CN104840442B - A kind of sustained-release tablet containing quetiapine fumarate and preparation method thereof - Google Patents
A kind of sustained-release tablet containing quetiapine fumarate and preparation method thereof Download PDFInfo
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- CN104840442B CN104840442B CN201510250204.5A CN201510250204A CN104840442B CN 104840442 B CN104840442 B CN 104840442B CN 201510250204 A CN201510250204 A CN 201510250204A CN 104840442 B CN104840442 B CN 104840442B
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- quetiapine fumarate
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Abstract
The present invention provides a kind of sustained-release tablet containing quetiapine fumarate, including quetiapine fumarate, slow-release material and other pharmaceutic adjuvants, the slow-release material is carbomer and the composition of hydroxyethyl cellulose, and each component weight percent proportioning is：Quetiapine fumarate is calculated as 12.5%~60% by Quetiapine, and slow-release material is 10%~40%, other pharmaceutic adjuvants are surplus.The present invention administration after can slow sustained release is to maintain effective treatment concentration as requested, so as to reach one day long-acting being administered once.Meanwhile sustained release tablets of the invention use dry granulation tablet forming technique, preparation process is simple, is conducive to industrialized production, can effectively reduce production cost.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be related to a kind of sustained-release tablet, particularly a kind of containing quetiapine fumarate
Sustained-release tablet and preparation method thereof.
Background technology
Quetiapine (Thiazep ine), i.e. 11- [4- [2 (2- hydroxyl-oxethyls) ethyl] -1- piperazinyls] dibenzo-[b,
F] [l, 4] sulphur azatropylidene is a kind of atypical antipsychotic agents, it is intracerebral various neurotransmitters receptor antagonist, anti-spirit
Anttdisease Mechanism may be mainly by blocking central dopamine D2Acceptor and 5-HT acceptors.Also have to histamine receptor and adrenocepter
Blocking effect, it is external clinical using the medicine as the schizoid first-line drug for the treatment of.
The pharmacokinetic studies of Quetiapine ordinary preparation the result shows that, its it is oral it is quick absorb, blood medicine is dense when about 1.0-1.8 is small
Peaking is spent, it is shorter to eliminate half-life period.It is administered daily 2-3 times so being used during domestic and international clinical treatment schizophrenia, this
Cause patient's body blood concentration fluctuation, bring larger side effect.A kind of therefore it provides Quetiapine treated with sustained release
Slow release formulation is always the ideal that those skilled in the art is pursued.
Quetiapine sustained release preparation (trade name：Seroquel XR) take the lead in listing abroad by AstraZeneca, its patent information
It is disclosed in US5948437 and the hydroxypropyl containing 5%~50% (weight) is claimed in disclosed Chinese patent CN101360504A
The sustained release preparation of methylcellulose.CN101002737A discloses a kind of containing Quetiapine and sustained release framework material and additives
Sustained release preparation, the sustained-release matrix material include hydrophilic gel matrix material, erodible framework material, water-insoluble material,
The erodible framework material is stearic acid, one or more kinds of any combination in hexadecanol, octadecyl alcolol.
One kind is claimed by Quetiapine, organic acid, water-soluble high-molecular material, enteric material, wax class and water in CN101091700A
Slow (control) release formulation composition of insoluble high molecular material, wherein using Enteric Materials as functional coatings material, resistance
Only medicine dissolution in gastric juice, wax class material and water-insoluble high molecular material are used to control the medicine in gastric juice or intestinal juice molten
Go out.CN101005829A discloses a kind of a variety of novel forms containing wax-like materials and effective dose Quetiapine and its salt, wherein wrapping
Include the formulation of sustained release.CN101347413A discloses a kind of Quetiapine for including pH dependent solubility sustained-release matrix materials
Sustained release preparation, is divided into common individual layer sustained release tablets and double-layer sustained release tablets.The framework material that the pH used is relied on, it is dissolved by stomach and intestine
The influence of road pH, due to differing greatly for interindividual gastrointestinal tract environment, especially between the patient of all ages and classes, this will
Cause the variability of preparation body absorption；Due to the characteristic of its water-insoluble, it makes sustained release preparation based on wax class material
The complexity of standby technique also limit the use of such material.Above in each disclosed patent, wet method system is used in embodiment
The technique or one-step palletizing of grain, technique is more complicated, and energy consumption is big, adds production cost.
The content of the invention
It is an object of the present invention to the sustained-release tablet containing quetiapine fumarate
It is a further object of the present invention 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 sustained-release tablet containing quetiapine fumarate, including quetiapine fumarate, slow-release material and other are medicinal auxiliary
Material, the slow-release material is carbomer and the composition of hydroxyethyl cellulose, and each component weight percent proportioning is：Fumaric acid
Quetiapine is calculated as 12.5%~60% by Quetiapine, and slow-release material is 10%~40%, other pharmaceutic adjuvants are surplus.
In the above-mentioned sustained-release tablet containing quetiapine fumarate, the combination of the carbomer and hydroxyethyl cellulose
Carbomer model carbopol 971P in thing, hydroxyethyl cellulose model Natrosol 250HX.
It is described with the gross weight meter of the sustained-release tablet in the above-mentioned sustained-release tablet containing quetiapine fumarate
Carbopol 971P be 5%~25%, 250 HX of Natrosol be 5%~35%
It is described with the gross weight meter of the sustained-release tablet in the above-mentioned sustained-release tablet containing quetiapine fumarate
The dosage of carbomer and hydroxy ethyl fiber promotor composition is not less than 15%.
It is described with the gross weight meter of the sustained-release tablet in the above-mentioned sustained-release tablet containing quetiapine fumarate
Hydroxyethyl cellulose dosage is not less than 10%
In the above-mentioned sustained-release tablet containing quetiapine fumarate, other described pharmaceutic adjuvants include pH adjusting agent,
The other kinds excipient such as diluent, lubricant.
In the above-mentioned sustained-release tablet containing quetiapine fumarate, the pH adjusting agent is selected from organic acid, organic acid
Or its alkali (soil) metal salt, such as sodium citrate or magnesia, with the gross weight meter of sustained-release tablet, the pH adjusting agent accounts for 10~
25%.
In the above-mentioned sustained-release tablet containing quetiapine fumarate, the diluent is lactose, or lactose and crystallite
Cellulose；Or sodium chloride, or sodium chloride and microcrystalline cellulose, with the gross weight meter of sustained-release tablet, the diluent accounts for 10~
30%
In the above-mentioned sustained-release tablet containing quetiapine fumarate, the lubricant is magnesium stearate, or stearic acid
Sodium, or calcium stearate, or sodium stearyl fumarate, with the gross weight meter of sustained-release tablet, the diluent accounts for 1%~3%.
The preparation method of the sustained-release tablet containing quetiapine fumarate, comprises the following steps：
1) quetiapine fumarate, carbomer, hydroxyethyl cellulose and other pharmaceutic adjuvants is taken to be uniformly mixed；
2) by the component dry granulation of mixing；
3) it is obtained particle and mix lubricant is uniform；
4) it is mixed mixture is tabletted.
Inventor passes through in-depth study, it is found that using the composition of carbomer and hydroxyethyl cellulose be framework material,
Slow sustained release can be obtained to maintain the sustained release preparation of effective treatment concentration, and slow release effect is better than individually using carbomer
Or hydroxyethyl cellulose is as framework material.Contain active ingredient richness horse in Quetiapine fumarate sustained-release tablets agent provided by the invention
Sour Quetiapine, high molecular slow-release framework material, and pharmaceutically acceptable excipient.Water soluble polymer framework material refers mainly to
The composition of carbomer and hydroxyethyl cellulose, pharmaceutically acceptable excipient include diluent, pH adjusting agent and lubricant
Deng.
In sustained release preparation provided by the invention containing quetiapine fumarate, the amount containing quetiapine fumarate (presses quinoline sulphur
Flat meter) can be 50mg, 150mg, 200mg, 300mg or 400mg etc.；
In sustained release preparation provided by the invention containing Quetiapine, with the gross weight meter of sustained release preparation, slow-release material weight
Percentage is 10%~40%, preferable scope 15%~30%.
Carbomer (carbopol) is that the acrylic acid of synthesis is with allyl sucrose or crosslinked with Allyl pentaerythritol ether
Acrylate copolymer, its drug release feature are leaned on the peeling of gel layer, Drug controlled release speed are achieveed the purpose that in a manner of corrosion.
It can be made into the medicine of Zero order release in sustained-release preparation, bioavilability can be increased, there is preferable internal external contact compatibility.It is preferred that
Carbopol 971P be lightly crosslinked carbopol, have more effectively control medicinal substances release.Hydroxyethyl cellulose
(Hydroxyethl cellulose, HEC) belongs to non-ionic water-soluble high molecular polymer, and molecular formula is (C12H21.5O8) n, its
The hydrophilic ethoxy of intramolecular content, easily dissolves in the hot water, and the hydroxyethyl cellulose matrix scaffold for carrying medicine shows expansion
The synchronism of scattered erosion front, has the potentiality for easily obtaining zero-order release.Preferable 250 HX of Natrosol are medium molecule
Magnitude is other, and the linear Release Performance of comparison can be obtained with medicine.When carbomer is shared with hydroxy ethyl fiber, collaboration sustained release can be produced
Effect.Firstly, since in acid medium, carbomer swelling degree is small, and for water soluble drug, drug release rate is very fast, when
When being shared with hydroxyethyl cellulose, hydroxyethyl cellulose swelling plays a major role in acid medium, when in entrance intestinal juice medium
When, the abundant swelling of carbomer, will play a major role, both, which share, will play more preferable slow release effect.Secondly, when both share
When, point covered with clouds reduces, this imply that two polymer reduce mutually its dissolubility, this can further slow down the corrosion speed of skeleton again,
So as to slow down drug release rate.
In the pharmaceutically acceptable excipient that the present invention uses, the diluent is selected from microcrystalline cellulose, lactose, sugarcane
Sugar, sodium chloride, preferably microcrystalline cellulose and lactose.The pH adjusting agent includes organic acid, organic acid alkali metal salt, such as Chinese holly
Rafter acid, sodium citrate, or alkaline earth oxide, such as magnesia, preferable pH adjusting agent are sodium citrate.The lubrication
Agent is selected from magnesium stearate, odium stearate, calcium stearate, talcum powder, superfine silica gel powder etc., and preferable lubricant is magnesium stearate.
The technique of this area routine can be used to be prepared Quetiapine fumarate sustained-release tablets provided by the invention, such as but
It is not limited to, according to a certain percentage mixes quetiapine fumarate, slow-release material and other excipient by appropriate mode, does
Method is pelletized, and is added lubricant and is mixed, tabletting, obtains Quetiapine fumarate sustained-release tablets agent.The tablet being prepared, can also be according to normal
Rule technology is coated tablet.
The slow release characteristic of Quetiapine fumarate sustained-release tablets agent provided by the invention is evaluated in In Vitro Dissolution method, is shown
It is sustainable release 8~24 it is small when, i.e., the insoluble drug release for having at least 85% at the end of this period comes out.
Compared with prior art, main advantages of the present invention are：
Sustained release preparation provided by the invention containing quetiapine fumarate has preferable sustained release performance, can be according to after administration
It is required that slow sustained release to be to maintain effective treatment concentration, so as to reach one day long-acting being administered once.Meanwhile the present invention
Sustained release tablets use dry granulation tablet forming technique, preparation process is simple, is conducive to industrialized production, can effectively reduce and be produced into
This.
Brief description of the drawings
Fig. 1 is contrast releasing curve diagram of the 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 1 to example 3.
Embodiment
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention
Rather than limit the scope of the invention.Unless otherwise stated, otherwise all percentage, ratio, ratio or number be by weight
Meter.
The slow release characteristic of preparation can be evaluated in In Vitro Dissolution method in the embodiment of the present invention, with reference to Chinese Pharmacopoeia 2010
Year two annex X D the first methods of drug release determination of version, it is every using the device of dissolution method (annex X C) the first method, rotating speed
Minutes 100 turns, first using hydrochloric acid solution (9 → 1000) 750ml for solvent discharge 2 it is small when.Then add 250ml's into medium
0.2mol/L sodium radio-phosphate,P-32 solutions, adjust pH to (6.8 ± 0.05), in accordance with the law with the hydrochloric acid solution or sodium hydroxide solution of 2mol/ml
Operation.After different time points sampling, absorbance is measured at 290nm wavelength, the accumulation that different time is calculated according to external standard method is released
High-volume.
1 embodiment 1-4 of table prepares the sustained-release tablet of quetiapine fumarate
According to the formula in table 1, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and
Sodium citrate is uniformly mixed, dry granulation, adds magnesium stearate afterwards, is mixed, tabletting.
2 embodiment 5-8 of table prepares the sustained-release tablet of quetiapine fumarate
According to the formula in table 2, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and
Sodium citrate is uniformly mixed, dry granulation, adds magnesium stearate afterwards, is mixed, tabletting.
3 embodiment 9-11 of table prepares the sustained-release tablet of quetiapine fumarate
According to the formula in table 3, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and
Sodium citrate is uniformly mixed, dry granulation, adds magnesium stearate afterwards, is mixed, tabletting.4 embodiment 12-13 of table prepares fumaric acid quinoline
The flat sustained-release tablet of sulphur
According to the formula in table 4, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and
Sodium citrate is uniformly mixed, dry granulation, adds magnesium stearate afterwards, is mixed, tabletting.5 embodiment 14-16 of table prepares fumaric acid quinoline
The flat sustained-release tablet of sulphur
According to the formula in table 5, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and
Sodium citrate is uniformly mixed, dry granulation, adds magnesium stearate afterwards, is mixed, tabletting.
6 comparative example 1-3 of table prepares the sustained-release tablet of quetiapine fumarate
According to the formula in table 6, by quetiapine fumarate, HPMC E100, HPMC E4M, microcrystalline cellulose, lactose and Chinese holly
Rafter acid sodium is uniformly mixed, and adds appropriate amount of water, and suitable softwood is made, and crosses 20 mesh sieve series wet granulars, and wet granular puts 70 DEG C of drying, dry particl
24 mesh sieve whole grains are crossed, add magnesium stearate afterwards, are mixed, tabletting.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all the present invention spirit and
All any modification, equivalent and improvement made within principle etc., are all contained within protection scope of the present invention.
Claims (4)
1. a kind of sustained-release tablet containing quetiapine fumarate,
It is characterized in that, it is made of the raw material and auxiliary material of following percentage by weight：
Quetiapine fumarate 44.2%, carbomer 10.6%, hydroxyethyl cellulose 12.5%, sodium citrate 10.4%, lactose
14.6%, microcrystalline cellulose 5.8%, magnesium stearate 1.9%；
Preparation process is as follows：
According to above-mentioned formula, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and sodium citrate
It is uniformly mixed, dry granulation, adds magnesium stearate afterwards, mixes, tabletting.
2. a kind of sustained-release tablet containing quetiapine fumarate, it is characterised in that by the raw material and auxiliary material of following percentage by weight
It is made：
Quetiapine fumarate 26.1%, carbomer 10.2%, hydroxyethyl cellulose 12.5%, sodium citrate 10.9%, lactose
14.8%, microcrystalline cellulose 23.6%, magnesium stearate 1.8%；
Preparation process is as follows：
According to above-mentioned formula, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and sodium citrate
It is uniformly mixed, dry granulation, adds magnesium stearate afterwards, mixes, tabletting.
3. a kind of sustained-release tablet containing quetiapine fumarate, it is characterised in that by the raw material and auxiliary material of following percentage by weight
It is made：
Quetiapine fumarate 53.1%, carbomer 9.2%, hydroxyethyl cellulose 12.3%, sodium citrate 9.5%, lactose
13.2%, microcrystalline cellulose 0.8%, magnesium stearate 1.8%；
Preparation process is as follows：
According to above-mentioned formula, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and sodium citrate
It is uniformly mixed, dry granulation, adds magnesium stearate afterwards, mixes, tabletting.
4. a kind of sustained-release tablet containing quetiapine fumarate, it is characterised in that by the raw material and auxiliary material of following percentage by weight
It is made：
Quetiapine fumarate 56.8%, carbomer 9.3%, hydroxyethyl cellulose 10.5%, sodium citrate 8.6%, lactose
11.7%, microcrystalline cellulose 1.5%, magnesium stearate 1.9%；
Preparation process is as follows：
According to above-mentioned formula, by quetiapine fumarate, carbomer, hydroxyethyl cellulose, microcrystalline cellulose, lactose and sodium citrate
It is uniformly mixed, dry granulation, adds magnesium stearate afterwards, mixes, tabletting.
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Citations (3)
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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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| WO2013074048A2 (en) * | 2011-08-08 | 2013-05-23 | Mahmut Bilgic | Tablet forms comprising quetiapine fumarate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (2)
| Title |
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| 富马酸喹硫平骨架缓释片的研发;何广卫，等;《广州化工》;20140731;第42卷(第13期);第47-51页 * |
| 骨架片在缓释给药系统中应用;平其能;《北方药学》;20140131;第11卷(第1期);第14页右栏第4.1.3小节 * |
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