CN101091700B - Composition of slow (controlled) releasing preparation of Quetiadine Hemifumarate, and application - Google Patents
Composition of slow (controlled) releasing preparation of Quetiadine Hemifumarate, and application Download PDFInfo
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- CN101091700B CN101091700B CN2007100434049A CN200710043404A CN101091700B CN 101091700 B CN101091700 B CN 101091700B CN 2007100434049 A CN2007100434049 A CN 2007100434049A CN 200710043404 A CN200710043404 A CN 200710043404A CN 101091700 B CN101091700 B CN 101091700B
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- quetiapine fumarate
- hydroxypropyl methylcellulose
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Abstract
The present invention discloses a quithiopine fumarate slow (controlled) release preparation and its application. Its preparation composition includes (by wt%) 27-50% of quithiopine fumarate, 2-7% of organic acid, 40-50% of water-soluble macromolecule, 2-7% of enteric solubility material, 0.1-2% of wax and 2-7% of water-insoluble macromolecule. Said preparation can be effectively used for curing schizophrenia.
Description
Technical field
The present invention relates to the quetiapine fumarate preparation, relate in particular to a kind of Boletic acid quetiapine oral sustained-release preparation.
Background technology
Quetiapine fumarate is a hexichol oxygen azatropylidene class medicine, is atypical antipsychotic agents.Its structure is similar with olanzapine to clozapine, is various neurotransmitters receptor antagonist in the brain, mainly plays antipsycholic action because of blocking central dopamine D2 receptor and 5-hydroxy tryptamine 2 (5-HT2) receptor.Histamine H receptor and adrenal gland α 1 receptor also there are blocking effect, muscarine and Benzodiazepine receptoroid are not had affinity.
The quetiapine fumarate clinical practice is in various schizophrenia.All effective to the schizoid positive symptom and negative symptoms, also can alleviate depression, anxiety and cognitive defect symptom that schizophrenia occurs together.
The external conventional oral dose of schizophrenia: predose is each 25mg, every day 2 times.Gave each 25～50mg on the 2nd～3, every day 2～3 times; But recruitment on the 4th is divided 2～3 times to 300～400mg every day, and effective dose is 300～400mg every day, divides and takes for 2～3 times.Maximal dose is 750mg every day.
The domestic conventional oral dose of schizophrenia: predose is each 25mg, every day 2 times.Each 25mg that increases every 1～3 day.Increase to therapeutic dose 300～600mg every day gradually, divide and take for 2～3 times.
Quetiapine fumarate is the 4th an atypical antipsychotics thing of listing after clozapine, risperidone, olanzapine, to schizoid evident in efficacy, especially the more traditional antipsychotic drug of its The extrapyramidal symptoms (EPS) obviously reduces, do not influence prolactin level, therefore the developing direction that meets current antipsychotic drug receives much concern.
The homemade quetiapine fumarate ordinary preparation of relative low price goes on the market at present, is non-sustained-release preparation, and preparation is short action time, again because of schizophrenia needs long-term prescription, makes troubles for patient and family members.Therefore, developing a kind of quetiapine fumarate slow releasing preparation is that patient and family members are desired.
Summary of the invention
The technical issues that need to address of the present invention are to disclose slow (control) release formulation compositions of a kind of quetiapine fumarate and application thereof, to overcome the defective that existing preparation exists, satisfy people's needs.
The component and the weight percent content of slow (control) release formulation compositions of quetiapine fumarate of the present invention comprise:
Quetiapine fumarate 27～50%
Water soluble polymer 40～50%
Wax class 0.1～2%
Water-insoluble macromolecule 2～7%
More than each percentages of ingredients sum be 100%;
Preferably, also comprise binding agent in the compositions in order to be convenient to prepare granule:
Quetiapine fumarate 42～47%
Organic acid 3～5%
Water soluble polymer 42～47%
Enteric material 3～5%
Wax class 0.1～2%
Water-insoluble macromolecule 4～5%
Binding agent 0.2～1.0%
More than each percentages of ingredients sum be 100%;
Preferably, for the ease of the preparation granule, comprise also in the compositions that percentage by weight is 0.5～0.8% binding agent:
Preferably, for the ease of a preparation tablet, also comprise lubricant in the compositions:
Quetiapine fumarate 42～47%
Organic acid 3～5%
Water soluble polymer 42～47%
Enteric material 3～5%
Wax class 0.1～2%
Water-insoluble macromolecule 3～5%
Binding agent 0.2～1.0%
Lubricant 0.5～2%
More than each percentages of ingredients sum be 100%.
Be more preferably:
Quetiapine fumarate 44%
Water soluble polymer 42%
Wax class 0.7%
Water-insoluble macromolecule 3%
Binding agent 0.3%
The organic acid effect is to increase the dissolubility of medicine in intestinal juice, and said organic acid is selected from tartaric acid, citric acid, lactic acid, para-amino benzoic acid, P-hydroxybenzoic acid or gentisic acid;
The effect of water soluble polymer is wetting agent and solubilizing agent, and water soluble polymer is selected from hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or polyvinyl alcohol;
The effect of enteric material is to stop the stripping of medicine in gastric juice, and enteric material is selected from phthalic acid hydroxypropyl methylcellulose, methacrylic acid-methylmethacrylate copolymer (L100 type, S100 type), EUDRAGIT L100-55 (L100-55 type), methacrylic acid-methacrylic acid copolymer (II number, III number).
The effect of wax class is the stripping of control medicine in intestinal juice, and said wax class is selected from hexadecanol, octadecanol or glyceryl monostearate;
The effect of water-insoluble macromolecular material is the stripping of control medicine in gastric juice or intestinal juice, and the water-insoluble macromolecule is selected from crylic acid resin, ethyl cellulose or cellulose acetate.
Crylic acid resin is: methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer (RL100 type, RS100 type).
Said binding agent is as hydroxypropyl methylcellulose;
Said lubricant is as Pulvis Talci;
Slow (control) release formulation compositions of quetiapine fumarate of the present invention can adopt method well known in the art, and preparation becomes capsule, tablet and granule;
Slow (control) release formulation preparation of compositions method of quetiapine fumarate of the present invention comprises the steps:
With quetiapine fumarate, organic acid, water soluble polymer and wax class mixing, add weight concentration and be 2～5% hydroxypropyl methylcellulose serosity and make soft material, granulate then, obtain granule, adopting weight concentration again is 5～10% enteric material and the high molecular alcohol mixture serosity coating of water-insoluble, 55～65 ℃ of dryings obtain quetiapine fumarate slow (control) and release the system granule;
Above-mentioned granule is incapsulated, be quetiapine fumarate slow (control) and release capsule;
Or with quetiapine fumarate, organic acid, water soluble polymer and wax class mixing, add weight concentration and be 2～5% hydroxypropyl methylcellulose serosity and make granule, add lubricant, tabletting, the employing weight concentration is 5～10% enteric material and the high molecular alcohol mixture serosity coating of water-insoluble again, 55～65 ℃ of dryings promptly get quetiapine fumarate slow (control) and release sheet;
Used alcoholic acid volumetric concentration is 85～100%.
Slow (control) release formulation compositions of quetiapine fumarate of the present invention can be used for the treatment of schizophrenia.
Quetiapine fumarate of the present invention slow (control) is released sheet, capsule and granule and is put on the patient who needs treatment by oral form, dosage is 300～400mg every day, and maximal dose is 750mg every day, one day oral 1 time, specifically can determine by the doctor according to patient's concrete condition.
Enter digestive tract after quetiapine fumarate slow (control) is released sheet, capsule and particulate oral, the release of medicine is controlled by the thickness of film and enteric material proportion, therefore can reach the purpose that slow (control) released, and only needs oral 1 time, and greatly facilitates patient in one day.
Description of drawings
Fig. 1 quetiapine fumarate slow (control) is released the external release profiles of sheet;
Fig. 2 quetiapine fumarate slow (control) is released the outer release profiles of capsule body;
Fig. 3 quetiapine fumarate sheet is released release curve in the sheet animal body with slow (control);
Fig. 4 quetiapine fumarate sheet is released release curve in the capsule animal body with slow (control).
The specific embodiment
Embodiment 1
With 100 gram quetiapine fumarates, 10 gram citric acid, 90 gram water-soluble high-molecular material polyvinylpyrrolidones and 2 gram wax class octadecanol mixings, add weight concentration and be 3% hydroxypropyl methylcellulose serosity and make soft material, granulate then, obtain granule, put in the coating machine, adopt the alcohol mixture serosity coating of 400ml enteric material and water-insoluble macromolecular material, 60 ℃ of dryings obtain quetiapine fumarate slow (control) and release the system granule.
Enteric material is phthalic acid hydroxypropyl methylcellulose (HPMCP-55), the water-insoluble macromolecular material is an ethyl cellulose, enteric material and water-insoluble macromolecular material the alcohol mixture serosity in, the content of enteric material is 0.035g/ml, the content of water-insoluble macromolecular material is 0.015g/ml, and used alcoholic acid volumetric concentration is 90%.
With 100 gram quetiapine fumarates, 5 gram tartaric acid, 50 gram water-soluble high-molecular material polyvinyl alcohol, 1 gram hexadecanol mixing, add weight concentration and be 3% hydroxypropyl methylcellulose serosity and make soft material, granulate then, obtain granule, add 1.5 gram Pulvis Talci mixings, use
The scrobicula stamping of 9mm.Get this sheet and put in the coating pan, adopt the alcohol mixture serosity coating of 100ml enteric material and water-insoluble macromolecular material, 60 ℃ of dryings obtain tablet.
Enteric material is methacrylic acid-methacrylic acid copolymer (II), the water-insoluble macromolecular material is methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer (RS-100), enteric material and water-insoluble macromolecular material the alcohol mixture serosity in, the content of enteric material is 0.075g/ml, and the content of water-insoluble macromolecular material is 0.025g/ml.Used alcoholic acid volumetric concentration is 85%.
Acrylic resin II is the above dissolved enteric material of a kind of pH6, and acrylic resin RS-100 is the undissolved material of a kind of water, can adopt the commercially available prod, as the product of Romo Co.,Ltd.
Embodiment 3
During the granule of embodiment 1 incapsulated, promptly obtain capsule.
Get the quetiapine fumarate slow (control) of embodiment 2 or embodiment 3 and release sheet or capsule, press Chinese Pharmacopoeia drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2005), dissolution (two appendix XC of Chinese Pharmacopoeia version in 2005) second subtraction unit, discharging liquid is 0.1mol/L hydrochloric acid solution 750ml, turn round and added 0.2mol/L phosphoric acid in 2 hours and receive solution 250ml (regulating pH value to 6.8 ± 0.05 with 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution in case of necessity), Revolution Per Minute 60 changes, operation in accordance with the law, but at 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, get solution 3ml respectively in 10 hours and 12 hours and filter, and in process container, replenish release liquid 3ml immediately; It is an amount of to get subsequent filtrate respectively, adds the quantitative dilution of water and makes the solution that contains 25 μ g among every 1ml approximately, according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2005 A), measures trap respectively at the wavelength place of 290nm; It is an amount of that in addition precision takes by weighing the quetiapine fumarate reference substance, be dissolved in water and quantitatively dilution make the solution that contains 30 μ g among every 1ml approximately, measure trap with method, calculate every/every stripping quantity respectively at different time.See Table 1 and table 2, release profiles is seen Fig. 1, Fig. 2.
Table 1 quetiapine fumarate slow (control) is released the external release test result of sheet
Table 2 quetiapine fumarate slow (control) is released capsule extracorporeal releasing test result
Embodiment 5
Adopt the method for Chinese Pharmacopoeia appendix regulation, quetiapine fumarate sheet and slow (control) are released sheet and capsule carries out the moving Herba Wedeliae Wallichii number test of animal body giving drugs into nose, the results are shown in Table 3 and table 4, the interior release curve of animal body is seen Fig. 3, Fig. 4.Among Fig. 3 and Fig. 4, curve 1 is a preparation of the present invention, and curve 2 is commercially available ordinary preparation.
Table 3 quetiapine fumarate sheet is released pharmacokinetic parameters (n=3) in the sheet animal body with slow (control)
Table 4 quetiapine fumarate sheet is released pharmacokinetic parameters (n=3) in the capsule animal body with slow (control)
Claims (7)
1. quetiapine fumarate sustained-release preparation compositions, component and weight percent content comprise:
Quetiapine fumarate 27～50%
Organic acid 2～7%
Water soluble polymer 40～50%
Enteric material 2～7%
Wax class 0.1～2%
Water-insoluble macromolecule 2～7%
More than each percentages of ingredients sum be 100%;
Described organic acid is selected from tartaric acid, citric acid, lactic acid, para-amino benzoic acid, P-hydroxybenzoic acid or gentisic acid;
Described water soluble polymer is selected from hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or polyvinyl alcohol;
Described enteric material is selected from phthalic acid hydroxypropyl methylcellulose, methacrylic acid-methylmethacrylate copolymer, EUDRAGIT L100-55;
Described wax class is selected from hexadecanol, octadecanol or glyceryl monostearate;
Described water-insoluble macromolecule is selected from crylic acid resin, ethyl cellulose or cellulose acetate;
Described crylic acid resin is: methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer.
2. quetiapine fumarate sustained-release preparation compositions is characterized in that, component and weight percent content comprise:
Quetiapine fumarate 42～47%
Organic acid 3～5%
Water soluble polymer 42～47%
Enteric material 3～5%
Wax class 0.1～2%
Water-insoluble macromolecule 4～5%
Binding agent 0.2～1.0%
More than each percentages of ingredients sum be 100%;
Described organic acid is selected from tartaric acid, citric acid, lactic acid, para-amino benzoic acid, P-hydroxybenzoic acid or gentisic acid;
Described water soluble polymer is selected from hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or polyvinyl alcohol;
Described enteric material is selected from phthalic acid hydroxypropyl methylcellulose, methacrylic acid-methylmethacrylate copolymer, EUDRAGIT L100-55;
Described wax class is selected from hexadecanol, octadecanol or glyceryl monostearate;
Described water-insoluble macromolecule is selected from crylic acid resin, ethyl cellulose or cellulose acetate;
Described crylic acid resin is: methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer.
3. quetiapine fumarate sustained-release preparation compositions is characterized in that, component and weight percent content comprise:
Quetiapine fumarate 42～47%
Organic acid 3～5%
Water soluble polymer 42～47%
Enteric material 3～5%
Wax class 0.1～2%
Water-insoluble macromolecule 3～5%
Binding agent 0.2～1.0%
Lubricant 0.1～5%
More than each percentages of ingredients sum be 100%;
Described organic acid is selected from tartaric acid, citric acid, lactic acid, para-amino benzoic acid, P-hydroxybenzoic acid or gentisic acid;
Described water soluble polymer is selected from hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or polyvinyl alcohol;
Described enteric material is selected from phthalic acid hydroxypropyl methylcellulose, methacrylic acid-methylmethacrylate copolymer, EUDRAGIT L100-55;
Described wax class is selected from hexadecanol, octadecanol or glyceryl monostearate;
Described water-insoluble macromolecule is selected from crylic acid resin, ethyl cellulose or cellulose acetate;
Described crylic acid resin is: methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer.
4. quetiapine fumarate sustained-release preparation compositions is characterized in that, component and weight percent content comprise:
Quetiapine fumarate 44%
Organic acid 4%
Water soluble polymer 42%
Enteric material 4%
Wax class 0.7%
Water-insoluble macromolecule 3%
Binding agent 0.3%
Lubricant 2%
More than each percentages of ingredients sum be 100%;
Described organic acid is selected from tartaric acid, citric acid, lactic acid, para-amino benzoic acid, P-hydroxybenzoic acid or gentisic acid;
Described water soluble polymer is selected from hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or polyvinyl alcohol;
Described enteric material is selected from phthalic acid hydroxypropyl methylcellulose, methacrylic acid-methylmethacrylate copolymer, EUDRAGIT L100-55;
Described wax class is selected from hexadecanol, octadecanol or glyceryl monostearate;
Described water-insoluble macromolecule is selected from crylic acid resin, ethyl cellulose or cellulose acetate;
Described crylic acid resin is: methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer.
5. quetiapine fumarate sustained-release preparation compositions according to claim 4 is characterized in that said binding agent is a hydroxypropyl methylcellulose; Said lubricant is a Pulvis Talci.
6. capsule, tablet or granule that contains each described quetiapine fumarate sustained-release preparation compositions of claim 1～5.
7. the application of each described quetiapine fumarate sustained-release preparation compositions of claim 1～5 in preparation treatment schizophrenia drug.
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| CN2007100434049A CN101091700B (en) | 2007-07-03 | 2007-07-03 | Composition of slow (controlled) releasing preparation of Quetiadine Hemifumarate, and application |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101375852B (en) * | 2008-07-24 | 2011-04-13 | 张宏宇 | Boletic acid quetiapine oral preparation and preparation method thereof |
| EP2355804A1 (en) * | 2008-11-26 | 2011-08-17 | Krka | Quetiapine composition |
| CN101940561A (en) * | 2010-09-14 | 2011-01-12 | 浙江华海药业股份有限公司 | Quetiapine fumarate 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 |
| CN106928369B (en) | 2012-08-21 | 2021-04-02 | 奥索临床诊断有限公司 | Antibodies to quetiapine and uses thereof |
| WO2014031665A1 (en) | 2012-08-21 | 2014-02-27 | Ortho-Clinical Diagnostics, Inc | Antibodies to quetiapine haptens and use thereof |
| CN104546787A (en) * | 2014-12-31 | 2015-04-29 | 深圳市国源医药科技有限公司 | Esomeprazole magnesium enteric-coated tablet containing esomeprazole magnesium pellets and preparation method of esomeprazole magnesium enteric-coated tablet |
| CN104546800A (en) * | 2015-01-07 | 2015-04-29 | 万特制药(海南)有限公司 | Quetiapine fumarate sustained-release capsule and preparation method thereof |
| CN104644644A (en) * | 2015-01-27 | 2015-05-27 | 美吉斯制药（厦门）有限公司 | Quetiapine fumarate pharmaceutical composition |
| EP3390455A1 (en) | 2015-12-17 | 2018-10-24 | Janssen Pharmaceutica NV | Antibodies to quetiapine and use thereof |
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