CN101164537B - High-efficient oral silibinin sustained-release preparation and preparation method thereof - Google Patents
High-efficient oral silibinin sustained-release preparation and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a high-effective oral silibinin (SLB) slow-released preparation. Its composition includes (by mass component portion) 1 portion of silibinin, 1.5-2.5 portions of polyvidone-K30, 0.23-0.58 portion of hydroxypropyl methyl cellulose 4000cPa.S, 0.46-1.38 portions of low-substituted hydroxypropyl cellulose. Said invention adopts the combination of solid dispersion technique and slow-released hydrophilic gel skeleton technique to raise the dissolubility of silibinin.
Description
Technical field:
The present invention relates to a kind of preparation method, particularly a kind of high-efficient oral silibinin sustained-release preparation and preparation method thereof of insoluble drug high-efficient oral slow releasing preparation.
Background technology:
Slow/controlled release preparation (sustained/controlled release preparations) has the blood concentration of reduction peak valley phenomenon, reduces medication number of times and toxic and side effects, improves advantages such as patient compliance, and clinical practice is increasingly extensive.Preparation slow/controlled release preparation needs elder generation with medicine dissolution usually, adds the slow/controlled release adjuvant again, adopts suitable technology to make the slow/controlled release preparation.Water soluble drug is easy to make the slow/controlled release preparation because of easily dissolving in the water, and the kind of listing is more at present.For poorly water soluble drugs, if utilize conventional slow/controlled release technology to prepare slow releasing preparation, because of drug solubility little, stripping is few, and vivo medicine concentration is low, is difficult to keep treatment concentration, usually need to adopt earlier the solubilising technology to increase the dissolubility of medicine, be raw material with the material behind the solubilising again, preparation slow/controlled release preparation, promptly first solubilising is slow release again.
The solubilising technology of insoluble drug mainly comprises: solid dispersion technology, cyclodextrin inclusion technique, micelle solubilising, microemulsion solubilising etc.Insoluble drug slow/controlled release preparation can be divided into because of the difference of release mechanism: types such as matrix type preparation, osmotic pump type preparation, film controlling type slow releasing preparation, slow release cyclodextrin clathrate, slow-release solid dispersion.Solid dispersion technology (solid dispersion, SD) be the effective ways that improve insoluble drug dissolubility and bioavailability, remarkable advantage with its preparation slow/controlled release preparation is: both can directly prepare, can make quick-releasing type SD earlier again, be raw material with quick-releasing type SD again, selects for use slow/controlled release material preparation slow/controlled release preparation (referring to Hu Daode, Pei Yuanying, Mao Danzhuo. the application of solid dispersion technology in sustained-release preparation. Chinese Journal of Pharmaceuticals, 2002,33 (5): 252; Hou Peng, Pan Weisan, Wu Xueming. the progress of solid dispersion technology in pharmaceutics. Chinese Journal of New Drugs, 2003,12 (4): 245; Zhen-ping Wei, Shi-rui Mao, Dian-zhou Bi, et al.Dissolution improvement of cisaprideby solid dispersion with HPMC.Journal of Chinese Pharmaceutical Science, 2004,13 (4): 254; ).The remarkable advantage of gel skeleton type slow release method is that preparation method is simple, does not need special installation, and adjuvant is easy to get, low price, and the influence factor is few in the preparation process, and favorable reproducibility is easy to suitability for industrialized production.
Silibinin (Silybin; SLB) be the flavone compound that extraction separation obtains from feverfew Herba Silybi mariani (Silybum marianus) fruit; because of it has significant protection and the effect of stable hepatocyte; various hepatic disease all there is in various degree therapeutical effect; now become ideal hepatic injury repair medicine; be widely used in the treatment acute, chronic hepatitis clinically; hepatopathy such as hepatic fibrosis and early stage liver cirrhosis [referring to: Flora K; Hahn M; Rahn H; et al.Milk thisle (silybummarianum) for the therapy of live disease.Am JGastroenterol; 1998,93 (13): 139.].Because SLB is insoluble in water, the shortcoming of existing conventional tablet, capsule preparations is that oral administration biaavailability is low, and elimination speed is fast in the body, the effective blood drug concentration weak point of holding time, and it is more that the patient takes number of times day.If be made into the high-efficient oral slow releasing preparation, can keep effective blood drug concentration in a long time, reduce the medication number of times, improve bioavailability.(application number: 200310105255.6) disclose a kind of " silibinin durative action preparation and preparation method thereof ", this is invented, and described medicine is actual to only limit to water miscible silybin-N-methylglucamine to Chinese patent application, is not the silibinin of slightly water-soluble; The actual preparation that is only applicable to the water-soluble drug sustained-release preparation of described preparation method; This invention does not provide measurement result in the relevant body, to prove beneficial effects such as the medication number of times reduces, bioavailability significantly improves.
Summary of the invention:
The present invention selects water-solubility carrier material polyvidone (PVP) for use, adopts solvent method to prepare silibinin (SLB) fast release solid dispersion, utilizes solid dispersion technology to improve the dissolubility of insoluble drug SLB; Be raw material with SLB fast release solid dispersion again, select to have the matrix type material hypromellose (HPMC) of slow releasing function, adopt wet granulation hydrogel skeleton type sustained release preparation; In order to prevent because of carrier material PVP moisture absorption influences slow releasing preparation stability, adopt packaging technique that slow releasing preparation is made coated tablet, improve stability of formulation.The present invention is based on " two release " mechanism of slow release behind the first rapid release, provide that a kind of release is steady, bioavailability is high, administration number of times is few, the high-efficient oral silibinin sustained-release preparation of good patient compliance, good stability.
Technical scheme of the present invention is as follows:
A kind of high-efficient oral silibinin (SLB) slow releasing preparation, it mainly is made up of following mass component:
1 part of silibinin; Polyvidone-K30 1.5-2.5 part;
Hypromellose 4000cPas 0.23-0.58 part; Low-substituted hydroxypropyl cellulose 0.46-1.38 part.
Above-mentioned oral silibinin sustained-release preparation during its mass component is formed, in order to absorb in the dissolubility that increases silibinin and the body, can add phosphatidase 10 .4-0.6 part.
Above-mentioned oral silibinin sustained-release preparation, its mass component can add IV acrylic resin 0.2-0.4 part in forming, and its objective is the dissolution rate of SLB under acid condition accelerated.
Above-mentioned oral silibinin sustained-release preparation for moisture absorption and the increase stability that prevents oral silibinin sustained-release preparation, can be made coated tablet with the oral silibinin sustained-release agent.
A kind of method for preparing above-mentioned high-efficient oral silibinin sustained-release preparation, it is made up of the following step basically:
After step 2. is got step 1. gained solid dispersion and hypromellose 4000cPas, low-substituted hydroxypropyl cellulose mixing, add an amount of 70% syrup and prepare soft material, cross 16 mesh sieves and obtain wet granular, take out after 30 minutes in 60 ℃ of bakings, cross 16 mesh sieve granulate, tabletting gets the slow releasing tablet nude film.
The schematic flow sheet of preparation process of the present invention is seen Fig. 1.
High-efficient oral silibinin sustained-release preparation of the present invention, the water-solubility carrier material can be selected PVP, Polyethylene Glycol (PEG), poloxamer F-68 etc. for use in the prescription, through screening, preferred PVP-K30; In order to absorb in the dissolubility that increases SLB and the body, added phospholipid in the solid dispersion; In order to control the rate of release of medicine, added the IV acrylic resin in the solid dispersion, the dissolution rate of SLB under acid condition accelerated; The sustained-release matrix material can be selected hypromellose (HPMC), sodium alginate for use, carbomer, and acrylic resin etc., through screening, preferred HPMC4000cPas; In order to control release rate of drugs,, also added low-substituted hydroxypropyl cellulose (L-HPC) except that selecting for use the sustained-release matrix material to slow down the release; Medium-sized HPMC50mPas of the preferred low viscosity of coating material and gastric solubility IV acrylic resin; The syrup of binding agent preferred 70%.
The invention has the beneficial effects as follows:
1. the present invention combines solid dispersion technology with slow release hydrogel matrix technology, " two release " principle according to slow release behind the first rapid release, preparation insoluble drug silibinin sustained-release preparation, its remarkable advantage is the dissolubility that has improved silibinin, realized the first quick acting in the oral back of slow releasing preparation, steadily slowly release again.Experimental result is as follows: select for use four kinds of media of 0.1%SLS of water, simulated gastric fluid, simulated intestinal fluid, PH6.8 that SLB raw material and pastille solid dispersion are carried out solubility test, the result shows: compare with the SLB raw material, pastille solid dispersion dissolubility in above-mentioned four kinds of media improves multiple and is followed successively by 1.73,1.72,3.01,6.44; Before and after the IV acrylic resin added, the external release curve of SLB solid dispersion in acid medium seen accompanying drawing 2-1～Fig. 2-2, and the result shows: do not add the solid dispersion of IV acrylic resin, the 2h cumulative release is 55.1% in acid medium; After adding the IV acrylic resin, made solid dispersion 2h cumulative release in acid medium reaches 69.3%, illustrate and add the IV acrylic resin, the rate of release of solid dispersion in acid medium obviously accelerated, add the solid dispersion that contains the IV acrylic resin in the sustained-release tablet recipe, help slow releasing tablet oral after release fast in the gastric acid environment in vivo, embody the rapid release behavior.Prepare the SLB slow releasing tablet with the solid dispersion that contains the IV acrylic resin, its external release curve is seen accompanying drawing 3, the result shows: slow releasing tablet rate of release in the intravital medium of simulation is constant, external release meets the zero order kinetics equation, 12h cumulative release amount reaches (prescription that meets slow releasing tablet) more than 80%, embodies the slow release behavior.
2. the prepared SLB slow releasing tablet of the present invention has added phospholipid during because of preparation fast release solid dispersion, can promote interior absorption of body of SLB, thereby improve the bioavailability of SLB slow releasing tablet, and in addition, SLB slow releasing tablet blood concentration peak valley phenomenon reduces, and the medication number of times reduces.SLB slow releasing tablet and control formulation be through the dog oral administration, measures drug-time curve, the results are shown in accompanying drawing 4, among the figure as seen: the Cf AUC of slow releasing tablet is significantly greater than control formulation, and bioavailability is more than 1.60 times of control formulation.The control formulation dosage is each 100mg, and every day three times, i.e. 300mg/ day, the dosage of slow releasing tablet can be designed as each 150mg, and day clothes twice are compared with control formulation, and the slow releasing tablet administration number of times reduces.
3. prepared coated its stability that increases of SLB slow releasing tablet of the present invention.The SLB slow releasing tablet is sealed, place the stability test case, place under RH75%, 40 ℃ of conditions, respectively at carrying out assay and drug release determination in 0,1,2,3 month, the result shows: the SLB slow releasing tablet is under the accelerated tests condition, and there are no significant changes for content and external release situation.
4. preparation method of the present invention is simple, does not need special installation, and adjuvant is easy to get, low price, and the influence factor is few in the preparation process, and favorable reproducibility is easy to advantages such as suitability for industrialized production.
Description of drawings
Fig. 1 is a preparation process schematic flow sheet of the present invention.
Fig. 2 is the external release curve of SLB solid dispersion.Fig. 2-1 does not wherein add the IV acrylic resin; Fig. 2-2 wherein adds the IV acrylic resin.
Fig. 3 is the external release curve of SLB slow releasing tablet of the present invention.
Fig. 4 is SLB slow releasing tablet of the present invention and the control formulation drug-time curve with dosage dog oral administration.
The specific embodiment
Following examples material therefor and instrument and equipment are:
Experiment material: phospholipid (Shanghai Taiwei Pharmaceutical Co., Ltd.), polyvidone-K30 (PVP-K30) (Shanghai Sheng Pu new material company limited), IV acrylic resin (Suzhou Li Xin pharmaceutcal corporation, Ltd), hypromellose 4000cPas (HPMC4000cPas) (Ka Lekang Shanghai branch company), low-substituted hydroxypropyl cellulose (L-HPC) (believing pharmaceutcal corporation, Ltd in the Jiangsu), 70% syrup (Chemical Reagent Co., Ltd., Sinopharm Group), polyethylene glycol 6000 (PEG6000) (Chemical Reagent Co., Ltd., Sinopharm Group), hypromellose 50mPas (HPMC50mPas) (mountains and rivers, Huainan pharmaceutic adjuvant company), dehydrated alcohol (Shanghai development chemical industry one factory).
Experimental apparatus: single punch tablet machine (the auspicious pharmaceutical machine in sky, Shanghai factory), ultraviolet spectrophotometer (Tianjin, UV-2401 island), medicament dissolution instrument (D-800L Radio Factory of Tianjin Univ.), Rotary Evaporators (Heidolph company, Germany), thermostat water bath (Jintan, Jiangsu Medical Instruments factory), stability test case (Minnesota Mining and Manufacturing Company), chromatograph of liquid (comprising: 510 pumps, Nova-pak C18 post, 486 UV-detector) (U.S. Waters company), desk type high speed refrigerated centrifuger (Biofuge Stratos Hereaus Germany).
1, takes by weighing SLB2g, PVP-K304g, phosphatidase 11 g, IV acrylic resin 0.6g is behind the adding 20ml anhydrous alcohol solution (can place 70 ℃ of water-bath accelerate dissolution in case of necessity), in 60 ℃ of water-baths, the 90rpm rotary evaporation is done near, fling to solvent fully in 70 ℃ of water-baths, put in-20 ℃ of refrigerators behind the 2h, place 60 ℃ of baking oven 12h, pulverize, cross 80 mesh sieves, get solid dispersion, standby.
2, get solid dispersion 7g,, behind the mixing, add an amount of 70% syrup and prepare soft material with HPMC4000cPas0.5g, L-HPC1g, cross 16 mesh sieves and obtain wet granular, take out after 30 minutes, cross 16 mesh sieve granulate in 60 ℃ of bakings, tabletting, pressure is controlled at 40-60N, gets 34 of slow releasing tablet nude films.
3, get the 0.058gIV acrylic resin and put in the beaker, add the 1.0ml dehydrated alcohol, make its dissolving, add 0.034gHPMC50mPas, it is scattered in the ethanol; Other gets 0.0088gPEG6000 and puts in the beaker, adds 0.2ml water, makes its dissolving; With above-mentioned two kinds of solution mixings, ultrasonic degas gets coating solution.Get 34 of slow releasing tablet nude films, place coating pan, be heated to 40-50 ℃ after, intermittently spray into coating solution, make its surperficial unlikely mistake wet and produce adhesion, evenly wrap up one deck clothing film until die surfaces, promptly get the silibinin sustained-release coated tablet.
1, takes by weighing SLB2g, PVP-K304g, phosphatidase 11 g, IV acrylic resin 0.6g is behind the adding 20ml anhydrous alcohol solution (can place 70 ℃ of water-bath accelerate dissolution in case of necessity), in 60 ℃ of water-baths, the 90rpm rotary evaporation is done near, fling to solvent fully in 70 ℃ of water-baths, put in-20 ℃ of refrigerators behind the 2h, place 60 ℃ of baking oven 12h, pulverize, cross 80 mesh sieves, get solid dispersion, standby.
2, get solid dispersion 7g,, behind the mixing, add an amount of 70% syrup and prepare soft material with HPMC4000cPas2g, L-HPC3g, cross 16 mesh sieves and obtain wet granular, take out after 30 minutes, cross 16 mesh sieve granulate in 60 ℃ of bakings, tabletting, pressure is controlled at 40-60N, gets 48 of slow releasing tablet nude films.
3, get the 0.07gIV acrylic resin and put in the beaker, add the 1.5ml dehydrated alcohol, make its dissolving, add 0.046gHPMC50mPas, it is scattered in the ethanol; Other gets 0.0136gPEG6000 and puts in the beaker, adds 0.35ml water, makes its dissolving; With above-mentioned two kinds of solution mixings, ultrasonic degas gets coating solution.Get 48 of slow releasing tablet nude films, place coating pan, be heated to 40-50 ℃ after, intermittently spray into coating solution, make its surperficial unlikely mistake wet and produce adhesion, evenly wrap up one deck clothing film until die surfaces, promptly get the silibinin sustained-release coated tablet.
1, takes by weighing SLB2g, PVP-K303g, phosphatidase 10 .8g, IV acrylic resin 0.4g is behind the adding 20ml anhydrous alcohol solution (can place 70 ℃ of water-bath accelerate dissolution in case of necessity), in 60 ℃ of water-baths, the 90rpm rotary evaporation is done near, fling to solvent fully in 70 ℃ of water-baths, put in-20 ℃ of refrigerators behind the 2h, place 60 ℃ of baking oven 12h, pulverize, cross 80 mesh sieves, get solid dispersion, standby.
2, get solid dispersion 6.3g,, behind the mixing, add an amount of 70% syrup and prepare soft material with HPMC4000cPas0.9g, L-HPC1.35g, cross 16 mesh sieves and obtain wet granular, take out after 30 minutes, cross 16 mesh sieve granulate in 60 ℃ of bakings, tabletting, pressure is controlled at 40-60N, gets 34 of slow releasing tablet nude films.
3, get the 0.054gIV acrylic resin and put in the beaker, add the 1.0ml dehydrated alcohol, make its dissolving, add 0.034gHPMC50mPas, it is scattered in the ethanol; Other gets 0.0095gPEG6000 and puts in the beaker, adds 0.25ml water, makes its dissolving; With above-mentioned two kinds of solution mixings, ultrasonic degas gets coating solution.Get 34 of slow releasing tablet nude films, place coating pan, be heated to 40-50 ℃ after, intermittently spray into coating solution, make its surperficial unlikely mistake wet and produce adhesion, evenly wrap up one deck clothing film until die surfaces, promptly get the silibinin sustained-release coated tablet.
Embodiment 4.
1, takes by weighing SLB2g, PVP-K305g, phosphatidase 11 .2g, IV acrylic resin 0.8g is behind the adding 20ml anhydrous alcohol solution (can place 70 ℃ of water-bath accelerate dissolution in case of necessity), in 60 ℃ of water-baths, the 90rpm rotary evaporation is done near, fling to solvent fully in 70 ℃ of water-baths, put in-20 ℃ of refrigerators behind the 2h, place 60 ℃ of baking oven 12h, pulverize, cross 80 mesh sieves, get solid dispersion, standby.
2, get solid dispersion 7g,, behind the mixing, add an amount of 70% syrup and prepare soft material with HPMC4000cPas1.5g, L-HPC2.5g, cross 16 mesh sieves and obtain wet granular, take out after 30 minutes, cross 16 mesh sieve granulate in 60 ℃ of bakings, tabletting, pressure is controlled at 40-60N, gets 44 of slow releasing tablet nude films.
3, get the 0.07gIV acrylic resin and put in the beaker, add the 1.3ml dehydrated alcohol, make its dissolving, add 0.044gHPMC50mPas, it is scattered in the ethanol; Other gets 0.0123gPEG6000 and puts in the beaker, adds 0.3ml water, makes its dissolving; With above-mentioned two kinds of solution mixings, ultrasonic degas gets coating solution.Get 44 of slow releasing tablet nude films, place coating pan, be heated to 40-50 ℃ after, intermittently spray into coating solution, make its surperficial unlikely mistake wet and produce adhesion, evenly wrap up one deck clothing film until die surfaces, promptly get the silibinin sustained-release coated tablet.
1, takes by weighing SLB2g, PVP-K304g, phosphatidase 11 g, IV acrylic resin 0.6g is behind the adding 20ml anhydrous alcohol solution (can place 70 ℃ of water-bath accelerate dissolution in case of necessity), in 60 ℃ of water-baths, the 90rpm rotary evaporation is done near, fling to solvent fully in 70 ℃ of water-baths, put in-20 ℃ of refrigerators behind the 2h, place 60 ℃ of baking oven 12h, pulverize, cross 80 mesh sieves, get solid dispersion, standby.
2, get solid dispersion 7g,, behind the mixing, add an amount of 70% syrup and prepare soft material with HPMC4000cPas1g, L-HPC2g, cross 16 mesh sieves and obtain wet granular, take out after 30 minutes, cross 16 mesh sieve granulate in 60 ℃ of bakings, tabletting, pressure is controlled at 40-60N, gets 40 of slow releasing tablet nude films.
3, get the 0.068gIV acrylic resin and put in the beaker, add the 1.2ml dehydrated alcohol, make its dissolving, add 0.04gHPMC50mPas, it is scattered in the ethanol; Other gets 0.0104gPEG6000 and puts in the beaker, adds 0.26ml water, makes its dissolving; With above-mentioned two kinds of solution mixings, ultrasonic degas gets coating solution.Get 40 of slow releasing tablet nude films, place coating pan, be heated to 40-50 ℃ after, intermittently spray into coating solution, make its surperficial unlikely mistake wet and produce adhesion, evenly wrap up one deck clothing film until die surfaces, promptly get the silibinin sustained-release coated tablet.
Embodiment 6.
1, takes by weighing SLB2g, PVP-K304g, phosphatidase 11 g, IV acrylic resin 0.6g is behind the adding 20ml anhydrous alcohol solution (can place 70 ℃ of water-bath accelerate dissolution in case of necessity), in 60 ℃ of water-baths, the 90rpm rotary evaporation is done near, fling to solvent fully in 70 ℃ of water-baths, put in-20 ℃ of refrigerators behind the 2h, place 60 ℃ of baking oven 12h, pulverize, cross 80 mesh sieves, get solid dispersion, standby.
2, get solid dispersion 7g,, behind the mixing, add an amount of 70% syrup and prepare soft material with HPMC4000cPas1g, L-HPC2g,. cross 16 mesh sieves and obtain wet granular, take out after 30 minutes, cross 16 mesh sieve granulate in 60 ℃ of bakings, tabletting, pressure is controlled at 40-60N, gets 40 of slow releasing tablet nude films.
3, get the 0.058gIV acrylic resin and put in the beaker, add the 1.2ml dehydrated alcohol, make its dissolving, add 0.038gHPMC50mPas, it is scattered in the ethanol; Other gets 0.011gPEG6000 and puts in the beaker, adds 0.3ml water, makes its dissolving; With above-mentioned two kinds of solution mixings, ultrasonic degas gets coating solution.Get 40 of slow releasing tablet nude films, place coating pan, be heated to 40-50 ℃ after, intermittently spray into coating solution, make its surperficial unlikely mistake wet and produce adhesion, evenly wrap up one deck clothing film until die surfaces, promptly get the silibinin sustained-release coated tablet.
Claims (3)
1. a high-efficient oral silibinin (SLB) slow releasing preparation is characterized in that it mainly is made up of following mass component:
1 part of silibinin; Polyvidone-K30 1.5-2.5 part;
Hypromellose 4000cPas 0.23-0.58 part; Low-substituted hydroxypropyl cellulose 0.46-1.38 part;
Phosphatidase 10 .4-0.6 part, and mentioned component is processed into the sustained release coating sheet.
According to claim 1 above-mentioned oral silibinin sustained-release preparation, it is characterized in that: during its mass component is formed, add IV acrylic resin 0.2-0.4 part.
3. method for preparing the described high-efficient oral silibinin sustained-release preparation of claim 1, it is made up of the following step:
Step 1. accurately takes by weighing silibinin, polyvidone-K30, phospholipid, IV acrylic resin, behind anhydrous alcohol solution, is evaporated to driedly, puts in-20 ℃ of refrigerators behind the 2h, places 60 ℃ of baking oven 12h, pulverizes, and crosses 80 mesh sieves, solid dispersion, standby;
After step 2. is got step 1 gained solid dispersion and hypromellose 4000cPas, low-substituted hydroxypropyl cellulose mixing, add 70% syrup and prepare soft material, cross 16 mesh sieves and obtain wet granular, take out after 30 minutes in 60 ℃ of bakings, cross 16 mesh sieve granulate, tabletting gets the slow releasing tablet nude film;
Step 3. is got the IV acrylic resin, adds dehydrated alcohol, makes its dissolving, adds hypromellose 50mPas, and it is scattered in the ethanol; Taking polyethylene glycol 6000 adds entry in addition, makes its dissolving; With above-mentioned two kinds of solution mixings, ultrasonic degas, coating solution, get the slow releasing tablet nude film that step 2 makes and place coating pan, be heated to 40-50 ℃ after, intermittently spray into coating solution, evenly wrap up one deck clothing film until die surfaces, promptly get the silibinin sustained-release coated tablet.
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| CN101444503B (en) * | 2008-12-31 | 2011-02-02 | 江苏大学 | Efficient long-acting silibinin preparation and preparation method thereof |
| CN101439025B (en) * | 2008-12-31 | 2011-05-11 | 江苏大学 | Silymarin high-efficient long-acting preparation and production method thereof |
| CN101444494B (en) * | 2008-12-31 | 2011-03-30 | 江苏大学 | Efficient long-acting sustained-release preparation of slightly soluble medicine and preparation method thereof |
| CN102846573B (en) * | 2012-09-06 | 2014-09-03 | 四川省中医药科学院 | Silibinin double-layer slow-release tablets and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144677A (en) * | 1995-01-18 | 1997-03-12 | 马道斯有限公司 | Flavanolignan preparation, its processing method and pharmaceutical compositions containing them |
| CN1543943A (en) * | 2003-11-26 | 2004-11-10 | 沈阳药科大学 | Oral silybin sustained release agent and preparation thereof |
| CN1569047A (en) * | 2003-07-13 | 2005-01-26 | 毛友昌 | Novel method for preparing a liver benefiting medicine and its preparation |
| CN1615844A (en) * | 2004-09-17 | 2005-05-18 | 董诗文 | Development of micro particle silybum marianum preparation |
| CN1660076A (en) * | 2004-12-16 | 2005-08-31 | 中国药科大学 | Preparation of slowly releasing silybum mariamum |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1144677A (en) * | 1995-01-18 | 1997-03-12 | 马道斯有限公司 | Flavanolignan preparation, its processing method and pharmaceutical compositions containing them |
| CN1569047A (en) * | 2003-07-13 | 2005-01-26 | 毛友昌 | Novel method for preparing a liver benefiting medicine and its preparation |
| CN1543943A (en) * | 2003-11-26 | 2004-11-10 | 沈阳药科大学 | Oral silybin sustained release agent and preparation thereof |
| CN1615844A (en) * | 2004-09-17 | 2005-05-18 | 董诗文 | Development of micro particle silybum marianum preparation |
| CN1660076A (en) * | 2004-12-16 | 2005-08-31 | 中国药科大学 | Preparation of slowly releasing silybum mariamum |
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| 张强，武凤兰.药剂学 第1版.北京大学医学出版社,2005,第512页. |
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