CN1977887B - Medicinal composition for treating hepatitis - Google Patents
Medicinal composition for treating hepatitis Download PDFInfo
- Publication number
- CN1977887B CN1977887B CN2005100454109A CN200510045410A CN1977887B CN 1977887 B CN1977887 B CN 1977887B CN 2005100454109 A CN2005100454109 A CN 2005100454109A CN 200510045410 A CN200510045410 A CN 200510045410A CN 1977887 B CN1977887 B CN 1977887B
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- salviae miltiorrhizae
- sophorae flavescentis
- radix salviae
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Abstract
The present invention discloses a medicine composition and its preparation method. Said medicine composition is mainly made u by using (by weight portion) 25-400 portions of silibinin or its derivative or silymarin, 4000-64000 portions of flavescent sophora root and 1000-90000 portions of salvia root. Said medicine composition can be made into various dosage forms, and can be used for curing acute and chronic hepatitides.
Description
1, technical field
The present invention relates to a kind of pharmaceutical composition of making by silibinin or derivatives thereof or silymarin, Radix Sophorae Flavescentis or its extraction and Radix Salviae Miltiorrhizae or its extract that is used for the treatment of hepatitis, and preparation method thereof, medical technical field belonged to.
2, background technology
Acute, chronic hepatitis is clinical frequently-occurring disease, commonly encountered diseases, especially the incidence rate of viral hepatitis is high since the seventies, make its ill crowd more and more big, become clinical difficult treatment as common viral hepatitis such as hepatitis B, hepatitis C, in addition become liver cirrhosis, the main inducing of onset of liver cancer.Because the cause of disease of this class disease is more, the virus difficulty of turning out cloudy, the course of disease is longer, and it is relatively poor that part patient lapses to prognosis, caused huge body and mind misery to the patient.Up to now, the medicine that is used for the treatment of acute, chronic hepatitis clinically is more, doctor trained in Western medicine mainly from antiviral, regulate aspects treatments such as immunity and liver function protecting, the traditional Chinese medical science is then from the determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs treatment of starting with.From clinical practice, Chinese medicine and western medicine all has certain curative effect aspect the liver function improving, but is shortening the course of treatment, promotes virus to turn out cloudy, aspects such as prevention liver cirrhosis, and medicine so far is still not fully up to expectations.For clinical liver disease provides effectively, efficient, long-acting, safe and reliable, the new drug for the treatment of both the principal and secondary aspects of a disease is still the problem that presses for solution.
Silibinin is that the processing of feverfew Herba Silybi mariani (Silybum marianum Gaertn) fruit extraction separation obtains.Silybin meglumine is the addition product of silibinin and meglumine, the soluble derivative that belongs to silibinin, recorded into the 10th 52 pages of national drug standards chemical drugs provincial standard rising national standards of National Drug Administration (Chinese Pharmacopoeia Commission's volume), wherein regulation is pressed dry product calculating, contains silymarin meglumine and must not be less than 96.0%; Contain silybin meglumine (C
25H
22O
10C
7H
17NO
5) must not be less than 75.0%.Silymarin is that the fruit of feverfew Herba Silybi mariani (Silybum marianum (L) Gaertn) is through extracting the bulky powder of refining gained, recorded into the 7th 30 pages of national drug standards chemical drugs provincial standard rising national standards of National Drug Administration (Chinese Pharmacopoeia Commission's volume), wherein regulation is pressed dry product calculating, the moisture silibin that flies calculates with silibinin, must not be less than 68%, contain silibinin and Isosilybin and must not be less than 30%.The effect that silybin meglumine has protection and stablizes liver plasma membrane, and can promote liver cell regeneration, medicine liver poisoning, various acute, chronic hepatitis, first cirrhosis, fatty liver there are good curative effect.
Radix Sophorae Flavescentis is the dry root of leguminous plant Radix Sophorae Flavescentis SopHora flavescens Ait., have another name called dry bones, careless Chinese scholartree, Chinese scholartree etc., have heat clearing and damp drying, parasite killing, antipruritic, the effect of calming the nerves.Radix Sophorae Flavescentis has the anti-liver injury effect.The main effective ingredient of Radix Sophorae Flavescentis is an alkaloids, and what content was the highest in the alkaloid is matrine and oxymatrine.Oxymatrine synthesizes rat fat-storing cell propagation and collagen inhibitory action.Matrine and oxymatrine have protective effect to hepatocyte, and alanine aminotransferase is reduced, and hepatic pathology changes and obviously alleviates.Effects such as the antiinflammatory of matrine and oxymatrine, immunosuppressant, removing free radical, diuresis and detoxifcation are the pharmacological basis of treatment various hepatic injurys, autoimmune disease and allergic disease.
Radix Salviae Miltiorrhizae is the dry root and rhizome of labiate Radix Salviae Miltiorrhizae Salvia miltiorrhiza Bge..Stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow are arranged, the effect of the relieving restlessness that clears away heart-fire.Studies show that of modern pharmacology, Radix Salviae Miltiorrhizae have microcirculation improvement, antiplatelet gathering and thrombosis, blood viscosity lowering, antioxidation, protection cerebral tissue ischemia/reperfusion injury, strengthen hypoxia-bearing capability, improve pharmacological actions such as renal function.Radix Salviae Miltiorrhizae antihepatitic activity mechanism has the free radical resisting peroxide injury with Radix Salviae Miltiorrhizae, promote the hepatocellular reparation of damage, suppress that inflammatory factor discharges, improves liver microcirculation, suppresses collagenation, promotes the degraded of pathology deposition collagen, the activatory pharmacological action of inhibition hepatic stellate cell (HSC) is relevant.Red sage root water soluble ingredient mainly is to be the phenolic acid compound of basic structure with the danshensu, and the Radix Salviae Miltiorrhizae total phenolic acids chemical compound has very strong antioxidation, can remove superoxide anion and hydroxy radical, suppresses lipid peroxidation, and then alleviates hepatic injury.
Utilize the interaction of silibinin or derivatives thereof or silymarin, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae at present, composition of prescription, preparation is used for the treatment of the medicine of hepatitis, does not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs, treat hepatitis better, 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 silibinin or derivatives thereof or silymarin, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae, three's weight proportion is: 25～400 parts of silibinin or derivatives thereof or silymarin, 4000～64000 parts of Radix Sophorae Flavescentiss, 1000～90000 parts of Radix Salviae Miltiorrhizaes, be preferably: 50～200 parts of silibinin or derivatives thereof or silymarin, 8000～32000 parts of Radix Sophorae Flavescentiss, 5000～45000 parts of Radix Salviae Miltiorrhizaes, the best is: 100 parts of silibinin or derivatives thereof or silymarin, 16000 parts of Radix Sophorae Flavescentiss, 15000 parts of Radix Salviae Miltiorrhizaes.
Radix Sophorae Flavescentis in the pharmaceutical composition of the present invention and Radix Salviae Miltiorrhizae can prepare extract with The suitable solvent and method, total extract is made arbitrary preparation with silibinin or derivatives thereof or silymarin and mixing acceptable accessories again, and main effective ingredient contained in the total extract is: Radix Sophorae Flavescentis total alkaloids and Radix Salviae Miltiorrhizae total phenolic acids.The total content of the main effective ingredient in the total extract is not less than 30%.
The derivant of the silibinin in the pharmaceutical composition of the present invention is preferably silybin meglumine.
Radix Sophorae Flavescentis can obtain Radix Sophorae Flavescentis total alkaloids through extracting processing with The suitable solvent, solvent wherein is preferably sour water or ethanol, the extracting method of Radix Sophorae Flavescentis total alkaloids can be in infusion process, percolation, decocting method, reflux extraction, continuous extraction, the resin method one or more, but also reference literature method preparation.
The preferred for preparation technology of Radix Sophorae Flavescentis that with Radix Sophorae Flavescentis total alkaloids is main effective ingredient is as follows:
Get the Radix Sophorae Flavescentis medical material, be ground into coarse powder, till the inanimate object alkali reaction, collect percolate with 0.2% hydrochloric acid percolation, and the strong acid type cationic resin by having handled well, after exchange finishes, resin is washed to neutrality with water drying.With the strong aqua ammonia resin that alkalizes, the apparatus,Soxhlet's of packing into is extracted into extracting solution inanimate object alkali reaction with the chloroform continuous backflow.The chloroform extracted solution anhydrous sodium sulfate dehydration, the reclaim under reduced pressure chloroform gets thick paste.
Radix Sophorae Flavescentis total alkaloids yield by this prepared is 2～5%, contains matrine (C
15H
24N
2O) and oxymatrine (C
15H
24N
2O
2) total amount be not less than 70%.
Radix Sophorae Flavescentis also can be by following prepared, but is not limited only to following method:
Technology one: get the Radix Sophorae Flavescentis medical material, be ground into coarse powder,, filter leachate with 95% soak with ethanol 5 times, it is 1.04～1.09 that thin film evaporation is concentrated into relative density, and distilling under reduced pressure eliminates ethanol, adds 2% hydrochloric acid of 2 times of volumes, fully stirs, placement is spent the night, and filters, and discards precipitate.Filtrate is washed with ether, discards ether solution, and filtrate is alkalized to pH9～10 with sodium hydroxide, and it is saturated to add sodium chloride, and to the inanimate object alkali reaction, distilling under reduced pressure gets brown thick paste shape material with chloroform extraction.Radix Sophorae Flavescentis total alkaloids yield by this prepared is not less than 0.8%, contains matrine (C
15H
24N
2O) and oxymatrine (C
15H
24N
2O
2) total amount be not less than 50%.
Technology two: get the Radix Sophorae Flavescentis medical material, be ground into coarse powder, add 2 times of amount strong aqua ammonia, moistening 1 hour, add chloroform and soak 4 times, filter, filtrate decompression reclaims chloroform, adds 2% hydrochloric acid of 2 times of volumes, fully stirs, and placement is spent the night, and filters, and discards precipitate.Filtrate is washed with ether, discards ether solution, and filtrate is alkalized to pH 9～10 with sodium hydroxide, and it is saturated to add sodium chloride, and to the inanimate object alkali reaction, distilling under reduced pressure gets brown thick paste shape material with chloroform extraction.Radix Sophorae Flavescentis total alkaloids yield by this prepared is not less than 1.5%, contains matrine (C
15H
24N
2O) and oxymatrine (C
15H
24N
2O
2) total amount be not less than 65%.
Radix Salviae Miltiorrhizae can obtain Radix Salviae Miltiorrhizae total phenolic acids through extracting processing with The suitable solvent, extracts solvent preferred water or ethanol, and the extracting method of Radix Salviae Miltiorrhizae can be infusion process, percolation, decocting method, reflux extraction or continuous extraction.As preparing Radix Salviae Miltiorrhizae total phenolic acids, can also prepare according to literature method by the method for water extract-alcohol precipitation.
The preferred for preparation technology of Radix Salviae Miltiorrhizae that with Radix Salviae Miltiorrhizae total phenolic acids is main effective ingredient is as follows:
Get Radix Salviae Miltiorrhizae, be ground into coarse grain, decoct with water three times, 2 hours for the first time, add 12 times of amounts of water, second and third time each 1.5 hours adds 10 times of amounts of water, and collecting decoction filters, and it is 1.17～1.20 (80 ℃) that filtrate decompression is concentrated into relative density.Add the ethanol precipitation secondary, make for the first time that to contain the alcohol amount be 75%, make that to contain the alcohol amount be 85% for the second time, respectively leave standstill 24h, reclaiming ethanol to relative density is 1.17～1.20 (80 ℃ of surveys), spray drying, promptly.
Radix Salviae Miltiorrhizae extract yield by this prepared is 1～3%, and the content of Radix Salviae Miltiorrhizae total phenolic acids is not less than 50%, and the content of salvianolic acid B is not less than 1.5%.
Radix Salviae Miltiorrhizae also can be by following prepared:
Technology one: get Radix Salviae Miltiorrhizae, decoct with water twice, each is 2 hours, add for the first time 12 times of amounts of water, for the second time add 10 times of amounts of water, collecting decoction filters, it is 1.17～1.20 (80 ℃) that filtrate is concentrated into relative density, add ethanol precipitation and make and contain alcohol amount and reach 75%, leave standstill 24h, reclaiming ethanol to relative density is 1.23～1.28 (80 ℃), vacuum drying (50 ℃), promptly.By the Radix Salviae Miltiorrhizae extract yield 2～4% of this prepared, the content of Radix Salviae Miltiorrhizae total phenolic acids is not less than 40%, and the content of salvianolic acid B is not less than 0.8%.
Technology two: get Radix Salviae Miltiorrhizae, add 85% alcohol reflux 2 hours, filter, decompression filtrate recycling ethanol is to thick paste; Medicinal residues add water (10 times of amounts) and decocted 1 hour, filter, and filtrate and above-mentioned thick paste merge, and are evaporated in right amount, and 50 ℃ of vacuum dryings are pulverized, and sieve, promptly.Radix Salviae Miltiorrhizae extract yield by this prepared is 3～5%, and the content of Radix Salviae Miltiorrhizae total phenolic acids is not less than 30%, and the content of salvianolic acid B is not less than 0.3%.
Radix Salviae Miltiorrhizae extract can be by above-mentioned prepared, but this should be interpreted as Radix Salviae Miltiorrhizae extract only limits to above-mentioned prepared in the pharmaceutical composition of the present invention.
Aforementioned pharmaceutical compositions, also available Radix Sophorae Flavescentis total alkaloids replace Radix Sophorae Flavescentis, Radix Salviae Miltiorrhizae total phenolic acids replacement Radix Salviae Miltiorrhizae to feed intake and make, and calculate with respect to the yield of medical material according to extract, and its ratio of weight and number is:
25～400 parts of silibinin or derivatives thereof or silymarin, 120～1920 parts of Radix Sophorae Flavescentis total alkaloidss, 30～1800 parts of Radix Salviae Miltiorrhizae total phenolic acidss; Be preferably: 50～200 parts of silibinin or derivatives thereof or silymarin, 240～960 parts of Radix Sophorae Flavescentis total alkaloidss, 100～900 parts of Radix Salviae Miltiorrhizae total phenolic acidss; Optimum is: 100 parts of silibinin or derivatives thereof or silymarin, 320～800 parts of Radix Sophorae Flavescentis total alkaloidss, 150～450 parts of Radix Salviae Miltiorrhizae total phenolic acidss.
In the aforementioned pharmaceutical compositions, the total content of matrine and oxymatrine is preferably and is not less than 50% in the Radix Sophorae Flavescentis total alkaloids, preferably is not less than 70%; The content of Radix Salviae Miltiorrhizae total phenolic acids is preferably and is not less than 30%, preferably is not less than 50%, and wherein the content of salvianolic acid B is preferably and is not less than 0.3%, preferably is not less than 1.5%.Radix Sophorae Flavescentis total alkaloids and Radix Salviae Miltiorrhizae total phenolic acids can be by above-mentioned prepared.
Radix Sophorae Flavescentis total alkaloids is re-refined after also can buying or buy from market except that available said method self-control.A plurality of manufacturer production Radix Sophorae Flavescentis total alkaloidss are arranged at present; as: Mudanjiang Flos Nelumbinis lake pharmacy responsibility company limited (the accurate word H23023277 of traditional Chinese medicines), the permanent pharmaceutical factory in Heilungkiang (the accurate word H23023278 of traditional Chinese medicines), Ningxia Flos cercis chinensis pharmaceutcal corporation, Ltd (the accurate word H64020285 of traditional Chinese medicines), Ningxia Boertaili Pharmaceutical Co., Ltd (the accurate word H64020287 of traditional Chinese medicines), its standard all meets the national drug standards (WS-10001-(HD-1106)-2002).
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.
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 heat clearing and damp drying that has, blood circulation invigorating efficacies new drug, can be used for this new drug treatment acute, chronic hepatitis, card belongs to dampness-heat in the liver and gallbladder disease person.
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.
Compositions 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) theory of Chinese medical science is thought, the pathogeny of hepatitis is very complicated, in general, often pent up puzzledly, with the passing of time injure internal organs and QI and blood by damp and hot heresy, cause cards such as asthenia of both the spleen and kidney, therefore damp and hot malicious heresy be the hepatitis initiating because of, it is the pathological changes center that the Liver Channel stasis of blood stagnates, at such etiology and pathogenesis, its Therapeutic Principle should be a heat clearing and damp drying, blood circulation promoting and blood stasis dispelling.In the pharmaceutical composition of the present invention, the same Herba Silybi mariani of silybin meglumine merit, but heat-clearing and toxic substances removing, 'Shugan Lidan '; The Radix Sophorae Flavescentis heat clearing and damp drying, the Radix Salviae Miltiorrhizae blood circulation promoting and blood stasis dispelling.Three medicine compatibilities, the effect of playing heat clearing and damp drying, 'Shugan Lidan ' altogether.
(3) studies have shown that by pharmacodynamic experiment first: the chmice acute hepatic injury due to pharmaceutical composition Abensanil of the present invention, D-Gal, the carbon tetrachloride has significant protective effect; the breeding of dhbv dna can be significantly suppressed, the rat liver fibrosis due to the carbon tetrachloride can be significantly resisted.Three medical instruments have synergistic function, and are evident in efficacy, produced beyond thought effect.
(4) each proportioning of pharmaceutical composition of the present invention is carried out pharmacodynamic study, drawn the optimal proportion of the present composition.
(5) the present invention is except that silybin meglumine, and Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae can feed intake with medical 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.
(6) confirm drug combination injection safety and stability of the present invention by specific safety test and stability experiment.
Below routine by experiment beneficial effect of further setting forth medicine of the present invention.The compositions of silybin meglumine, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae hereinafter to be referred as
The SKD compositionsUsed Radix Sophorae Flavescentis total alkaloids is taken from embodiment 1 in the experimental example, and Radix Salviae Miltiorrhizae total phenolic acids is taken from embodiment 2.
Experimental example 1 SKD compositions drug combination drug efficacy study
Test sample 0.9% normal saline, self-control;
The silybin meglumine injection, self-control, 2ml:100mg;
Lightyellow sophora root injection, self-control, 5ml contains Radix Sophorae Flavescentis total alkaloids 481.6mg (being equivalent to Radix Sophorae Flavescentis 16g);
Radix Salviae Miltiorrhizae Injection, self-control; 5ml contains Radix Salviae Miltiorrhizae total phenolic acids 301.5mg (being equivalent to Radix Salviae Miltiorrhizae 15g);
The different proportionings of SKD composite injection (silybin meglumine+Radix Sophorae Flavescentis+Radix Salviae Miltiorrhizae), self-control, preparation method is with reference to embodiment 3.
Laboratory animal ICR mice, body weight 18～25g, male and female half and half.
Experimental technique is got 140 of mices, is divided into 14 groups at random, and 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.
Conclusion is compared with the blank group, and the active of model group ALT and LPO significantly raises, and difference is (P＜0.01) extremely significantly, illustrates that modeling is reliable.Compare with model group, active obviously reduce (P＜0.05, P＜0.01) of each proportioning group ALT of silybin meglumine group, Radix Sophorae Flavescentis group, Radix Salviae Miltiorrhizae group and SKD compositions and LPO 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 SKD compositions all is better than single silybin meglumine, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae used, and illustrates that silybin meglumine, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae three medicines share, and have synergistic function.In each proportioning group of SKD compositions, the most remarkable with silybin meglumine+Radix Sophorae Flavescentis+Radix Salviae Miltiorrhizae (100mg+16g+15g) group curative effect.
The influence of table 1 SKD 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 silybin meglumine group,
#P＜0.05,
##P＜0.01;
Compare with the Radix Sophorae Flavescentis group,
ΔP＜0.05,
The Δ ΔP＜0.01; Compare with the Radix Salviae Miltiorrhizae group,
☆P＜0.05,
☆ ☆P＜0.01.
Experimental example 2 SKD compositionss cause the protective effect of chmice acute hepatic injury to D-Gal
Test sample: 0.9% normal saline, self-control;
The silybin meglumine injection, self-control, 2ml:100mg;
SKD composite injection (silybin meglumine+Radix Sophorae Flavescentis+Radix Salviae Miltiorrhizae 100mg+16g+15g), self-control, preparation method is with reference to embodiment 3.
Laboratory animal: ICR mice, body weight 20～25g, male and female half and half.
Experimental technique: get 60 of mices, be divided into 6 groups at random, be respectively blank group, model group, silybin meglumine group, the basic, normal, high dosage group of SKD composite injection, 10 every group.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 1h pneumoretroperitoneum injecting normal saline the last time, the D-Gal 500g/kg of the equal lumbar injection 100g/L of all the other each treated animals.Put to death animal behind the 24h and get blood, centrifugal, get serum, automatic clinical chemistry analyzer detects, and the detection index is glutamic oxaloacetic transaminase, GOT (AST), serum albumin (ALB).The animal docking is got the blood slide method and is measured animal clotting time (CT) before putting to death.The results are shown in Table 2.
Conclusion: compare with the blank group, the activity of model group glutamic oxaloacetic transaminase, GOT (AST) extremely significantly raise (P＜0.001), serum albumin (ALB) numbers of poles significantly reduces (P＜0.01), and clotting time (CT) utmost point significant prolongation (P＜0.001) illustrates that modeling is reliable.Compare with model group; active (P＜0.05 that obviously reduces of silybin meglumine group, each dosage group glutamic oxaloacetic transaminase, GOT (AST) of SKD compositions; P＜0.01); serum albumin (ALB) numbers of poles significantly increases (P＜0.01); clotting time (CT) extremely significantly shortens (P＜0.001); illustrate that each medicine all has hepatoprotective effect, hepatic injury has protective effect to the D-Gal induced mice.Each dosage group curative effect of SKD compositions all is better than list and uses silybin meglumine, illustrates that silybin meglumine, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae three medicines share, and have synergistic function.The wherein middle and high dosage group of SKD compositions protective effect more obvious (P＜0.01).
Table 2 SKD compositions causes the influence of acute liver damage mice serum AST, ALB content and clotting time (CT) to D-Gal
Compare with the blank group
◇ ◇P＜0.01,
◇ ◇ ◇P＜0.001; Compare with model group,
*P＜0.05,
*P＜0.01; Compare with the silybin meglumine group,
#P＜0.05,
##P＜0.01
Experimental example 3 SKD compositionss are to carbon tetrachloride (CCl
4) cause the protective effect of chmice acute hepatic injury
Test sample: 0.9% normal saline, self-control;
The silybin meglumine injection, self-control, 2ml:100mg;
SKD composite injection (silybin meglumine+Radix Sophorae Flavescentis+Radix Salviae Miltiorrhizae 100mg+16g+15g), self-control, preparation method is with reference to embodiment 3.
Laboratory animal: ICR mice, body weight 22～26g, male and female half and half.
Experimental technique: get 60 of mices, be divided into 6 groups at random, be respectively blank group, model group, silybin meglumine group, the basic, normal, high dosage group of SKD composite injection, 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.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 is calculated liver exponential sum spleen index.The results are shown in Table 3.
Table 3 SKD compositions is to the influence of acute liver damage Mouse Liver, spleen index and Serum ALT, AST content due to the CCl4
Compare with the blank group
◇P＜0.05,
◇ ◇P＜0.01; Compare with model group,
*P＜0.05,
*P＜0.01; Compare with the silybin meglumine 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 extremely significantly 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, the middle and high dosage group of SKD compositions Mouse Liver index, spleen index reduce (P＜0.05), liver, splenomegaly alleviate, and each dosage group Serum ALT of SKD compositions, 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.Each dosage group curative effect of SKD compositions all is better than list and uses silybin meglumine, illustrates that silybin meglumine, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae three medicines share, and have synergistic function.Wherein middle and high dosage group better efficacy (P＜0.05 or P＜0.01).
The anti-dhbv dna effect of experimental example 4 SKD compositionss
Test sample: 0.9% normal saline, self-control;
The injection acyclovir, Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group;
The silybin meglumine injection, self-control, 2ml:100mg;
SKD composite injection (silybin meglumine+Radix Sophorae Flavescentis+Radix Salviae Miltiorrhizae 100mg+16g+15g), self-control, preparation method is with reference to embodiment 3.
Laboratory animal: commercially available 1 age in days Beijing duck;
DHBV (DHB) positive serum, microbiology teaching and research room of Medical Center of Fudan University.
Experimental technique:
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.
Drug therapy filters out 36 of the positive ducks that infect successfully, is divided into 6 groups at random, 6 every group, is respectively blank group, silybin meglumine group, positive controls, the basic, normal, high dosage group of SKD composite injection, 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 acyclovir (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 DHBV-DNADot Blot method, with hybridization spot absorbance (A) as specimen DHBV-DNA level value.The results are shown in Table 4.
Table 4SKD 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 utmost point 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 SKD compositions all has inhibitory action to DHBV, and does not have knock-on after the drug withdrawal, and wherein middle and high dosage group inhibitory action is more obvious.Each administration group curative effect of SKD compositions all is better than list and uses silybin meglumine, illustrates that silybin meglumine, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae three medicines share, and have synergistic function.
The Hepar Mus fibrosis effect of the experimental example 5 SKD compositions Chinese People's Anti-Japanese Military and Political College
Test sample: 0.9% normal saline, self-control;
The silybin meglumine injection, self-control, 2ml:100mg;
SKD composite injection (silybin meglumine+Radix Sophorae Flavescentis+Radix Salviae Miltiorrhizae 100mg+16g+15g), self-control, preparation method is with reference to embodiment 3.
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 60 of Liver Fibrosis Model rats, be divided into 6 groups at random, be respectively model group, silybin meglumine group, the basic, normal, high dosage group of SKD composite injection, 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.Silybin meglumine group, the basic, normal, high dosage group of SKD composite injection be 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 5.
Table 5SKD 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 silybin meglumine group,
#P＜0.05,
##P＜0.01.
Conclusion: compare with the blank group, model group rat blood serum ALT, AST, HA, LN content have utmost point significant difference (P＜0.001), illustrate that model stability is reliable.Silybin meglumine, SKD combination treatment heptic fibrosis rat blood serum ALT and AST all are lower than model group, and difference has significance (P＜0.05 or P＜0.01), and prompting silybin meglumine, SKD compositions have the effect of falling enzyme and liver function protecting; Serum HA and LN level all significantly are lower than model group behind silybin meglumine, the SKD combination treatment, difference has significance (P＜0.05 or P＜0.01), prompting silybin meglumine, SKD compositions all can be improved the hepatic fibrosis serological index, have the effect of anti-hepatic fibrosis.Wherein, SKD compositions group curative effect is better than the silybin meglumine group, and prompting silybin meglumine, Radix Sophorae Flavescentis and Radix Salviae Miltiorrhizae three medicines share, and synergistic function is arranged.
Experimental example 6 injected in mice administration acute toxicity testings
(1) experimental technique
Test sample: the SKD composite injection, dosage form: liquid drugs injection, specification: 10ml derives from embodiment 3;
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: tail vein injection SKD composite injection 0.2ml/10g, lumbar injection SKD composite injection 0.2ml/10g, 2 times on the one.
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 the SKD composite injection is 0.4ml/10g to the maximum tolerated dose of male and female mouse vein and intraperitoneal injection, be equivalent to 100 times of maximum consumption 20ml of the 50kg body weight day for human beings.Show this product low toxicity, safe.
Experimental example 7 SKD composite injection stability experiments
Test sample: the SKD composite injection, dosage form: liquid drugs injection, specification: 10ml derives from embodiment 3;
Investigation project: character, pH value, clarity.
Long-time stability experimental technique and result: this product compositions 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 this composite injection 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.Embodiment 3～12 used Radix Sophorae Flavescentis total alkaloidss are taken from embodiment 1, and Radix Salviae Miltiorrhizae total phenolic acids is taken from embodiment 2.
The preparation of embodiment 1 Radix Sophorae Flavescentis total alkaloids
Get the Radix Sophorae Flavescentis medical material, be ground into coarse powder, till the inanimate object alkali reaction, filter percolate, and by cationic resin with 0.2% hydrochloric acid percolation, after exchange finishes, with resin wash to neutral, drying.With the strong aqua ammonia resin that alkalizes, the apparatus,Soxhlet's of packing into is extracted into extracting solution inanimate object alkali reaction with the chloroform continuous backflow.The chloroform extracted solution anhydrous sodium sulfate dehydration, the reclaim under reduced pressure chloroform gets thick paste.
Differentiate
(1) get the about 10mg of this product, add 1% hydrochloric acid solution 10ml and make dissolving, filter, filtrate splits in three test tubes, adds the bismuth potassium iodide experiment in the pipe and generates red-brown precipitation; Add test solution of mercuric potassium iodide in one pipe, generate the yellow-white precipitation; Add the experiment of potassium iodide iodine in another pipe, generate brown precipitation.
(2) it is an amount of to get this product, adds ethanol and makes the solution that every 1ml contains 4mg, as need testing solution.Other gets Radix Sophorae Flavescentis medicinal powder 0.5g, adds chloroform 25ml, strong ammonia solution 0.3ml, and placement is spent the night, and filters, and filtrate evaporate to dryness, residue add ethanol 0.5ml makes dissolving, in contrast medical material solution.Get matrine again and the oxymatrine reference substance is an amount of, add ethanol respectively and make the solution that every 1ml contains 2mg, in contrast product solution.Drawing above-mentioned four kinds of each 2ul of solution, put respectively on same silica gel g thin-layer plate, is developing solvent with chloroform-methanol-dense ammonia examination night (50: 6: 3), launches, and takes out, and dries, and spray is with bismuth potassium iodide test solution.In the test sample chromatograph, with the corresponding position of control medicinal material on, show the speckle of same color; With the corresponding position of reference substance chromatograph on, show two speckles of same color.
Assay photograph high performance liquid chromatography (" appendix VID of Chinese pharmacopoeia version in 2000) measure.
Chromatographic condition and system suitability test are filler with amino bonded silica gel; With acetonitrile-dehydrated alcohol-3% phosphoric acid solution (75: 10: 15) is mobile phase; The detection wavelength is 220nm.Number of theoretical plate calculates by the oxymatrine peak should be not less than 2000.
The preparation precision of reference substance solution takes by weighing the matrine reference substance, the oxymatrine reference substance is an amount of, adds acetonitrile-dehydrated alcohol (80: 20) dissolving respectively, and make every 1ml and contain matrine 0.05mg, the solution of oxymatrine 0.15mg, promptly.
The about 0.3g of this product powder (crossing sieve No. three) is got in the preparation of need testing solution, and accurate the title decides, and puts in the tool plug conical flask, add strong ammonia solution 0.5ml, the accurate chloroform 20ml that adds, close plug claims to decide weight, supersound process (power 250W, frequency 33kHz) 30 minutes, claim again to decide weight, supply the weight that subtracts mistake with chloroform, shake up, filter.Precision is measured subsequent filtrate 5ml, by neutral alumina post (100～200 orders, 5g, internal diameter 1cm), successively with chloroform, each 20ml eluting of chloroform-methanol (7: 3), collects eluent, reclaims solvent to doing residue
Add dehydrated alcohol and make dissolving in right amount, and be transferred in the 10ml measuring bottle, add dehydrated alcohol and be diluted to scale, shake up, promptly.
Accurate respectively above-mentioned reference substance solution each 5 μ l and need testing solution 5～10 μ l of drawing of algoscopy inject chromatograph of liquid, measure, promptly.
Make three batches of Radix Sophorae Flavescentis total alkaloidss according to above-mentioned technology, extract yield and content see the following form.By the result as can be known, the Radix Sophorae Flavescentis total alkaloids yield is 2～5%, and content is not less than 70%.
The yield of table 6 Radix Sophorae Flavescentis total alkaloids and content
The preparation of embodiment 2 Radix Salviae Miltiorrhizae total phenolic acidss
Get Radix Salviae Miltiorrhizae, be ground into coarse grain, decoct with water three times, 2 hours for the first time, add 12 times of amounts of water, second and third time each 1.5 hours adds 10 times of amounts of water, and collecting decoction filters, and it is 1.17～1.20 (80 ℃) that filtrate decompression is concentrated into relative density.Add the ethanol precipitation secondary, make for the first time that to contain the alcohol amount be 75%, make that to contain the alcohol amount be 85% for the second time, respectively leave standstill 24h, reclaiming ethanol to relative density is 1.17～1.20 (80 ℃ of surveys), spray drying, promptly.
Differentiate
Get this product 0.2g, porphyrize adds 70% methanol 25ml, and reflux 1 hour filters, and filtrate evaporate to dryness, residue add 70% methanol 1ml makes dissolving, as need testing solution.Other gets the salvianolic acid B reference substance, adds 70% methanol and makes the solution that every 1ml contains 2mg, in contrast product solution.Use tlc determination, draw above-mentioned two kinds of each 5ul 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 toluene-chloroform-ethyl acetate-methanol-formic acid (2: 3: 4: 0.5: 2).
In the test sample chromatograph, with reference substance chromatograph relevant position on, show the speckle of same color.
Assay
Total phenolic content is measured colorimetry
The preparation precision of reference substance solution takes by weighing the protocatechualdehyde reference substance 1mg that is dried to constant weight in 105 ℃, is dissolved in water, and is settled to 100ml.The preparation precision of need testing solution takes by weighing sample 50mg, put in the 50ml volumetric flask, thin up to scale precision is measured 0.1ml and is put and add ethanol 5ml in the 25ml volumetric flask, adds 0.3% sodium lauryl sulphate 2ml, 0.6% potassium ferricyanide-0.9% ferric oxide (face and use preceding mixed in equal amounts) 1ml, so 5min is placed in the dark place, add the 0.1mol/L hydrochloric acid solution to scale, shake up, after 20min is placed in the dark place, put in the lena colorimetric pool, the 72Onm place measures.
The assay high performance liquid chromatography of salvianolic acid B
Chromatographic condition and system suitability experiment are filler with the octadecylsilane chemically bonded silica; With methanol-acetonitrile-formic acid-water (30: 10: 1: 59) be mobile phase; The detection wavelength is 286nm.Theoretical cam curve is calculated by the danshensu peak should be not less than 1500.
It is an amount of that the preparation precision of reference substance solution takes by weighing the salvianolic acid B reference substance, adds 75% methanol and make the solution that every 1ml contains 0.14mg, promptly.
The about 0.2g of this product is got in the preparation of need testing solution, and accurate the title decides, and puts in the tool plug conical flask, and the accurate 75% methanol 50ml that adds claims to decide weight, reflux 1h takes out, and puts coldly, claims to decide weight again, supplies with 75% methanol to subtract weight loss, shake up, filter, get subsequent filtrate, promptly.
Accurate respectively reference substance solution and each 20ul of need testing solution of drawing of algoscopy injects chromatograph of liquid, measures, promptly.
The content of the yield of table 7 Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids and salvianolic acid B
According to above-mentioned technology, make Radix Salviae Miltiorrhizae extract three batch samples, its content and yield see the above table.By the result as can be seen, the Radix Salviae Miltiorrhizae extract yield by this prepared is 1～3%, and the content of Radix Salviae Miltiorrhizae total phenolic acids is not less than 50%, and the content of salvianolic acid B is not less than 1.5%.
The preparation of embodiment 3 SKD compositions aqueous injection
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 10000ml
Prepare 1000 altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
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) Radix Sophorae Flavescentis total alkaloids is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Radix Salviae Miltiorrhizae total phenolic acids and silybin meglumine 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 4 SKD composition powder injections
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Polyoxyethylene sorbitan monoleate 20g
Mannitol 400g
Sterile water for injection adds to 8000ml
Prepare 1000 altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
Preparation technology:
1) vessel of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
2) take by weighing supplementary material according to recipe quantity.
3) Radix Sophorae Flavescentis total alkaloids is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Radix Salviae Miltiorrhizae total phenolic acids and silybin meglumine 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 5 SKD compositions sodium chloride transfusion
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Polyoxyethylene sorbitan monoleate 20g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
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) Radix Sophorae Flavescentis total alkaloids is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Radix Salviae Miltiorrhizae total phenolic acids and silybin meglumine 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 6 SKD compositions glucose infusion liquids
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Polyoxyethylene sorbitan monoleate 20g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
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) Radix Sophorae Flavescentis total alkaloids is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Radix Salviae Miltiorrhizae total phenolic acids and silybin meglumine 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 7 SKD composition tablets
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Starch 50.0g
Microcrystalline Cellulose 50.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5.0g
Carboxymethylstach sodium 10.0g
Prepare 2000 altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
Preparation technology:
1) it is standby Radix Sophorae Flavescentis total alkaloids, silybin meglumine and Radix Salviae Miltiorrhizae total phenolic acids pulverize separately to be crossed 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with silybin meglumine, Radix Salviae Miltiorrhizae total phenolic acids, Radix Sophorae Flavescentis total alkaloids, 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 8 SKD composition capsules
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Starch 20.0g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5.0g
Prepare 2000 altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
Preparation technology:
1) it is standby Radix Sophorae Flavescentis total alkaloids, silybin meglumine and Radix Salviae Miltiorrhizae total phenolic acids pulverize separately to be crossed 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with silybin meglumine, Radix Salviae Miltiorrhizae total phenolic acids, Radix Sophorae Flavescentis total alkaloids, 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.
The preparation of embodiment 9 SKD composition granules
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Icing Sugar 600.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
Preparation technology:
1) it is standby sucrose to be pulverized 100 mesh sieves.It is standby that Radix Sophorae Flavescentis total alkaloids, silybin meglumine and Radix Salviae Miltiorrhizae total phenolic acids pulverize separately are crossed 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) the method mix homogeneously that Radix Sophorae Flavescentis total alkaloids, silybin meglumine, Radix Salviae Miltiorrhizae total phenolic acids 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 10 SKD composition dripping agent
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Polyethylene glycol 6000 1000g
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
Preparation technology:
Pulverized behind 100 mesh sieves Radix Sophorae Flavescentis total alkaloids, silybin meglumine and Radix Salviae Miltiorrhizae total phenolic acids standby.With polyethylene glycol 6000 heating and melting in water-bath, treat to add Radix Sophorae Flavescentis total alkaloids, silybin meglumine and Radix Salviae Miltiorrhizae total phenolic acids 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 11 SKD composition soft agent
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Soybean oil 300.0g
Soybean phospholipid 40g
Cera Flava 40g
Prepare 2000 altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
Preparation technology:
With the soybean oil of recipe quantity and soybean phospholipid, Cera Flava heating and melting, mixing is put coldly, adds silybin meglumine, Radix Salviae Miltiorrhizae total phenolic acids, Radix Sophorae Flavescentis total alkaloids and grinds well, and is pressed into soft capsule and gets final product.
The preparation of the soft oral fluid agent of embodiment 12 SKD compositionss
Prescription:
Silybin meglumine 100.0g
Radix Sophorae Flavescentis total alkaloids 481.6g (being equivalent to Radix Sophorae Flavescentis 16kg)
Radix Salviae Miltiorrhizae total phenolic acids 301.5g (being equivalent to Radix Salviae Miltiorrhizae 15kg)
Polyoxyethylene sorbitan monoleate 20g
Sodium benzoate 15g
Stevioside 20g
Purified water adds to 10000ml
Prepare 1000 altogether
Annotate: the total content of main effective ingredient is 71.7% in the Chinese medicine total extract.
Preparation technology
1) Radix Sophorae Flavescentis total alkaloids is added in the water of dosing amount 30% the heated and stirred dissolving fully.Radix Salviae Miltiorrhizae total phenolic acids and silybin meglumine are 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 (5)
1. pharmaceutical composition for the treatment of hepatitis, it is characterized in that, said composition is made by following bulk drugs: silybin meglumine, Radix Sophorae Flavescentis total alkaloids and Radix Salviae Miltiorrhizae total phenolic acids, its weight proportion is: 25～400 parts of silybin meglumines, 120～1920 parts of Radix Sophorae Flavescentis total alkaloidss, 30～1800 parts of Radix Salviae Miltiorrhizae total phenolic acidss.
2. pharmaceutical composition as claimed in claim 1, the weight proportion of its crude drug is: 50～200 parts of silybin meglumines, 240～960 parts of Radix Sophorae Flavescentis total alkaloidss, 100～900 parts of Radix Salviae Miltiorrhizae total phenolic acidss.
3. pharmaceutical composition as claimed in claim 2, the weight proportion of its crude drug is: 100 parts of silybin meglumines, 320～800 parts of Radix Sophorae Flavescentis total alkaloidss, 150～450 parts of Radix Salviae Miltiorrhizae total phenolic acidss.
4. as the described arbitrary pharmaceutical composition of claim 1-3, it is characterized in that the total content of matrine and oxymatrine is not less than 50% in the described Radix Sophorae Flavescentis total alkaloids; The content of Radix Salviae Miltiorrhizae total phenolic acids is not less than 30%, and wherein the content of salvianolic acid B is not less than 0.3%.
5. as the described arbitrary pharmaceutical composition of claim 1-3, it is characterized in that said composition can make clinically any or pharmaceutically acceptable dosage form with mixing acceptable accessories.
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| CN2005100454109A CN1977887B (en) | 2005-12-05 | 2005-12-05 | Medicinal composition for treating hepatitis |
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