CN104840442A - Sustained-release tablet containing quetiapine fumarate and preparation method of sustained-release tablet - Google Patents
Sustained-release tablet containing quetiapine fumarate and preparation method of sustained-release tablet Download PDFInfo
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Abstract
The invention provides a sustained-release tablet containing quetiapine fumarate. The sustained-release tablet comprises the following components according to weight percent: 12.5% to 60% of the quetiapine fumarate according to quetiapine, 10% to 40% of sustained-release material and other pharmaceutic adjuvants as the rest, wherein the sustained-release material is a composition of carbomer and hydroxyethyl cellulose. After being dosed, the sustained-release tablet can slowly and continuously release as required, so as to maintain the effective treatment concentration, thereby achieving a long-acting effect by dosing once a day. Additionally, according to the sustained-release tablet, a dry granulation tableting process is adopted, the preparation process is simple, large-scale industrial production is facilitated, and the production cost can be effectively reduced.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of slow releasing tablet, particularly a kind of slow releasing tablet containing quetiapine fumarate and preparation method thereof.
Background technology
Quetiapine (Thiazep ine), i.e. 11-[4-[2 (2-hydroxyl-oxethyl) ethyl]-1-piperazinyl] dibenzo-[b, f] [1,4] sulfur azatropylidene, it is a kind of atypical antipsychotic agents, it is various neurotransmitters receptor antagonist in brain, and psychosis mechanism may mainly through blocking central dopamine D
2receptor and 5-HT receptor.Also have blocking effect to histamine receptor and adrenoceptor, abroad clinical using this medicine as treatment schizoid first-line drug.
The pharmacokinetic studies result of Quetiapine ordinary preparation shows, its oral quick absorption, about 1.0-1.8 hour blood drug level peaking, and the elimination half-life is shorter.So all adopt daily 2-3 time during domestic and international clinical treatment schizophrenia, this causes blood concentration fluctuation in patient body, brings larger side effect.Therefore, provide that a kind of to treat by the quetiapine sustained release dosage form of sustained release be the ideal that those skilled in the art pursues always.
Quetiapine sustained release preparation (trade name: Seroquel XR) is taken the lead in going on the market abroad by AstraZeneca, and its patent information is disclosed in the claimed slow releasing preparation containing the hydroxypropyl methylcellulose of 5% ~ 50% (weight) of US5948437 and disclosed Chinese patent CN101360504A.CN101002737A discloses a kind of slow releasing preparation containing Quetiapine and slow release framework material and additives, described sustained-release matrix material comprises hydrophilic gel matrix material, erodible framework material, water-insoluble material, and described erodible framework material is one or more the combination in any in stearic acid, hexadecanol, octadecanol.Claimed a kind of slow (control) release formulation compositions by Quetiapine, organic acid, water-soluble high-molecular material, enteric material, wax class and water-insoluble macromolecular material of CN101091700A; wherein adopt Enteric Materials as functional coatings material; stop medicine stripping in gastric juice, wax class material and water-insoluble macromolecular material are for controlling the drug-eluting in gastric juice or intestinal juice.CN101005829A discloses a kind of multiple novel form containing wax-like materials and effective dose Quetiapine and salt thereof, comprising the dosage form of sustained release.CN101347413A discloses a kind of quetiapine sustained release preparation comprising pH dependent solubility sustained-release matrix material, is divided into common monolayer slow releasing tablet and double-layer sustained release tablets.The framework material that the pH used relies on, it dissolves by the impact of gastrointestinal tract pH, and due to differing greatly of interindividual gastrointestinal tract environment, between the patient of especially all ages and classes, this will cause the variability of preparation body absorption; Slow releasing preparation based on wax class material is due to its water-insoluble characteristic, and the complexity of its preparation technology also limit the use of such material.Above in each disclosed patent, all adopt technique or the one-step palletizing of wet granulation in embodiment, technique is more complicated, and energy consumption is large, adds production cost.
Summary of the invention
One object of the present invention is the slow releasing tablet containing quetiapine fumarate
Another object of the present invention is to provide the preparation method of above-mentioned Quetiapine fumarate sustained-release tablets agent.
The present invention is realized by following technical scheme:
A kind of slow releasing tablet containing quetiapine fumarate, comprise quetiapine fumarate, slow-release material and other pharmaceutic adjuvants, described slow-release material is the compositions of carbomer and hydroxyethyl-cellulose, and each composition weight per distribution ratio is: quetiapine fumarate counts 12.5% ~ 60% by Quetiapine, slow-release material is 10% ~ 40%, and other pharmaceutic adjuvants are surplus.
Above-mentioned containing in the slow releasing tablet of quetiapine fumarate, in described carbomer and the compositions of hydroxyethyl-cellulose, carbomer model is carbopol 971P, and hydroxyethyl-cellulose model is Natrosol 250HX.
Contain in the slow releasing tablet of quetiapine fumarate above-mentioned, with the total weight of described slow releasing tablet, described carbopol 971P is 5% ~ 25%, and described Natrosol 250 HX is 5% ~ 35%
Contain in the slow releasing tablet of quetiapine fumarate above-mentioned, with the total weight of described slow releasing tablet, the consumption of described carbomer and hydroxy ethyl fiber promotor composition is not less than 15%.
Contain in the slow releasing tablet of quetiapine fumarate above-mentioned, with the total weight of described slow releasing tablet, described hydroxyethyl-cellulose consumption is not less than 10%
Contain in the slow releasing tablet of quetiapine fumarate above-mentioned, other described pharmaceutic adjuvants comprise the other kinds excipient such as pH adjusting agent, diluent, lubricant.
Contain in the slow releasing tablet of quetiapine fumarate above-mentioned, described pH adjusting agent is selected from organic acid, organic acid or its alkali (soil) slaine, such as sodium citrate or magnesium oxide, with the total weight of slow releasing tablet, described pH adjusting agent accounts for 10 ~ 25%.
Containing in the slow releasing tablet of quetiapine fumarate, described diluent is lactose above-mentioned, or lactose and microcrystalline Cellulose; Or sodium chloride, or sodium chloride and microcrystalline Cellulose, with the total weight of slow releasing tablet, described diluent accounts for 10 ~ 30%
Contain in the slow releasing tablet of quetiapine fumarate above-mentioned, described lubricant is magnesium stearate, or sodium stearate, or calcium stearate, or sodium stearyl fumarate, and with the total weight of slow releasing tablet, described diluent accounts for 1% ~ 3%.
The preparation method of the described slow releasing tablet containing quetiapine fumarate, comprises the following steps:
1) quetiapine fumarate, carbomer, hydroxyethyl-cellulose and other pharmaceutic adjuvant mix homogeneously is got;
2) by the component dry granulation of mixing;
3) by obtained granule and mix lubricant even;
4) mixed mixture is pressed into tablet.
Inventor is through deep research, find that the compositions using carbomer and hydroxyethyl-cellulose is framework material, can obtain slow sustained release to maintain the slow releasing preparation of effectively treatment concentration, and slow release effect is better than adopting separately carbomer or hydroxyethyl-cellulose as framework material.Containing active component quetiapine fumarate in Quetiapine fumarate sustained-release tablets agent provided by the invention, high molecular slow-release framework material, and pharmaceutically acceptable excipient.Water soluble polymer framework material mainly refers to the compositions of carbomer and hydroxyethyl-cellulose, and pharmaceutically acceptable excipient comprises diluent, pH adjusting agent and lubricant etc.
Provided by the invention containing in the slow releasing preparation of quetiapine fumarate, the amount (by Quetiapine) containing quetiapine fumarate can be 50mg, 150mg, 200mg, 300mg or 400mg etc.;
Provided by the invention containing in the slow releasing preparation of Quetiapine, with the total weight of slow releasing preparation, slow-release material percentage by weight is 10% ~ 40%, preferred scope 15% ~ 30%.
Carbomer (carbopol) is the acrylic acid and allyl sucrose or the acrylate copolymer crosslinked with Allyl pentaerythritol ether that synthesize, and its drug release feature peeling off by gel layer, reaches the object of Drug controlled release speed in the mode of corrosion.In sustained-release preparation, can be made into the medicine of Zero order release, can bioavailability be increased, have the compatibility of good inside and outside.Preferred carbopol 971P is lightly crosslinked carbopol, has the release of more effective control medicinal substances.Hydroxyethyl-cellulose (Hydroxyethlcellulose, HEC) belongs to non-ionic water-soluble high molecular polymer, and molecular formula is (C
12h
21.5o
8) n, the hydrophilic ethoxy of its molecule intensive amount, easily dissolves in the hot water, and the hydroxyethyl-cellulose matrix scaffold of medicine carrying demonstrates the synchronicity of the erosion front of diffusion, has the potentiality easily obtaining zero-order release.Preferred Natrosol 250 HX is intermediate molecular weight rank, can obtain more linear Release Performance by medicine.When carbomer and hydroxy ethyl fiber share, collaborative slow releasing function can be produced.First, due in acid medium, carbomer swelling degree is little, and concerning water soluble drug, drug release rate comparatively, when share with hydroxyethyl-cellulose, in acid medium, hydroxyethyl-cellulose swelling plays a major role, when entering in intestinal juice medium, and the abundant swelling of carbomer, to play a major role, both share and will play better slow release effect.Secondly, when both share, point covered with clouds reduces, and this imply that two polymer reduce mutually its dissolubility, the corrosion speed of this skeleton that can slow down further again, thus the drug release rate that slows down.
In the pharmaceutically acceptable excipient that the present invention uses, described diluent is selected from microcrystalline Cellulose, lactose, sucrose, sodium chloride, preferably microcrystalline cellulose and lactose.Described pH adjusting agent comprises organic acid, organic acid alkali metal salt, such as citric acid, sodium citrate, or alkaline earth oxide, such as magnesium oxide, and preferred pH adjusting agent is sodium citrate.Described lubricant is selected from magnesium stearate, sodium stearate, calcium stearate, Pulvis Talci, micropowder silica gel etc., and preferred lubricant is magnesium stearate.
The technique of this area routine can be used to prepare Quetiapine fumarate sustained-release tablets provided by the invention, such as but not limited to, according to certain ratio, quetiapine fumarate, slow-release material and other excipient are mixed by suitable mode, dry granulation, add lubricant mixing, tabletting, obtains Quetiapine fumarate sustained-release tablets agent.The tablet prepared, conveniently technology can also carry out coating to tablet.
The slow release characteristic of Quetiapine fumarate sustained-release tablets agent provided by the invention is evaluated with In Vitro Dissolution method, shows sustainable release 8 ~ 24 hours, namely has the drug release of at least 85% out at the end of section at this moment.
Compared with prior art, major advantage of the present invention is:
Slow releasing preparation containing quetiapine fumarate provided by the invention has good sustained release performance, effectively can treat concentration by slow sustained release as requested, thus reach the long-acting be administered once for a day after administration to maintain.Meanwhile, slow releasing tablet of the present invention adopts dry granulation tablet forming technique, and preparation technology is simple, is conducive to industrialized great production, effectively can reduces production cost.
Accompanying drawing explanation
Fig. 1 is the contrast releasing curve diagram of embodiment 1 to example 11;
Fig. 2 is embodiment 7, example 12, the contrast releasing curve diagram of example 13;
Fig. 3 is embodiment 7, example 14, example 15, the contrast releasing curve diagram of example 16;
Fig. 4 is embodiment 7, the contrast releasing curve diagram of comparative example's 1 to example 3.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.Unless otherwise indicated, otherwise all percent, ratio, ratio or number by weight.
In the embodiment of the present invention, the slow release characteristic of preparation can In Vitro Dissolution method be evaluated, with reference to Chinese Pharmacopoeia version in 2010 two annex X D drug release determination first methods, adopt the device of dissolution method (annex X C) first method, first 100 turns per minute of rotating speed is that solvent discharges 2 hours with hydrochloric acid solution (9 → 1000) 750ml.Then in medium, add the 0.2mol/L sodium radio-phosphate,P-32 solution of 250ml, with the hydrochloric acid solution of 2mol/ml or sodium hydroxide solution adjustment pH to (6.8 ± 0.05), operate in accordance with the law.After different time points sampling, measure absorbance in 290nm wavelength place, calculate the cumulative release amount of different time according to external standard method.
Table 1 embodiment 1-4 prepares the slow releasing tablet of quetiapine fumarate
According to the formula in table 1, by quetiapine fumarate, carbomer, hydroxyethyl-cellulose, microcrystalline Cellulose, lactose and sodium citrate mix homogeneously, dry granulation, after add magnesium stearate, mixing, tabletting.
Table 2 embodiment 5-8 prepares the slow releasing tablet of quetiapine fumarate
According to the formula in table 2, by quetiapine fumarate, carbomer, hydroxyethyl-cellulose, microcrystalline Cellulose, lactose and sodium citrate mix homogeneously, dry granulation, after add magnesium stearate, mixing, tabletting.
Table 3 embodiment 9-11 prepares the slow releasing tablet of quetiapine fumarate
According to the formula in table 3, by quetiapine fumarate, carbomer, hydroxyethyl-cellulose, microcrystalline Cellulose, lactose and sodium citrate mix homogeneously, dry granulation, after add magnesium stearate, mixing, tabletting.
Table 4 embodiment 12-13 prepares the slow releasing tablet of quetiapine fumarate
According to the formula in table 4, by quetiapine fumarate, carbomer, hydroxyethyl-cellulose, microcrystalline Cellulose, lactose and sodium citrate mix homogeneously, dry granulation, after add magnesium stearate, mixing, tabletting.
Table 5 embodiment 14-16 prepares the slow releasing tablet of quetiapine fumarate
According to the formula in table 5, by quetiapine fumarate, carbomer, hydroxyethyl-cellulose, microcrystalline Cellulose, lactose and sodium citrate mix homogeneously, dry granulation, after add magnesium stearate, mixing, tabletting.
Table 6 comparative example 1-3 prepares the slow releasing tablet of quetiapine fumarate
According to the formula in table 6, by quetiapine fumarate, HPMC E100, HPMC E4M, microcrystalline Cellulose, lactose and sodium citrate mix homogeneously, add water appropriate, make suitable soft material, cross 20 mesh sieve wet granulars, wet granular puts 70 DEG C of oven dry, dry granule crosses 24 mesh sieve granulate, after add magnesium stearate, mixing, tabletting.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., be all included within protection scope of the present invention.
Claims (10)
1. the slow releasing tablet containing quetiapine fumarate, comprise quetiapine fumarate, slow-release material and other pharmaceutic adjuvants, it is characterized in that described slow-release material is the compositions of carbomer and hydroxyethyl-cellulose, and each composition weight per distribution ratio is: quetiapine fumarate counts 12.5% ~ 60% by Quetiapine, slow-release material is 10% ~ 40%, and other pharmaceutic adjuvants are surplus.
2. the slow releasing tablet containing quetiapine fumarate according to claim 1, is characterized in that, in described carbomer and the compositions of hydroxyethyl-cellulose, carbomer model is carbopol 971P, and hydroxyethyl-cellulose model is Natrosol 250 HX.
3. the slow releasing tablet containing quetiapine fumarate according to claim 2, it is characterized in that, with the total weight of described slow releasing tablet, described carbopol 971P is 5% ~ 25%, and described Natrosol 250 HX is 5% ~ 35%.
4. the slow releasing tablet containing quetiapine fumarate according to claim 1, it is characterized in that, with the total weight of described slow releasing tablet, the consumption of described carbomer and hydroxy ethyl fiber promotor composition is not less than 15%.
5. the slow releasing tablet containing quetiapine fumarate according to claim 4, it is characterized in that, with the total weight of described slow releasing tablet, described hydroxyethyl-cellulose consumption is not less than 10%.
6. the slow releasing tablet containing quetiapine fumarate according to claim 1, it is characterized in that, other described pharmaceutic adjuvants comprise the other kinds excipient such as pH adjusting agent, diluent, lubricant.
7. the slow releasing tablet containing quetiapine fumarate according to claim 6, it is characterized in that, described pH adjusting agent is sodium citrate or magnesium oxide, and with the total weight of slow releasing tablet, described pH adjusting agent accounts for 10 ~ 25%.
8. the slow releasing tablet containing quetiapine fumarate according to claim 6, it is characterized in that, described diluent is lactose, or lactose and microcrystalline Cellulose; Or sodium chloride, or sodium chloride and microcrystalline Cellulose, with the total weight of slow releasing tablet, described diluent accounts for 10 ~ 30%.
9. the slow releasing tablet containing quetiapine fumarate according to claim 6, it is characterized in that, described lubricant is magnesium stearate, or sodium stearate, or calcium stearate, or sodium stearyl fumarate, with the total weight of slow releasing tablet, described diluent accounts for 1% ~ 3%.
10. the preparation method of the slow releasing tablet containing quetiapine fumarate according to claim 1, is characterized in that comprising the following steps:
1) quetiapine fumarate, carbomer, hydroxyethyl-cellulose and other pharmaceutic adjuvant mix homogeneously is got;
2) by the component dry granulation of mixing;
3) by obtained granule and mix lubricant even;
4) mixed mixture is pressed into tablet.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114814045A (en) * | 2022-06-27 | 2022-07-29 | 湖南慧泽生物医药科技有限公司 | Method for determining in-vitro release degree of quetiapine fumarate sustained release tablets |
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| CN101912374A (en) * | 2010-08-08 | 2010-12-15 | 浙江华海药业股份有限公司 | Quetiapine sustained release tablet and preparation method thereof |
| CN102218042A (en) * | 2011-05-26 | 2011-10-19 | 青岛黄海制药有限责任公司 | Sustained release tablet of quetiapine fumarate composition and preparation method of sustained release tablet |
| WO2013074048A2 (en) * | 2011-08-08 | 2013-05-23 | Mahmut Bilgic | Tablet forms comprising quetiapine fumarate |
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| CN101002737A (en) * | 2005-09-26 | 2007-07-25 | 刘凤鸣 | Slow release preparation of Kui-Liu-Ping |
| CN101912374A (en) * | 2010-08-08 | 2010-12-15 | 浙江华海药业股份有限公司 | Quetiapine sustained release tablet and preparation method thereof |
| CN102218042A (en) * | 2011-05-26 | 2011-10-19 | 青岛黄海制药有限责任公司 | Sustained release tablet of quetiapine fumarate composition and preparation method of sustained release tablet |
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| CN114814045A (en) * | 2022-06-27 | 2022-07-29 | 湖南慧泽生物医药科技有限公司 | Method for determining in-vitro release degree of quetiapine fumarate sustained release tablets |
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