CN102579405A - Ticlopidine hydrochloride sustained-release capsule and preparation method thereof - Google Patents
Ticlopidine hydrochloride sustained-release capsule and preparation method thereof Download PDFInfo
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- CN102579405A CN102579405A CN2012100209874A CN201210020987A CN102579405A CN 102579405 A CN102579405 A CN 102579405A CN 2012100209874 A CN2012100209874 A CN 2012100209874A CN 201210020987 A CN201210020987 A CN 201210020987A CN 102579405 A CN102579405 A CN 102579405A
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Abstract
The invention discloses a sustained-release capsule containing ticlopidine hydrochloride and a preparation method thereof. The ticlopidine hydrochloride sustained-release capsule consists of a sustained-release micropill and a hollow capsule, and the sustained-release micropill comprises the following components by weight percent: 75 to 97 percent of drug-contained pellet and 3 to 25 percent of sustained-release coating layer. The ticlopidine hydrochloride sustained-release capsule consists of tens of thousands of sustained-release micropills with homogenous size, mistake or flaw of individual micropill on the preparation are free from producing serious influencing on the drug release action of the entire medicine, so that the sustained-release capsule is safer than a sustained-release tablet, smaller irritation on the stomach and intestines is caused, drug blood concentration is more stable, bioavailability is higher, and the drug can be continuously released in 12 hours to resist thrombus. The drug-contained pellets are prepared through an extruding rolling method, and a fluidized bed is used for coating the sustained-releasing coating layer, so that the technique is simple, and industrialized mass production is easy to realize.
Description
Technical field
The present invention relates to the technical field of ticlopidine hydrochloride slow releasing preparation, relate in particular to a kind of ticlopidine hydrochloride slow releasing capsule and preparation method thereof.It belongs to a kind of slow releasing preparation of antithrombotic.
Background technology
Thrombotic disease is because the lumen of vessels that causes of thrombosis is narrow and inaccessible, makes main organs generation ischemia and infraction and causes the various diseases of malfunction.It belongs to is cardiovascular and cerebrovascular disease, and cardiovascular and cerebrovascular diseases such as global annual cerebral thrombosis, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis seize 1,200 ten thousand people's life, near 1/4 of the total death toll in the world, become the No.1 formidable enemy of human health.The number that China dies from cardiovascular and cerebrovascular disease every year reaches more than 2,600,000 people, and the patient of survival 75% is disabled, and is wherein heavy residual more than 40%; And the morbidity crowd of cerebral thrombosis apoplexy reaches 7,000,000; Wherein 1,000,000 people are dead, and most of survivor leaves sequela, need long-term being in hospital or family's treatment.Antithrombotic is used for the prevention and the treatment of thrombotic disease, and to put prevention first, clinical treatment and the prevention that is mainly used in acute myocardial infarction and apoplexy thromboembolism can reduce infraction rate and mortality rate again; Can be used for preventing the treatment of cardiac valve replacement postoperative thrombosis, periphery obliterative vascular disease, intermittent claudication, unstable angina pectoris etc.Antithrombotic is divided into anticoagulant, platelet aggregation inhibitor and thrombolytic medicine.
Ticlopidine (Ticlopidine) is an anticoagulant.Hematoblastic activation receives influence of various factors, and wherein adenosine diphosphate (ADP) (ADP) plays a crucial role.When adenosine diphosphate (ADP) with after its specific receptor combines, but the fibrinogen deceptor (glycoprotein IIB-IIIa complex) on activated blood platelet film surface and makes its binding fiber proteinogen and then causes platelet aggregation (the I phase assembles).In addition, can discharge adenosine diphosphate (ADP) again behind the platelet activation, cause platelet further to assemble (the II phase assembles).Ticlopidine has powerful inhibitory action to the inductive platelet aggregation of ADP (comprise I phase and II phase assemble), and persistent.In addition, ticlopidine can reduce fibrinogen concentration and viscosity of blood, and improves whole blood and erythrocytic filtration rate.Be used for the thromboembolism that prevention of brain blood vessel, cardiovascular and peripheral arteriosclerosis occur together clinically; Comprising first and carbuncle in the occipital region apoplexy again; Temporal cerebral ischemia seizure and uniocular vision disappearance, coronary heart disease and intermittent claudication etc.; When also can be used for the cardiac surgery operation extracorporeal circulation, lose with the prevention platelet.
The dissolubility of ticlopidine hydrochloride in water is about 76mg/ml, and pKa value 7.64 is height dissolving high osmosis (ClassI class) medicine, and the half-life is 6 hours, and oral back is prone to absorb, and protein binding rate is 98%, and bioavailability is about 80%.Its biopharmaceutics characteristic shows the suitable slow releasing preparation that is developed as.
The combination of ticlopidine composition (patent No.: US20090297597, WO2007011473 that accent is released; ELAN drugmaker); That describe is ticlopidine hydrochloride slow releasing preparation and the preparation technology thereof who discharged in 12 hours once a day; This slow releasing preparation contains the ticlopidine hydrochloride granule of rapid release and the ticlopidine hydrochloride granule of slow release; Both mix the back according to a certain percentage and form, and oral back immediate release section can provide the drug level that reaches treatment fast, and slow-released part can slowly discharge the treatment concentration that medicine was kept 12 hours.
Domestic existing ticlopidine hydrochloride slow releasing tablet is produced listing, belongs to matrix sustained release tablet, and slow releasing tablet partial breakage and defective when producing can cause the prominent of total formulation to release generation, so safety is relatively poor.Temporarily do not have slow releasing capsule production listing and registration to declare, the ticlopidine hydrochloride slow releasing capsule that develop once a day, 12 hours discharges has the good clinical application advantage.
Summary of the invention
The objective of the invention is to overcome the shortcoming and defect of prior art, a kind of have persistent, medicining times is few, blood drug level is steady, safety is higher ticlopidine hydrochloride slow releasing capsule are provided.Based on this, the present invention also provides a kind of method for preparing of ticlopidine hydrochloride slow releasing capsule.
The diameter that micropill is made up of medicine and adjuvant is about the miniature spherical entity of 1mm; According to different therapeutic doses and requirement; Micropill is that the medicine with dose is dispersed in 1,100 miniature spherical compartments; Error or the defective of indivedual micropills in preparation is unlikely to the drug release behavior of whole preparation is affected greatly, and significantly reduced the prominent generation of releasing of medicine.There is bigger contact surface the oral back of micropill with the gastrointestinal tract surface, and absorption is good and little to partial zest, and simultaneously, micropill is different with tablet, and the former does not receive the gastric emptying factor affecting basically, so the infiltration rate of medicine is even, individual bioavailability difference is also little.Micropill has advantages such as particle diameter is even, good fluidity, difficult crushing; Particularly the fine pellet core surface coatings, to process location, sustained-release preparation, technology simple; Can avoid coatings such as other solid preparations such as tablet inhomogeneous, may cause that the medicine sky is released, the risk of pulse.By the slow releasing capsule that the micropill of different pharmaceutical is formed, can increase advantages such as stability of drug, raising curative effect, reduction poisonous side effect of medicine.
For solving above technical problem, technical scheme of the present invention is:
A kind of slow releasing capsule of ticlopidine hydrochloride is made up of slow-release micro-pill and Capsules two parts, counts by weight percentage, and said slow-release micro-pill is made up of 75～97% the sustained release coating layer that contains pill core and 3～25%, wherein:
Containing pill core comprises: ticlopidine hydrochloride 40～65% and excipient 27～57%, binding agent 3～8%, more than the percentage by weight of each component all to contain the total weight of pill core.
The sustained release coating layer comprises: slow-release material 3～25%, antiplastering aid 15～80%, plasticizer 10～30%, porogen 3～30% and opacifier 0.5～5%; More than in each component; The percentage by weight of slow-release material to be containing the total weight of pill core, and the percentage by weight of antiplastering aid, plasticizer, porogen and opacifier is all with the total weight of slow-release material.
Preferably, said excipient is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, starch, dextrin, the sucrose.
Preferably, said binding agent is one or more the mixture in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, the carboxymethyl cellulose.
Said slow-release material is methacrylic resin polymer or ethyl cellulose; Preferably; The methacrylic resin polymer is one or more the mixture among Eudragit NE30D, Eudragit RS30D, Eudragit RL30D, Eudragit RS, the Eudragit RL, and ethyl cellulose is Surelease or Aquacoat.
Preferably, said antiplastering aid is one or more the mixture in Pulvis Talci, magnesium stearate, silicon dioxide, the titanium dioxide.
Preferably, said plasticizer is one or more the mixture in diethyl phthalate, dibutyl phthalate, triethyl citrate, ATBC, dibutyl sebacate, the glycerol.
Preferably, said porogen is one or more the mixture in lactose, polyvinylpyrrolidone, polyethylene glycols, the hydroxypropyl emthylcellulose.
Preferably, said opacifier is one or more the mixture in titanium dioxide, color lake, the ferrum oxide.
The release in vitro degree of the ticlopidine hydrochloride slow releasing capsule that above-mentioned optimizing prescriptions makes is: 1 hour 25～50%, and 2 hours 45～70%, 6 hours＞75%.
Preferably, described ticlopidine hydrochloride slow releasing capsule adopts extrudes the spheronization preparation, comprises the steps:
(1) contain the preparation of pill core: with ticlopidine hydrochloride and excipient mix homogeneously, the purification of aqueous solutions that adds binding agent is processed soft material, adopts to extrude spheronization and process 20～40 purposes and contain pill core, drying.
(2) bag slow release layer: will contain pill core and place fluid bed, bag sustained release coating liquid makes slow-release micro-pill.
(3) ripening: slow-release micro-pill was placed 35 ℃～55 ℃ baking oven matured 8～24 hours.
(4) process capsule: the slow-release micro-pill after the ripening is filled in the Capsules.
Device parameter in the coating process, intake 20～30HZ, EAT are 35～55 ℃, and temperature of charge is 25～45 ℃, and atomizing pressure is 1.0bar, and hydrojet speed is 2～4g/min.
Thermostatic drying chamber is adopted in ripening, and temperature is controlled at 30 ℃～50 ℃, and the curing time is 8～24 hours.
The ticlopidine hydrochloride slow releasing capsule that the present invention makes is made up of 1,100 uniform slow-release micro-pill of particle diameter; Error or the defective of indivedual micropills in preparation is unlikely drug release behavior to total formulation and produces and have a strong impact on; Therefore more safer than slow releasing tablet, littler to the gastrointestinal zest, blood drug level is more steady; Bioavailability is higher, and taking 1 time in one day can lasting release in 12 hours.
Method for preparing employing of the present invention is extruded round as a ball method preparation and is contained pill core, and particle diameter is 20～40 orders, adopts fluid bed bag sustained-release coating layer, and technology is simple, is easy to industrialized great production.
Description of drawings
Fig. 1～Fig. 3: the ticlopidine hydrochloride slow releasing capsule that makes for the embodiment of the invention one～embodiment three releasing curve diagram of 1,2,4,6,8,12 hour in external multiple release medium.
The specific embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, the present invention is done further detailed description below in conjunction with specific embodiment.
Embodiment one:
1, contain the preparation of pill core:
Preparation technology: with the method mix homogeneously that ticlopidine hydrochloride and microcrystalline Cellulose, lactose adopt equivalent to increase progressively, process soft material, adopt and extrude round as a ball machine-processed micropill with purified water; The sieve plate particle diameter is 0.8mm, and 60 ℃ of oven dryings sieve; Choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
The Sulisi of recipe quantity is joined in the purified water, it is fully disperseed, stir 45min, will contain pill core and place fluid bed, adjust each technological parameter, guarantee fluidized state, coating increases weight to 10%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 45～55 ℃, temperature of charge: 40～45 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 50 ℃ of baking oven matured 12 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours; Measure trap, calculating cumulative release degree with the UV method in the 233nm wavelength.The result is following:
Embodiment two:
1, contain the preparation of pill core:
Preparation technology: with the method mix homogeneously that ticlopidine hydrochloride and lactose, microcrystalline Cellulose adopt equivalent to increase progressively, process soft material, adopt and extrude round as a ball machine-processed micropill with purified water; The sieve plate particle diameter is 0.8mm, and 60 ℃ of oven dryings sieve; Choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
With the Pulvis Talci and the titanium dioxide of recipe quantity, join and stir 45min in the purified water, add the strange NE30D aqueous dispersion of You Te it is fully disperseed, continue to stir 45min, subsequent use.To contain pill core and place fluid bed, and regulate each technological parameter, and guarantee fluidized state, coating increases weight to 3%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 35～45 ℃, temperature of charge: 30～35 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 40 ℃ of baking oven matured 24 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours; Measure trap, calculating cumulative release degree with the UV method in the 233nm wavelength.The result is following:
Embodiment three:
1, contain the preparation of pill core:
Preparation technology: with the method mix homogeneously that ticlopidine hydrochloride and microcrystalline Cellulose, mannitol adopt equivalent to increase progressively, PVP-K30 is dissolved in the purified water, and above-mentioned mixed powder is processed soft material; Round as a ball machine-processed micropill is extruded in employing; The sieve plate particle diameter is 0.8mm, and 60 ℃ of oven dryings sieve; Choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
With the Pulvis Talci and the titanium dioxide of recipe quantity, join and stir 45min in the purified water, add triethyl citrate, the strange RS30D of You Te and RL30D aqueous dispersion it is fully disperseed, continue to stir 45min, subsequent use.To contain pill core and place fluid bed, and regulate each technological parameter, and guarantee fluidized state, coating increases weight to 10%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 35～45 ℃, temperature of charge: 30～35 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 40 ℃ of baking oven matured 24 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours; Measure trap, calculating cumulative release degree with the UV method in the 233nm wavelength.The result is following:
Compliance test result
External release test:
Get slow releasing capsule that embodiment one, two, three makes as sample; Pressing the UV method detects; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium, carried out the release in vitro degree respectively at 1,2,4,6,8,12 hour and measure, detect among data and Fig. 1～Fig. 3 and can find out by the release degree; 3 lot sample article discharge in 12 hours evenly in multiple release medium; All meet one-level release dynamic process, be illustrated in the external slow release characteristic that has, the further research of release in the body.
More than the present invention has been carried out detailed introduction, use concrete example in the literary composition principle of the present invention and embodiment set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (4)
1. the slow releasing capsule of a ticlopidine hydrochloride is characterized in that, is made up of slow-release micro-pill and Capsules two parts, counts by weight percentage, and said slow-release micro-pill is made up of 75～97% the sustained release coating layer that contains pill core and 3～25%, wherein:
Containing pill core comprises: ticlopidine hydrochloride 40～65%, excipient 27～57%, binding agent 3～8%, more than the percentage by weight of each component to contain the total weight of pill core.
The sustained release coating layer comprises: slow-release material 3～25%, antiplastering aid 15～80%, plasticizer 10～30%, porogen 3～30% and opacifier 0.5～5%; More than in each component; The percentage by weight of slow-release material to be containing the total weight of pill core, and the percentage by weight of antiplastering aid, plasticizer, porogen and opacifier is all with the total weight of slow-release material.
2. ticlopidine hydrochloride slow releasing capsule according to claim 1 is characterized in that,
Said excipient is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, starch, dextrin, the sucrose.
Said binding agent is one or more the mixture in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, the carboxymethyl cellulose.
Said slow-release material is one or more a mixture of methacrylic resin polymer or ethyl cellulose.
Said antiplastering aid is one or more the mixture in Pulvis Talci, magnesium stearate, silicon dioxide, the titanium dioxide.
Said plasticizer is one or more the mixture in diethyl phthalate, dibutyl phthalate, triethyl citrate, ATBC, dibutyl sebacate, the glycerol.
Said porogen is one or more the mixture in lactose, polyvinylpyrrolidone, polyethylene glycols, the hydroxypropyl emthylcellulose.
Said opacifier is one or more the mixture in titanium dioxide, color lake, the ferrum oxide.
3. ticlopidine hydrochloride slow releasing capsule according to claim 1 is characterized in that, the release in vitro degree is: 1 hour 25～50%, and 2 hours 45～70%, 6 hours＞75%.
4. the method for preparing of ticlopidine hydrochloride slow releasing capsule according to claim 1 comprises the steps:
(1) contains the preparation of pill core: with ticlopidine hydrochloride and excipient mix homogeneously, process soft material, adopt and extrude spheronization and process 20～40 purposes and contain pill core, drying with purified water.
(2) bag slow release layer: will contain pill core and place fluid bed, bag sustained release coating liquid makes slow-release micro-pill.
(3) ripening: slow-release micro-pill was placed 35 ℃～55 ℃ baking oven matured 8～24 hours.
(4) process capsule: the slow-release micro-pill after the ripening is filled in the Capsules.
Device parameter in the coating process, intake 20～30HZ, EAT are 35～55 ℃, and temperature of charge is 25～45 ℃, and atomizing pressure is 1.0bar, and hydrojet speed is 2～4g/min.
Thermostatic drying chamber is adopted in ripening, and temperature is controlled at 30 ℃～50 ℃, and the curing time is 8～24 hours.
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| CN2012100209874A CN102579405A (en) | 2012-01-17 | 2012-01-17 | Ticlopidine hydrochloride sustained-release capsule and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277684A (en) * | 2005-09-30 | 2008-10-01 | 弗拉梅技术公司 | Microparticles with modified release of at least one active principle and oral galenic form comprising same |
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
| CN101652128A (en) * | 2007-03-02 | 2010-02-17 | 法纳姆公司 | Sustained release compositions using wax-like materials |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277684A (en) * | 2005-09-30 | 2008-10-01 | 弗拉梅技术公司 | Microparticles with modified release of at least one active principle and oral galenic form comprising same |
| CN101652128A (en) * | 2007-03-02 | 2010-02-17 | 法纳姆公司 | Sustained release compositions using wax-like materials |
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
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