CN102614130A - Carvedilol sulfate sustained release preparation - Google Patents
Carvedilol sulfate sustained release preparation Download PDFInfo
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- CN102614130A CN102614130A CN2011100331496A CN201110033149A CN102614130A CN 102614130 A CN102614130 A CN 102614130A CN 2011100331496 A CN2011100331496 A CN 2011100331496A CN 201110033149 A CN201110033149 A CN 201110033149A CN 102614130 A CN102614130 A CN 102614130A
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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 that micropill that active component disengaged by control is formed, be used to treat cardiovascular disease, comprise hypertension, congestive heart failure, atherosclerosis and angina pectoris.
Background technology
(Carvedilol is a kind of to β Car) to carvedilol
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 U.S. Pat 4503067 of Wiedemann etc., chemistry (±) 1-by name (9H-carbazole-4-base oxygen base)-3-[[2-(2-methoxyl group phenoxy group) ethyl] amino]-2-propanol, and structural formula does
It also has α 1 receptor retardation, no intrinsic sympathomimetic acitivity concurrently.This double pharmacological action can make carvedilol not have to expand merely the side reaction (like reflex tachycardia and peripheral vascular resistance) that the retardance of blood vessel or beta-receptor brings.It generally seldom or not influences healthy volunteer's heart rate or cardiac index influence; Be the 3rd generation beta-receptor blockader a kind of new product; By the exploitation of U.S. Smithkline Beecham company, become at present the highest beta-blocker of chronic heart failure evaluation both at home and abroad.Compare with similar medicine metoprolol, these article total effective rate is high and occur that heart failure increases the weight of and atrioventricular block example number (AVB) is low.SV can reduce during these article treatment exercise induced hypertension.Compare with metoprolol with propranolol, these article are seldom influential to tranquillization or exercise induced hypertension patient's heart rate.
Carvedilol contains the Alpha-hydroxy secondary amine functional groups; The pKa value is 7.8, and dissolubility relatively low (＜1 μ g/ml) is when pH value reduces; The carvedilol dissolubility improves; Near pH=5, reach stationary value, promptly at room temperature saturation solubility is about 23 μ g/ml when pH=7, is about 100 μ g/ml at pH=5.Some salt and/or the novel crystal forms of carvedilol have bigger water solublity, chemical stability etc.; Can absorb and to have obtained the whole body system levels of drugs of expecting or prolonging through keeping gastrointestinal, particularly maintain the absorption that the pH value of drug solubility minimum gets neutral region.The free radical form of carvedilol is the racemic mixture of R (+) and R (-) enantiomer, and wherein R (-) mapping body surface shape is located non-selective β-adrenoreceptor retardance, and R (+) and R (-) enantiomer all show α-adrenoreceptor and can get blocking activity.Unusual characteristic that these are relevant with raceme carvedilol mixture or characteristic are because two kinds of additional pharmacological actions: i.e. the non-heart selectivity β-adrenoreceptor of mixed venous and arteries expansion can block.Therefore, develop the good carvedilol salt of a kind of result of use, it also is significant making it have higher water solublity, chemical stability/keep or prolong drug level or absorption level (promptly as in gastrointestinal pH neutral zone etc.) with respect to the carvedilol base.Reported at present phosphate, the mesylate of 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, is respectively fast release micropill and two kinds of controlled release micro pills, and fast release micropill discharges medicine through time-dependent; Just getting into behind the gastrointestinal tract can rapid delivery of pharmaceuticals; Two kinds of controlled release micro pills rely on through pH and discharge medicine, and wherein first kind of controlled release micro pill begins to discharge medicine in the pH5.5 medium, and second kind of controlled release micro pill begins to discharge medicine in the pH6.4 medium.Compare 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 drugs approved by FDA at present; Be used for the treatment of three kinds of cardiovascular disease: left ventricular insufficiency and mild to moderate heart failure behind hypertension, the myocardial infarction are 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, the continuous release from the sour environment to the neutral environment in gastrointestinal tract of control medicine is significant.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.
Comprising three parts in the Carbediolo controlled release formulation that International Application No. WO 2005051322 provides, is respectively fast release micropill part, first kind of controlled release micro pill part and second kind of controlled release micro pill part, and its medicament contg ratio is 1: 3: 4.Fast release micropill discharges medicine through time-dependent; Just getting into behind the gastrointestinal tract can rapid delivery of pharmaceuticals, and two kinds of controlled release micro pills are then fully through relying on the release medicine through pH, when preparation is transported to the environment pH value and is 5.5 in gastrointestinal tract; First kind of controlled release micro pill begins to discharge medicine; When preparation was transported to the environment pH value and is 6.4 in gastrointestinal tract, second kind of controlled release micro pill began to discharge medicine, so the drug release characteristics of this controlled release preparation is equivalent to three kinds of micropills the adding up of different time points pulse release when gastrointestinal tract is transported; Curve presented a diphasic curve model when this drug release characteristics had also caused medicine; There are two blood drug level peaks, occurred first blood drug level peak at 1～3 hour, occurred second blood drug level peak at 5～10 hours.And find that this method is bad to the controlled-release effect of carvedilol sulfate after utilizing this patented method to prepare the slow releasing preparation of carvedilol sulfate, there is evident difference in release in vitro, is difficult to meet the demands.
Research worker has been carried out a large amount of experiments to the carvedilol slow releasing preparation; The unexpected slow-release micro-pill of finding that the micropill in a kind of and the International Application No. WO 2005051322 has diverse release in vitro characteristic, said slow-release micro-pill just begin 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; The medicament contg ratio 1 of control fast release micropill part and slow-release micro-pill part: 5-9; Preferred 1: 5.5-8.5; Preferably 1: 7, wherein fast release micropill discharged medicine through time-dependent, guaranteed to get into the gastrointestinal tract rapid delivery of pharmaceuticals; Slow-release micro-pill relies on the release medicine jointly through time and pH, and beginning can slowly discharge medicine in the environment of gastrointestinal tract pH1.0.Through the drug ratio of two kinds of micropills and the Overlay of slow releasing pharmaceutical micropill and fast release micropill; Reach the effect that better controlling discharges; The slow releasing preparation that constitutes through these two kinds of micropills has tangible prescription, the simple advantage of technology than three kinds of micropills in the International Application No. WO 2005051322; Practice thrift production cost, solved the defective at two blood drug level peaks of WO2005051322 slow releasing preparation, and can reach the good result that the control drug slow discharges fully.
Also can add a small amount of enteric coated micropill in the slow releasing preparation of the present invention more optimizes the effect in whole release later stage.Therefore; The slow releasing preparation that relates in this patent can also be controlled by the micropill of three kinds of different release characteristics; Be 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, preferred 1: 6-8: 1, preferably 1: 8: 1.Behind the drug administration, at first fast release micropill discharges medicine through time-dependent, gets into the gastrointestinal tract rapid delivery of pharmaceuticals; Simultaneously, slow-release micro-pill relies on the release medicine jointly through time and pH, in the surrounding medium of gastrointestinal tract pH1.0, slowly discharges medicine, controls the releasing effect of medicine jointly with fast release micropill; Enteric coated micropill relies on through pH and discharges medicine, in gastrointestinal tract pH5.5 medium, begins to discharge medicine, optimizes the 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 the 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.
Only contain fast release micropill and slow-release micro-pill in the slow releasing preparation and when not containing enteric coated micropill, the content of dispersion of fast release micropill part is 10%～20% of an accumulated dose, the content of dispersion that slow release is released the micropill part is 80%～90% of an accumulated dose.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 10%～15% of an accumulated dose; The content of dispersion of enteric coated micropill part is 10%～15% of an accumulated dose, and the content of dispersion that slow release is released the micropill part is 70%～80% of an accumulated dose; 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 the slow releasing preparation involved in the present invention just begins slowly to discharge medicine in the surrounding medium of gastrointestinal tract pH1.0; Wherein preceding 2 h drug mainly only discharge small amount of drug under one's belt the time; Mainly partly discharge medicine during this period of time by fast release micropill; When medicine got into intestinal, slow-release micro-pill continued to discharge medicine, reaches the releasing effect of the whole slow releasing preparation of control.If contain enteric coated micropill, then enteric coated micropill reaches at 5.5 o'clock at environment pH and begins 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 in intestinal, to transport; The release medicine that this slow-release micro-pill continues too, thus guarantee that carvedilol sulfate slow releasing preparation of the present invention can discharge medicine at whole gastrointestinal tract between transit period all the time, and keep the steady release of medicine relatively; Thereby make carvedilol sulfate slow releasing preparation involved in the present invention prolong blood drug level level in the body than quick releasing formulation; Curve when presenting a level and smooth medicine in vivo reaches the blood drug level peak at 2～7h, and the back 24h blood drug level level of taking medicine is taken once at a distance from 12h with conventional carvedilol is every; 2 times on the one; The blood drug level of taking medicine behind the 24h of back is on close level, and area under the drug-time curve (AUC) is taken once at a distance from 12h with conventional carvedilol is every, and 2 times on the one area under the drug-time curve (AUC) is suitable.And carvedilol sulfate slow releasing preparation involved in the present invention is because the difference of the difference of micropill release characteristic curve when having caused medicine only a blood drug level peak occurred at 2～7 hours, and curve is more steady during medicine, has more embodied the advantage of slow releasing preparation.
Slow-release micro-pill
Core of the present invention just is to study and obtains a kind of slow-release micro-pill that satisfies certain release request, and through using the combination of this slow-release micro-pill and fast release micropill to obtain releasing effect good slow release preparation.
Slow-release micro-pill of the present invention comprises the ball heart, medicated layer and slow release layer three parts, the optional sealing coat that contains.Drug-loaded layer is wrapped in outside the ball heart, and slow release layer is wrapped in outside the drug-loaded layer, at the optional sealing coat that contains between the drug-loaded layer and the ball heart, between drug-loaded layer and the slow release layer.Drug-loaded layer contains carvedilol sulfate anhydride or solvate, chooses wantonly to contain acceptable auxiliary on binding agent, solubilizing agent, sweller or other preparations, and the main purpose of this one deck is to satisfy carrying medicament.
Concrete slow-release micro-pill of the present invention contains drug-loaded layer and slow release layer, and said drug-loaded layer contains carvedilol sulfate analog, and carvedilol sulfate analog is selected from one or more in carvedilol sulfate or the carvedilol sulfate hydrate.Specifically can be carvedilol sulfate monohydrate.Carvedilol sulfate analog is in carvedilol sulfate, and its content is 7-72mg.
Said slow release layer makes this slow-release micro-pill in the pH1.0 medium, discharge 0-30% carvedilol sulfate 1 hour the time, in the time of 8 hours, discharges 25%～90% carvedilol sulfate, in the time of 24 hours, discharges greater than 75% carvedilol sulfate; Preferred this slow-release micro-pill discharges 0-10% carvedilol sulfate 1 hour the time in the pH1.0 medium, in the time of 8 hours, discharge 35%～70% carvedilol sulfate, in the time of 24 hours, discharges greater than 85% carvedilol sulfate.Those skilled in the art can select conventional to use the film forming macromolecular material, as long as guarantee that finally medicine satisfies the effect that above-mentioned releasing effect can reach whole slow releasing preparation sustained release, for sustained release trend more accurate.Contain two types of film property polymer in the slow release layer; First kind polymer has been to dissolve point at pH5-6 and be higher than dissolved polymers under the condition of this pH; Second base polymer has been that molten point is pH6.5-7.5 and is being higher than dissolved polymers or water-insoluble polymer under the condition of this pH; With the total weight of the first kind polymer and second base polymer, first kind polymer proportion is greater than the second base 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, cellulose acetate phthalate ester (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS, L type or M type); Said second base 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).
Find through experiment,,, contain one or more plasticizers in the slow release layer therefore as reasonable embodiment if select suitable plasticizers can make the releasing effect of slow-release micro-pill better.Find that through more multiple plasticizer Oleum Ricini is particularly suitable for the present invention, effect is best; Find that in addition triethyl citrate, diethyl phthalate also can be used for the present invention.The weight ratio of plasticizer in slow release layer is 25-50%, and be preferred 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 second base polymer accounts for three's gross weight ratio, preferred 20～35%.
Two types of film property polymer in the slow release layer of slow-release micro-pill can all be the acrylic resin base polymers; Preferably contain EUDRAGIT S100 C type (Eudragit L100-55) and EUDRAGIT S100 Type B (Eudragit S100); Most preferably film forming polymer is two kinds of EUDRAGIT S100 C type (Eudragit L100-55) and EUDRAGIT S100 Type Bs (Eudragit S100); The weight ratio of wherein said EUDRAGIT S100 C type (Eudragit L100-55) in slow release layer is 30～45%, and the weight ratio of EUDRAGIT S100 Type B (Eudragit S100) in slow release layer is 20～30%.
As preferred forms; Contain EUDRAGIT S100 C type (EudragitL100-55), EUDRAGIT S100 Type B (Eudragit S100) and Oleum Ricini in the slow release layer; With their total restatement; EUDRAGIT S100 C type (Eudragit L100-55) is 30～40%, and EUDRAGIT S100 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 medicine load on ball in the heart, and the reasonable specific embodiment of effect is that binding agent is a polyvidon; Or/and sweller is a cross-linked pvp; Or/and being selected from, solubilizing agent is in poloxamer 188 (Lutrol F 68), polyoxyethylene hydrogenated Oleum Ricini (CremophorRH 40) or the polyglycol distearate 15 (Solutol HS 15) one or more.
Fast release micropill
Fast release micropill of the present invention comprises the ball heart, drug-loaded layer, chooses wantonly to contain sealing coat, and drug-loaded layer is wrapped in outside the ball heart, can also increase by a sealing coat between the drug-loaded layer and the ball heart or outside the drug-loaded layer.Drug-loaded layer contains carvedilol sulfate anhydride or solvate.Drug-loaded layer can have one or more in binding agent, sweller, the 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 poloxamer 188 (Lutrol F68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40) or the polyglycol distearate 15 (Solutol HS 15).
Enteric coated micropill
Though slow releasing preparation of the present invention is as long as just can reach the effect that better controlled discharges through fast release micropill and two kinds of micropill combinations of slow-release micro-pill.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 small adjustment
Enteric coated micropill comprises the ball heart, medicated layer and enteric layer three parts, the optional sealing coat that contains.Drug-loaded layer is wrapped in outside the ball heart, and enteric layer is wrapped in outside the drug-loaded layer, at the optional sealing coat that contains between the drug-loaded layer and the ball heart, between drug-loaded layer and the enteric layer.Drug-loaded layer contains carvedilol sulfate anhydride or solvate.Can contain in binding agent, sweller, the solubilizing agent one or more.Preferred adhesive is polyvidon (PVP); Sweller is cross-linked pvp (CPVP), and solubilizing agent is selected from one or more in poloxamer 188 (Lutrol F 68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40) or the polyglycol distearate 15 (Solutol HS 15).
At least contain a kind of enteric solubility film property polymer in the enteric layer, preferred enteric layer contains plasticizer.Wherein the film property high molecular polymer is the conventional enteric macromolecular material that uses in this area, and this enteric macromolecular material guarantees that micropill begins to discharge medicine in intestinal.Enteric solubility film property polymer is selected from the conventional enteric material in this area, for example one or more in Eudragit L100-55, EudragitL100, Eudragit S100, Acrycoat L100D, Acrycoa S100, cellulose acetate phthalate ester (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC) or the Lac.Plasticizer is selected from one or more in triethyl citrate, Oleum Ricini, Polyethylene Glycol or the diethyl phthalate.Specifically can adopt EUDRAGIT S100 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 10%～20% of an accumulated dose, and the content of dispersion that slow release is released the micropill part is 80%～90% of an accumulated dose.
When 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 an accumulated dose; The content of dispersion of enteric coated micropill part is 10%～15% of an accumulated dose, and the content of dispersion that slow release is released the micropill part is 70%～80% of an accumulated dose.
When carvedilol sulfate slow releasing preparation of the present invention only contained fast release micropill and two kinds of micropills of slow-release micro-pill, it was that 1.1mg is to 9mg that fast release micropill partly 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 was made up of fast release micropill, enteric coated micropill and slow-release micro-pill, it was that 0.9mg is to 7.2mg that fast release micropill partly contains carvedilol sulfate; It is that 0.9mg is to 7.2mg that enteric coated micropill partly contains carvedilol sulfate; It is that 7.2mg is to 57.6mg that slow-release micro-pill partly contains carvedilol sulfate.
Binding agent in the 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 an acceptable auxiliary on polyvidon (PVP), polyoxyethylene (PEO), hydroxypropyl cellulose (HPC), hypromellose (HPMC) and other preparations.Preferably polyethylene pyrrolidone (PVP) wherein.
Sweller in the 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 the 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 poloxamer 188 (LutrolF 68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40), polyglycol distearate 15 (Solutol HS 15).
Micropill also can contain antiplastering aid in the carvedilol sulfate slow releasing preparation of the present invention, for example one or more mixture in Pulvis Talci, magnesium stearate, glyceryl behenate, the enuatrol.Preferably talc powder, magnesium stearate.
Micropill in the carvedilol sulfate slow releasing preparation of the present invention can contain sealing coat, and it contains a kind of thin film coating material at least, and thin film coating material can be HPMC, HPC, PVP, Polyethylene Glycol, Opadry, Kollicoat IR etc.Wherein preferred HPMC, HPC.
Micropill combined effect through two or three different drug release characteristics in the carvedilol sulfate slow releasing preparation of the present invention; Thereby make carvedilol sulfate slow releasing preparation involved in the present invention prolong blood drug level level in the body than quick releasing formulation; Curve when presenting a level and smooth medicine in vivo reaches the blood drug level peak at 2～7h, and the back 24h blood drug level level of taking medicine is taken once at a distance from 12h with conventional carvedilol is every; 2 times on the one; The blood drug level of taking medicine behind the 24h of back is on close level, and area under the drug-time curve (AUC) is taken once at a distance from 12h with conventional carvedilol is every, and 2 times on the one area under the drug-time curve (AUC) is suitable.
Description of drawings
The release profiles contrast of Fig. 1, embodiment 2 and embodiment 7.
Curve when Fig. 2, embodiment 7 carvedilol sulfate slow releasing capsule body giving drugs into nose.
Curve when Fig. 3, embodiment 18 carvedilol sulfate slow releasing capsule body giving drugs into nose.
Curve during the body giving drugs into nose of Fig. 4, the Coreg CR of GSK company.
The specific embodiment
Slow releasing preparation drug release determination method
When the present invention spends in the release of mensuration slow releasing preparation,, adopt the device of dissolution method second method, release medium 900ml according to 2005 editions two appendix XD first methods of Chinese Pharmacopoeia; Rotating speed is 100rpm, and temperature is 37 ℃, respectively through 1,4; 8,12,18,24 hours; Get solution 6ml, carry out HPLC as test liquid and measure, calculate the burst size of every capsules at different time.Employed release medium is the 0.1mol/L hydrochloric acid solution.
The preparation of embodiment 1 sulphuric acid carvedilol monohydrate
Be exemplary illustration preparation effect of the present invention, the application's embodiment is content and the effect that example compares the explanation invention with carvedilol sulfate monohydrate.
The embodiment 25 of International Application No. WO 2005051322 has provided the method for preparing of sulphuric acid carvedilol.Those skilled in the art can prepare pharmaceutical raw material according to the record of above-mentioned document.The employed carvedilol sulfate of the application embodiment monohydrate is the carvedilol sulfate monohydrate for preparing according to following method.
In the 50L agitated reactor, drop into carvedilol 2.7kg, acetone 26.3kg, 35 ℃ were stirred 20 minutes; Dissolving slowly adds the aqueous solution 4.1kg that contains 98% sulphuric acid 182ml, stirs 1 hour; Be cooled to 0-10 ℃ and stirred 2 hours, centrifugally get rid of filter, filter cake was with acetone (1: 1; V/V) hot air circulation drying oven is put in 1.5L * 2 washings, and 50 ℃ of dryings are no less than 12 hours.Get sulphuric acid carvedilol monohydrate 2.68kg～2.9kg, yield 87%～94%, purity >=99%.These article are about 101 ℃ of incipient meltings, and sample becomes similar dope then, until about 184 ℃, become supernatant liquid.
The carvedilol slow releasing preparation of embodiment 2 International Application No. WO 2005051322
Embodiment according to International Application No. WO 2005051322 prepares carvedilol sulfate slow releasing preparation.
The fast release micropill prescription
| Carvedilol sulfate monohydrate | 9g |
| PVP | 2g |
PVP adding carvedilol soluble in water sulfate is made drug suspension, use the Glatt fluid bed that drug suspension is sprayed on ball in the heart.
Postpone releasing micropills I prescription
| Carvedilol sulfate monohydrate | 27g |
| Cross-linked pvp | 30g |
| PVP | 30g |
| Cremophor?RH?40 | 2g |
With carvedilol sulfate, cross-linked pvp, PVP, the Cremophor RH 40 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, hydrogenated vegetable oil (Lubritab) are prepared coating solution with an amount of magnesium stearate with 95% ethanol in 75: 25 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares delay releasing micropills I in the heart.
Postpone releasing micropills II prescription
| Carvedilol sulfate monohydrate | 36g |
| Cross-linked pvp | 12g |
| PVP | 12g |
| Cremophor?RH?40 | 3g |
With carvedilol sulfate, cross-linked pvp, PVP, the Cremophor RH 40 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, EudragitS100 hydrogenated vegetable oil (Lubritab) are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 25: 35: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.Fast release micropill, delay releasing micropills I and three kinds of micropills of delay releasing micropills II prepare final slow releasing capsule in 1: 3: 4 ratio fill capsule of drug loading.Measure its release degree in 0.1mol/LHCl, the result sees table 3 and Fig. 1.
The result can find out from the release degree; Sample according to the enforcement of International Application No. WO 2005051322 preparation; 1 hour mainly is after fast release micropill has discharged medicine; Postpone releasing micropills I and postpone releasing micropills II and basically no longer discharge medicine, confirmed and postpone releasing micropills I in the International Application No. WO 2005051322 and when pH5.5, begin to discharge, when pH6.4, begin to discharge and postpone releasing micropills II.But the final release of medicine is incomplete.
Embodiment 3
Preparation 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 |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, Eudragit S100, Oleum Ricini are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 35: 25: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.Measure its release degree.The result sees Fig. 1.
Can find out that from this release profiles slow-release micro-pill of the present invention has tangible 24 hours sustained releasing character 0.1mol/L hydrochloric acid.Slow-release micro-pill initial stage drug release of the present invention is slower, behind 1h, just begins slowly to discharge medicine.After increasing the fast release micropill part, these article also can discharge medicine rapidly effectively at the release initial stage, make can reach effective blood drug concentration rapidly after taking medicine.
Embodiment 4
Preparation 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 |
PVP adding carvedilol soluble in water sulfate, cross-linked pvp and Lutrol F 68 are made drug suspension, use the Glatt fluid bed that drug suspension is sprayed on ball in the heart.
The slow-release micro-pill that the fast release micropill of getting the foregoing description 4 preparation and embodiment 3 prepare in 1: 4 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 3.
Embodiment 6
The slow-release micro-pill that the fast release micropill of getting the foregoing description 4 preparation and embodiment 3 prepare in 1: 5.5 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 3.
Embodiment 7
The slow-release micro-pill that the fast release micropill of getting the foregoing description 4 preparation and embodiment 3 prepare in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 3.See Fig. 1 with the release profiles contrast of the slow releasing capsule of embodiment 2 preparation.
Embodiment 8
The slow-release micro-pill that the fast release micropill of getting the foregoing description 4 preparation and embodiment 3 prepare in 1: 8.5 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 3.
Embodiment 9
The slow-release micro-pill that the fast release micropill of getting the foregoing description 4 preparation and embodiment 3 prepare in 1: 10 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 3.
Preparation 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 |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, Eudragit S100, Oleum Ricini are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 25: 35: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.Measure its release degree.The result sees Fig. 1.
Conclusion: can find out the increase along with fast release micropill part content of dispersion, the initial stage burst size of these article obviously increases, and the rate of release at initial stage is too fast, causes the prominent phenomenon of releasing of medicine to increase drug risk easily; Along with the minimizing of fast release micropill part content of dispersion, the initial stage burst size of these article obviously reduces, and the rate of release at initial stage is slow excessively, is difficult to rise rapidly onset.These article fast release micropill and slow-release micro-pill part content of dispersion are 1: 4 or 1: though also can use in 10 o'clock, if in order to be effective better, preferably the two proportion control is 1: between the 5.5-8.5, be 1: 7 through relatively finding the optimization ratio.
Reach releasing effect preferably, the ratio of the polymer that uses in the slow release layer of slow-release micro-pill must be controlled.Can find out that by experimental result the consumption of first kind polymer need be higher than the consumption of second base polymer, just can reach the releasing effect of slow-release micro-pill of the present invention.If the consumption of second base polymer is higher than first kind polymer, then the releasing effect of slow-release micro-pill is relatively poor, and the slow releasing preparation that contains slow-release micro-pill is difficult to reach the release request of expection.
Embodiment 11
Slow releasing preparation by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
The fast release micropill prescription:
| Carvedilol sulfate monohydrate | 9g |
| PVP | 2.7g |
PVP adding carvedilol soluble in water sulfate is made drug suspension, use the Glatt fluid bed that drug suspension is sprayed on ball in the heart.
The slow-release micro-pill prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Cremophor?RH?40 | 5g |
With carvedilol sulfate, cross-linked pvp, PVP, the Cremophor RH 40 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, EudragitS100, triethyl citrate are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 40: 25: 35 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.Prepare in 1: 7 ratio fill capsule of drug loading in fast release micropill and slow release, measure the release degree, the result sees table 3.
Table 3 release degree result
Embodiment 12
Slow releasing preparation by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol?F?68 | 4.725g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, Eudragit S100, diethyl phthalate are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 35: 25: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.
The fast release micropill that slow-release micro-pill and the embodiment 4 of preparation prepared in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 4.
Embodiment 13
Slow releasing preparation slow release ball prescription by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol?F?68 | 4.725g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again with hydroxypropyl methyl cellulose phthalate (HPMCP; HP-55), Eudragit S100, Oleum Ricini prepare slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 35: 25: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.
The fast release micropill that slow-release micro-pill and the embodiment 4 of preparation prepared in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 4.
Embodiment 14
Slow releasing preparation by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol?F?68 | 4.725g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again with hydroxypropyl methylcellulose acetate succinate (HPMCAS; The L type), hydroxypropyl methylcellulose acetate succinate (HPMCAS; The H type), Oleum Ricini prepares the slow release layer coating solution in 35: 25: 40 ratio and an amount of magnesium stearate with 95% ethanol, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.
The fast release micropill that slow-release micro-pill and the embodiment 4 of preparation prepared in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 4.
Slow releasing preparation by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol?F?68 | 4.725g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, ethyl cellulose, Oleum Ricini are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 40: 20: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.
The fast release micropill that slow-release micro-pill and the embodiment 4 of preparation prepared in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 4.
Embodiment 16
Slow releasing preparation by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol?F?68 | 4.725g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100, Eudragit RS, Oleum Ricini are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 40: 20: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.
The fast release micropill that slow-release micro-pill and the embodiment 4 of preparation prepared in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 4.
Embodiment 17
Slow releasing preparation by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| ?Lutrol?F?68 | 4.725g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100, Eudragit RL, Oleum Ricini are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 40: 20: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.The fast release micropill that slow-release micro-pill and the embodiment 4 of preparation prepared in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 4.
Embodiment 18
Slow releasing preparation by carvedilol sulfate fast release micropill and slow-release micro-pill preparation
Slow release ball prescription
| Carvedilol sulfate monohydrate | 63g |
| Cross-linked pvp | 18.9g |
| PVP | 18.9g |
| Lutrol?F?68 | 4.725g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, NATROSOL 250, Oleum Ricini are prepared slow release layer coating solution with an amount of magnesium stearate with 95% ethanol in 40: 20: 40 ratio, with the Glatt fluid bed coating solution is sprayed on the medicine carrying ball and prepares slow-release micro-pill in the heart.The fast release micropill that slow-release micro-pill and the embodiment 4 of preparation prepared in 1: 7 ratio fill capsule of drug loading, and is measured its release in fast release micropill and slow release, and the result sees table 4.
Table 4 release degree result
Conclusion: can not play too big influence though it has been generally acknowledged that the plasticizer in the coatings, can find out, when selecting some plasticizer, can more optimize to the releasing effect of slow-release micro-pill of the present invention through above-mentioned experiment to the character of coating.See that from measuring the result compare other plasticizers, Oleum Ricini, triethyl citrate, diethyl phthalate can both make the releasing effect of slow releasing preparation better, particularly Oleum Ricini is best suited for plasticizer of the present invention.
Investigate through the test of the polymer 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, cellulose acetate phthalate ester (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 of first kind polymer manufacture slow-release micro-pill; Eudragit S100, EudragitRL, Eudragit RS, Acrycoa S100, hydroxypropyl methylcellulose acetate succinate (HPMCAS; The H type), carboxymethylethylcellulose (CMEC) and ethyl cellulose polymer properties such as (EC) be similar, all can be used as the polymeric material that second base polymer prepares slow-release micro-pill.Can be used between these polymer of this first and second type, the slow-release micro-pill of preparing all has good slow release effect.See from experimental result; First and second best base polymer of result of use still is that first-selected Eudragit L100-55 and Eudragit S100 are used; 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
Preparation carvedilol sulfate enteric coated micropill
The enteric coated pill prescription
| Carvedilol sulfate monohydrate | 7.2g |
| Cross-linked pvp | 2.16g |
| PVP | 2.16g |
| Lutrol?F?68 | 0.54g |
With carvedilol sulfate, cross-linked pvp, PVP, the Lutrol F 68 compounding pharmaceutical suspensions of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, Oleum Ricini, magnesium stearate, are sprayed on the medicine carrying ball with the Glatt fluid bed with coating solution and prepare enteric coated micropill in the heart with 95% ethanol preparation slow release layer coating solution in the ratio that is fit to.
Get the fast release micropill of the foregoing description 4 preparation, the enteric coated micropill of embodiment 19 preparations and the slow-release micro-pill of embodiment 3 preparations, in 1: 1: 5 ratio fill capsule of drug loading, and measure its release in fast release micropill and slow release, the result sees table 5.
Embodiment 21
Get the fast release micropill of the foregoing description 4 preparation, the enteric coated micropill of embodiment 19 preparations and the slow-release micro-pill of embodiment 3 preparations, in 1: 1: 6 ratio fill capsule of drug loading, and measure its release in fast release micropill and slow release, the result sees table 5.
Embodiment 22
Get the fast release micropill of the foregoing description 4 preparation, the enteric coated micropill of embodiment 19 preparations and the slow-release micro-pill of embodiment 3 preparations, in 1: 1: 7 ratio fill capsule of drug loading, and measure its release in fast release micropill and slow release, the result sees table 5.
Embodiment 23
Get the fast release micropill of the foregoing description 4 preparation, the enteric coated micropill of embodiment 19 preparations and the slow-release micro-pill of embodiment 3 preparations, in 1: 1: 8 ratio fill capsule of drug loading, and measure its release in fast release micropill and slow release, the result sees table 5.
Embodiment 24
Preparation carvedilol sulfate enteric coated micropill
The enteric coated micropill prescription:
| Carvedilol sulfate monohydrate | 9g |
| Cross-linked pvp | 9g |
| PVP | 4.5g |
| Cremophor?RH?40 | 0.72g |
With carvedilol sulfate, cross-linked pvp, PVP, the Cremophor RH40 compounding pharmaceutical suspension of recipe quantity, use the Glatt fluid bed that drug suspension is sprayed on ball and prepare the medicine carrying ball heart in the heart, make drug loading between 10%～50%.Again Eudragit L100-55, triethyl citrate, magnesium stearate, are sprayed on the medicine carrying ball with the Glatt fluid bed with coating solution and prepare enteric coated micropill in the heart with 95% ethanol preparation slow release layer coating solution in the ratio that is fit to.
Get the fast release micropill of the foregoing description 11 preparation, the enteric coated micropill of embodiment 24 preparations and the slow-release micro-pill of embodiment 11 preparations, in 1: 1: 8 ratio fill capsule of drug loading, and measure its release in fast release micropill and slow release, the result sees table 5.
Table 5 release degree result
Conclusion: after can finding out the interpolation 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 the slow-release micro-pill content of dispersion, medicine finally can not discharge fully.Therefore these article fast release micropill, enteric coated micropill and slow-release micro-pill part content of dispersion are 1: 1: 6-8 can realize utilizing enteric coated micropill to optimize releasing effect, and experimental result finds that it is best that the 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 preparations is carried out the pharmacokinetics test of Beagle dog, and the result sees Fig. 2,3, curve when Fig. 4 is the body giving drugs into nose of the Coreg CR of GSK company.
Can find out from the comparison of Fig. 2, Fig. 3 and Fig. 4; This patent embodiment 7 and 23 sulphuric acid carvedilol slow releasing capsule present a level and smooth medicine in vivo the time curve; Has only a blood drug level peak; And there are two blood drug level peaks in GlaxoSmithKline PLC company carvedilol phosphate salts slow releasing preparation curve when presenting the medicine of a two-phase in vivo.
Claims (29)
1. slow-release micro-pill, this slow-release micro-pill contains drug-loaded layer and slow release layer,
Said drug-loaded layer contains carvedilol sulfate analog, and carvedilol sulfate analog is selected from one or more in carvedilol sulfate or the carvedilol sulfate hydrate;
Said slow release layer makes this slow-release micro-pill in the pH1.0 medium, discharge 0-30% carvedilol sulfate 1 hour the time; In the time of 8 hours, discharge 25%～90% carvedilol sulfate; In the time of 24 hours, discharge greater than 75% carvedilol sulfate; Contain two types of film property polymer in this slow release layer; First kind polymer has been to dissolve point at pH5-6 and be higher than dissolved polymers under the condition of this pH, and second base polymer has been to dissolve to put to be pH6.5-7.5 and to be higher than dissolved polymers or water-insoluble polymer under the condition of this pH that first kind polymer proportion is greater than the second base polymer proportion.
2. slow-release micro-pill according to claim 1; Wherein said slow release layer makes this slow-release micro-pill in the pH1.0 medium, discharge 0-10% carvedilol sulfate 1 hour the time; In the time of 8 hours, discharge 35%～70% carvedilol sulfate, in the time of 24 hours, discharge greater than 85% carvedilol sulfate.
3. slow-release micro-pill according to claim 1 and 2, wherein said first and second base polymer is selected from one or more acrylic resin base polymer or cellulose derivatives,
Preferably; Said first kind polymer is selected from one or more Eudragit L100-55, Eudragit L100, Acrycoat L100D, cellulose acetate phthalate ester (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS, L type or M type); Second base polymer is selected from one or more EudragitS100, Eudragit RL, Eudragit RS, Acrycoa S100, hydroxypropyl methylcellulose acetate succinate (HPMCAS, H type), carboxymethylethylcellulose (CMEC) or ethyl cellulose (EC).
4. according to any described slow-release micro-pill of claim 1-3, contain one or more plasticizers in the wherein said slow release layer, the plasticizer that send is selected from triethyl citrate, Oleum Ricini or diethyl phthalate, and preferred plasticizer is an Oleum Ricini.
5. slow-release micro-pill according to claim 4, the weight ratio of wherein said plasticizer in slow release layer is 25-50%, and be preferred 30～50%, most preferably 35～40%.
6. according to claim 4 or 5 described slow-release micro-pill, 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, is preferably 30～40%; It is 10～30% that second base polymer accounts for three's gross weight ratio, preferred 20～35%.
7. according to any described slow-release micro-pill of claim 1-6; Two types of film property polymer in the wherein said slow release layer all are the acrylic resin base polymers; Preferably contain EUDRAGIT S100 C type (Eudragit L100-55) and EUDRAGIT S100 Type B (EudragitS100), most preferably film forming polymer is EUDRAGIT S100 C type (Eudragit L100-55) and EUDRAGIT S100 Type B (Eudragit S100).
8. slow-release micro-pill according to claim 7; The weight ratio of wherein said EUDRAGIT S100 C type (Eudragit L100-55) in slow release layer is 30～45%, and the weight ratio of EUDRAGIT S100 Type B (Eudragit S100) in slow release layer is 20～30%.
9. according to any described slow-release micro-pill of claim 1, contain EUDRAGIT S100 C type (Eudragit L100-55), EUDRAGIT S100 Type B (Eudragit S100) and Oleum Ricini in the wherein said slow release layer.
10. slow-release micro-pill according to claim 9; Wherein with EUDRAGIT S100 C type (Eudragit L100-55), EUDRAGIT S100 Type B (Eudragit S100) and the total restatement of Oleum Ricini; EUDRAGIT S100 C type (Eudragit L100-55) is 30～40%; EUDRAGIT S100 Type B (Eudragit S100) is 20～30%, and Oleum Ricini is 30～40%.
11. slow-release micro-pill according to claim 1 in the wherein said drug-loaded layer, contains one or more of binding agent, sweller, solubilizing agent.
12. slow-release micro-pill according to claim 11, in the wherein said drug-loaded layer,
Binding agent is a polyvidon; Or/and
Sweller is a cross-linked pvp; Or/and
Solubilizing agent is selected from and is in poloxamer 188 (Lutrol F 68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40) or the polyglycol distearate 15 (Solutol HS 15) one or more.
13. slow-release micro-pill according to claim 1, wherein said carvedilol sulfate analog is a carvedilol sulfate monohydrate.
14. slow-release micro-pill according to claim 1, wherein said carvedilol sulfate analog is in carvedilol sulfate, and its content is 7-72mg.
15. slow releasing preparation that contains carvedilol sulfate analog; Wherein contain the fast release micropill and any described slow-release micro-pill of claim 1-14 of carvedilol sulfate analog, carvedilol sulfate analog is selected from one or more in carvedilol sulfate or the carvedilol sulfate hydrate.
16. slow releasing preparation according to claim 15; Wherein this carvedilol sulfate slow releasing preparation is made up of fast release micropill and slow-release micro-pill; The content of dispersion of fast release micropill part is 10%～20% of an accumulated dose weight, and the content of dispersion that slow release is released the micropill part is 80%～90% of an accumulated dose weight.
17. slow releasing preparation according to claim 15, wherein the part by weight of the medicament contg of the fast release micropill of this carvedilol sulfate slow releasing preparation part and slow-release micro-pill part is 1: 5-9, preferred 1: 5.5-8.5, preferably 1: 7.
18. slow releasing preparation according to claim 15 also contains the enteric coated micropill of carvedilol sulfate in the wherein said slow releasing preparation.
19. slow releasing preparation according to claim 18; The content of dispersion of wherein said fast release micropill part is 10%～15% of an accumulated dose weight; The content of dispersion of enteric coated micropill part is 10%～15% of an accumulated dose weight, and the content of dispersion that slow release is released the micropill part is 70%～80% of an accumulated dose weight.
20. slow releasing preparation according to claim 18; Wherein the part by weight of the medicament contg of the fast release micropill of this carvedilol sulfate slow releasing preparation part, enteric coated micropill part and slow-release micro-pill part is 0.9-1.1: 0.9-1.1: 6-10; Preferred 1: 1: 6-8, preferably 1: 1: 8.
21. slow releasing preparation according to claim 18, 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.
22. slow releasing preparation according to claim 15 wherein only contains two kinds of micropills of fast release micropill and slow-release micro-pill and when not containing enteric coated micropill, it is that 1.1mg is to 9mg that fast release micropill partly contains carvedilol sulfate; It is that 7.8mg is to 63mg that slow-release micro-pill contains carvedilol sulfate.
23. according to any described slow releasing preparation of claim 15-18, wherein said fast release micropill partly contains drug-loaded layer, wherein said drug-loaded layer contains one or more in binding agent, sweller, the solubilizing agent, preferably contains three kinds of compositions simultaneously.
24. slow releasing preparation according to claim 23; 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 poloxamer 188 (Lutrol F 68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40) or the polyglycol distearate 15 (Solutol HS 15).
25. according to any described slow releasing preparation of claim 18-21, wherein said enteric coated micropill contains drug-loaded layer and enteric layer, wherein said drug-loaded layer contains one or more in binding agent, sweller, the solubilizing agent; At least contain a kind of enteric solubility film property polymer in the described enteric layer, preferred enteric layer contains plasticizer.
26. slow releasing preparation according to claim 25; Binding agent in the 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 poloxamer 188 (Lutrol F 68), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH 40) or the polyglycol distearate 15 (Solutol HS 15).
27. slow releasing preparation according to claim 25, 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, Acrycoa S100, cellulose acetate phthalate ester (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC) or the Lac.
28. slow releasing preparation according to claim 25, 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 the diethyl phthalate.
29. slow releasing preparation according to claim 25, the film property high molecular polymer of wherein said enteric coated micropill enteric layer are EUDRAGIT S100 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 |
| CN108707204A (en) * | 2018-07-04 | 2018-10-26 | 吉林大学 | Hydrogen peroxide response type targeted medicament carrying nano material and preparation method |
| CN111405895A (en) * | 2017-12-29 | 2020-07-10 | 江苏恒瑞医药股份有限公司 | Controlled release pharmaceutical composition and preparation method thereof |
| CN116725985A (en) * | 2023-06-02 | 2023-09-12 | 石家庄四药有限公司 | Micropill combined urapidil sustained-release capsule and preparation method thereof |
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| 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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| 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 |
| CN111405895A (en) * | 2017-12-29 | 2020-07-10 | 江苏恒瑞医药股份有限公司 | Controlled release pharmaceutical composition and preparation method thereof |
| CN111405895B (en) * | 2017-12-29 | 2022-10-21 | 江苏恒瑞医药股份有限公司 | Controlled release pharmaceutical composition and preparation method thereof |
| CN108707204A (en) * | 2018-07-04 | 2018-10-26 | 吉林大学 | Hydrogen peroxide response type targeted medicament carrying nano material and preparation method |
| CN116725985A (en) * | 2023-06-02 | 2023-09-12 | 石家庄四药有限公司 | Micropill combined urapidil sustained-release capsule 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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