CN100584348C - Anti-hepatitis medical combination - Google Patents

Anti-hepatitis medical combination Download PDF

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CN100584348C
CN100584348C CN200610043897A CN200610043897A CN100584348C CN 100584348 C CN100584348 C CN 100584348C CN 200610043897 A CN200610043897 A CN 200610043897A CN 200610043897 A CN200610043897 A CN 200610043897A CN 100584348 C CN100584348 C CN 100584348C
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radix rhodiolae
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tiopronin
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CN101062084A (en
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黄振华
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Jiangyin Tianjiang Pharmaceutical Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

Disclosed is a novel pharmaceutical composition for treating liver diseases and process for preparation, wherein the pharmaceutical composition mainly comprises glycyrrhizic acid or its pharmaceutically acceptable salts, tiopronin, kurarinone, one or more of silybin or its derivatives or silymarin, rhodiola rosea or rhodiola rosea, the composition can be prepared into any one of the pharmaceutically acceptable dosage forms, preferably injections and oral preparations.

Description

A kind of pharmaceutical composition of anti-hepatitis
1, technical field
The invention belongs to medical technical field, relate to a kind of pharmaceutical composition of mainly making and preparation method thereof by one or more and Radix Rhodiolae in glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone and silibinin or derivatives thereof or the silymarin or Radix Rhodiolae extract.
2, background technology
Hepatic disease comprises hepatitis, liver cirrhosis, hepatocarcinoma etc. substantially.The viral hepatitis that is caused by hepatitis virus is one of serious infectious disease in the whole world always, commonly encountered diseases of China and frequently-occurring disease especially, 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.
Glycyrrhizic acid is the refining extract of the root and rhizome of glycyrrhizic legume, Glycyrrhiza glabra L., Glycyrrhiza inflata Bat..By the refining glycyrrhizic acid that extracts of Radix Glycyrrhizae the effect of 17-hydroxy-11-dehydrocorticosterone sample is arranged, can improve the concentration of hepatitis patient serum's hydrocortisone, reduce interleukin-6 and tumor necrosis factor in chronic hepatitis patient serum and the periphery mononuclearcell, alleviate the immunopathogenesis reaction, promote liver function recovery, remove symptom, dwindle hepatosplenomegaly, it is fast to fall enzyme, and the jaundice eliminating subcutaneous ulcer is remarkable.Monoammonium glycyrrhizinate and diammonium glycyrrhizinate are respectively the mono-ammonium and the di-ammonium salts of glycyrrhizic acid.Monoammonium glycyrrhizinate has certain auxiliary treatment effect to various acute, chronic hepatitis, hepatic fibrosis, toxic hepatitis, traumatic hepatitis and cancer.Diammonium glycyrrhizinate is the positive oleanane of 20 β-carboxyl-11 oxo-12-alkene-3 β base-2-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid di-ammonium salts, molecular formula C 42H 68N 2O 16, have stronger antiinflammatory, protect liver plasma membrane and improve the effect of liver function, can hinder the deactivation of cortisone and aldosterone, thus the effect of performance steroid sample, but do not have the untoward reaction of 17-hydroxy-11-dehydrocorticosterone.
Tiopronin chemistry N-(2-mercapto radical propionyl group) by name-glycine is a kind of glycine derivative that contains free sulfhydryl groups.Tiopronin has recorded into new drug the 43rd 139 pages of the standards (Chinese Pharmacopoeia Commission's volume) of becoming a full member, and wherein regulation press dry product calculating, contains C 5H 9NO 3S must not be less than 98.0%.The clinical liver function that is used to improve all kinds of acute, chronic hepatitis of tiopronin, the treatment of fatty liver, alcoholic liver, drug induced hepatic injury and the detoxifcation of heavy metal; Tiopronin can reduce the toxic and side effects of chemicotherapy, and can prevent the peripheral leukocytes minimizing of caused by radiotherapy and chemotherapy and the generation of secondary tumor; Early senile cataract and vitreous opacity are had significant therapeutic effect.The tiopronin structural formula is as follows:
Figure C20061004389700031
The tiopronin structural formula
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 recorded into the 16th 363 pages of national drug standards chemical drugs provincial standard rising national standards (Chinese Pharmacopoeia Commission's volume), and wherein regulation contains oxymatrine (C 15H 24N 2O 2) must not be less than 98.0%.Kurarinone has good antivirus action, in recent years the basis and the clinical research of oxymatrine are found, this active component has the effect of good anti-hepatitis virus (HBV) and hepatitis C virus (HCV), its mechanism of action is the generation of the inducing cell inner cell factor such as IFN, IL-2 etc., thereby strengthen the degraded of HBV and HCV gene outcome, its chemical constitution and purine are similar, can disturb the synthetic of HBV and HCV nucleic acid in cell or body.In addition, kurarinone improves multiple pharmacological effect such as hepatocyte function, anti-hepatic fibrosis, adjusting immunity, antiinflammatory, antitumor, removing free radical and radioprotective in addition.The leukopenia that the low leukocyte counts that clinical treatment that is mainly used in chronic viral hepatitis B and tumor radiotherapy, chemotherapy cause and other reasons cause.The structural formula of oxymatrine is as follows:
Figure C20061004389700041
The oxymatrine structural formula
Silibinin is that the processing of feverfew Herba Silybi mariani (Silybum marianum L.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 Herba Silybi mariani 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 Rhodiolae is the dry herb of Crassulaceae Rhodida plant Radix Rhodiolae (R..hodiola Sachalinensis.A.Bor.) or Rhodiola kirilowii (Regel) Maxim. (R.Kirilowii (Regel) Regel[Sedum Ki rilowii Regel]).Be stated from the Four-Volume Medical Code the earliest, be Tibetan's medication commonly used.Effect with strengthening the body resistance, YIN and YANG balance regulating, vigorate qi and replenish the blood, freeing vessels and nourishing heart, nourishing the brain and improving intelligence, nourishing and fit keeping function.Modern pharmacology studies show that, the main effective ingredient Radix Rhodiolae polysaccharide of Radix Rhodiolae has defying age, resisting fatigue, antiviral, anti-hypoxia, immunomodulating, resisting microwave radiation, intervention fibrosis effect and to the dual regulation of blood pressure, blood glucose.
At present, utilize the interaction of one or more and Radix Rhodiolae or Radix Rhodiolae polysaccharide in glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone and silibinin or derivatives thereof or the silymarin, composition of prescription is used to prepare the medicine for the treatment of hepatic disease, does not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs, enlarge medicine variety, better treat hepatic disease, improve patient's quality of life, the invention provides a kind of new pharmaceutical composition and preparation method thereof, this pharmaceutical composition is mainly made by one or more and Radix Rhodiolae in glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone and silibinin or derivatives thereof or the silymarin or Radix Rhodiolae polysaccharide, being used for the treatment of aspects such as hepatitis, hepatic injury, hepatic fibrosis, produced beyond thought effect.
Aforementioned pharmaceutical compositions, the parts by weight of its crude drug are: 4～800 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 20～500 parts of tiopronins, 80～2000 parts of kurarinones, 20～500 parts of silibinin or derivatives thereof or silymarin, 200～5000 parts of Radix Rhodiolaes, be preferably: 10～400 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 50～200 parts of tiopronins, 200～800 parts of kurarinones, 50～200 parts of silibinin or derivatives thereof or silymarin, 500～2000 parts of Radix Rhodiolaes, optimum is: 20～200 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 100 parts of tiopronins, 400 parts of kurarinones, 100 parts of silibinin or derivatives thereof or silymarin, 1000 parts of Radix Rhodiolaes.
The glycyrrhizic acid pharmaceutically acceptable salt can be slaine or organic nitrogen salt, and slaine can be sodium salt, potassium salt, magnesium salt, calcium salt, zinc salt, and organic nitrogen salt can be monoammonium glycyrrhizinate and diammonium glycyrhetate, preferred monoammonium glycyrrhizinate and diammonium glycyrrhizinate.Wherein, the optimum umber of monoammonium glycyrrhizinate is: 40 parts, the optimum umber of diammonium glycyrrhizinate is: 150 parts.The derivant of silibinin is preferably silybin meglumine.
Radix Rhodiolae in the pharmaceutical composition of the present invention can obtain Radix Rhodiolae extract through extracting processing with The suitable solvent and method, Radix Rhodiolae extract again with glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone and silibinin or derivatives thereof or silymarin in one or more and mixing acceptable accessories make arbitrary preparation.Extract solvent preferred water and ethanol, extracting method can be infusion process, seepage method, decocting method, reflux extraction or continuous extraction.The main effective ingredient of Radix Rhodiolae extract is a Radix Rhodiolae polysaccharide, and content of effective is not less than 30%, preferably is not less than 80%.
The invention provides a kind of preferred Radix Rhodiolae extraction process, specific as follows:
Get the Radix Rhodiolae medical material, pulverize, cross 40 mesh sieves, add 8～14 times of water gagings, soak half an hour, put into supersound extraction and irritate, supersound extract 0.5～1h, frequency of oscillation is 20～80kHz, extracts 3～4 times, and merge extractive liquid, filters, and filtrate decompression is condensed into extractum.The water that in extractum, adds 60 ℃～80 ℃ of 30～40 times of amounts, stir, leave standstill, inclining supernatant, be evaporated to and contain the 1g medical material in the 1ml medicinal liquid, adding ethanol is 70%～90% to containing the alcohol amount, leaves standstill 24h, filters, collecting precipitation, with the water dissolution of precipitation with 20～30 times of amounts, heat when under agitation dripping 1% tannic acid, boil the centrifugal disgorging in back, continue to add tannic acid to solution and do not produce muddiness, add ethanol again to containing the alcohol amount, leave standstill 24h, filter to 80%, collecting precipitation, precipitation with the dehydrated alcohol cyclic washing repeatedly is dissolved in water again, is 10000～20000 ultrafilter membrane ultrafiltration with molecular cut off, collect and do not pass through liquid, concentrating under reduced pressure, drying promptly gets Radix Rhodiolae polysaccharide.
The yield of the Radix Rhodiolae extract by this prepared is 1.8～2.5%, and the content of polysaccharide is not less than 80% in the Radix Rhodiolae extract.
Method one: get the Radix Rhodiolae medical material, pulverize, put in the flask, this flask is put into MCL-3 type continuous microwave reactor, and adjustment power is 560W, extracting in water three times, add 6～8 times of amounts of water at every turn, reacted sucking filtration 20 minutes～1 hour, merging filtrate, filtrate water-bath are concentrated into 1/3 o'clock of original volume, add defat with petroleum ether, water liquid adds 0.1% activated carbon decolorizing, filters, and filtrate adds ethanol to be made and contain the alcohol amount and reach 80%, standing over night, filter, filtering residue acetone cyclic washing adds the water heating for dissolving after volatilizing solvent, heat when under agitation dripping 1% tannic acid, boil the centrifugal disgorging in back, continue to add tannic acid to solution and do not produce muddiness, add ethanol again and make and contain alcohol amount and reach 80%, standing over night, filter, filtering residue with absolute ethanol washing repeatedly volatilizes solvent, vacuum drying gets Radix Rhodiolae polysaccharide.
The yield of the Radix Rhodiolae extract by this prepared is 2～3%, and the content of polysaccharide is not less than 50% in the Radix Rhodiolae extract.
Radix Rhodiolae can also extract preparation by the following method, but be not limited only to following method except that adopting the said method extraction:
Method two: get the Radix Rhodiolae medical material and put in the flask, this flask is put into MCL-3 type continuous microwave reactor, use 250ml petroleum ether (60～90 ℃), ether and 80% alcohol reflux successively, adjustment power is 400W, response time is 20min, extracting solution discards, and after medicinal residues volatilize solvent, puts into MCL-3 type continuous microwave reactor again, extracting in water three times, add 8 times of water gagings at every turn, extract 20min, adjustment power is 560W.Be evaporated to half volume, add 0.1% active carbon, decolouring, filter, it is 80% to containing the alcohol amount that filtrate adds ethanol, standing over night, filter, filtering residue adds the water heating for dissolving again with dehydrated alcohol, acetone cyclic washing, leave standstill, the centrifugal precipitation of going, it is 80% to containing the alcohol amount that supernatant adds ethanol again, standing over night is filtered filtering residue dehydrated alcohol cyclic washing, volatilize ethanol, 60 ℃ of oven dry get Radix Rhodiolae polysaccharide.
The yield of the Radix Rhodiolae extract by this prepared is 2.5～3.5%, and the content of polysaccharide is not less than 30% in the Radix Rhodiolae extract.
Pharmaceutical composition of the present invention can also be with glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone, the preparation that directly feeds intake of in silibinin or derivatives thereof or the silymarin one or more and Radix Rhodiolae polysaccharide, calculate with respect to the yield of medical material according to extract, the raw material medicines in portions by weight number of pharmaceutical composition of the present invention is: 4～800 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 20～500 parts of tiopronins, 80～2000 parts of kurarinones, 20～500 parts of silibinin or derivatives thereof or silymarin, 1～100 part of Radix Rhodiolae polysaccharide, be preferably: 10～400 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 50～200 parts of tiopronins, 200～800 parts of kurarinones, 50～200 parts of silibinin or derivatives thereof or silymarin, 10～50 parts of Radix Rhodiolae polysaccharides, optimum is: 20～200 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 100 parts of tiopronins, 400 parts of kurarinones, 100 parts of silibinin or derivatives thereof or silymarin, 18～25 parts of Radix Rhodiolae polysaccharides.
In the crude drug of aforementioned pharmaceutical compositions in the Radix Rhodiolae polysaccharide content of polysaccharide be not less than 30%, preferably be not less than 80%.
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 weight proportion between each composition is constant.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.
Multiple pharmacologically actives such as pharmaceutical composition of the present invention has antiviral, improves hepatocyte function, anti-hepatic fibrosis, adjusting immunity, antiinflammatory, removing free radical can be used for the treatment of various hepatic disease: comprise the liver injury that viral, drug toxicity, ethanol toxicity (comprising alcoholic fatty liver, alcoholic fibrosis, alcoholic cirrhosis, acute alcoholic hepatitis) and other chemical substance toxicity cause.
Pharmaceutical composition of the present invention can add one or more pharmaceutically acceptable carriers, is applied to the patient of this treatment of needs in the mode of oral or parenteral.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 pharmaceutical composition of the present invention is injection and 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 is when making oral formulations, and selectable filler has: starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Selectable binding agent has: sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, pregelatinized Starch etc.; Selectable disintegrating agent has: dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Selectable lubricant has: magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
Pharmaceutical composition of the present invention in order to increase its dissolubility, can add cosolvents such as polyoxyethylene sorbitan monoleate 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 glucose.Can add excipient in the powder pin, for example, mannitol, glucose, lactose, dextran, sorbitol, sucrose, glycine, sodium chloride etc.
The present composition has the following advantages:
(1) provides a kind of one or more and Radix Rhodiolae or its extract compatibility by in glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone, silibinin or derivatives thereof or the silymarin first, be used for the treatment of pharmaceutical composition of hepatic disease and preparation method thereof, satisfied urgent clinical needs;
(2) first the interaction and the composition of prescription of pharmaceutical composition of the present invention carried out pharmacology pharmacodynamic research, find present composition Abensanil, carbon tetrachloride, the mouse liver injury that D-Gal causes has protective effect, anti-dhbv dna effect is arranged, and raising immunity, and pharmaceutical composition of the present invention and single with glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone, silibinin or derivatives thereof or silymarin are compared, significant difference is all remarkable, show Radix Rhodiolae or its extract and glycyrrhizic acid or its pharmaceutically acceptable salt, tiopronin, kurarinone, silibinin or derivatives thereof or silymarin share the treatment hepatic disease, Synergistic, effect is remarkable, and consequently those skilled in the art institute is beyond thought;
(3) each preparation process thereof of pharmaceutical composition of the present invention is simple, and drug quality is uniform and stable;
(4) stability experiment that carries out shows that the every index of medicine composition injection of the present invention is all more stable, has guaranteed safety of clinical administration;
(5) pharmaceutical composition drug combination determined curative effect of the present invention, and reduced relative dosage, be with a wide range of applications.
Below routine by experiment beneficial effect of further setting forth pharmaceutical composition of the present invention.In the following experimental example: the compositions of Radix Rhodiolae or Radix Rhodiolae polysaccharide and monoammonium glycyrrhizinate or diammonium glycyrrhizinate hereinafter to be referred as The HG compositionsThe compositions of Radix Rhodiolae or Radix Rhodiolae polysaccharide and tiopronin hereinafter to be referred as The HL compositionsThe compositions of Radix Rhodiolae or Radix Rhodiolae polysaccharide and kurarinone hereinafter to be referred as The HK compositions;The compositions of Radix Rhodiolae or Radix Rhodiolae polysaccharide and silibinin hereinafter to be referred as The HS compositionsRadix Rhodiolae polysaccharide used in the experimental example is all taken from embodiment 1.
The protective effect of experimental example 1 HG, HL, HK, the hepatic injury of HS compositions Abensanil induced mice
Test sample: blank group: 0.9% normal saline, self-control;
Diammonium glycyrrhizinate group: diammonium glycyrrhizinate injection, specification: 10ml:150mg, self-control;
Tiopronin group: tiopronin injection, 2ml:0.1g, the wide pharmaceutical Co. Ltd in Shenyang;
Kurarinone group: Matrine Injection, 2ml:0.2g, Tianjin Biochemical Pharmaceutical Factory;
Silybin meglumine group: silybin meglumine injection, 2ml:100mg, self-control;
HG injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 1 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HL injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 2 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HK injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 3 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HS injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 4 among the embodiment 3) is divided into basic, normal, high three dosage groups.
Laboratory animal: ICR mice, body weight 18～25g, male and female half and half.
Experimental technique: get 190 of mices, be divided into 19 groups of blank groups, model group, Radix Rhodiolae polysaccharide group, diammonium glycyrrhizinate group, tiopronin group, kurarinone group, silybin meglumine group, HG, HL, HK, each dosage group of HS compositions at random, 10 every group.Blank group and model group tail vein injection saline every day 20ml/kg, 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 be tail vein injection 6h pneumoretroperitoneum injection with acetaminophen 300mg/kg the last time, 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.
Experimental result: see Table 1.
(1) compare with the blank group, the active of model group ALT and LPO significantly raises, and difference is (p＜0.01) extremely significantly, and the modeling success is described.
(2) compare with model group; active obviously reduce (p＜0.05) of diammonium glycyrrhizinate group, tiopronin group, kurarinone group and silybin meglumine group ALT and LPO; active significantly reduce (p＜0.01) of HG, HL, HK, each dosage group ALT of HS compositions and LPO illustrates that the hepatic injury of the equal Abensanil induced mice of each administration group has protective effect.
(3) compare with the Radix Rhodiolae polysaccharide group, the activity of HG, HL, HK, each dosage group ALT of HS compositions and LPO all significantly reduces (p＜0.01).
(4) compare with the diammonium glycyrrhizinate group, the activity of each dosage group ALT of HG compositions and LPO all significantly reduces (p＜0.01).
(5) compare with the tiopronin group, the activity of each dosage group ALT of HL compositions and LPO all significantly reduces (p＜0.01).
(6) compare active obviously reduce (p＜0.05) of HK compositions low dose group ALT and LPO, active significantly reduce (p＜0.01) of HK combination object height, middle dosage group ALT and LPO with the kurarinone group.
(7) compare with the silybin meglumine group, the activity of HS compositions high, medium and low dosage group ALT and LPO all significantly reduces (p＜0.01).
Conclusion: compare with diammonium glycyrrhizinate, tiopronin, kurarinone or silybin meglumine with single, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used, and all can significantly reduce the activity of ALT and LPO.And effect is relevant with dosage, the high dose group best results.Prompting, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used, and enhancing human body immunity power is repelled abnormal cell, treating both the principal and secondary aspects of a disease, Synergistic.
The influence of table 1HG, HL, HK, HS compositions Abensanil damage murine liver tissue ALT and LPO
Figure C20061004389700091
Annotate: compare with the blank group, ﹠amp; ﹠amp;P＜0.01; Compare with model group, *P＜0.05, *P＜0.01; Compare with the Radix Rhodiolae polysaccharide group, P＜0.01; Compare with the diammonium glycyrrhizinate group, $P＜0.05, $$P＜0.01; Compare with the tiopronin group, #P＜0.05, ##P＜0.01; Compare with the kurarinone group, %P＜0.05, %%P＜0.01; Compare with the silybin meglumine group, △P＜0.05, △ △P＜0.01.
Experimental example 2HG, HL, HK, HS compositions are to carbon tetrachloride (CCl 4 ) cause the protective effect of chmice acute hepatic injury
Test sample: chemical pure CCl 4, Chengdu associating chemical reagent institute;
Blank group: 0.9% normal saline, self-control;
Diammonium glycyrrhizinate group: diammonium glycyrrhizinate injection, specification: 10ml:150mg, self-control;
Tiopronin group: tiopronin injection, 2ml:0.1g, the wide pharmaceutical Co. Ltd in Shenyang;
Kurarinone group: Matrine Injection, 2ml:0.2g, Tianjin Biochemical Pharmaceutical Factory;
Silybin meglumine group: silybin meglumine injection, 2ml:100mg, self-control;
HG injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 1 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HL injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 2 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HK injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 3 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HS injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 4 among the embodiment 3) is divided into basic, normal, high three dosage groups.
Laboratory animal: ICR mice, body weight 22～27g, male and female half and half.
Experimental technique: get 190 of mices, be divided into 19 groups at random, be respectively blank group, model group, Radix Rhodiolae polysaccharide group, diammonium glycyrrhizinate group, tiopronin group, kurarinone group, silybin meglumine group, HG, HL, HK, each dosage group of HS compositions, 10 every group.Blank group and model group tail vein injection saline every day 20ml/kg, 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 2.
Table 2HG, HL, HK, HS compositions are to CCl 4Due to the influence of acute liver damage Mouse Liver, spleen index and Serum ALT, AST content
Annotate: compare with the blank group, $P＜0.05, $$P＜0.01; Compare with model group, *P＜0.05, *P＜0.01; Compare with the Radix Rhodiolae polysaccharide group, P＜0.01; Compare with the diammonium glycyrrhizinate group, ﹠amp;P＜0.05, ﹠amp; ﹠amp;P＜0.01; Compare with the tiopronin group, #P＜0.05, ##P＜0.01; Compare with the kurarinone group, %P＜0.05, %%P＜0.01; Compare with the silybin meglumine group, △ △P＜0.01.
Experimental result: see Table 2.
(1) compares CCl with the blank group 4Model group Mouse Liver index, spleen index all obviously increase (p＜0.05), CCl 4Model group mice serum ALT, AST value all significantly increase (p＜0.01), and injected in mice CCl is described 4Hepar damnification behind the peanut oil solution, the modeling success.
(2) compare with model group; diammonium glycyrrhizinate group, tiopronin group, kurarinone group, silybin meglumine group Mouse Liver index, spleen index, ALT, AST value all obviously reduce (p＜0.05); HG, HL, HK, each dosage group Mouse Liver index of HS compositions, spleen index, ALT, AST value significantly reduce (p＜0.01), illustrate that each medicine all has protective effect to acute liver damage due to the CCl4.
(3) compare with the Radix Rhodiolae polysaccharide group, HG, HL, HK, each dosage group Mouse Liver index of HS compositions, spleen index obviously reduce (p＜0.05), and ALT, AST value significantly reduce (p＜0.01).
(4) compare with the diammonium glycyrrhizinate group, HG compositions low dose group Mouse Liver index, spleen index, ALT, AST value obviously reduce (p＜0.05), and HG combination object height, middle dosage group Mouse Liver index, spleen index, ALT, AST value significantly reduce (p＜0.01).
(5) compare with the tiopronin group, HL compositions low dose group Mouse Liver index, spleen index, ALT, AST value obviously reduce (p＜0.05), and HL combination object height, middle dosage group Mouse Liver index, spleen index, ALT, AST value significantly reduce (p＜0.01).
(6) compare with the kurarinone group, HK compositions low dose group Mouse Liver index, spleen index, ALT, AST value obviously reduce (p＜0.05), and HK combination object height, middle dosage group Mouse Liver index, spleen index, ALT, AST value significantly reduce (p＜0.01).
(7) compare with the silybin meglumine group, each dosage group Mouse Liver index of HS compositions, spleen index, ALT, AST value all significantly reduce (p＜0.01).
Conclusion: compare with diammonium glycyrrhizinate, tiopronin, kurarinone or silybin meglumine with single, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used, and all can significantly reduce Mouse Liver index, spleen index, ALT, AST value.And effect is relevant with dosage, the high dose group best results.Prompting, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used treating both the principal and secondary aspects of a disease, Synergistic.
Experimental example 3HG, HL, HK, HS compositions cause the protective effect of chmice acute hepatic injury to D-Gal
Test sample: blank group: 0.9% normal saline, self-control;
Diammonium glycyrrhizinate group: diammonium glycyrrhizinate injection, specification: 10ml:150mg, self-control;
Tiopronin group: tiopronin injection, 2ml:0.1g, the wide pharmaceutical Co. Ltd in Shenyang;
Kurarinone group: Matrine Injection, 2ml:0.2g, Tianjin Biochemical Pharmaceutical Factory;
Silybin meglumine group: silybin meglumine injection, 2ml:100mg, self-control;
HG injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 1 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HL injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 2 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HK injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 3 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HS injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 4 among the embodiment 3) is divided into basic, normal, high three dosage groups.
Laboratory animal: ICR mice, body weight 20～25g, male and female half and half.
Experimental technique: get 190 of mices, be divided into 19 groups at random, be respectively blank group, model group, Radix Rhodiolae polysaccharide group, diammonium glycyrrhizinate group, tiopronin group, kurarinone group, silybin meglumine group, HG, HL, HK, each dosage group of HS compositions, 10 every group.Blank group and model group tail vein injection saline every day 20ml/kg, 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 3.
Table 3HG, HL, HK, HS compositions cause the acute liver damage mice to D-Gal
The influence of serum AST, ALB content and clotting time (CT)
Figure C20061004389700121
Annotate: compare with the blank group, ◇ ◇P＜0.01, ◇ ◇ ◇P＜0.001; Compare with model group, *P＜0.05, *P＜0.01; Compare with the Radix Rhodiolae polysaccharide group, P＜0.01; Compare with the diammonium glycyrrhizinate group, ﹠amp;P＜0.05, ﹠amp; ﹠amp;P＜0.01; Compare with the tiopronin group, #P＜0.05, ##P＜0.01; Compare with the kurarinone group, %P＜0.05, %%P＜0.01; Compare with the silybin meglumine group, △ △P＜0.01.
Experimental result: see Table 3.
(1) compare with the blank group, the activity of model group glutamic oxaloacetic transaminase, GOT (AST) extremely significantly raises (p＜0.001), and serum albumin (ALB) quantity significantly reduces (p＜0.01), and clotting time (CT) utmost point significant prolongation (p＜0.001) illustrates that modeling is reliable.
(2) compare with model group; the diammonium glycyrrhizinate group; the tiopronin group; the kurarinone group; active obviously reduce (p＜0.05) of silybin meglumine group glutamic oxaloacetic transaminase, GOT (AST); serum albumin (ALB) quantity obviously increases (p＜0.05); clotting time (CT) obviously shortens (p＜0.05); active significantly reduce (p＜0.01) of each dosage group glutamic oxaloacetic transaminase, GOT (AST) of each compositions; serum albumin (ALB) quantity significantly increases (p＜0.01); clotting time (CT) significantly shortens (p＜0.01); illustrate that each medicine all has hepatoprotective effect, hepatic injury has protective effect to the D-Gal induced mice.
(3) compare with the Radix Rhodiolae polysaccharide group, active significantly reduce (p＜0.01) of HG, HL, HK, each dosage group mice glutamic oxaloacetic transaminase, GOT (AST) of HS compositions, serum albumin (ALB) quantity significantly increases (p＜0.01), and clotting time (CT) significantly shortens (p＜0.01).
(4) compare with the diammonium glycyrrhizinate group, active obviously reduce (p＜0.05) of HG compositions low dose group mice glutamic oxaloacetic transaminase, GOT (AST), serum albumin (ALB) quantity obviously increases (p＜0.05), active significantly reduce (p＜0.01) of HG combination object height, middle dosage group mice glutamic oxaloacetic transaminase, GOT (AST), serum albumin (ALB) quantity significantly increases (p＜0.01), in the HG compositions, low dose group clotting time of mice (CT) obviously shortens (p＜0.05), HG compositions high dose group clotting time of mice (CT) significantly shortens (p＜0.01).
(5) compare with the tiopronin group, the activity of each dosage group glutamic oxaloacetic transaminase, GOT (AST) of HL compositions all significantly reduces (p＜0.01), HL combination object height, middle dosage group mice serum albumin (ALB) quantity significantly increase (p＜0.01), clotting time (CT) significantly shortens (p＜0.01), HL compositions low dose group mice serum albumin (ALB) quantity obviously increases (p＜0.05), and clotting time (CT) obviously shortens (p＜0.05).
(6) compare with the kurarinone group, active obviously reduce (p＜0.05) of HK compositions low dose group mice glutamic oxaloacetic transaminase, GOT (AST), active significantly reduce (p＜0.01) of HK combination object height, middle dosage group mice glutamic oxaloacetic transaminase, GOT (AST), serum albumin (ALB) quantity of each dosage group mice of HK compositions all significantly increases (p＜0.01), and clotting time (CT) all significantly shortens (p＜0.01).
(7) compare with the silybin meglumine group, the activity of each dosage group mice glutamic oxaloacetic transaminase, GOT (AST) of HS compositions all significantly reduces (p＜0.01), serum albumin (ALB) quantity all significantly increases (p＜0.01), and clotting time (CT) all significantly shortens (p＜0.01).
Conclusion: compare with diammonium glycyrrhizinate, tiopronin, kurarinone or silybin meglumine with single, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used, all can significantly reduce the activity of mice glutamic oxaloacetic transaminase, GOT (AST), significantly increase the quantity of serum albumin (ALB), significantly shorten clotting time (CT).And effect is relevant with dosage, the high dose group best results.Prompting, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used, treating both the principal and secondary aspects of a disease, Synergistic has better hepatoprotective effect.
Experimental example 4HG, HL, HK, the anti-dhbv dna effect of HS compositions
Test sample: blank group: 0.9% normal saline, self-control;
The injection acyclovir, 0.25g, Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group;
Diammonium glycyrrhizinate group: diammonium glycyrrhizinate injection, specification: 10ml:150mg, self-control;
Tiopronin group: tiopronin injection, 2ml:0.1g, the wide pharmaceutical Co. Ltd in Shenyang;
Kurarinone group: Matrine Injection, 2ml:0.2g, Tianjin Biochemical Pharmaceutical Factory;
Silybin meglumine group: silybin meglumine injection, 2ml:100mg, self-control;
HG injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 1 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HL injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 2 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HK injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 3 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HS injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 4 among the embodiment 3) is divided into basic, normal, high three dosage groups.
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 114 of the positive ducks that infect successfully, be divided into 19 groups at random, be respectively blank group, model group, Radix Rhodiolae polysaccharide group, diammonium glycyrrhizinate group, tiopronin group, kurarinone group, silybin meglumine group, HG, HL, HK, each dosage group of HS compositions, 6 every group.Blank group intraperitoneal injection of saline every day 20ml/kg, every day 2 times, 14d continuously; Administration group intraperitoneal injection, every day 2 times, dosage sees the following form, continuously 14d.Positive drug is as the treatment matched group, and (ACV) presses the 100mg/kg lumbar injection with acyclovir, and 2 times/d, 2 weeks of administration.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-DNA Dot Blot method, with hybridization spot absorbance (A) as specimen DHBV-DNA level value.The results are shown in Table 4.
Table 4HG, HL, HK, HS compositions are to the inhibitory action of DHBV-DNA
Figure C20061004389700141
Annotate: compare with the blank group, *P＜0.05, *P＜0.01; Compare with the Radix Rhodiolae polysaccharide group, P＜0.01; Compare with the diammonium glycyrrhizinate group, ﹠amp;P＜0.05; Compare with the tiopronin group, #P＜0.05; Compare with the kurarinone group, %P＜0.05; Compare with the silybin meglumine group, △P＜0.05.
Experimental result: see Table 4.
(1) compare with the blank group, positive control (acyclovir) the group DHBV-DNA titre of the 7th day and the 14th day after administration all significantly reduces (p＜0.01), but significantly rising again after the drug withdrawal does not have significance (p＞0.05) with comparing difference before the administration; Diammonium glycyrrhizinate group, tiopronin group, kurarinone group, the silybin meglumine group DHBV-DNA titre of the 7th day and the 14th day after administration all has obvious reduction (p＜0.05), still has notable difference after the drug withdrawal with before the administration, no rebound phenomenon; The DHBV-DNA titre of HG, HL, each dosage group of each compositions of HK, HS the 7th day and the 14th day after administration all significantly reduces (p＜0.01), after the drug withdrawal with still there were significant differences before the administration, no rebound phenomenon
(2) compare with the Radix Rhodiolae polysaccharide group, HG, HL, HK, each dosage group of HS compositions DHBV-DNA titre of 7 days after the 7th day and the 14th day after the administration and drug withdrawal all significantly reduces (p＜0.01).
(3) compare with the diammonium glycyrrhizinate group, each dosage group of HG compositions DHBV-DNA titre of 7 days after the 7th day and the 14th day after the administration and drug withdrawal all obviously reduces (p＜0.05).
(4) compare with the tiopronin group, each dosage group of HL compositions DHBV-DNA titre of 7 days after the 7th day and the 14th day after the administration and drug withdrawal all obviously reduces (p＜0.05).
(5) compare with the kurarinone group, each dosage group of HK compositions DHBV-DNA titre of 7 days after the 7th day and the 14th day after the administration and drug withdrawal all obviously reduces (p＜0.05).
(6) compare with the silybin meglumine group, each dosage group of HS compositions DHBV-DNA titre of 7 days after the 7th day and the 14th day after the administration and drug withdrawal all obviously reduces (p＜0.05).
Conclusion: experimental result shows that pharmaceutical composition of the present invention has tangible anti-dhbv dna effect, and does not have rebound phenomenon.Compare with diammonium glycyrrhizinate, tiopronin, kurarinone or silybin meglumine with single, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used, the DHBV-DNA titre all obviously reduces, show that forming compositions uses, treating both the principal and secondary aspects of a disease, Synergistic has better therapeutic effect.
The immunocompetence of experimental example 5HG, HL, HK, HS compositions
Test sample and material:
The blank group: 0.9% normal saline solution, commercial;
Diammonium glycyrrhizinate group: diammonium glycyrrhizinate injection, specification: 10ml:150mg, self-control;
Tiopronin group: tiopronin injection, 2ml:0.1g, the wide pharmaceutical Co. Ltd in Shenyang;
Kurarinone group: Matrine Injection, 2ml:0.2g, Tianjin Biochemical Pharmaceutical Factory;
Silybin meglumine group: silybin meglumine injection, 2ml:100mg, self-control;
HG injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 1 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HL injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 2 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HK injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 3 among the embodiment 3) is divided into basic, normal, high three dosage groups;
HS injection group: self-control (prescription and preparation method are referring to aqueous injection prescription 4 among the embodiment 3) is divided into basic, normal, high three dosage groups.
Laboratory animal grouping: 180 of Kunming kind children Mus, the male and female dual-purpose, body weight 11g～15g, be divided into 18 groups at random, be respectively blank group, Radix Rhodiolae polysaccharide group, diammonium glycyrrhizinate group, tiopronin group, kurarinone group, silybin meglumine group, HG, HL, HK, each dosage group of HS compositions, 10 every group.
Experimental technique: each experimental group children Mus is the lumbar injection relative medicine respectively, and all dosage only all are configured to 0.3ml/, matched group lumbar injection equivalent normal saline, administration 7d, every day 1 time.Behind last administration 24h, pluck the eyeball sacrificed by exsanguination, weigh and thymus, spleen weight, calculate thymus or spleen index, heavy (the mg)/body weight (g) of thymus or spleen index=thymus or spleen the results are shown in Table 5.
Experimental result: see Table 5.
(1) compare with the blank group, the Radix Rhodiolae polysaccharide group can obviously increase thymus and the spleen weight (p＜0.05) of young Mus; HG, HL, each dosage group of each compositions of HK, HS all can significantly increase thymus and the spleen weight (p＜0.05, p＜0.01) of young Mus.
(2) compare with the Radix Rhodiolae polysaccharide group, HG, HL, each dosage group of each compositions of HK, HS all can significantly increase thymus and the spleen weight (p＜0.05, p＜0.01) of young Mus.
(3) compare with the diammonium glycyrrhizinate group, each dosage group of HG compositions all can significantly increase thymus and the spleen weight (p＜0.05, p＜0.01) of young Mus.
(4) compare with the tiopronin group, each dosage group of HL compositions all can significantly increase thymus and the spleen weight (p＜0.05, p＜0.01) of young Mus.
(5) compare with the kurarinone group, each dosage group of HK compositions all can significantly increase thymus and the spleen weight (p＜0.05, p＜0.01) of young Mus.
(6) compare with the silybin meglumine group, each dosage group of HS compositions all can significantly increase thymus and the spleen weight (p＜0.05, p＜0.01) of young Mus.
Each group of table 5 to mouse immune organ weight's influence (x ± s, n=10)
Figure C20061004389700161
Annotate: compare with the blank group, *P＜0.05, *P＜0.01; Compare with the Radix Rhodiolae polysaccharide group, P＜0.05, P＜0.01; Compare with the diammonium glycyrrhizinate group, ﹠amp;P＜0.05, ﹠amp; ﹠amp;P＜0.01; Compare with the tiopronin group, #P＜0.05, ##P＜0.01; Compare with the kurarinone group, %P＜0.05, %%P＜0.01; Compare with the silybin meglumine group, △P＜0.05, △ △P＜0.01.
Conclusion: experimental result shows, compare with diammonium glycyrrhizinate, tiopronin, kurarinone or silybin meglumine with single, any compatibility in Radix Rhodiolae or Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate, tiopronin, kurarinone or the silybin meglumine is used, thymus and the spleen weight of children Mus all significantly increase, and the property of comparing with the Radix Rhodiolae polysaccharide group that there were significant differences shows that forming compositions uses synergistic function is arranged.
Experimental example 6HG, HL, HK, HS composite injection stability experiment
Test sample: HG injection: self-control (prescription and preparation method are referring to aqueous injection prescription 1 among the embodiment 3);
HL injection: self-control (prescription and preparation method are referring to aqueous injection prescription 2 among the embodiment 3);
HK injection: self-control (prescription and preparation method are referring to aqueous injection prescription 3 among the embodiment 3);
HS injection: self-control (prescription and preparation method are referring to aqueous injection prescription 4 among the embodiment 3).
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 this product 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.Radix Rhodiolae polysaccharide used among the embodiment 2～8 is all taken from embodiment 1.
The preparation of embodiment 1 fine Herba hylotelephii erythrosticti polysaccharide
Get the Radix Rhodiolae medical material, pulverize, cross 40 mesh sieves, add 10 times of water gagings, soak half an hour, put into supersound extraction and irritate, supersound extract 40min, frequency of oscillation is 60kHz, extracts 3 times, and merge extractive liquid, filters, and filtrate decompression is condensed into extractum.In extractum, add the water of 60 ℃ of 30 times of amounts, stir, leave standstill, inclining supernatant, is evaporated to contain the 1g medical material in the 1ml medicinal liquid, and adding ethanol is 80% to containing the alcohol amount, leave standstill 24h, filter collecting precipitation, precipitation is added the water dissolution of 30 times of amounts, under agitation drip 1% tannic acid, heat, boil the centrifugal disgorging in back, continue to add tannic acid to solution and do not produce muddiness, adding ethanol again is 80% to containing the alcohol amount, leave standstill 24h, filter, collecting precipitation, precipitation is with the dehydrated alcohol cyclic washing repeatedly, be dissolved in water again, with molecular cut off is 10000～20000 ultrafilter membrane ultrafiltration, collects by liquid concentrating under reduced pressure, drying promptly gets Radix Rhodiolae polysaccharide.
The discriminating of Radix Rhodiolae polysaccharide:
The preparation of reference substance solution: precision takes by weighing the D-glucose, D-fructose reference substance is an amount of, adds 70% ethanol and is settled to 5ml, and the concentration that makes the D-glucose is 10mg/ml, and the concentration of D-fructose is 20mg/ml.
The preparation of need testing solution: get Radix Rhodiolae polysaccharide 5mg, add the 5ml water dissolution, add purified treatment in the D101 macroporous resin column, use the distilled water eluting, collect water elution liquid 20ml, water bath method is settled to 5ml with 70% dissolve with ethanol.
Above-mentioned two kinds of solution are put respectively in same silica gel G-0.3mol/L NaH 2PO 4The 3%CMC-Na plate on, with n-butyl alcohol-acetone-water (10: 10: 2.5) or n-butyl alcohol-methanol-acetone-water (10: 4: 8: 2.5) saturated 30min, launch, take out, spray aniline-phthalic acid-n-butyl alcohol reagent behind the airing, in 105 ℃ of baking 10min.In the chromatograph, with the corresponding position of reference substance on, show the speckle of same color.
The assay of Radix Rhodiolae polysaccharide:
The preparation of standard curve: precision takes by weighing the about 50mg of D-glucose reference substance (105 ℃ are dried to constant weight), puts in the 100ml volumetric flask, and the adding distil water dissolving also is diluted to scale.
Accurate above-mentioned solution 1.0,2.0,3.0,4.0 and the 5.0ml of drawing places the 50ml volumetric flask respectively, adds water to scale and shakes up.Above-mentioned each each 2.0ml of concentration solution of accurate absorption, accurate in addition absorption distilled water 2ml puts in the tool plug test tube as blank, adds 5% phenol solution 1.0ml mixing respectively, add concentrated sulphuric acid 5.0ml rapidly, shake up the back and place 5min, put and heat 15min in the boiling water bath, put then and cool off 30min in the psychrolusia, measure trap at wavelength 510nm place, with concentration is abscissa, and trap is a vertical coordinate, paints standard curve.
The preparation of test sample: precision takes by weighing 105 ℃ of Radix Rhodiolae polysaccharide 50mg that are dried to constant weight, and totally 3 parts, put heating for dissolving in the small beaker, move in the 1000ml measuring bottle, add water to scale, shake up, promptly.
Measure: accurate above-mentioned 3 kinds of each 2ml of need testing solution of absorption, press standard curve from " accurate above-mentioned each each 2.0ml of concentration solution of absorption " method operation afterwards, measure trap, bring in the standard curve, reading, promptly.
Prepare three batches of Radix Rhodiolae polysaccharides according to the method described above, polyoses content and yield see Table 6.As can be seen from the results, the yield of the Radix Rhodiolae polysaccharide that obtains by this technology is 1.8～2.5%, and the content of Radix Rhodiolae polysaccharide is not less than 80%.
The assay result and the yield of table 6 Radix Rhodiolae extract
Figure C20061004389700181
The preparation of embodiment 2HG, HL, HK, HS composition powder injection
1, prescription:
Prescription 1:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Monoammonium glycyrrhizinate 40g
Polyoxyethylene sorbitan monoleate 35g
Mannitol 300g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 2:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Tiopronin 100g
Polyoxyethylene sorbitan monoleate 35g
Mannitol 300g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 3:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Kurarinone 400g
Polyoxyethylene sorbitan monoleate 35g
Mannitol 300g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 4:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Silybin meglumine 100g
Polyoxyethylene sorbitan monoleate 35g
Mannitol 300g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
2, concrete steps:
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) get the sterile water for injection of dosing amount 60%, Radix Rhodiolae polysaccharide and mannitol are added the heated and stirred dissolving fully, the polyoxyethylene sorbitan monoleate heated and stirred of getting the sterile water for injection adding recipe quantity of dosing amount 20% is dissolved fully, it is complete to add monoammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine stirring and dissolving again, two solution mix homogeneously are added 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 0.22 μ m.
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-40 ℃ 3 hours, low-temperature vacuum drying-40 ℃～0 ℃ 35 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 3HG, HL, HK, HS compositions aqueous injection
1, prescription:
Prescription 1:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Diammonium glycyrrhizinate 150g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 2:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Tiopronin 100g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 3:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Kurarinone 400g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 4:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Silybin meglumine 100g
Water for injection adds to 5000ml
Prepare 1000 altogether
2, concrete steps:
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) get the water for injection of dosing amount 60%, add the Radix Rhodiolae polysaccharide and the diammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine stirring and dissolving of recipe quantity, 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 0.45 μ m.
6) clarity of inspection solution, the inspection of semifinished product.
7) with liquid medicine filling, sealing by fusing in glass ampule.
8) 100 ℃ of flowing steam sterilizations are 30 minutes.
9) while hot sample being put into 0.01% methylene blue solution hunts leak.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 4HG, HL, HK, the transfusion of HS compositions sodium chloride
1, prescription:
Prescription 1:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Monoammonium glycyrrhizinate 40g
Polyoxyethylene sorbitan monoleate 100g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Tiopronin 100g
Polyoxyethylene sorbitan monoleate 100g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Kurarinone 400g
Polyoxyethylene sorbitan monoleate 100g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 4:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Silybin meglumine 100g
Polyoxyethylene sorbitan monoleate 100g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
2, concrete steps:
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) polyoxyethylene sorbitan monoleate is made into 20% solution with water for injection, Radix Rhodiolae polysaccharide and monoammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine is added heated and stirred make dissolving fully, with the water for injection dissolving of dosing amount 30% fully sodium chloride.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 0.45 μ m.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) fill is in corresponding volumetrical infusion bottle.
8) 115 ℃ of pressure sterilizings are 30 minutes.
9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5HG, HL, HK, HS compositions glucose infusion liquid
1, prescription:
Prescription 1:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Diammonium glycyrrhizinate 150g
Polyoxyethylene sorbitan monoleate 100g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Tiopronin 100g
Polyoxyethylene sorbitan monoleate 100g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Kurarinone 400g
Polyoxyethylene sorbitan monoleate 100g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 4:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Silybin meglumine 100g
Polyoxyethylene sorbitan monoleate 100g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
2, concrete steps:
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) polyoxyethylene sorbitan monoleate is made into 20% solution with water for injection, Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine are added the heated and stirred dissolving fully, with the water for injection dissolving of dosing amount 30% fully glucose.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 0.45 μ m.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) fill is in corresponding volumetrical infusion bottle.
8) 115 ℃ of pressure sterilizings are 30 minutes.
9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6HG, HL, HK, HS composition tablet
1, prescription:
Prescription 1:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Diammonium glycyrrhizinate 150g
Pregelatinized Starch 120.0g
Low-substituted hydroxypropyl cellulose 20g
Microcrystalline Cellulose 100.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Carboxymethylstach sodium 10.0g
Prepare 1000 altogether
Prescription 2
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Tiopronin 100g
Pregelatinized Starch 120.0g
Low-substituted hydroxypropyl cellulose 30g
Microcrystalline Cellulose 80.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Carboxymethylstach sodium 10.0g
Prepare 1000 altogether
Prescription 3:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Kurarinone 400g
Pregelatinized Starch 130.0g
Low-substituted hydroxypropyl cellulose 30g
Microcrystalline Cellulose 90.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 4.0g
Carboxymethylstach sodium 15.0g
Prepare 1000 altogether
Prescription 4:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Silybin meglumine 100g
Pregelatinized Starch 120.0g
Low-substituted hydroxypropyl cellulose 20g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Carboxymethylstach sodium 10.0g
Prepare 1000 altogether
2, concrete steps:
1) it is standby Radix Rhodiolae polysaccharide and diammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine to be pulverized 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 Radix Rhodiolae polysaccharide, diammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine, pregelatinized Starch, low-substituted hydroxypropyl cellulose, 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 7HG, HL, HK, HS composition capsule
1, prescription:
Prescription 1:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Monoammonium glycyrrhizinate 40g
Pregelatinized Starch 100.0g
Microcrystalline Cellulose 40.0g
Low-substituted hydroxypropyl cellulose 10g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Prepare 1000 altogether
Prescription 2:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Tiopronin 100g
Pregelatinized Starch 100.0g
Microcrystalline Cellulose 40.0g
Low-substituted hydroxypropyl cellulose 10g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Prepare 1000 altogether
Prescription 3:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Kurarinone 400g
Pregelatinized Starch 150.0g
Microcrystalline Cellulose 40.0g
Low-substituted hydroxypropyl cellulose 10g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Prepare 1000 altogether
Prescription 4:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Silybin meglumine 100g
Pregelatinized Starch 100.0g
Microcrystalline Cellulose 40.0g
Low-substituted hydroxypropyl cellulose 10g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Prepare 1000 altogether
2, concrete steps:
1) it is standby Radix Rhodiolae polysaccharide and monoammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine to be pulverized 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 Radix Rhodiolae polysaccharide, monoammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine, pregelatinized Starch, microcrystalline Cellulose, low-substituted hydroxypropyl 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 8HG, HL, HK, HS composition granule
1, prescription:
Prescription 1:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Monoammonium glycyrrhizinate 40g
Icing Sugar 4000.0g
Solid flavoring orange essence 20g
50% ethanol is an amount of
Prepare 1000 bags altogether
Prescription 2:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Tiopronin 100g
Icing Sugar 4000.0g
Solid flavoring orange essence 20g
50% ethanol is an amount of
Prepare 1000 bags altogether
Prescription 3:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Kurarinone 400g
Icing Sugar 4000.0g
Solid flavoring orange essence 20g
50% ethanol is an amount of
Prepare 1000 bags altogether
Prescription 4:
Radix Rhodiolae polysaccharide 20g (being equivalent to Radix Rhodiolae 1kg)
Silybin meglumine 100g
Icing Sugar 4000.0g
Solid flavoring orange essence 20g
50% ethanol is an amount of
Prepare 1000 bags altogether
2, concrete steps:
1) it is standby sucrose to be pulverized 100 mesh sieves, and it is standby that Radix Rhodiolae polysaccharide and monoammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine were pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) the method mix homogeneously that Radix Rhodiolae polysaccharide, monoammonium glycyrrhizinate/tiopronin/kurarinone/silybin meglumine, solid flavoring orange essence and Icing Sugar are progressively increased with equivalent, it is an amount of to add 50% ethanol, 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) screened out thick or meticulous granule.
8) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
9) packing, finished product is examined entirely, the packing warehouse-in.

Claims (4)

1. pharmaceutical composition for the treatment of hepatic disease, it is characterized in that, this pharmaceutical composition is made by glycyrrhizic acid or its pharmaceutically acceptable salt and Radix Rhodiolae polysaccharide, and its parts by weight are: 4～800 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 1～100 part of Radix Rhodiolae polysaccharide.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, this pharmaceutical composition is made by following bulk drugs: 10～400 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 10～50 parts of Radix Rhodiolae polysaccharides.
3. pharmaceutical composition as claimed in claim 2 is characterized in that, this pharmaceutical composition is made by following bulk drugs: 20～200 parts of glycyrrhizic acid or its pharmaceutically acceptable salts, 18～25 parts of Radix Rhodiolae polysaccharides.
4. as claim 1,2 or 3 described pharmaceutical compositions, it is characterized in that this pharmaceutical composition is made clinically any or pharmaceutically acceptable dosage form.
CN200610043897A 2006-04-29 2006-04-29 Anti-hepatitis medical combination Expired - Fee Related CN100584348C (en)

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CN102150749A (en) * 2011-03-09 2011-08-17 北京桑普生物化学技术有限公司 Animal feed additive composition containing silymarin or derivatives of silymarin and application thereof
CN102860416B (en) * 2011-03-09 2014-12-10 北京桑普生物化学技术有限公司 Composition containing silymarin or derivatives of silymarin and application of composition for protection of animal livers
CN103054929A (en) * 2011-10-24 2013-04-24 中国医学科学院药物研究所 Rhodiola extract and pharmaceutical composition thereof as well as application of rhodiola extract in treatment of fatty liver disease
CN106990201B (en) * 2017-05-09 2018-11-23 山东省中医药研究院 A kind of specificity discrimination method of Chinese medicine honey toast medicine materical crude slice
US11458104B1 (en) 2018-06-21 2022-10-04 Mission Pharmacal Company Enteric coated tiopronin tablet

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