CN1541665A - Sustained release medicine for treating hepatitis and its preparing process - Google Patents
Sustained release medicine for treating hepatitis and its preparing process Download PDFInfo
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- CN1541665A CN1541665A CNA03117776XA CN03117776A CN1541665A CN 1541665 A CN1541665 A CN 1541665A CN A03117776X A CNA03117776X A CN A03117776XA CN 03117776 A CN03117776 A CN 03117776A CN 1541665 A CN1541665 A CN 1541665A
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Abstract
The present invention provides one kind of hepatitis treating delayed releasing preparation and its preparation process, and is especially is delayed releasing preparation prepared through mixing extractive of Penthorum chinense Pursh and pharmaceutically acceptable supplementary material. The delayed releasing preparation contains gallic acid in 2.05-2.32 wt% and quercetin in 3.26-3.49 wt%. The semi-finished product has low dry paste yield and high active component content. The preparation has determined effective components, high content, small dosage, obvious curative effect, low toxic side effect and novel preparation form.
Description
Technical field
The invention provides a kind of slow releasing preparation for the treatment of hepatitis and preparation method thereof, specifically, be to be the slow releasing preparation that raw material and slow releasing preparation adjuvant pharmaceutically commonly used are mixed with, the invention still further relates to the preparation method of this slow releasing preparation with Herba Lysimachiae Clethroids (Penthorum chinense Pursh).
Background technology
China's hepatitis B virus carriers is that the important source of infection is gone up by society up to 1.2 hundred million more than, brings very big misery to the people, has also brought great financial burden to entire society, is that hepatitis B is prevented and treated the important step in the process and actively take to treat.
The three kind new medicine GANSU KELI of having gone on the market are that Sichuan doctor pharmaceutcal corporation, Ltd of Lang Jiu group quotes Miao ethnic group's tradition proved recipe, the exclusive valuable ingredient of Chinese medicine of employing Wumeng Shan Mountain virgin forest---the Gulin Herba Lysimachiae Clethroids is a primary raw material, the folk prescription Chinese medicine preparation that gets through traditional aqueous extraction-alcohol precipitation technology preparation.This product all has significant curative effect to chronic active hepatitis, hepatitis B, acute viral hepatitis, to have that reducing enzyme and treating jaundice is fast, titre descends fast, the sign doing well,improving is fast, appetite is promoted characteristics fast, that the spirit recovery is fast, also has function of resisting hepatitis B virus simultaneously.Studies confirm that through clinical control, GANSU KELI reaches 90.1% for the clinical obvious effective rate of treatment chronic active hepatitis, treatment acute icterohepatitisshock clinical recovery rate reaches 96.3%, and the clinical recovery of children's acute hepatitis B is reached 90.48%, does not clinically see invalid case and toxicity.
The GANSU KELI curative effect is clear and definite, but there are a series of problems, fall behind such as dosage form, dosage is bigger, the patient needs long-term prescription, takes inconvenience, the more important thing is that the material base of its effect is not clear, cause big encirclement of having produced this medicine at present, the patient has also eaten a large amount of invalid components when drawing effective ingredient.
Summary of the invention
At above problem, purpose of the present invention just provides a kind of slow releasing preparation for the treatment of hepatitis, and it is a kind of new dosage form.
Another object of the present invention provides the preparation method of the slow releasing preparation of this treatment hepatitis.
Herba Lysimachiae Clethroids is the herb of dicotyledon medicine saxifragaceae plant Herba Lysimachiae Clethroids; Slightly warm in nature, sweet in the mouth is nontoxic, has detumescencing diuresis, and the effect of circulation of qi promoting is gone into Liver and kidney two warps, has the wet effect of aquation that restores menstrual flow and invigorates blood circulation, goes.
The invention provides a kind of slow releasing preparation for the treatment of hepatitis, it is the slow releasing preparation that the adjuvant by extract that contains Herba Lysimachiae Clethroids (Penthorumchinense Pursh) and pharmaceutically acceptable slow releasing preparation is mixed and made into.The adjuvant of described pharmaceutically acceptable slow releasing preparation is any one or a few a mixture of ethyl cellulose, ethylmethylcellulose, ethylhydroxyethylcellulose, polyethylene, polrvinyl chloride, polyvinylacetate, polymethacrylates, silicone rubber, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, carboxylic polrvinyl.The principle of these slow-release auxiliary material is that ethyl cellulose (EC) is insoluble framework material, and chemical property is stable, and nontoxic, parmacodynamics-less activity is widely used in the slow-release solid dispersion, had good sustained release effect; Hydroxypropyl methylcellulose (HPMC) is a hydrophilic gel matrix material, meets water or Digestive system and expands, and forms the gel barrier and the character of tool control medicine stripping, the hydroxypropyl methylcellulose consumption after a little while, share with ethyl cellulose, the effect of certain porogen is arranged, thereby improve the stripping of medicine.Select for use ethyl cellulose and hydroxypropyl methylcellulose to regulate the dissolution rate of medicine according to a certain percentage so examine filter.
Particularly, the adjuvant of described pharmaceutically acceptable slow releasing preparation is: ethyl cellulose, hydroxypropyl methylcellulose, wherein mixing the ratio range that uses is 2: 1～1: 2.
Said slow releasing preparation is slow releasing capsule, slow releasing tablet, sustained-release granular formulation, slow releasing pill, slow releasing capsule specifically.
Containing gallic acid, Quercetin in the described slow releasing preparation, is benchmark with the slow releasing preparation drug weight, and content is respectively 2.05%～2.32% and 3.26%～3.49%.
The present invention also provides the preparation method of the slow releasing preparation of this treatment hepatitis, and it comprises following steps:
A, preparation contain the semi-finished product of Herba Lysimachiae Clethroids (Penthorum chinense Pursh) extract;
B, a step gained semi-finished product are mixed with the adjuvant of pharmaceutically acceptable slow releasing preparation, make slow-releasing agent.
Wherein the concrete steps of a are:
I, get Herba Lysimachiae Clethroids and decoct with water, filter, medicinal liquid is centrifugal, gets supernatant, and is standby;
Ii, the supernatant that the i step is obtained, by macroporous adsorbent resin, absorption effective ingredient wherein;
Iii, adsorbed the macroporous resin of medicinal liquid, the impurity that water flush away interlaminar resin is not adsorbed, the reuse organic solvent elutes effective ingredient, reclaims the organic solvent concentrate drying, promptly gets semi-finished product.
Wherein Herba Lysimachiae Clethroids decocts with water and decocts twice, each one hour in the step I.Used macroporous adsorbent resin is AB-8 type, D101 type, D140 type, D141 type, S-8 type, NKA-9 type, ZTC among the step I i.
Be specially the AB-8 type.
Used organic solvent is an ethanol among the step I ii, and the concrete grammar that ethanol is washed resin is with 6BV～12BV/h speed eluting with 50%～80% ethanol.
The present invention also provides the application of this slow releasing preparation in preparation treatment hepatitis medicine.Particularly, the application in preparation treatment chronic active hepatitis medicine, hepatitis B, acute viral hepatitis medicine.
By preparing the semi-finished product that dried cream yield is low, active component content is high.The medicine semi-finished product are mixed with the granule that becomes to contain some, a certain size aperture hole with the slow releasing preparation adjuvant that pharmaceutically uses, control the rate of release of medicine in digestive tract by curved degree in hole, aperture and the hole of grain skeleton and medicine autolysis degree, to reach slow release effect.This slow releasing preparation has that effective ingredient is clear and definite, content is high, dosage is little, evident in efficacy, toxic and side effects is low, the dosage form novel and beautiful.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
Below the specific embodiment by example forms, foregoing of the present invention is described in further detail again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Description of drawings
Fig. 1: the semi-finished product technological process of production and technological parameter
Fig. 2: preparations shaping technological process and technological parameter
Fig. 3: gallic acid reference substance chromatogram
Fig. 4: Quercetin reference substance chromatogram
Fig. 5: medicine chromatogram of the present invention
Fig. 6: the release in vitro of the three batches of medicines of the present invention line (is index with the gallic acid) of writing music
Fig. 7: the release in vitro of the three batches of medicines of the present invention line (is index with the Quercetin) of writing music
The specific embodiment
The present invention is the slow releasing preparation that the adjuvant by extract that contains Herba Lysimachiae Clethroids (Penthorum chinense Pursh) and pharmaceutically acceptable slow releasing preparation is mixed and made into.It comprises that preparing the semi-finished product and the gained semi-finished product that contain Herba Lysimachiae Clethroids (Penthorum chinense Pursh) extract mixes with the adjuvant of pharmaceutically acceptable slow releasing preparation, makes slow-releasing agent.The specific embodiment is:
Example 1 Herba Lysimachiae Clethroids (Penthorum chinense Pursh) semi-finished product production technology
Get Herba Lysimachiae Clethroids 1000g, add water 12200ml and be dipped to the heart, heating decocted one hour, filtered, and add water 10000ml again and decoct twice, each one hour, filter, merge medicinal liquid.Liquor strength is counted 0.04～0.1g crude drug/ml with medical material content, counts 6.65～16.4mg/ml with extractum content.Medicinal liquid is cooled to room temperature, and high speed centrifugation 20～30 minutes makes medicinal liquid reach clarification.Supernatant is regulated pH value to 4～6, and going up in weight in wet base is on the AB-8 type macroporous adsorbent resin of 500g, and last sample flow velocity is 4BV～8BV/h (BV is the resin bed volume).After treating completion of the sample, leave standstill half an hour～1 hour, reuse 6BV～10BV distilled water is crossed resin column with 6BV～12BV/h velocity flow, and it is almost colourless to be washed till effluent, till the molish reaction negative.Reuse 2BV～4BV 50%～80% ethanol is with 6BV～12BV/h speed, and eluting is adsorbed composition, and it is almost colourless to be washed till effluent.Collect pure washing liquid, decompression recycling ethanol, concentrated medicament, vacuum drying gets semi-finished product again.The about 20g of gained semi-finished product, dried cream yield is 1.8～2.5%.Wherein macroporous adsorbent resin can also be used D101 type (Chemical Plant of Nankai Univ.), D140, D141 (Chenguang Chemical Inst., Ministry of Chemical Industry), S-8 type, NKA-9 type (Chemical Plant of Nankai Univ.), ZTC replacements such as (the flavone special use: Tianjin became the clarification technique company limited in positive day) except AB-8 type (Chemical Plant of Nankai Univ.).
Example 2 preparations shaping technologies
Get ethyl cellulose 5～10g, hydroxypropyl methylcellulose 5～10g, add 500～1000ml, 70～95% dissolve with ethanols, add 250g Herba Lysimachiae Clethroids semi-finished product again, it is dissolved in the adjuvant solution, reclaim under reduced pressure is finished ethanol, the thick extractum of gained adds 25～50g lactose, and mix homogeneously is used 95% alcohol granulation, cross 16 mesh sieves, 50 ℃ of baking half an hour, after 14 mesh sieve granulate, the gained granule is adorned 1000 of No. 1 capsules.
Example 3 gallic acids, quercetin content are measured
Contain gallic acid and Quercetin in the medicine of the present invention, adopt HPLC respectively two kinds of compositions to be carried out assay.
1, the assay of gallic acid
1.1 instrument and reagent
AgilentHPLC1100 type system of Hewlett-Packard, the P-586MMX200 of Hewlett-Packard microcomputer.
The gallic acid reference substance: Nat'l Pharmaceutical ﹠ Biological Products Control Institute provides.
Reagent: methanol is that high performance liquid chromatography is pure; Water is double distilled water.
1.2 chromatographic condition
Chromatographic column: ODS-3 (250 * 4.6mm, 5 μ m); Mobile phase: acetonitrile: 0.05%H
3PO
4(5: 95); Flow velocity: 1ml/min; Ultraviolet detection wavelength: 275nm; Chromatographic column temperature: 30 ℃; Detection sensitivity: 0.04AUFS.
1.3 sample determination
The preparation precision of need testing solution takes by weighing drug substance contents 0.2g of the present invention, puts in the 50ml conical flask, adds that methanol 25ml is ultrasonic to make dissolving, is transferred in the 50ml measuring bottle, adds methanol constant volume again, shakes up, with the filtering with microporous membrane of 0.45um, as need testing solution.
It is an amount of that the gallic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds methanol and makes the solution that every 1ml contains 0.012mg, in contrast product solution.
Accurate reference substance solution and each the 20 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.The results are shown in Table 1:
The assay result of gallic acid in table 1 medicine of the present invention
Lot number gallic acid content (mg/g) meansigma methods (mg/g)
001001 20.4 21.0 20.2 20.5
001002 21.4 20.9 21.2 21.2
001003 23.7 22.8 23.1 23.2
2, the assay of Quercetin
2.1 instrument and reagent
AgilentHPLC1100 type system of Hewlett-Packard, the P-586MMX200 of Hewlett-Packard microcomputer.
The Quercetin reference substance: Nat'l Pharmaceutical ﹠ Biological Products Control Institute provides.
Reagent: methanol is that high performance liquid chromatography is pure; Water is double distilled water.
2.2 chromatographic condition
Chromatographic column: ODS-3 post (250 * 4.6mm, 5 μ m); Mobile phase: methanol-0.2% phosphoric acid solution (55: 50); Flow velocity: 1ml/min; Ultraviolet detection wavelength: 360nm; Chromatographic column temperature: 40 ℃; Detection sensitivity: 0.04AUFS.
2.3 sample determination
The preparation precision of need testing solution takes by weighing medicine 0.2g of the present invention, puts in the 50ml round-bottomed flask, adds 3% hydrochloric acid methanol liquid 25ml, reflux 1.5 hours, cooling adds methanol constant volume to 50ml, shake up, with the filtering with microporous membrane of 0.45um, as need testing solution.
It is an amount of that the Quercetin reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds methanol and makes the solution that every 1ml contains 0.012mg, in contrast product solution.
Accurate reference substance solution and each the 20 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.The results are shown in Table 2:
The assay result of Quercetin in table 2 medicine of the present invention
Lot number quercetin content (%) meansigma methods (%)
001001 3.39 3.44 3.38 3.40
001101 3.27 3.21 3.33 3.27
010101 3.20 3.31 3.28 3.26
The outer drug release determination of example limbs
Common liver is revived capsule in contrast, as dissolution medium, adopts commentaries on classics basket method to measure with the PH=7.4 phosphate buffer.Be specially rotating speed 100 ± 1r/min, 37 ± 0.5 ℃ of temperature, release medium are the phosphate buffer of 900mlPH=7.4.Under these conditions, in different time points sampling 5ml (adding the 5ml dissolution medium after the sampling immediately), add phosphoric acid and transfer PH=3-4, with ethyl acetate extraction three times, each 10ml, combining extraction liquid, reclaim ethyl acetate, residue adds dissolve with methanol and becomes 10ml, measures its absorbance in the 275nm place, and calculates release.
Method by example 1 and example 2 makes three batch samples (001001; 001002; 001003), and gallic acid is measured in employing, the Quercetin burst size is an index, investigates the release of medicine of the present invention, measures its release in vitro degree by preceding method, the results are shown in following table:
The release in vitro degree measurement result of table 3 three batch samples (is index with the gallic acid)
The lot number time (h)
1 2 4 6 8 10 12
001001 26.3 35.2 51.0 62.5 77.1 83.4 88.7
27.1 35.4 51.4 60.4 75.4 82.1 87.6
26.5 36.1 49.8 61.4 78.9 84.6 86.2
26.0 34.9 52.1 62.8 74.8 80.5 88.4
25.8 36.3 51.7 59.8 77.5 81.7 83.9
27.2 35.6 51.2 61.7 74.0 81.7 83.0
001002 24.0 32.6 53.4 62.8 74.1 84.4 87.0
23.1 31.9 52.8 63.5 73.6 84.7 89.5
23.8 32.0 54.9 63.3 75.2 86.0 91.3
24.5 33.3 50.1 60.4 72.6 83.5 86.2
25.6 32.5 49.9 61.6 72.0 82.8 89.9
23.8 31.4 52.2 63.5 73.4 85.1 91.1
001003 25.4 34.2 54.9 63.4 74.0 80.1 85.3
23.2 33.8 53.6 64.3 75.1 80.9 85.9
24.9 35.4 54.7 65.1 73.6 81.2 84.2
24.8 35.9 54.6 62.2 73.2 82.4 84.1
25.1 33.1 52.0 63.7 75.5 81.5 83.3
25.7 32.9 55.0 64.3 74.8 82.8 84.8
001001 26.5 35.6 51.2 61.4 76.3 82.3 86.3
X±SD ±0.57 ±0.53 ±0.78 ±1.17 ±1.85 ±1.44 ±2.38
001002 24.1 32.3 52.2 62.5 73.5 84.4 89.2
X±SD ±0.84 ±0.66 ±1.93 ±1.26 ±1.13 ±1.14 ±2.12
001003 24.9 34.2 54.1 63.8 74.4 81.5 84.6
X±SD ±0.87 ±1.21 ±1.16 ±0.99 ±0.90 ±0.99 ±0.93
The release in vitro degree measurement result of table 4 three batch samples (is index with the Quercetin)
The lot number time (h)
1 2 4 6 8 10 12
001001 27.4 37.6 56.2 67.9 77.9 87.3 95.6
28.0 38.0 56.9 67.0 76.3 88.8 96.4
27.9 36.4 57.3 65.2 76.2 85.9 94.3
29.3 36.2 57.6 66.7 77.0 87.6 96.2
26.4 38.1 56.4 64.4 75.6 86.2 96.8
24.3 36.1 58.8 68.3 76.3 88.0 97.4
001002 24.9 35.8 55.5 65.1 73.2 88.1 94.3
23.6 34.2 55.0 64.3 72.1 87.6 94.6
25.8 36.2 56.8 66.5 74.7 87.2 93.7
27.3 35.8 58.3 63.7 73.5 86.3 92.8
24.2 34.1 56.6 63.2 72.9 85.4 92.2
26.4 34.9 57.4 65.5 72.2 85.8 94.9
001003 25.3 35.3 55.1 63.2 75.1 84.2 94.4
25.8 35.9 55.7 63.0 74.4 84.1 94.1
24.7 34.4 54.6 60.5 73.6 83.3 95.8
26.6 34.0 56.4 64.3 75.5 82.9 93.2
25.5 33.2 56.0 62.8 74.8 85.0 95.5
24.0 36.1 53.3 62.6 73.8 84.4 92.7
001001 27.2 37.1 57.2 66.6 76.6 87.3 96.1
X±SD ±1.71 ±0.93 ±0.94 ±1.52 ±0.80 ±1.10 ±1.07
001002 25.4 35.2 56.6 64.7 73.1 86.7 93.8
X±SD ±1.39 ±0.89 ±1.21 ±1.22 ±0.96 ±1.07 ±1.06
001003 25.3 34.9 55.2 62.7 74.5 84.0 94.3
X±SD ±0.90 ±1.26 ±1.12 ±1.25 ±0.74 ±0.76 ±1.23
Conclusion: common liver Soviet Union capsule is very fast in external release, almost is all to discharge after the capsule disintegrate.Drug release of the present invention is slow, and the effect that reaches slow release is described.
Study human hepatitis B pathogeny, virus replication and screen effective medicine as the hepatitis B animal model with the DHBV infected duck, generally acknowledged by Chinese scholars.Document has reported that relevant Herba Lysimachiae Clethroids extract is effective in cure at the antagonism DHB; And the protecting liver and detoxication effect is arranged.
Below by testing the beneficial effect of further setting forth medicine of the present invention.
Test a medicine of the present invention in intravital pharmacokinetics of Canis familiaris L. and pharmacodynamics
1, medicine of the present invention is at the intravital pharmacokinetic of Canis familiaris L.
(derive from the semi-finished product of slow releasing capsule by having compared medicine of the present invention and liver Soviet Union conventional capsule, it is directly encapsulated and get not add slow-release auxiliary material) the release in vitro degree after, the release that shows medicine of the present invention is considerably slower than liver Soviet Union conventional capsule, because gallic acid is one of effective ingredient in the medicine of the present invention, for whether the variation of examining or check the release in vitro degree causes medicine body giving drugs into nose dynamic (dynamical) variation of generation of the present invention, die with gallic acid as one of them characteristic component, thereby set up the processing that Canis familiaris L. is taken blood sample behind the medicine of the present invention, the content assaying method of gallic acid, and compared medicine of the present invention and liver Soviet Union conventional capsule in the intravital pharmacokinetics process of Canis familiaris L..
1.1 instrument and reagent
Agilent 1100 type HPLC systems (Hewlett-Packard)
LD4-2 low speed centrifuge (Beijing Medical Centrifugal Machine Factory)
TGL-16G table model high speed centrifuge (Shanghai medical analytical instrument factory)
The quick vortex mixer of XK96-A (Jiangyan City, Jiangsu Xin Kang instrument plant)
Medicine of the present invention (self-control, lot number: 001003, specification: the 0.28g/ grain)
Liver Soviet Union conventional capsule (self-control, lot number: 001003, specification: the 0.26g/ grain)
Gallic acid reference substance (Chinese biological goods calibrating institute, lot number: 0831-9501 uses for containing to survey)
1.2 method
Adopt the random experiments method for designing, 4 Canis familiaris L.s are divided into two groups at random, fasting 12 hours, get blank serum, irritate stomach medicine 0.211g/kg of the present invention more respectively, the conventional capsule 0.185g/kg of liver Soviet Union (be equivalent to the 16.67g crude drug, clinical Coming-of-Age Day is used 20 times of dosage) gets blood 5ml behind the filling stomach in official hour, room temperature is placed 30min, centrifugal 10min in low speed centrifuge gets blood serum sample 2ml, adds the HCl 1ml of 2mol/L again, quick mixing, add methanol 5ml, quick mixing 5min on quick centrifuge, low-speed centrifugal, get supernatant, again precipitation is added methanol 5ml, quick mixing 5min, low-speed centrifugal, supernatant is merged, water bath method, residue add 1ml methanol makes dissolving, high speed centrifugation 10min, get supernatant, measure the content of gallic acid in the different time blood serum sample by above-mentioned chromatographic condition.
Behind the table 5 single oral dose medicine of the present invention in the blood serum sample gallic acid through the time blood drug level (μ g/ml)
Time (h) 123456789 10
1 3.32 5.81 10.45 18.25 21.57 20.20 16.17 12.44 6.64 1.33
2 4.01 6.34 10.71 19.69 23.32 19.97 16.23 12.58 5.97 1.40
X 3.67 6.08 10.58 18.97 22.45 20.09 16.20 12.51 6.31 1.37
Gallic acid behind the table 6 single oral dose liver Soviet Union capsule in the blood serum sample through the time blood drug level (μ g/ml)
Time (h) 123456789 10
1 13.27 23?22 28.20 24.89 16.59 9.95 4.98 1.67 --- ---
2 11.54 22.61 25.38 23.11 14.63 7.57 4.05 1.32 --- ---
X 12.41 23.92 26.79 24.00 15.61 8.76 4.52 1.50 --- ---
Annotate: through the time blood drug level, be meant in the back different time sections of taking medicine, measure blood drug level, judge medicine LADME situation in vivo with this, select this index can reflect slow release effect.
1.3 result treatment
1.3.1 medicine of the present invention and conventional capsule are in the intravital pharmacokinetic parameters of Canis familiaris L.
Through 3P87 pharmacokinetics program his-and-hers watches 5, table 6 column data handle select the chamber model (Liang Wenquan. Biopharmaceutics and Pharmacokinetics. People's Health Publisher .2000 June), this program is the experimental design method a kind of commonly used in the pharmacological evaluation.(" degree of fitting parameter " is that pharmacological evaluation is carried out a kind of method that science is handled to experimental data to goodness of fit parameter, makes experimental data close with actual value as far as possible.) see Table 7 respectively, table 8, the assay between the model of chamber sees Table 9, table 10.
Table 7 medicine of the present invention on average through the time blood drug level goodness of fit parameter
Rec. No.Weighted Goodness Max. Max. Run
No.?Mean WT sum of R R of Error Error AIC
No. Comp Squares Squares Fit C-CI ％ Test
1 1 1 1 0.154E+03 0.8203 0.6484 5.067 6.33 98.7 58.372 3
2 1 1 2 0.198E+03 0.8164 0.5480 7.035 8.27 123.1 64.882 3
3 1 1/C 1 0.161E+02 0.8267 0.9632 1.638 9.76 50.5 35.791 3
4 1 1/C 2 0.196E+02 0.8640 0.9552 2.215 10.06 79.6 41.769 2
5 1 1/C/C 1 0.148E+01 0.8197 0.9966 0.496 12.84 57.2 11.911 3
6 1 1/C/C 2 0.153E+01 0.8691 0.9965 0.619 12.69 56.5 16.269 2
Table 8 liver Soviet Union capsule on average through the time blood drug level goodness of fit parameter
Rec. No. Weighted Goodness Max. Max. Run
No. Mean WT sum of R R of Error Error AIC
No. Comp Squares Squares Fit C-CI ％ Test
1 1 1 1 0.386E+02 0.9746 0.9409 3.106 3.743 76.3 37.225 3
2 1 1 2 0.880E+03 0.5873 -.3470 20.976 23.92 100.0 66.239 1
3 1 1/C 1 0.621E+01 0.9453 0.9905 1.246 5.86 172.7 22.611 3
4 1 1/C 2 0.444E+02 0.5716 0.9320 4.713 23.92 100.0 42.349 1
5 1 1/C/C 1 0.101E+01 0.8966 0.9985 0.503 8.70 48.4 8.080 3
6 1 1/C/C 2 0.262E+01 0.5719 0.9960 1.144 23.92 100.0 19.697 1
Table 9 medicine of the present invention on average through the time blood drug level chamber model between the F check
Between?1?and?2?compartment
F value(Weight?1) -.4440145
P?value P＞0.05
F value(Weight?1/C) -.3589132
P?value P＞0.05
F value(Weight?1/C/C) -7.036652E-02
Pvalue P＞0.05
Table 10 liver Soviet Union conventional capsule on average through the time blood drug level chamber model between the F check
Between 1?and?2?compartment
F value(Weight?1) -.9561386
P?value P＞0.05
F value(Weight?1/C) -.8601718
P?value P＞0.05
F value(Weight?1/C/C) -.6140975
P?value P＞0.05
By table 9, table 10 as seen, difference that there are no significant between each chamber model.Again according in table 7, the table 8, press the minimum principle of AIC, medicine of the present invention and conventional capsule all select one-compartment model, weight (weight refers to a certain index shared significance level in weighing the experimental result quality) for 1/C/C to individuality through the time blood drug level data carry out match.Calculate respectively organize pharmacokinetic parameters according to see Table 11, table 12:
Table 11 medicine of the present invention is in the intravital pharmacokinetic parameters of Canis familiaris L.
No A Ke Ka t
1/2(Ka) t
1/2(Ke)?T(peak) C(max) AUC CL/F(s)
Mg/ml 1/h 1/h h h h μg/ml (μg/ml)*h mg/h/μg/ml
1 149.2440 0.3927 0.4676 1.4824 1.7651 2.3307 9.5703 60.8638 1.9322
2 160.0600 0.3946 0.4694 1.4767 1?7565 2.3206 10.2064 64.6259 1.8197
mean 154.6520 0.3937 0.4685 1.4795 1.7608 2.3257 9.8884 62.7448 1.8759
Table 12 liver Soviet Union conventional capsule is in the intravital pharmacokinetic parameters of Canis familiaris L.
No A Ke Ka t
1/2(Ka)?t
1/2(Ke) T(peak) C(max) AUC CL/F(s)
Mg/ml 1/h 1/h h h h μg/ml (μg/ml)*h mg/h/μg/ml
1 2120.4993 0.5819 0.5979 1.1593 1.1911 1.6952 21.1260 97.3606 1.2079
2 2105.1035 0.6089 0.6247 1.1095 1.1383 1.6213 19.8150 87.3320 1.3466
mean 2112.8013 0.5954 0.6113 1.1344 1.1647 1.6582 20.4705 92.3463 1.2772
Table 13 medicine of the present invention and conventional capsule pharmacokinetic parameters are according to comparing
Parameter A UC (0 → ∞) Cmax Tmax MRT
Slow releasing capsule 117.6458 21.57 5 5.5410
121.7367 23.32 5 5.4598
Average 119.6912 22.45 5 5.5004
Conventional capsule 124.1798 28.20 3 3.5625
112.2835 25.38 3 3.5282
Average 117.6517 26.79 3 3.4838
T test value in groups
0.2322 2.6153 44.3570
P＞0.05 P＞0.05 P＜0.01
Annotate: t
0.05,2=4.303; t
0.01,2=9.925
The average that is meant two groups is in groups carried out the T check, judges according to gained T value size whether two groups of data have significant difference.
As can be seen from Table 13, (AUC refers to area under the drug-time curve to the Cmax of medicine of the present invention and conventional capsule (maximum plasma concentration), can reflect medicine interior cumulative release amount of a period of time in vivo with AUC.) there was no significant difference, and peak time is 1.67 times of conventional capsule, mean residence time (MRT) has utmost point significant difference, shows that medicine of the present invention has tangible slow releasing function, in vivo the higher blood drug level of the maintenance of long period.
2, medicine of the present invention is in the intravital pharmacodynamic studies of Canis familiaris L.
The release in vitro degree of medicine of the present invention and liver Soviet Union conventional capsule, medicine of the present invention and liver Soviet Union conventional capsule are in the intravital pharmacokinetics of Canis familiaris L., the result shows that the release in vitro of medicine of the present invention is considerably slower than liver Soviet Union conventional capsule, medicine of the present invention shows for kinetics at Canis familiaris L. body giving drugs into nose, the peak time of medicine of the present invention, eliminate all slow in the body than liver Soviet Union conventional capsule, in order to examine or check medicine release in vitro of the present invention, whether the change of pharmacokinetics has caused the change of the drug effect of medicine of the present invention, so with SGPT (serum glutamic pyruvic transminase) is index, but normally whether the lesion degree of this index specificity reflection liver, function.Measure Canis familiaris L. and give the intravital SGPT content of different time behind the medicine of the present invention.Thereby estimate the pharmacodynamics of medicine of the present invention.
2.1 instrument and reagent
Beckman 700 type full automatic biochemical apparatus (U.S. Beckman company); LDR4-8.4C low speed refrigerated centrifuge (Beijing centrifuge factory); Alanine transaminase (ALT/GPT) test kit, specification: 4*50ml, lot number: 000601); Medicine of the present invention (self-control).
2.2 experimental subject
8 of hybrid dogs, body weight 10-15kg, male and female half and half.
2.3 test method
8 hybrid dogs are divided into 4 groups at random, 2 every group, fasting 16 hours, CCL
4Liver injury model group, medicine group of the present invention, the equal lumbar injection 40% carbon tetrachloride peanut oil solution 0.2ml/kg of liver Soviet Union's conventional capsule group, normal control group lumbar injection isometric(al) normal saline.Medicine of the present invention and conventional capsule are irritated stomach respectively and are given medicine 0.211g/kg of the present invention, the conventional capsule content 0.185g/kg of liver Soviet Union (be equivalent to the 16.67g crude drug, clinical Coming-of-Age Day is used 20 times of dosage), normal control group and CCL
4The liver injury model matched group is irritated stomach and is given the isometric(al) distilled water, and successive administration is after 3 days, and 16h carries out the last administration after modeling.Gather experimental dog venous blood respectively at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h after the last administration, after leaving standstill 1 hour, 2500rpm, separation of serum, test sera SGPT value on Beckman 700 type full automatic biochemical apparatus.SGPT raises and shows the liver damage aggravation, and the rising suppression ratio can reflect the protective effect of medicine to liver, and suppression ratio is high more, and then protective effect is strong more.
2.4 result of the test
SGPT value in the different time serum behind the table 14 Canis familiaris L. filling stomach medicine of the present invention
SGPT value (U/mmol) after the administration of group clothes
15min 30min 1h 2h 4h 6h 8h 12h 16h 24h 36h 48h
Normal control group 78.32 85.39 79.45 80.64 77.98 81.56 80.38 89.42 92.03 77.83 75.31 71.59
±17.23 ±20.18 ±19.24 ±21.60 ±17.32 ±21.33 ±24.58 ±20.38 ±26.41 ±19.40 ±20.68 ±15.71
CCL4 hepatic injury 375.2 389.3 385.7 389.4 423.5 441.3 447.8 513.1 487.6 421.3 372.7 319.5
Model group ± 75.46 ± 89.12 ± 87.55 ± 81.51 ± 72.36 ± 81.60 ± 79.56 ± 123.6 ± 91.25 ± 115.6 ± 128.4 ± 97.56
SGPT value 379.1 355.9 385.5 382.9 443.1 441.1 457.1 473.8 429.8 441.3 394.9 346.3
Rate of rise (%)
Liver Soviet Union slow release 365.3 341.7 311.7 301.9 327.5 331.2 347.5 420.7 417.5 401.5 367.8 311.5
Capsules group ± 61.57 ± 77.28 ± 60.32 ± 78.82 ± 63.57 ± 75.60 47.83 ± 78.42 ± 41.44 ± 63.42 ± 75.34 ± 10.34
SGPT value 366.4 300.2 292.3 274.4 320.0 306.1 332.3 370.5 353.6 415.9 388.4 335.1
Rate of rise (%)
SGPT value 3.35 15.65 20.18 23.78 28.34 30.60 27.30 21.80 17.73 5.76 3.23 1.64
Rising suppression ratio (%)
Liver revives common 357.4 336.8 310.2 289.6 322.4 351.8 389.1 460.8 441.7 419.6 373.6 316.4
Capsules group ± 81.62 ± 71.23 ± 78.16 ± 63.45 ± 80.32 ± 59.62 ± 85.43 ± 79.32 ± 69.83 ± 75.42 ± 71.52 ± 85.72
The SGPT value
Rate of rise (%) 356.3 294.4 290.4 259.1 32.24 331.3 384.1 415.2 380.0 439.1 396.1 342.0
SGPT value 6.01 17.28 24.16 32.33 27.23 24.89 15.97 12.37 11.42 2.20 1.89 1.24
Rising suppression ratio (%)
2.5 result treatment
2.5.1 medicine of the present invention and conventional capsule pharmacodynamics parameter are relatively
Handle through 14 column data of 3P87 pharmacokinetics program his-and-hers watches and to select that suitable chamber model, goodness of fit parameter see Table 15 respectively, table 16, the assay between the model of chamber sees Table 17, table 18.
The goodness of fit parameter of table 15 average drug effect-time of medicine of the present invention
Rec. No. Weighted Goodness Max. Max. Run
No. Mean WT sum of R R of Error Error AIC
No. Comp Squares Squares Fit C-CI ％ Test
1 1 1 1 0.688E+02 0.9747 0.9486 2.765 4.00 114.6 56.772 4
2 1 1 2 0.157E+02 0.9941 0.9883 1.617 2.40 48.9 45.040 9
3 1 1/C 1 0.442E+01 0.9706 0.9967 0.743 4.16 40.5 25.831 5
4 1 1/C 2 0.172E+01 0.9932 0.9987 0.536 2.35 40.8 18.532 6
5 1 1/C/C 1 0.313E+00 0.9644 0.9998 0.198 4.40 32.4 -5.946 5
6 1 1/C/C 2 0.245E+00 0.9862 0.9998 0.202 3.57 36.3 -4.902 6
The goodness of fit parameter of table 16 liver Soviet Union's average drug effect-time of conventional capsule
Rec. No. Weighted Goodness Max. Max. Run
No. Mean WT sum of R R of Error Error AIC
No. Comp Squares Squares Fit C-CI ％ Test
1 1 1 1 0.317E+02 0.9875 0.9749 1.991 2.93 80.1 49.482 9
2 1 1 2 0.309E+02 0.9877 0.9756 2.268 2.88 83.6 53.154 9
3 1 1/C 1 0.383E+01 0.9875 0.9970 0.692 3.25 74.3 24.105 9
4 1 1/C 2 0.293E+01 0.9871 0.9977 0.699 3.76 55.2 24.907 10
5 1 1/C/C 1 0.124E+01 0.9814 0.9990 0.394 4.83 71.1 10.606 7
6 1 1/C/C 2 0.410E+00 0.9831 0.9997 0.261 5.16 45.2 1.302 7
F check between the average drug effect of table 17 medicine of the present invention-time chamber model
Between?1?and?2?compartment
F value(Weight?1) 10.14769
P?value P＜0.05
F value(Weight?1/C) 4.692236
P?value P＞0.05
F value(Weight?1/C/C) .8381525
P?value P＞0.05
Table 18 liver Soviet Union conventional capsule on average through the time blood drug level chamber model between the F check
Between?1?and?2?compartment
F value(Weight?1) 8.311858E-02
P?value P＞0.05
F value(Weight?1/C) .9163609
P?value P＞0.05
F value(Weight?1/C/C) 6.091291
P?value p＜0.05
By table 17, table 18 as seen, when weight is 1, between the medicament chamber model of the present invention significant difference is arranged.When weight is 1/C/C, there is significance poor between the liver Soviet Union conventional capsule chamber model.According to the minimum principle of AIC, press AIC value in table 15, the table 16 again, medicine of the present invention should selection, one-compartment model, weight are that 1/C/C carries out match to average drug effect-time data; It is that 1/C/C carries out match to average drug effect-time data that liver Soviet Union conventional capsule is selected two-compartment model, weight, and each pharmacodynamics parameter of calculating is according to seeing Table 19:
Table 19 medicine of the present invention is in the intravital pharmacodynamics parameter of Canis familiaris L.
No A Ke Ka t
1/2(Ka)?t
1/2(Ke)?T(peak) C(max) AUC CL/F(s)
μg/ml 1/h 1/h h h h μg/ml (μg/ml)*h mg/h/μg/ml
1 39.3382 0.0698 1.2075 0.5740 9.9316 2.6831 31.1177 531.0672 0.2214
2 42.1205 0.0703 0.8335 0.8316 9.8584 3.3621 30.7109 548.5365 0.2144
mean?40.7293 0.0701 1.0205 0.7028 9.8950 3.0226 30.9143 539.8019 0.2179
Table 20 liver Soviet Union conventional capsule is in the intravital pharmacodynamics parameter of Canis familiaris L.
No A α B β Ka t
1/2(Ka)?t
1/2α t
1/2β K21 K10
μg/ml 1/h μg/ml 1/h 1/h h h h 1/h 1/h
1 50.8605 0.1511 1.3980 0.0086 1.0634 0.6518 4.5868 80.5029 0.0130 0.1001
2 53.7540 0.1457 1.3645 0.0007 0.9814 0.7063 4.7575 1007.1641 0.0049 0.0205
mean?52.3073 0.1484 1.3812 0.0046 1.0224 0.6791 4.6721 543.8335 0.0089 0.0603
Table 21 medicine of the present invention and conventional capsule pharmacodynamics parameter are relatively
Parameter A UC (0 → ∞) SGPT rising suppression ratio max (%) Tmax (h) MRT (h)
Slow releasing capsule 576.01 72 30.10 6 15.8789
590.9988 31.10 6 15.4249
Average 583.5081 30.60 6 15.6519
Conventional capsule 398.8494 32.01 2 12.7539
438.2022 32.65 2 14.2610
Average 418.5258 32.33 2 13.5074
The T test value 7.8366 2.9138 2.7250 in groups
P＜0.05 P＞0.05 P＞0.05
Annotate: t
0.05,2=4.303; t
0.01,2=9.925
As can be seen from Table 21, the AUC and the conventional capsule of medicine of the present invention have significant difference, and Tmax (blood drug level maximum time time) is 3 times of conventional capsule, MRT, maximum SGPT rising suppression ratio there was no significant difference.
2.5.2 medicine of the present invention is at the correlation research of intravital pharmacokinetics of Canis familiaris L. and pharmacodynamics:
Table 22 gallic acid the intravital blood drug level of Canis familiaris L. and medicine of the present invention to the Canis familiaris L. body in the influence of SGPT
Time (h) 12468
Blood drug level (μ g/ml) 3.67 6.08 18.97 20.09 12.51
SGPT rising suppression ratio (%) 20.18 23.78 28.34 30.60 27.30
With gallic acid in the medicine of the present invention at the intravital blood drug level C of Canis familiaris L. (g/ml) as independent variable, medicine of the present invention carries out linear regression to SGPT rising suppression ratio P (%) in the Canis familiaris L. body as dependent variable, getting equation is: P=19.539+0.530C, r=0.956, df=n-2=3, look into correlation coefficient according to critical phase to being worth r
3,0.05=0.878, r＞r
3,0.05, show pharmacokinetics and pharmacodynamics significant correlation.
2.3 conclusion
Further prove the slow release effect of slow releasing capsule by the purpose of this experiment, because only prove that by pharmacokinetics the slow release of its blood drug level still can not prove absolutely its slow release effect, having only in conjunction with special pharmacology's index variation further to prove its slow release effect.Slow releasing capsule is exactly that slow release, minimizing are taken number of times and reached the purpose that makes things convenient for the patient than the advantage of conventional capsule.
Selection, pharmacokinetics, the estimation of pharmacodynamics parameter and the examination of inside and outside dependency, pharmacokinetics and pharmacodynamics dependency from above chamber model, show that medicine of the present invention is an one-compartment model at the intravital pharmacokinetics of Canis familiaris L., pharmacodynamics, and have preferably inside and outside, medicine moving-the drug effect dependency.Mean residence time is all long than liver Soviet Union conventional capsule in peak time and the body, has reached slow release effect preferably.
Mode by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Embodiment 1: Herba Lysimachiae Clethroids (Penthorum chinense Pursh) semi-finished product production technology
Get Herba Lysimachiae Clethroids 1000g, add water 12200ml and be dipped to the heart, heating decocted one hour, filtered, and add water 10000ml again and decoct twice, each one hour, filter, merge medicinal liquid.Liquor strength is counted 0.08g crude drug/ml with medical material content, counts 13.124mg/ml with extractum content.Medicinal liquid is cooled to room temperature, and high speed centrifugation 30 minutes makes medicinal liquid reach clarification.Supernatant is regulated pH value to 5, and going up in weight in wet base is on the AB-8 type macroporous adsorbent resin of 500g, and last sample flow velocity is 6BV/h (BV is the resin bed volume).After treating completion of the sample, left standstill 45 minutes, reuse 8BV distilled water is crossed resin column with the 10BV/h velocity flow, and it is almost colourless to be washed till effluent, till the molish reaction negative.Reuse 3BV 70% ethanol is with 10BV/h speed, and eluting is adsorbed composition, and it is almost colourless to be washed till effluent.Collect pure washing liquid, decompression recycling ethanol, concentrated medicament, vacuum drying gets semi-finished product again.The about 20g of gained semi-finished product, dried cream yield is 2.1%.
The moulding process of embodiment 2 slow releasing capsulees
Get ethyl cellulose 5g, hydroxypropyl methylcellulose 5g, add 1000ml 85% dissolve with ethanol, add 250g Herba Lysimachiae Clethroids semi-finished product again, it is dissolved in the adjuvant solution, reclaim under reduced pressure is finished ethanol, the thick extractum of gained adds the 25g lactose, and mix homogeneously is used 95% alcohol granulation, cross 16 mesh sieves, 50 ℃ of baking half an hour, after 14 mesh sieve granulate, the gained granule is adorned 1000 of No. 1 capsules.
Embodiment 3 slow releasing tablet preparation technologies:
The same slow releasing capsule of semi-finished product technology with ethyl cellulose (EC) 3.3g, hydroxypropyl methylcellulose (HPMC15KM) 6.6g, adds 1000ml 85% dissolve with ethanol, add 250g Herba Lysimachiae Clethroids semi-finished product again, it is dissolved in the adjuvant solution, reclaim under reduced pressure is finished ethanol, the thick extractum of gained adds the 25g lactose, mix homogeneously is used 95% alcohol granulation, crosses 16 mesh sieves, 50 ℃ are dried by the fire half an hour, after 14 mesh sieve granulate, tabletting, promptly.
Embodiment 4 sustained-release granular formulation preparation technologies: semi-finished product technology is the same, preparations shaping technology is: ethyl cellulose (EC) 6.6g, hydroxypropyl methylcellulose (HPMC15KM) 3.3g, add 1000ml 85% dissolve with ethanol, add 250g Herba Lysimachiae Clethroids semi-finished product again, it is dissolved in the adjuvant solution, reclaim under reduced pressure is finished ethanol, the thick extractum of gained adds lactose 10g, an amount of mixing of sucrose 15g, 95% alcohol granulation, cross a sieve (12～14 order) extruding and granulate, 60 ℃ are dried by the fire half an hour, make moisture in 2%, cross No. four sieves (60 order) and remove fine particle, promptly.
The preparation of embodiment 5 slow release honeyed pill:
Semi-finished product technology is the same, and preparations shaping technology is: ethyl cellulose (EC) 5g, hydroxypropyl methylcellulose (HPMC15KM) 5g add 1000ml 85% dissolve with ethanol, add 250g Herba Lysimachiae Clethroids semi-finished product again, it is dissolved in the adjuvant solution, reclaim under reduced pressure is finished ethanol, the thick extractum of gained adds lactose 25 an amount of mixings, and sieve was pulverized in 70 ℃ of oven dry No. six, get fine powder, add the abundant mixing of an amount of refined honey, the pill piece, use automatic pellet processing machine pill bar, gradation, round, the pill grain, 80 ℃ of dryings, promptly.
Claims (13)
1, a kind of slow releasing preparation for the treatment of hepatitis is characterized in that it is the slow releasing preparation that the adjuvant by extract that contains Herba Lysimachiae Clethroids (Penthorumchinense Pursh) and pharmaceutically acceptable slow releasing preparation is mixed and made into.
2, according to the slow releasing preparation of the described treatment hepatitis of claim 1, it is characterized in that the adjuvant of described pharmaceutically acceptable slow releasing preparation is: the mixture of any one or a few in ethyl cellulose, ethylmethylcellulose, ethylhydroxyethylcellulose, polyethylene, polrvinyl chloride, polyvinylacetate, polymethacrylates, silicone rubber, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, the carboxylic polrvinyl.
3, according to the slow releasing preparation of the described treatment hepatitis of claim 2, it is characterized in that the adjuvant of described pharmaceutically acceptable slow releasing preparation is: ethyl cellulose, hydroxypropyl methylcellulose, wherein mixing the ratio range that uses is 1: 2～2: 1.
4, the slow releasing preparation of treatment hepatitis according to claim 1 is characterized in that said slow releasing preparation is slow releasing capsule, slow releasing tablet, sustained-release granular formulation, slow releasing pill.
5, the slow releasing preparation of treatment hepatitis according to claim 4 is characterized in that said slow releasing preparation is a slow releasing capsule.
6, according to the slow releasing preparation of claim 4,5 described treatment hepatitis, it is characterized in that it contains gallic acid, Quercetin, be benchmark with the slow releasing preparation drug weight, gallic acid content is 2.05%～2.32%, quercetin content is 3.26%～3.49%.
7, the preparation method of the slow releasing preparation of the described treatment hepatitis of claim 1, it comprises following steps:
A, preparation contain the semi-finished product of Herba Lysimachiae Clethroids (Penthorum chinense Pursh) extract;
B, a step gained semi-finished product are mixed with the adjuvant of pharmaceutically acceptable slow releasing preparation, make slow releasing preparation.
8, according to the preparation method of the slow releasing preparation of the described treatment hepatitis of claim 7, it is characterized in that the concrete steps of step a are:
I, get Herba Lysimachiae Clethroids and decoct with water, filter, medicinal liquid is centrifugal, gets supernatant, and is standby;
Ii, the supernatant that the i step is obtained, by macroporous adsorbent resin, absorption effective ingredient wherein;
Iii, adsorbed the macroporous resin of medicinal liquid, the impurity that water flush away interlaminar resin is not adsorbed, the reuse organic solvent elutes effective ingredient, reclaims the organic solvent concentrate drying, promptly gets semi-finished product.
9, the preparation method of the slow releasing preparation of described according to Claim 8 treatment hepatitis is characterized in that macroporous adsorbent resin used among the concrete steps ii of step a is AB-8 type, D101 type, D140 type, D141 type, S-8 type, NKA-9 type, ZTC.
10, according to the preparation method of the slow releasing preparation of the described treatment hepatitis of claim 9, it is characterized in that macroporous adsorbent resin used among the concrete steps ii of step a is the AB-8 type.
11, the preparation method of the slow releasing preparation of described according to Claim 8 treatment hepatitis is characterized in that organic solvent used among the concrete steps iii of step a is an ethanol.
12,, it is characterized in that it is with 6BV～12BV/h speed eluting with 50%～80% ethanol that ethanol among the concrete steps iii of step a is washed the concrete grammar of resin according to the preparation method of the slow releasing preparation of the described treatment hepatitis of claim 11.
13, the application of the described slow releasing preparation of claim 1～6 in preparation treatment hepatitis medicine.
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| CN102824325A (en) * | 2012-09-24 | 2012-12-19 | 盐城师范学院 | Quercetin sustained release tablet and preparing method thereof |
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| CN102824325A (en) * | 2012-09-24 | 2012-12-19 | 盐城师范学院 | Quercetin sustained release tablet and preparing method thereof |
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