coating solution in the ratio of 35: 25: 40 and appropriate magnesium stearate with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.
Fast release micropill prepared by the slow-release micro-pill of preparation and embodiment 4,, and measures it and discharges in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 4.
Embodiment 15
The slow releasing preparation of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, ethyl cellulose, Oleum Ricini are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 40: 20: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.
Fast release micropill prepared by the slow-release micro-pill of preparation and embodiment 4,, and measures it and discharges in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 4.
Embodiment 16
The slow releasing preparation of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100, Eudragit RS, Oleum Ricini are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 40: 20: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.
Fast release micropill prepared by the slow-release micro-pill of preparation and embodiment 4,, and measures it and discharges in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 4.
Embodiment 17
The slow releasing preparation of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100, Eudragit RL, Oleum Ricini are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 40: 20: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.Fast release micropill prepared by the slow-release micro-pill of preparation and embodiment 4,, and measures it and discharges in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 4.
Embodiment 18
The slow releasing preparation of being prepared by carvedilol sulfate fast release micropill and slow-release micro-pill
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol F 68 | 4.725g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again Eudragit L100-55, carboxyethyl cellulose, Oleum Ricini are prepared to slow release layer coating solution in ratio and the appropriate magnesium stearate of 40: 20: 40 with 95% ethanol, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart slow-release micro-pill.Fast release micropill prepared by the slow-release micro-pill of preparation and embodiment 4,, and measures it and discharges in the drug loading ratio fill capsule of 1: 7 in fast release micropill and slow release, the results are shown in Table 4.
Table 4 release result
Conclusion: although it has been generally acknowledged that the plasticizer in coatings can not play too large impact to the character of coating, can find out by above-mentioned experiment, can more optimize the releasing effect of slow-release micro-pill of the present invention in the time selecting some plasticizer.From measurement result, compare other plasticizers, Oleum Ricini, triethyl citrate, diethyl phthalate can make the releasing effect of slow releasing preparation better, and particularly Oleum Ricini is best suited for plasticizer of the present invention.
Investigate by the polymer test in the slow release layer of slow-release micro-pill of the present invention, can find out and adopt Eudragit L100-55, Eudragit L100, Acrycoat L100D, CAP (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS, L-type or M type) etc. polymer property similar, all can be used as the polymeric material that first kind polymer is prepared slow-release micro-pill; Eudragit S100, EudragitRL, Eudragit RS, Acrycoa S100, hydroxypropyl methylcellulose acetate succinate (HPMCAS, H type), the polymer property such as carboxymethylethylcellulose (CMEC) and ethyl cellulose (EC) is similar, all can be used as the polymeric material that Equations of The Second Kind polymer is prepared slow-release micro-pill.Between these polymer of this first and second class, can be used in conjunction with, the slow-release micro-pill of preparing all has good slow release effect.From the experimental results, first and second base polymer that result of use is best or first-selected Eudragit L100-55 and Eudragit S100 are used in conjunction with, the two polymer coating material as slow-release micro-pill makes the final release of slow-release micro-pill more complete, has the releasing effect of more optimizing.
Embodiment 19
Prepare carvedilol sulfate enteric coated micropill
Enteric coated pill prescription
| Carvedilol sulfate monohydrate | 7.2g |
| Cross-linked pvp | 2.16g |
| PVP | 2.16g |
| Lutrol F 68 | 0.54g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Lutrol F 68 compounding pharmaceutical suspensions, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again by Eudragit L100-55, Oleum Ricini, magnesium stearate in 95% ethanol preparation slow release layer coating solution for applicable ratio, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart enteric coated micropill.
Embodiment 20
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4, enteric coated micropill prepared by embodiment 19 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 1: 5 in fast release micropill and slow release, the results are shown in Table 5.
Embodiment 21
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4, enteric coated micropill prepared by embodiment 19 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 1: 6 in fast release micropill and slow release, the results are shown in Table 5.
Embodiment 22
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4, enteric coated micropill prepared by embodiment 19 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 1: 7 in fast release micropill and slow release, the results are shown in Table 5.
Embodiment 23
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 4, enteric coated micropill prepared by embodiment 19 and embodiment 3,, and measure it and discharge in the drug loading ratio fill capsule of 1: 1: 8 in fast release micropill and slow release, the results are shown in Table 5.
Embodiment 24
Prepare carvedilol sulfate enteric coated micropill
Enteric coated micropill prescription:
| Carvedilol sulfate monohydrate | 9g |
| Cross-linked pvp | 9g |
| PVP | 4.5g |
| Cremophor RH 40 | 0.72g |
By the carvedilol sulfate of recipe quantity, cross-linked pvp, PVP, Cremophor RH40 compounding pharmaceutical suspension, use Glatt fluid bed that drug suspension is sprayed on to ball and prepare in the heart the medicine carrying ball heart, make drug loading between 10%～50%.Again by Eudragit L100-55, triethyl citrate, magnesium stearate in 95% ethanol preparation slow release layer coating solution for applicable ratio, with Glatt fluid bed, coating solution is sprayed on to medicine carrying ball and prepares in the heart enteric coated micropill.
Embodiment 25
Get slow-release micro-pill prepared by fast release micropill prepared by above-described embodiment 11, enteric coated micropill prepared by embodiment 24 and embodiment 11,, and measure it and discharge in the drug loading ratio fill capsule of 1: 1: 8 in fast release micropill and slow release, the results are shown in Table 5.
Table 5 release result
Conclusion: can find out and add after enteric coated micropill, can more optimize whole releasing effect.The content of dispersion ratio of fast release micropill, enteric coated micropill and three kinds of micropills of slow-release micro-pill part content of dispersion selects suitable ratio releasing effect better.Can find out the minimizing along with slow-release micro-pill content of dispersion, medicine finally can not discharge completely.Therefore this product fast release micropill, enteric coated micropill and slow-release micro-pill part content of dispersion are 1: 1: 6-8 can realize and utilize enteric coated micropill to optimize releasing effect, experimental result discovery, and it is best that three reaches 1: 1: 8 o'clock effect.
Embodiment 26
The pharmacokinetics test of Beagle dog
The sulphuric acid carvedilol slow releasing capsule of embodiment 7 and 23 preparation is carried out to the pharmacokinetics test of Beagle dog, the results are shown in Figure 2,3, Fig. 4 is curve when medicine in the body of the Coreg CR of GSK company.
From relatively can finding out of Fig. 2, Fig. 3 and Fig. 4, the sulphuric acid carvedilol slow releasing capsule of this patent embodiment 7 and 23 present in vivo a level and smooth medicine time curve, only has a peak concentration, and there are two peak concentrations in GlaxoSmithKline PLC company carvedilol phosphate salts slow releasing preparation curve while presenting in vivo the medicine of a two-phase.
Claims (32)
1. contain a slow releasing preparation for carvedilol sulfate analog, wherein contain fast release micropill and the slow-release micro-pill of carvedilol sulfate analog, wherein,
This carvedilol sulfate slow releasing preparation is made up of fast release micropill and slow-release micro-pill, and the content of dispersion of fast release micropill part is 10%～20% of accumulated dose weight, and the content of dispersion of slow-release micro-pill part is 80%～90% of accumulated dose weight; Or,
In described slow releasing preparation, also contain the enteric coated micropill of carvedilol sulfate, the content of dispersion of wherein said fast release micropill part is 10%～15% of accumulated dose weight, the content of dispersion of enteric coated micropill part is 10%～15% of accumulated dose weight, and the content of dispersion of slow-release micro-pill part is 70%～80% of accumulated dose weight;
Wherein said slow-release micro-pill contains drug-loaded layer and slow release layer,
Described drug-loaded layer contains carvedilol sulfate analog, and carvedilol sulfate analog is selected from one or more in carvedilol sulfate or carvedilol sulfate hydrate;
In described drug-loaded layer, also contain binding agent, sweller, solubilizing agent; Binding agent is selected from polyvidon (PVP), polyoxyethylene (PEO), hydroxypropyl cellulose (HPC), hypromellose (HPMC), sweller is selected from cross-linked pvp (CPVP), cross-linked carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, and solubilizing agent is selected from poloxamer, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, tween, polyglycol distearate;
Described slow release layer makes this slow-release micro-pill in pH1.0 medium, discharge 0-30% carvedilol sulfate 1 hour time, in the time of 8 hours, discharge 25%～90% carvedilol sulfate, in the time of 24 hours, discharge and be greater than 75% carvedilol sulfate, in this slow release layer, contain two class film property polymer, first kind polymer has been the molten polymer dissolving at pH5-6 and under the condition higher than this pH, Equations of The Second Kind polymer has been that molten point is pH6.5-7.5 and the polymer dissolving under the condition higher than this pH or water-insoluble polymer, first kind polymer proportion is greater than Equations of The Second Kind polymer proportion,
Described first kind polymer is selected from one or more Eudragit L100-55, Eudragit L100, Acrycoat L100D, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate L-type or M type; Equations of The Second Kind polymer is selected from one or more Eudragit S100, Eudragit RL, Eudragit RS, Acrycoat S100, hydroxypropyl methylcellulose acetate succinate H type, carboxymethylethylcellulose (CMEC) or ethyl cellulose (EC);
In wherein said slow release layer, contain one or more plasticizers, the weight ratio of wherein said plasticizer in slow release layer is 25-50%;
Wherein, with first and second base polymer and the total restatement of plasticizer, it is 20～50% that described first kind polymer accounts for three's gross weight ratio; It is 10～30% that Equations of The Second Kind polymer accounts for three's gross weight ratio.
2. slow releasing preparation according to claim 1, wherein said slow release layer makes this slow-release micro-pill in pH1.0 medium, discharge 0-10% carvedilol sulfate 1 hour time, in the time of 8 hours, discharge 35%～70% carvedilol sulfate, in the time of 24 hours, discharge and be greater than 85% carvedilol sulfate.
3. slow releasing preparation according to claim 1 and 2, wherein said plasticizer is selected from triethyl citrate, Oleum Ricini or diethyl phthalate.
4. slow releasing preparation according to claim 1 and 2, wherein said plasticizer is Oleum Ricini.
5. slow releasing preparation according to claim 1, the weight ratio of wherein said plasticizer in slow release layer is 30～50%.
6. slow releasing preparation according to claim 1, the weight ratio of wherein said plasticizer in slow release layer is 35～40%.
7. slow releasing preparation according to claim 1, wherein, with first and second base polymer and the total restatement of plasticizer, it is 30～40% that described first kind polymer accounts for three's gross weight ratio; It is 20～30% that Equations of The Second Kind polymer accounts for three's gross weight ratio.
8. slow releasing preparation according to claim 1, two class film property polymer in wherein said slow release layer are all acrylic resin base polymers, contain methacrylic acid copolymer C type (Eudragit L100-55) and methacrylic acid copolymer Type B (Eudragit S100).
9. slow releasing preparation according to claim 1, two class film property polymer in wherein said slow release layer are respectively methacrylic acid copolymer C type (Eudragit L100-55) and methacrylic acid copolymer Type B (Eudragit S100).
10. slow releasing preparation according to claim 8, the weight ratio of wherein said methacrylic acid copolymer C type (Eudragit L100-55) in slow release layer is 30～45%, and the weight ratio of methacrylic acid copolymer Type B (Eudragit S100) in slow release layer is 20～30%.
11. slow releasing preparation according to claim 1, contain methacrylic acid copolymer C type (Eudragit L100-55), methacrylic acid copolymer Type B (Eudragit S100) and Oleum Ricini in wherein said slow release layer.
12. slow releasing preparation according to claim 11, wherein with methacrylic acid copolymer C type (Eudragit L100-55), methacrylic acid copolymer Type B (Eudragit S100) and the total restatement of Oleum Ricini, methacrylic acid copolymer C type (Eudragit L100-55) is 30～40%, methacrylic acid copolymer Type B (Eudragit S100) is 20～30%, and Oleum Ricini is 30～40%.
13. slow releasing preparation according to claim 12, in wherein said drug-loaded layer,
Binding agent is polyvidon; Or/and
Sweller is cross-linked pvp; Or/and
Solubilizing agent is selected from as one or more in PLURONICS F87 (Lutrol F68), polyoxyethylene hydrogenated Oleum Ricini or Solutol HS15 (Solutol HS15).
14. slow releasing preparation according to claim 1, wherein said carvedilol sulfate analog is carvedilol sulfate monohydrate.
15. slow releasing preparation according to claim 1, wherein said carvedilol sulfate analog is in carvedilol sulfate, and its content is 7-72mg.
16. slow releasing preparation according to claim 1, wherein, this carvedilol sulfate slow releasing preparation is made up of fast release micropill and slow-release micro-pill, and the part by weight of the fast release micropill part of this carvedilol sulfate slow releasing preparation and the medicament contg of slow-release micro-pill part is 1:5-9.
17. slow releasing preparation according to claim 16, wherein the part by weight of the fast release micropill part of this carvedilol sulfate slow releasing preparation and the medicament contg of slow-release micro-pill part is 1:5.5-8.5.
18. slow releasing preparation according to claim 16, wherein the part by weight of the fast release micropill part of this carvedilol sulfate slow releasing preparation and the medicament contg of slow-release micro-pill part is 1:7.
19. slow releasing preparation according to claim 1, in wherein said slow releasing preparation, also contain the enteric coated micropill of carvedilol sulfate, wherein the part by weight of the medicament contg of the fast release micropill part of this carvedilol sulfate slow releasing preparation, enteric coated micropill part and slow-release micro-pill part is 0.9-1.1:0.9-1.1:6-10.
20. slow releasing preparation according to claim 19, wherein the part by weight of the medicament contg of the fast release micropill part of this carvedilol sulfate slow releasing preparation, enteric coated micropill part and slow-release micro-pill part is 1:1:6-8.
21. slow releasing preparation according to claim 19, wherein the part by weight of the medicament contg of the fast release micropill part of this carvedilol sulfate slow releasing preparation, enteric coated micropill part and slow-release micro-pill part is 1:1:8.
22. slow releasing preparation according to claim 1, the medicament contg of wherein said fast release micropill part, enteric coated micropill part and slow-release micro-pill part is 0.9-7.2mg:0.9-7.2mg:7-58mg.
23. slow releasing preparation according to claim 1, during wherein only containing fast release micropill and two kinds of micropills of slow-release micro-pill and containing enteric coated micropill, it is that 1.1mg is to 9mg that fast release micropill part contains carvedilol sulfate; It is that 7.8mg is to 63mg that slow-release micro-pill contains carvedilol sulfate.
24. slow releasing preparation according to claim 1, wherein said fast release micropill part contains drug-loaded layer, and wherein said drug-loaded layer contains one or more in binding agent, sweller, solubilizing agent.
25. slow releasing preparation according to claim 24, drug-loaded layer wherein contains binding agent, sweller, solubilizing agent simultaneously.
26. slow releasing preparation according to claim 24, wherein said binding agent is selected from polyvidon (PVP), sweller is selected from cross-linked pvp (CPVP), and solubilizing agent is selected from one or more in PLURONICS F87 (Lutrol F68), polyoxyethylene hydrogenated Oleum Ricini or Solutol HS15 (Solutol HS15).
27. slow releasing preparation according to claim 1, wherein said enteric coated micropill contains drug-loaded layer and enteric layer, and wherein said drug-loaded layer contains one or more in binding agent, sweller, solubilizing agent; In described enteric layer, at least contain a kind of enteric solubility film property polymer.
28. slow releasing preparation according to claim 27, wherein said enteric layer contains plasticizer.
29. slow releasing preparation according to claim 27, binding agent in wherein said enteric coated micropill drug-loaded layer is polyvidon (PVP), sweller is cross-linked pvp (CPVP), and solubilizing agent is selected from one or more in PLURONICS F87 (Lutrol F68), polyoxyethylene hydrogenated Oleum Ricini or Solutol HS15 (Solutol HS15).
30. slow releasing preparation according to claim 27, the enteric solubility film property polymer in the enteric layer of wherein said enteric coated micropill is selected from one or more in Eudragit L100-55, Eudragit L100, Eudragit S100, Acrycoat L100D, Acrycoat S100, CAP (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC) or Lac.
31. slow releasing preparation according to claim 27, the plasticizer in the enteric layer of wherein said enteric coated micropill is selected from one or more in triethyl citrate, Oleum Ricini, Polyethylene Glycol or diethyl phthalate.
32. slow releasing preparation according to claim 27, the film property high molecular polymer of wherein said enteric coated micropill enteric layer is methacrylic acid copolymer C type (EudragitL100-55), plasticizer is triethyl citrate and/or Oleum Ricini.
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| CN103751117A (en) * | 2014-01-23 | 2014-04-30 | 合肥合源医药科技股份有限公司 | Carvedilol sustained-release capsule |
| CN104306347A (en) * | 2014-09-19 | 2015-01-28 | 万特制药(海南)有限公司 | Carvedilol double-layer sustained release tablet and prepetition method of carvedilol double-layer sustained release tablet |
| TW201929839A (en) * | 2017-12-29 | 2019-08-01 | 大陸商江蘇恒瑞醫藥股份有限公司 | Controlled release pharmaceutical composition and preparation method thereof |
| CN108707204B (en) * | 2018-07-04 | 2020-09-15 | 吉林大学 | Hydrogen peroxide response type targeted drug-loaded nano material and preparation method thereof |
| CN116725985B (en) * | 2023-06-02 | 2024-03-05 | 石家庄四药有限公司 | Micropill combined urapidil sustained-release capsule and preparation method thereof |
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2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051322A2 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Controlled release pharmaceutical formulations comprising carvedilol, free based and its salts |
| CN1923166A (en) * | 2006-09-07 | 2007-03-07 | 何岩 | Carbediolo controlled release formulation |
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