CN1970001B - Pharmaceutical composition comprising kurarinone, magnolia vine fruit and ginseng for treating hepatitis - Google Patents
Pharmaceutical composition comprising kurarinone, magnolia vine fruit and ginseng for treating hepatitis Download PDFInfo
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- CN1970001B CN1970001B CN2005101045532A CN200510104553A CN1970001B CN 1970001 B CN1970001 B CN 1970001B CN 2005101045532 A CN2005101045532 A CN 2005101045532A CN 200510104553 A CN200510104553 A CN 200510104553A CN 1970001 B CN1970001 B CN 1970001B
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Abstract
Disclosed is a pharmaceutical composition and its preparation, wherein the constituents include (by weight ratio) flavescent sophora root extract 50-2000 parts, schisandra fruit 500-20000 parts, ginseng 500-20000 parts, or flavescent sophora root extract 50-2000 parts, schisandra fruit extract 15-600 parts, ginseng polysaccharides 6-240 parts, or flavescent sophora root extract 50-2000 parts, schisandra fruit extract 15-600 parts, ginseng saponins 6-240 parts. The pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dose forms, and can be used for treating hepatitis A, hepatitis B and hepatitis C.
Description
1, technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of hepatitis class disease of making by kurarinone, Fructus Schisandrae Chinensis or its extract and Radix Ginseng or its extract and preparation method thereof, belong to medical technical field.
2, background technology
China is the district occurred frequently of viral hepatitis, has the crowd of 8%-10% to be hepatitis B virus carriers approximately, is about 1.3 hundred million people, account for 1/3 of global hepatitis B virus carriers, wherein have 3,000 ten thousand people to suffer from chronic hepatitis approximately, it is about about 1,400,000 that average year is sent out case load, annual because of hepatitis about 300,000 people that die that die of illness.Hepatitis C virus carrier 0.38 hundred million people adds the hepatitis of other types, suffers from nearly 200,000,000 people of total number of persons of hepatitis, estimate every year due to illness virus hepatitis cause direct economic loss 30,000,000,000～50,000,000,000 RMB.Therefore, the medicine of hepatitis is treated in research and development safely and effectively, becomes the problem that presses for solution.
Kurarinone is the alkaloid that extracts from leguminous plant Herba Sophorae alopecuroidis, Radix Sophorae Flavescentis, and Main Ingredients and Appearance is the N-oxysophocarpine of oxymatrine and minute quantity.Kurarinone has good antihepatitic activity: use the clinical symptoms of Oxymatrine in Treating Chronic Hepatitis B, as weak, poor appetite and abdominal distention etc., effective percentage is about 90%.Liver, splenomegaly have retraction in various degree, and periphery leukopenia and thrombocytopenia are had certain rising effect.Particularly aspect the improving of liver function effect, obtain good efficacy.
Kurarinone
Fructus Schisandrae Chinensis be magnoliaceae schisandra Schisandra chinensis (Turcz.) Baill. and schisandra chinensis Schisandrasphenanthera Rehd.et Wils. dry mature fruit.Sour in the mouth, sweet, warm in nature, return lung, the heart, kidney channel, have the convergence astringent or styptic treatment for spontaneous sweating, supplementing QI for promoting the production of body fluid, the effect of kidney calming.Modern study shows that Fructus Schisandrae Chinensis has following pharmacological action: 1. can strengthen cerebral cortex excitement and process of inhibition, make its mutual balance.2. obvious sedation, with synergism such as pentobarbital sodium, chlorpromazine, the convulsions that the antagonism beta stimulant causes has the characteristics of tranquilizer.3. regulate immunity, stablize the liver cell film, protect organelle, nucleus, promote pathological repair, improve liver function.
Radix Ginseng is the dry root and rhizome of Araliaceae Radix Ginseng Panax ginseng C.A.Mey..Sweet in the mouth, little hardship, property is flat; Return spleen, lung, heart channel; Have strongly invigorating primordial QI, multiple arteries and veins takes off admittedly, and invigorating the spleen to benefit the lung promotes the production of body fluid, the effect of calming the nerves.Modern study shows that Radix Ginseng has following pharmacological action: 1. Radix Ginseng can stimulating central nervous system system, accelerate the conduction of neural impulse, strengthen trained reflex, improve analytic function.2. can excited hypophysis-interrenal system, the adrenal cortex reinforcing function improves the body resistance that stimulates of bad condition to external world.3. strong effect is arranged, body is strengthened disease resistance, raising work is renderd a service, and reduces fatigue, and weight increase improves sleep etc.4. this product can make cardiac contractile force strengthen in a small amount in right amount, and palpitating speed has the effect of similar cardiotonic glycoside.5. Radix Ginseng also has the effect of promoting sexual gland hormone sample, can promote men and women's gonad function.6. blood sugar lowering, and have synergism with islets of langerhans.7. improve digestive and absorptive functions, appetite stimulator promotes proteinic synthetic.8. also influential to metabolism, hyperglycemia there is inhibitory action, again can the cholesterol regulating metabolism, suppress the generation of hypercholesterolemia.9. Radix Ginseng can also diuresis, and its effect is similar to desoxycortone, may be because the aldosterone secretion is increased, thereby promotes sodium retention and make the minimizing of urinating.
At present, utilize the interaction of kurarinone, Fructus Schisandrae Chinensis and Radix Ginseng, composition of prescription is used to prepare the medicine for the treatment of the hepatitis aspect, does not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs, better treat diseases such as hepatitis, improve the people ' s health level, the invention provides a kind of new pharmaceutical composition and preparation method thereof.
Pharmaceutical composition of the present invention is mainly made by following bulk drugs: 50～2000 parts of kurarinones, 500～20000 parts of Fructus Schisandrae Chinensis, 500～20000 parts of Radix Ginsengs, be preferably: 100～800 parts of kurarinones, 1000～10000 parts of Fructus Schisandrae Chinensis, 1000～10000 parts of Radix Ginsengs, the best is: 400 parts of kurarinones, 3000 parts of Fructus Schisandrae Chinensis, 4000 parts of Radix Ginsengs.
Fructus Schisandrae Chinensis in the crude drug of aforementioned pharmaceutical compositions, Radix Ginseng can prepare extract with The suitable solvent and method, total extract is made arbitrary preparation with other crude drug and mixing acceptable accessories again, and main effective ingredient contained in the total extract is: Fructus Schisandrae Chinensis lignin (as schisandrin), ginseng polysaccharide or Radix Ginseng total saponins.
Fructus Schisandrae Chinensis mentioned above can obtain Fructus Schisandrae Chinensis extrat through extracting processing with The suitable solvent, wherein solvent preferred water or alcohol, and the extracting method of Fructus Schisandrae Chinensis can be infusion process, percolation, decocting method, supercritical CO
2Extraction, reflux extraction or continuous extraction.As preparing Fructus Schisandrae Chinensis extrat by water extract-alcohol precipitation, ethanol percolation, alcohol extraction upper prop.
The invention provides a kind of preferred extraction process of Fructus Schisandrae Chinensis extrat, detailed process is as follows:
Get schisandra chinensis medicinal material, be ground into coarse powder, decoct with water secondary, per 2 hours, filter, filtrate is concentrated into the concentrated solution of relative density 1.10～1.15, add ethanol and make and contain alcohol amount and reach 60%, cold preservation was placed 24 hours, filtered, filtrate recycling ethanol also is concentrated into the concentrated solution of relative density 1.10～1.15, adds ethanol again and makes and contain the alcohol amount and reach 80%, and cold preservation was placed 24 hours, filter, filtrate recycling ethanol also is concentrated into the thick paste of relative density 1.30～1.35, vacuum drying, promptly.
By the Fructus Schisandrae Chinensis extrat of this prepared, yield is 2～4%, and schisandrin content is not less than 10%, and ether-soluble extractives content is not less than 30%.
Fructus Schisandrae Chinensis also can be by following prepared, but is not limited only to following method:
Method 1: get schisandra chinensis medicinal material, be ground into coarse powder, add 60% ethanol and decoct secondary, per 2 hours, filter, filtrate recycling ethanol also is concentrated into the concentrated solution of relative density 1.10～1.15, adds ethanol again and makes and contain the alcohol amount and reach 80%, and cold preservation was placed 24 hours, filter, filtrate recycling ethanol also is concentrated into the thick paste of relative density 1.30～1.35, vacuum drying, promptly.By the Fructus Schisandrae Chinensis extrat of this prepared, yield is 1～5%, and schisandrin content is not less than 6%, and ether-soluble extractives content is not less than 20%.
Method 2: get schisandra chinensis medicinal material, be ground into coarse powder, decoct with water secondary, per 2 hours, filter, filtrate is concentrated into the concentrated solution of relative density 1.10～1.15, add ethanol and make and contain alcohol amount and reach 70%, cold preservation was placed 24 hours, filtered, filtrate recycling ethanol also is concentrated into the concentrated solution of relative density 1.10～1.15, adds ethanol again and makes and contain the alcohol amount and reach 90%, and cold preservation was placed 24 hours, filter, filtrate recycling ethanol also is concentrated into the thick paste of relative density 1.30～1.35, vacuum drying, promptly.By the Fructus Schisandrae Chinensis extrat of this prepared, yield is 1.5～5.5%, and schisandrin content is not less than 8%, and ether-soluble extractives content is not less than 25%.
Radix Ginseng mentioned above can obtain Radix Ginseng extract through extracting processing with The suitable solvent, extract solvent preferred water or ethanol, extracting method can be infusion process, percolation, decocting method, reflux extraction or continuous extraction, the effective ingredient of extract is ginseng polysaccharide or Radix Ginseng total saponins, and content of effective preferably is not less than 50%.
But also reference literature method preparation of the extracting method of Radix Ginseng: can be as the ginseng polysaccharide according to Chinese patent application CN200410000209.4 preparation, Radix Ginseng total saponins can prepare according to Chinese patent application CN00110418.7.
The invention provides the preferred extraction process of Radix Ginseng, detailed process is as follows:
With polysaccharide be main effective ingredient Radix Ginseng extract (hereinafter to be referred as: the preferred for preparation technology ginseng polysaccharide) is as follows:
Get the ginseng crude drug, chopping is used 75% ethanol, reflux, extract, 4 hours, filter, medicinal residues dry, and decoct with water five times, merge decoction liquor, add 0.3% active carbon, stirred 30 minutes, standing over night filters, filtrate is crossed resin column, collects effluent, and concentrating under reduced pressure adds ethanol and makes and contain the alcohol amount and reach 95%, cold preservation filters, and gets precipitation and uses washing with acetone, drains acetone, taking-up is deposited in 60～80 ℃ of dryings, pulverizes, and gets powder promptly.
By the Radix Ginseng extract of this prepared, yield is 0.5～2%, and ginseng polysaccharide's content is not less than 50%.
The ginseng polysaccharide also can be by following prepared, but is not limited only to following method:
Method 1: get Radix Ginseng, chopping adds the water reflux, extract, three times, each 2 hours, add 10 times of amounts of water for the first time, two, three times is 8,8 times of amounts, collecting decoction, filter, it is 1.16～1.24 that filtrate decompression is concentrated into relative density, crosses macroporous resin column, collect effluent, be evaporated to the thick paste shape, vacuum drying, promptly.By the Radix Ginseng extract of this prepared, yield is 4～6%, and ginseng polysaccharide's content is not less than 40%.
Method 2: get Radix Ginseng, 80% ethanol is used in chopping, reflux, extract, 3 hours filters, and medicinal residues dry, decoct with water three times, each 1.5 hours, add 10 times of amounts of water, merge decoction liquor, filter, it is 1.15～1.20 that filtrate decompression is concentrated into relative density, crosses macroporous resin, effluent is evaporated to the thick paste shape, and spray drying promptly.By the Radix Ginseng extract of this prepared, yield is 2～4%, and ginseng polysaccharide's content is not less than 45%.
The invention provides with total saponins be main effective ingredient Radix Ginseng extract (hereinafter to be referred as Radix Ginseng total saponins) preferred for preparation technology, specific as follows:
Get the ginseng crude drug, be ground into particulate, add 10 times of amount alcohol reflux secondaries, each 3 hours, merge extractive liquid,, cold preservation filters, and filtrate recycling ethanol also is concentrated into thick paste, add water to an amount of (making every 1ml be equivalent to crude drug 1g), stir evenly, cold preservation filters, filtrate is added on the macroporous resin column of having handled well, water with 2V～3V column volume carries out eluting earlier, discards water lotion, 80% ethanol elution of 3 times of column volumes of reuse, collect eluent, reclaim ethanol and be evaporated to the thick paste of relative density 1.30～1.35, vacuum drying, promptly.
By the Radix Ginseng total saponins extract that this prepared obtains, yield is 1～2%, and Radix Ginseng total saponins content is not less than 50%, ginsenoside Re, ginsenoside Rg
1Content is not less than 30%.
Radix Ginseng total saponins also can be by following prepared, but is not limited only to following method:
Method 1: get the ginseng crude drug, be ground into particulate, add the alcohol reflux secondary, each 4 hours, add 10 times of amounts of alcohol, merge extractive liquid, at every turn, cold preservation, filter, filtrate recycling ethanol also is concentrated into thick paste, and thin up to relative density is 1.15～1.20, add 1/2 times of saturated n-butanol extraction of water gaging 3 times, merge n-butyl alcohol liquid, the reclaim under reduced pressure n-butyl alcohol is to the thick paste shape, and spray drying promptly.By the Radix Ginseng extract of this prepared, yield is 4～5%, and Radix Ginseng total saponins content is not less than 35%, ginsenoside Re, ginsenoside Rg
1Content and be not less than 20%.
Method 2: get the ginseng crude drug, be ground into particulate, add alcohol reflux three times, add for the first time 10 times of amounts of alcohol, two, three times is 8,8 times of amounts, each 2 hours, merge extractive liquid, filters, and reclaims ethanol and is concentrated into thick paste, add water in right amount, stir evenly cold preservation, filter, filtrate adds 3 concentrating under reduced pressure of 1/2 times of saturated n-butanol extraction of water gaging, merges n-butyl alcohol liquid, the reclaim under reduced pressure n-butyl alcohol is to the thick paste shape, and spray drying promptly.By the Radix Ginseng extract of this prepared, yield is 3～5%, and Radix Ginseng total saponins content is for being not less than 40%, ginsenoside Re, ginsenoside Rg
1Content and be no less than 20%.
Pharmaceutical composition of the present invention can also be made by kurarinone, Fructus Schisandrae Chinensis extrat, ginseng polysaccharide or Radix Ginseng total saponins.Calculate with respect to the yield of medical material according to extract, compound medicine of the present invention can have following two kinds of different proportionings, is respectively by ratio of weight and the number of copies:
Proportioning 1: 50～2000 parts of kurarinones, 15～600 parts of Fructus Schisandrae Chinensis extrats, 6～240 parts of ginseng polysaccharides; Be preferably: 100～800 parts of kurarinones, 30～300 parts of Fructus Schisandrae Chinensis extrats, 12～120 parts of ginseng polysaccharides; Optimum is: 400 parts of kurarinone extracts, 60～120 parts of Fructus Schisandrae Chinensis extrats, 20～80 parts of ginseng polysaccharides.
Proportioning 2: 50～2000 parts of kurarinones, 15～600 parts of Fructus Schisandrae Chinensis extrats, 6～240 parts of Radix Ginseng total saponinss; Be preferably: 100～800 parts of kurarinones, 30～300 parts of Fructus Schisandrae Chinensis extrats, 12～120 parts of Radix Ginseng total saponinss; Optimum is: 400 parts of kurarinone extracts, 60～120 parts of Fructus Schisandrae Chinensis extrats, 20～80 parts of Radix Ginseng total saponinss.
In the said ratio, schisandrin content preferably is not less than 5% in the Fructus Schisandrae Chinensis extrat, and the ether extract content preferably is not less than 15%; Ginseng polysaccharide's content preferably is not less than 30%, and Radix Ginseng total saponins content preferably is not less than 30%, and ginsenoside Re wherein and ginsenoside Rg1's content preferably are not less than 15%.
More than form to be by weight as proportioning, when producing, can or reduce according to the corresponding proportion increase, as large-scale production can be unit with the kilogram, or be unit with the ton, small-scale production can be unit with the gram also, weight can increase or reduce, but the constant rate of weight proportion between each composition.
More than form,, can make the preparation of 100～10000 consumptions,, can be made into 100～10000,1～10 of each consumption as injection as if being unit with the gram.As tablet, can be made into 100～10000, take 1～10 at every turn.
The ratio of above weight proportion obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.The consumption of drug component of the present invention is groped to sum up to draw through the inventor in a large number, and each amounts of components all has better curative effect in above-mentioned weight portion scope.
The invention provides a kind of medicine that is used to prepare treatment hepatitis class disease, can be used for various types of hepatitis such as hepatitis A, hepatitis B, hepatitis C.
Pharmaceutical composition of the present invention can add one or more pharmaceutically acceptable carriers, with oral, snuffing is gone into or the mode of parenteral is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, soft capsule, dispersible tablet, oral liquid, granule, chewable tablet, oral cavity disintegration tablet, drop pill, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule, make liquid preparation such as water or oil-suspending agent or other liquid preparation such as syrup etc.; When being used for parenteral, can be made into solution, water or the oil-suspending agent etc. of injection, as liquid drugs injection, freeze-dried powder, aseptic powder injection, transfusion etc.The preferred dosage form of this compositions is injection or oral formulations.
Pharmaceutical composition of the present invention can adopt the conventional method production in the existing pharmaceutical field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant of pharmaceutical field routine etc.
Pharmaceutical composition of the present invention in order to increase its dissolubility, can add solubilizing agents such as Tween-80 when making injection.Can add the isoosmotic adjusting agent that is used to regulate osmotic pressure in the transfusion, for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol and dextran etc., preferred sodium chloride or glucose.Can add excipient in the powder pin, for example, mannitol, glucose etc.
Pharmaceutical composition of the present invention has the following advantages:
(1) the invention provides a kind of new pharmaceutical composition that is used for the treatment of hepatitis, satisfied clinical needs.
(2) studies have shown that by pharmacodynamic experiment first: the chmice acute hepatic injury due to pharmaceutical composition Abensanil of the present invention, the carbon tetrachloride has protective effect, can suppress the breeding of dhbv dna, the rat liver fibrosis due to can anti-carbon tetrachloride.Three medical instruments have synergistic function, and are evident in efficacy.This is that those of ordinary skills are unexpected.
(3) each proportioning of the present composition is carried out pharmacodynamic study, drawn the optimal proportion of the present composition.
(4) the present invention can directly feed intake with raw material or extract, and preparation technology is simple, can make between the different batches medicine mass discrepancy little, and drug quality is more uniform and stable.
(5) confirm drug combination injection safety and stability of the present invention by specific safety test and stability experiment.
(6) kurarinone has good antihepatitic activity, and Fructus Schisandrae Chinensis and Radix Ginseng are done to assist and can be significantly improved anti-hepatitis curative effect, the drug combination determined curative effect, and reduced relative dosage, be with a wide range of applications.
Below example is further set forth the beneficial effect of medicine of the present invention by experiment, and these experimental examples comprise the pharmacodynamic experiment of pharmaceutical composition of the present invention, kurarinone, Fructus Schisandrae Chinensis extrat and ginseng polysaccharide's compositions hereinafter to be referred as
The KWR composition I, the compositions of kurarinone, Fructus Schisandrae Chinensis extrat and Radix Ginseng total saponins hereinafter to be referred as
KWR composition I IUsed Fructus Schisandrae Chinensis extrat is taken from embodiment 1 in the experimental example, and the ginseng polysaccharide gets
From embodiment 2, Radix Ginseng total saponins is taken from embodiment 3.
Experimental example 1 KWR compositions drug combination drug efficacy study
Test sample: blank group: 0.9% normal saline solution, self-control;
Model group: 0.9% normal saline solution, self-control;
Kurarinone group: Matrine Injection, Tianjin Biochemical Pharmaceutical Factory;
Fructus Schisandrae Chinensis group: Fructus Schisandrae Chinensis extrat injection, self-control;
Ginseng polysaccharide group: the ginseng polysaccharide, the made ginseng polysaccharide of embodiment 1 is taken from self-control;
The Radix Ginseng total saponins group: Radix Ginseng total saponins, the made Radix Ginseng total saponins of embodiment 2 is taken from self-control;
The different proportioning groups of KWR composition I: the different proportionings of KWR composition I injection (kurarinone+Fructus Schisandrae Chinensis extrat+ginseng polysaccharide), self-control (preparation method is referring to embodiment 4);
The different proportioning groups of KWR composition I I: the different proportionings of KWR composition I I injection (kurarinone+Fructus Schisandrae Chinensis extrat+Radix Ginseng total saponins), self-control (preparation method is referring to embodiment 5).
Laboratory animal: ICR mice, body weight 18～25g, male and female half and half.
Experimental technique: get 180 of mices, be divided into 18 groups at random, 10 every group, group sees the following form.Blank group and model group tail vein injection saline every day 20ml/kg Mus are heavy, every day 1 time, 10d continuously; The administration of administration group tail vein injection, every day 1 time, dosage sees the following form, continuously 10d.The blank group is tail vein injection 6h pneumoretroperitoneum injecting normal saline the last time.Model group and administration group tail vein injection 6h pneumoretroperitoneum injection with acetaminophen 300mg/kg Mus the last time are heavy, each group breaks end behind intraperitoneal injection of saline and acetaminophen 16h, get blood, liver, carry out the test of biochemical indicator Serum ALT (glutamate pyruvate transaminase) and hepatic tissue LPO (lipid peroxide), the results are shown in Table 1.
The influence of table 1KWR compositions Abensanil damage murine liver tissue ALT and LPO
Compare with the blank group,
◇ ◇P＜0.01; Compare with model group,
*P＜0.05,
*P＜0.01; Compare with the kurarinone group, #P＜0.05,
##P＜0.01; Compare with the Fructus Schisandrae Chinensis group,
△P＜0.05,
△ △P＜0.01; Organize comparison with the ginseng polysaccharide,
☆P＜0.05,
☆ ☆P＜0.01; Compare with the Radix Ginseng total saponins group,
﹠amp;P＜0.05,
﹠amp; ﹠amp;P＜0.01.
Conclusion: compare with the blank group, the active of model group ALT and LPO significantly raises, and significant difference (P＜0.01) illustrates that modeling is reliable.Compare with model group; active (P＜0.05 that obviously reduces of kurarinone group, Fructus Schisandrae Chinensis group, ginseng polysaccharide's group, Radix Ginseng total saponins group and KWR composition I and each proportioning group ALT of KWR composition I I and LPO; P＜0.01), illustrates that the hepatic injury of the equal Abensanil induced mice of each medicine has protective effect.Wherein each proportioning group better efficacy (P＜0.01) of KWR composition I and KWR composition I I all is better than single kurarinone, Fructus Schisandrae Chinensis, ginseng polysaccharide or Radix Ginseng total saponins used, and illustrates that kurarinone, Fructus Schisandrae Chinensis and Radix Ginseng three medicines share, and have synergistic function.In KWR composition I and each proportioning group of KWR composition I I, all remarkable with kurarinone+Fructus Schisandrae Chinensis+Radix Ginseng (400mg+3g+4g) group curative effect.
Experimental example 2 KWR compositionss are to carbon tetrachloride (CCl
4) cause the protective effect of chmice acute hepatic injury
Test sample: blank group: 0.9% normal saline solution, self-control;
Model group: 0.9% normal saline solution, self-control;
Kurarinone group: Matrine Injection, Tianjin Biochemical Pharmaceutical Factory, 2ml:0.2g;
The basic, normal, high dosage group of KWR composition I: KWR composition I injection, self-control (preparation method is referring to embodiment 4);
The basic, normal, high dosage group of KWR composition I I: KWR composition I I injection, self-control (preparation method is referring to embodiment 5).
Laboratory animal: ICR mice, body weight 22～24g, male and female half and half.
Experimental technique: get 90 of mices, be divided into 9 groups at random, be respectively blank group, model group, kurarinone group, the basic, normal, high dosage group of KWR composition I and the basic, normal, high dosage group of KWR composition I I, 10 every group.Blank group and model group tail vein injection saline every day 20ml/kg Mus are heavy, every day 1 time, 7d continuously; The administration of administration group tail vein injection, every day 1 time, dosage sees the following form, continuously 7d.The blank group is tail vein injection 2h pneumoretroperitoneum injection Oleum Arachidis hypogaeae semen 10ml/kg the last time, the equal lumbar injection 0.12%CCl of all the other each treated animals
4Peanut oil solution 10ml/kg, overnight fasting.Sacrificed by decapitation animal behind the 16h, the value of getting serologic test ALT, AST.After broken end is got blood, cut open the belly immediately and take out liver, spleen, inhale the liquid of dehematizing, cut off fat, mesentery, the weight of the liver of accurately weighing, spleen.The results are shown in Table 2.
Table 2 KWR compositions is to CCl
4Due to the influence of acute liver damage Mouse Liver, spleen index and Serum ALT, AST content
Compare with the blank group
◇P＜0.05,
◇ ◇P＜0.01; Compare with model group,
*P＜0.05,
*P＜0.01; Compare with the kurarinone group,
#P＜0.05,
##P＜0.01
Conclusion: CCl
4Model group Mouse Liver index, the normal control group mice numerical value of spleen index increase (P＜0.05), CCl
4Model group mice serum ALT, the normal control group mice numerical value of AST value increase (P＜0.01), and injected in mice CCl is described
4Hepar damnification behind the peanut oil solution, the modeling success, model stability is reliable.Compare with model group, KWR composition I and the middle and high dosage group of KWR composition I I Mouse Liver index, spleen index reduce (P＜0.05), liver, splenomegaly alleviate, each dosage group Serum ALT of KWR composition I and KWR composition I I, AST value obviously reduce (P＜0.05 or P＜0.01), illustrate that the present composition is to CCl
4Due to acute liver damage protective effect is arranged.Wherein each dosage group curative effect of compositions all is better than singly using kurarinone, illustrates that kurarinone, Fructus Schisandrae Chinensis and Radix Ginseng three medicines share, and have synergistic function.
Experimental example 3 KWR group contains the anti-dhbv dna effect of thing
Test sample: blank group: 0.9% normal saline solution, self-control;
Kurarinone group: Matrine Injection, Tianjin Biochemical Pharmaceutical Factory, 2ml:0.2g;
Positive controls: injection acyclovir, Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group;
The basic, normal, high dosage group of KWR composition I: KWR composition I injection, self-control (preparation method is referring to embodiment 4);
The basic, normal, high dosage group of KWR composition I I: KWR composition I I injection, self-control (preparation method is referring to embodiment 5).
Laboratory animal: commercially available 1 age in days Beijing duck;
DHBV (hepatitis B virus) positive serum, microbiology teaching and research room of Medical Center of Fudan University.
Experimental technique:
4.1 the animal model Beijing duck is got blood through sufficient intravenous injection 0.2mlDHBV positive serum behind the 7d, separation of serum, and-20 ℃ of preservations are to be checked.
4.2 Drug therapy filters out 54 of the positive ducks that infect successfully, is divided into 9 groups at random, is respectively blank group, kurarinone group, positive controls, the basic, normal, high dosage group of KWR composition I and the basic, normal, high dosage group of KWR composition I I, 6 every group.The blank group is irritated stomach normal saline 20ml/kg every day, every day 2 times, 14d continuously; Administration group gastric infusion, every day 2 times, dosage sees the following form, continuously 14d.Positive drug is pressed 100mg/kg with ACV and is irritated stomach, 2 times/d, 2 weeks of administration as the treatment matched group.Be respectively applied for (1d), the 7th day (T of medication before the medicine
7), the 14th day (T of medication
14) and drug withdrawal after the 7th day (P
7).Get blood from duck lower limb shin vein, separation of serum ,-20 ℃ of preservations are to be checked.Adopt the DHBV-DNADotBlot method, with hybridization spot absorbance (A) as specimen DHBV-DNA level value.The results are shown in Table 3.
Table 3 KWR compositions is to the inhibitory action of DHBV-DNA
Annotate: compare with the blank group
◇P＜0.05,
◇ ◇P＜0.01; With compare before the administration
@P＜0.05,
@@P＜0.01.
Conclusion: positive control (acyclovir) group after administration the 7th day and the 14th day, with before the administration and with the blank group relatively, difference has significance (P＜0.01), but significantly rising again after the drug withdrawal does not have significance (P＞0.05) with comparing difference before the administration.Various dose KWR composition I and KWR composition I I all have inhibitory action to DHBV, and do not have knock-on after the drug withdrawal, and wherein middle and high dosage group inhibitory action is more obvious.The all excellent son of each administration group curative effect of KWR composition I and KWR composition I I is single uses kurarinone, illustrates that kurarinone, Fructus Schisandrae Chinensis and Radix Ginseng three medicines share, and have synergistic function.
The Hepar Mus fibrosis effect of the experimental example 4 KWR compositions Chinese People's Anti-Japanese Military and Political College
Test sample: blank group: 0.9% normal saline solution, self-control;
Model group: 0.9% normal saline solution, self-control;
Kurarinone group: Matrine Injection, Tianjin Biochemical Pharmaceutical Factory, 2ml:0.2g;
The basic, normal, high dosage group of KWR composition I: KWR composition I injection, self-control (preparation method is referring to embodiment 4);
The basic, normal, high dosage group of KWR composition I I: KWR composition I I injection, self-control (preparation method is referring to embodiment 5).
Laboratory animal: the Wistar rat, body weight 180～230g, male.
Experimental technique: get 10 of healthy rats, subcutaneous injection Oleum Arachidis hypogaeae semen 3ml/kg, every day 1 time, totally 10 weeks, group in contrast.The Liver Fibrosis Model group is used 40%CCl
4Peanut oil solution is pressed the 3ml/kg subcutaneous injection, 2 times weekly, in totally 8 weeks, induces Liver Fibrosis Model.Get 80 of Liver Fibrosis Model rats, be divided into 8 groups at random, be respectively model group, kurarinone group, the basic, normal, high dosage group of KWR composition I and the basic, normal, high dosage group of KWR composition I I, 10 every group.Except that matched group, all the other each groups continue with 40%CCl
4Peanut oil solution 3ml/kg subcutaneous injection, every day 1 time.The basic, normal, high dosage group of kurarinone group, the basic, normal, high dosage group of KWR composition I and KWR composition I I is the gastric infusion relative medicine simultaneously, and dosage sees the following form.Continue 2 weeks of administration.Slaughter rat after 10 weeks, blood 2ml gets in the sterile working, separation of serum, and-20 ℃ of preservations detect hepatic fibrosis index with radioimmunology: hyaluronic acid (HA) and laminin (LN); Detect glutamate pyruvate transaminase (ALT) and glutamic oxaloacetic transaminase, GOT (AST) with biochemical process, adopt automatic clinical chemistry analyzer to detect.The results are shown in Table 4.
Table 4 KWR compositions is to CCl
4Due to the influence of serological index of hepatic fibrosis rats
Compare with the blank group
◇ ◇ ◇P＜0.001; Compare with model group,
*P＜0.05,
*P＜0.01: compare with the kurarinone group,
#P＜0.05.
Conclusion: compare with the blank group, model group rat blood serum ALT, AST, HA, LN content have significant difference, illustrate that model stability is reliable.Kurarinone, KWR composition I and KWR composition I I treatment heptic fibrosis rat blood serum ALT and AST all are lower than model group, difference has significance (P＜0.05 or P＜0.01), and prompting kurarinone, KWR composition I and KWR composition I I have the effect of falling enzyme and liver function protecting; Kurarinone, KWR composition I and KWR composition I I treatment back serum HA and LN level all significantly are lower than model group, difference has significance (P＜0.05 or P＜0.01), prompting kurarinone, KWR composition I and KWR composition I I all have the hepatic fibrosis of improvement serological index, have the effect of anti-hepatic fibrosis.Wherein, KWR composition I and KWR composition I I group curative effect are better than the kurarinone group, and prompting kurarinone, Fructus Schisandrae Chinensis and Radix Ginseng three medicines share, and synergistic function is arranged.
Experimental example 5 injected in mice administration acute toxicity testings
(1) experimental technique
Test sample: KWR composite injection I, dosage form: liquid drugs injection, specification: 5ml derives from embodiment 4;
KWR composite injection II, dosage form: liquid drugs injection, specification: 5ml derives from embodiment 5.
Animal subject: mice, each 5 of every group of male and female, male body weight 25～28g, female body weight 21～24g.
Route of administration: intravenous injection, lumbar injection.
Observation item: death toll, general state, body weight, cut open inspection, half lethal dose.
(2) experimental result
Require to carry out prerun according to acute toxicity testing, lumbar injection and intravenous injection two route of administration all can't be measured the median lethal dose(LD 50) of medicine, also do not see tangible toxic reaction, so carry out maximum dosage-feeding experiment in a day.Dosage: the tail vein is injected KWR composite injection I, each 0.1ml/10g of KWR composite injection II respectively, and the abdominal cavity is injected KWR composite injection I, each 0.1ml/10g of KWR composite injection II, 2 times on the one respectively.
Death toll: do not occur dead.
General state: no abnormality seen changes.
Body weight: in administration preceding 1 day, administration day, measured in 1,3,7,14 day after the administration; No abnormality seen changes.
Cut open inspection: the heart, liver, lung, kidney etc. organize no abnormality seen to change.
(3) conclusion
Occur death in this experiment, infer that KWR composite injection I, II are 0.2ml/10g to the maximum tolerated dose of male and female mouse vein and intraperitoneal injection, are equivalent to 100 times of maximum consumption 10ml of the 50kg body weight day for human beings.Show this product low toxicity, safe.
Experimental example 6 KWR composite injection stability experiments
Test sample: KWR composite injection I, dosage form: liquid drugs injection, specification: 5ml derives from embodiment 4;
KWR composite injection II, dosage form: liquid drugs injection, specification: 5ml derives from embodiment 5.
Investigation project: character, pH value, clarity
Long-time stability experimental technique and result: each compositions of this product is put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 6 months, 12 months, every index has no significant change, and experimental result shows that the long-term placement of each composite injection of this product is basicly stable.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The adjuvant of each dosage form can be replaced with acceptable accessories in following examples, perhaps reduces, increases.Used Fructus Schisandrae Chinensis extrat is taken from embodiment 1 among the embodiment 4～17, and the ginseng polysaccharide takes from embodiment 2, and Radix Ginseng total saponins is taken from embodiment 3.
The preparation of embodiment 1 Fructus Schisandrae Chinensis extrat
Get schisandra chinensis medicinal material, be ground into coarse powder, decoct with water 2 times, per 2 hours, filter, filtrate is concentrated into the concentrated solution of relative density 1.10～1.15, add ethanol and make and contain alcohol amount and reach 60%, cold preservation was placed 24 hours, filtered, filtrate recycling ethanol also is concentrated into the concentrated solution of relative density 1.10～1.15, adds ethanol again and makes and contain the alcohol amount and reach 80%, and cold preservation was placed 24 hours, filter, filtrate recycling ethanol also is concentrated into the thick paste of relative density 1.30～1.35, vacuum drying, promptly.
By the Fructus Schisandrae Chinensis extrat that this technology makes, yield is 2～4%.Schisandrin content is not less than 10% in the extract; Ether-soluble extractives content is not less than 30%.
The discriminating of Fructus Schisandrae Chinensis extrat
Get this product powder 1g, add chloroform 20ml, reflux 20 minutes filters, and filtrate evaporate to dryness, residue add chloroform 1ml makes dissolving, as need testing solution.Other gets Fructus Schisandrae Chinensis control medicinal material 1g, shines medical material solution in pairs with legal system.Get the deoxyschizandrin reference substance again, add chloroform and make the solution that every 1ml contains 1mg, in contrast product solution.According to the thin layer chromatography test, draw each 2 μ l of above-mentioned three kinds of solution, put in same silica gel G F respectively
254On the lamellae, be developing solvent, launch, take out, dry, put under the ultra-violet lamp (254nm) and inspect with the upper solution of petroleum ether (30～60 ℃)-Ethyl formate-formic acid (15: 5: 1).In the test sample chromatograph, with control medicinal material and the corresponding position of reference substance chromatograph on, show the speckle of same color.
The assay of Fructus Schisandrae Chinensis extrat
The assay of schisandrin
Measure according to high performance liquid chromatography (appendix VID).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Methanol-water (13: 7) is a mobile phase; The detection wavelength is 250nm.Number of theoretical plate calculates by the schisandrin peak should be not less than 2000.
Schisandrin reference substance 15mg is got in the preparation of reference substance solution, accurate claims surely, puts in the 50ml measuring bottle, with dissolve with methanol and be diluted to scale, shakes up, and promptly gets (every 1ml contains schisandrin 0.3mg).
The about 0.1g of this product powder is got in the preparation of need testing solution, and accurate the title decides, and puts in the 25ml measuring bottle, adds the about 20ml of methanol, and supersound process (power 250W, frequency 44kHz) 20 minutes is taken out, and adds methanol to scale, shakes up, and filters, promptly.
Accurate respectively reference substance solution and each the 10 μ l of test solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.
The assay of ether-soluble extractives
Measure according to volatility ether determination of extractives method (appendix X).
Get this product powder (cross No. four sieve) 4g, put in the phosphorus pentoxide desiccator dry 12 hours, put in the apparatus,Soxhlet's, it is an amount of to add diethyl ether, reflux 8 hours is got ether solution, puts in the evaporating dish that is dried to constant weight, place, fling to ether, residue was put in the phosphorus pentoxide desiccator dry 18 hours, accurate claim fixed, slowly be heated to 105 ℃, and be dried to constant weight in 105 ℃.It subtracts the weight that weight loss is volatility ether extractum.Calculate the ether extract content.
According to above-mentioned technology, make three batches of Fructus Schisandrae Chinensis extrat samples, its content and yield see the following form.By the result as can be seen, by the Fructus Schisandrae Chinensis extrat of this prepared, yield is 2～4%, and the content of schisandrin is not less than 10% in the extract, and ether-soluble extractives content is not less than 30%.
Embodiment 2 is that the Radix Ginseng extract of main effective ingredient is ginseng polysaccharide's preparation with polysaccharide
Get Radix Ginseng, chopping is used 75% ethanol, reflux, extract, 4 hours, filter, medicinal residues dry, and decoct with water five times, merge decoction liquor, add 0.3% active carbon, stirred 30 minutes, standing over night filters, filtrate is crossed resin column, collects effluent, and concentrating under reduced pressure adds ethanol and makes and contain the alcohol amount and reach 95%, cold preservation filters, and gets the precipitation washing with acetone, drain acetone, take out and be deposited in 60～80 ℃ of dryings, pulverize promptly.
Ginseng polysaccharide's identification experiment
(1) gets the about 0.2g of this product, after adding water 5ml dissolving, add 5 of alkaline cupric tartrate test solutions, heating promptly produces red precipitate, cooling, filter, get filtrate add 1 of hydrochloric acid make acid, heating in water bath 10 minutes, put cold, regulate pH value to neutral, add alkaline cupric tartrate test solution 0.5ml, heating in water bath promptly produces red copper oxidule precipitation.
(2) get the about 0.2g of this product, add water 2ml dissolving after, add 5% alpha-Naphthol alcoholic solution 0.5ml and shake up, slowly add sulphuric acid 3ml, two liquid level intersection displaing amaranth rings.
Ginseng polysaccharide's assay
The preparation precision of reference substance solution takes by weighing 60 ℃ of vacuum dryings to the about 100mg of the galacturonic acid of constant weight, puts in the 100ml measuring bottle, adds water to scale, shakes up.Precision is measured 10ml, puts in the 100ml measuring bottle, adds water to scale, shakes up, promptly.
The preparation precision of need testing solution takes by weighing this product 50mg, puts in the 100ml measuring bottle, is dissolved in water and is diluted to scale, shakes up, promptly.
The algoscopy precision is measured each 1ml of reference substance solution, need testing solution and water, the accurate respectively 0.25mol/L Borax sulfuric acid solution 6ml that adds, put in the water-bath heating 30 minutes, put cold, the accurate respectively again 0.125% carbazole ethanol solution 0.4ml that adds, put in the water-bath and heated 10 minutes, put and be chilled to room temperature,, measure trap at 530nm wavelength place according to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B) experiment, calculate, promptly.
According to above-mentioned technology, make Radix Ginseng extract three batch samples, its content and yield see the following form.By the result as can be seen, by ginseng polysaccharide in ginseng polysaccharide's extract of this prepared, yield is 0.5～2%, and ginseng polysaccharide's content is not less than 50%.
Embodiment 3 is that the Radix Ginseng extract of main effective ingredient is the preparation of Radix Ginseng total saponins with total saponins
Radix Ginseng total saponins preparation technology:
Get the ginseng crude drug, be ground into particulate, the alcohol reflux secondary, each 3 hours, add 10 times of amounts of alcohol, merge extractive liquid,, cold preservation at every turn, filter, filtrate recycling ethanol also is concentrated into thick paste, adds water to an amount of (making every 1ml be equivalent to crude drug 1g), stirs evenly, cold preservation, filter, filtrate is added on the macroporous resin column of having handled well, and the water with 2V～3V column volume carries out eluting earlier, discard water lotion, 80% ethanol elution of 3 times of column volumes of reuse is collected eluent, reclaims ethanol and is evaporated to the thick paste of relative density 1.30～1.35, vacuum drying, promptly.
The discriminating of Radix Ginseng total saponins
Get this product 0.5g, add water 0.5ml and stir moistening, add water-saturated n-butanol 10ml, supersound process 30 minutes is drawn supernatant and is added 3 times of amount ammonia solutions, shakes up, and places layering, gets upper strata liquid evaporate to dryness, and residue adds methanol 1ml makes dissolving, as need testing solution.Other gets ginsenoside Re, Rg1 reference substance, adds methanol and makes the mixed solution that every 1ml contains 2mg, in contrast product solution.Draw above-mentioned two kinds of each 2ul of solution, put respectively on same silica gel g thin-layer plate, (15: 40: 22: 10) lower floor's solution of placing below 10 ℃ was developing solvent with chloroform-ethyl acetate-methanol-water, launch, take out, dry, spray is with 10% ethanol solution of sulfuric acid, it is clear to be heated to speckle colour developing at 105 ℃, puts under the ultra-violet lamp (365nm) and inspects.In the test sample chromatograph, with reference substance chromatograph relevant position on show the fluorescence speckle of same color.
Determination of Total Saponin Content in Panax Ginseng
Reference substance solution preparation: get ginsenoside R
G1The about 10mg of reference substance through 60 ℃ of vacuum dryings 2 hours, accurately claims surely, puts in the 100ml measuring bottle, with anhydrous alcohol solution and be diluted to scale, shakes up, and makes every 1ml and contains R
G1The solution of reference substance 0.1mg, promptly.
The need testing solution preparation: precision takes by weighing this product 50mg, puts in the 50ml measuring bottle, adds dehydrated alcohol and is diluted to scale, shakes up, and precision is measured 2ml, puts in the 10ml measuring bottle, adds dehydrated alcohol and is diluted to scale, shakes up, promptly.
The algoscopy precision is measured need testing solution and each 1ml of reference substance solution, puts respectively in the 10ml tool plug test tube, and evaporate to dryness in water-bath is put cold, add 5% vanillin glacial acetic acid solution 0.2ml, add perchloric acid 0.8ml again, in 60 ℃ of insulations 15 minutes, be cooled to room temperature, add glacial acetic acid 5ml, shake up; Make blank simultaneously.According to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B), measure trap at 560nm wavelength place, calculate, promptly.
Ginsenoside Re, ginsenoside Rg1's assay
Chromatographic condition and system suitability experiment are filler with the octadecylsilane chemically bonded silica; With acetonitrile-water (22: 78) is mobile phase; The detection wavelength is 203nm.Number of theoretical plate calculates by the ginsenoside Re peak should be not less than 2000.
The preparation precision of reference substance solution takes by weighing the ginsenoside Rg
1Reference substance, Re reference substance are an amount of, add methanol and make the mixed solution that every 1ml contains 0.2mg.
This product 0.2g is got in the preparation of need testing solution, and accurate the title decides, the accurate water-saturated n-butanol 30ml that adds, close plug, placement is spent the night, supersound process (power 250W, frequency 50kHz) 30 minutes, filter, discard filtrate just, precision is measured subsequent filtrate 15ml, puts evaporate to dryness in the evaporating dish, and residue adds dissolve with methanol and is transferred in the 5ml volumetric flask, add methanol and be diluted to scale, shake up, filter, get subsequent filtrate promptly.
Accurate respectively reference substance and each 20ul of need testing solution of drawing of algoscopy injects chromatograph of liquid, measures, promptly.The results are shown in following table.
According to above-mentioned technology, make Radix Ginseng total saponins three batch samples, its content and yield see the following form.By the result as can be seen, the Radix Ginseng total saponins extract yield that obtains by this prepared is 1～2%, and Radix Ginseng total saponins content is not less than 50%, ginsenoside Re, ginsenoside Rg
1Content is not less than 30%.
The preparation of embodiment 4 KWR composition I aqueous injection
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 10.0g
Water for injection adds to 5000ml
Prepare 1000 altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) kurarinone and ginseng polysaccharide are added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat is added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) with the solution sealing by fusing in glass ampule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.01% methylene blue solution hunts leak.
11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 KWR composition I I aqueous injection
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 20.0g
Water for injection adds to 5000ml
Prepare 1000 altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) kurarinone is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat and Radix Ginseng total saponins are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) with the solution sealing by fusing in glass ampule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.01% methylene blue solution hunts leak.
11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 KWR composition I injectable powder
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 10.0g
Mannitol 400.0g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Preparation technology:
1) vessel of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) kurarinone and ginseng polysaccharide are added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat is added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, add sterile water for injection to full dose.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
Implement the preparation of 7 KWR composition I I injectable powder
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 20.0g
Mannitol 400.0g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Preparation technology:
1) vessel of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) kurarinone is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat and Radix Ginseng total saponins are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, add sterile water for injection to full dose.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 KWR composition I sodium chloride transfusion
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 10.0g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) kurarinone and ginseng polysaccharide are added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat is added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.With sodium chloride with an amount of water for injection dissolving fully, merge above-mentioned solution, benefit adds to the full amount of water for injection.
3) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
4) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
5) through the microporous filter membrane fine straining of 0.45um.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) fill is in the infusion bottle of 100ml.
8) 115 ℃ of pressure sterilizings are 30 minutes.
9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 KWR composition I I sodium chloride transfusion
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 20.0g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) kurarinone is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat and Radix Ginseng total saponins are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.With sodium chloride with an amount of water for injection dissolving fully, merge above-mentioned solution, benefit adds to the full amount of water for injection.
3) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
4) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
5) through the microporous filter membrane fine straining of 0.45um.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) fill is in the infusion bottle of 100ml.
8) 115 ℃ of pressure sterilizings are 30 minutes.
9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 KWR composition I glucose infusion liquids
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 10.0g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) kurarinone and ginseng polysaccharide are added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat is added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, benefit adds to the full amount of water for injection.Glucose is complete with the water for injection dissolving of dosing amount 40%, heated and boiled 15 minutes.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 11 KWR composition I I glucose infusion liquids
Prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 20.0g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) kurarinone is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Schisandrae Chinensis extrat and Radix Ginseng total saponins are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, benefit adds to the full amount of water for injection.Glucose is complete with the water for injection dissolving of dosing amount 40%, heated and boiled 15 minutes.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 12 KWR composition tablets
KWR composition I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Starch 40.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5.0g
Carboxymethylstach sodium 10.0g
Prepare 1000 altogether
KWR composition I I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Starch 40.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5.0g
Carboxymethylstach sodium 10.0g
Prepare 1000 altogether
Preparation technology:
1) it is standby kurarinone, ginseng polysaccharide's (or Radix Ginseng total saponins) and Fructus Schisandrae Chinensis extrat pulverize separately to be crossed 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with ginseng polysaccharide's (or Radix Ginseng total saponins), Fructus Schisandrae Chinensis extrat, kurarinone, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) the sheet weight sheet of determining according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 13 KWR composition capsules
KWR composition I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Starch 20.0g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5.0g
Prepare 1000 altogether
KWR composition I I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Starch 20.0g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5.0g
Prepare 1000 altogether
Preparation technology:
1) it is standby kurarinone, ginseng polysaccharide's (or Radix Ginseng total saponins) and Fructus Schisandrae Chinensis extrat pulverize separately to be crossed 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with ginseng polysaccharide's (or Radix Ginseng total saponins), Fructus Schisandrae Chinensis extrat, kurarinone, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
Implement the preparation of 14 KWR composition granules
KWR composition I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
KWR composition I I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Preparation technology:
1) it is standby sucrose to be pulverized 100 mesh sieves.It is standby that kurarinone, ginseng polysaccharide's (or Radix Ginseng total saponins) and Fructus Schisandrae Chinensis extrat pulverize separately are crossed 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) the method mix homogeneously that kurarinone, ginseng polysaccharide's (or Radix Ginseng total saponins), Fructus Schisandrae Chinensis extrat and Icing Sugar are progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material,
4) cross 20 mesh sieve system granules.
5) granule is dried under 60 ℃ condition.
6) dried granule is crossed 18 mesh sieve granulate.
7) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
8) packing, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 15KWR composition dripping agent
KWR composition I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Polyethylene glycol 6000 1000g
KWR composition I I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Polyethylene glycol 6000 1000g
Preparation technology:
Pulverized behind 100 mesh sieves kurarinone, ginseng polysaccharide's (or Radix Ginseng total saponins) and Fructus Schisandrae Chinensis extrat standby.With polyethylene glycol 6000 heating and melting in water-bath, treat to add kurarinone, ginseng polysaccharide's (or Radix Ginseng total saponins) and Fructus Schisandrae Chinensis extrat after whole fusions, stirring and dissolving, 60 mesh sieves filter, and keep 60 ℃ to splash in the liquid paraffin that is chilled to below 10 ℃ and make ball.
The preparation of embodiment 16 KWR composition soft agent
KWR composition I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Soybean oil 300.0g
Soybean phospholipid 40.0g
Cera Flava 20.0g
Prepare 1000 altogether
KWR composition I I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Soybean oil 300.0g
Soybean phospholipid 40.0g
Cera Flava 20.0g
Prepare 1000 altogether
Preparation technology:
With the soybean oil of recipe quantity and soybean phospholipid, Cera Flava heating and melting, mixing is put coldly, adds ginseng polysaccharide's (or Radix Ginseng total saponins), Fructus Schisandrae Chinensis extrat, kurarinone and grinds well, and is pressed into soft capsule and gets final product.
The preparation of embodiment 17 KWR composition oral liquid agent
KWR composition I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Ginseng polysaccharide 48.0g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 10g
Sodium benzoate 15g
Stevioside 10g
Purified water adds to 10000ml
Prepare 1000 altogether
KWR composition I I prescription:
Kurarinone 400.0g
Fructus Schisandrae Chinensis extrat 90.3g (being equivalent to Fructus Schisandrae Chinensis 3g)
Radix Ginseng total saponins 48.4g (being equivalent to Radix Ginseng 4g)
Polyoxyethylene sorbitan monoleate 20.0g
Sodium benzoate 15g
Stevioside 20.0g
Purified water adds to 10000ml
Prepare 1000 altogether
Preparation technology:
1) with heated and stirred dissolving in the water of kurarinone and ginseng polysaccharide's (or Radix Ginseng total saponins) adding dosing amount 30% fully.Fructus Schisandrae Chinensis extrat is added low amounts of water, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, add purified water to full dose.
2) sodium benzoate and stevioside is complete with the water dissolution of dosing amount 20%.
3) merge above-mentioned two solution, mend and add water to full dose.
4) filtering with microporous membrane of mistake 0.8um.
5) semi-finished product chemical examination.
6) fill.Finished product is examined entirely, the packing warehouse-in.
Claims (3)
1. pharmaceutical composition for the treatment of hepatitis is characterized in that said composition made by following bulk drugs: 400 parts of kurarinones, 60～120 parts of Fructus Schisandrae Chinensis extrats, 20～80 parts of ginseng polysaccharides; Perhaps be: 400 parts of kurarinones, 60～120 parts of Fructus Schisandrae Chinensis extrats, 20～80 parts of Radix Ginseng total saponinss, schisandrin content is not less than 5% in the described Fructus Schisandrae Chinensis extrat, and the ether extract content is not less than 15%; Ginseng polysaccharide's content is not less than 30%; Radix Ginseng total saponins content is not less than 30%, ginsenoside Re wherein and ginsenoside Rg
1Content is not less than 15%.
2. pharmaceutical composition as claimed in claim 1 is characterized in that this pharmaceutical composition and mixing acceptable accessories make clinically any or pharmaceutically acceptable dosage form.
3. pharmaceutical composition as claimed in claim 2 is characterized in that clinically or pharmaceutically acceptable dosage form is injection or oral formulations.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005101045532A CN1970001B (en) | 2005-11-22 | 2005-11-22 | Pharmaceutical composition comprising kurarinone, magnolia vine fruit and ginseng for treating hepatitis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005101045532A CN1970001B (en) | 2005-11-22 | 2005-11-22 | Pharmaceutical composition comprising kurarinone, magnolia vine fruit and ginseng for treating hepatitis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1970001A CN1970001A (en) | 2007-05-30 |
| CN1970001B true CN1970001B (en) | 2011-07-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005101045532A Expired - Fee Related CN1970001B (en) | 2005-11-22 | 2005-11-22 | Pharmaceutical composition comprising kurarinone, magnolia vine fruit and ginseng for treating hepatitis |
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| CN106075277A (en) * | 2016-06-13 | 2016-11-09 | 山东中医药大学 | A kind of preparation method of Oxymatrine-phospholipid Complex enteric-soluble controlled-release capsule |
| CN108685885B (en) * | 2017-07-11 | 2023-11-17 | 南华大学 | Pharmaceutical composition containing schizandrin A and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1602917A (en) * | 2004-07-28 | 2005-04-06 | 贵阳云岩西创药物科技开发有限公司 | 'Shengmai' formulation and its preparation process |
| CN1650996A (en) * | 2003-12-06 | 2005-08-10 | 山东绿叶天然药物研究开发有限公司 | Medicinal composition, its preparation method and application |
| CN1686388A (en) * | 2005-04-11 | 2005-10-26 | 北京正大绿洲医药科技有限公司 | Kangai drip pill for treating tumour, hepatitis B and its preparation method |
-
2005
- 2005-11-22 CN CN2005101045532A patent/CN1970001B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1650996A (en) * | 2003-12-06 | 2005-08-10 | 山东绿叶天然药物研究开发有限公司 | Medicinal composition, its preparation method and application |
| CN1602917A (en) * | 2004-07-28 | 2005-04-06 | 贵阳云岩西创药物科技开发有限公司 | 'Shengmai' formulation and its preparation process |
| CN1686388A (en) * | 2005-04-11 | 2005-10-26 | 北京正大绿洲医药科技有限公司 | Kangai drip pill for treating tumour, hepatitis B and its preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 张晶等.中药五味子化学成分和药理作用研究及临床应用.上海预防医学杂志9 4.1997,9(4),189-190. * |
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| CN1970001A (en) | 2007-05-30 |
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