CN1391928A - Medicine Qingyedan for curing hepatitis and its preparing method - Google Patents
Medicine Qingyedan for curing hepatitis and its preparing method Download PDFInfo
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Abstract
The present invention relates to Chinese medicine, named Qingyedan, prepared based on civil traditional recipe and through modern scientific and technological improvement. It has the functions of clearing away heat and toxic matter, promoting diuresis and diminishing inflammation. It can protect liver against damage, reduce glutamate pyruvate transminase, promote regeneration of liver cell, restore the normal structure of liver tissue, improve liver microcirculation, increase the blood flow amount of liver, strengthen body's immunity and promote reconstruction of immunity. It is used in treating various acute and chronic viral hepatitis, early-stage hepatic cirrhosis, etc.
Description
The present invention relates to a kind of medicine for the treatment of hepatitis, be the Chinese patent medicine of feedstock production---Swertia mileensis T.N. Ho et W. L. Shi specifically, the invention still further relates to the preparation method of this medicine with Gentianaceae Swertia plant S.macrosperma (Swertia macrosperma C.B.Clarke).
Viral hepatitis is the pernicious infectious disease that seriously jeopardizes human health even life, and its sickness rate occupy the 3rd in Notifiable disease, is only second to flu and diarrhoea.China is the severely afflicated area of hepatitis, and first, second, third, fourth, penta 5 type hepatitis all have generation and popular at home, and particularly hepatitis B have 6-7 hundred million people once to infect hepatitis B virus approximately, and 2,800 ten thousand chronic viral hepatitis B patients almost accounts for whole world sum half.At present, the compound hepatitis of chronic hepatitis B and multiple cross infection still there is not specific drug.
Gentianaceae Swertia plant mostly can be used for the treatment of liver and gall diseases, accounts for critical role in medications among the people such as Tibetan, the Mongols, the Yi nationality, distributed over Yunnan, Sichuan and Guizhou, Bai nationality, Naxi.This platymiscium mostly is distributed in southwestern mountainous region, and most kind distributions are narrow, and increment is little, and resource is very limited, only uses for the local resident.S.macrosperma is widely distributed in Zhaotong, the Lincang Prefecture in Yunnan, aboundresources.This plant is the medicinal kind of folk tradition, and popular name is Swertia mileensis T.N. Ho et W. L. Shi, Herba Swertiae Mileensis, big Herba vallisneriae Spiralis etc., does not see that successive dynasties book on Chinese herbal medicine, each province, district's drug standard, the Sanitation Ministry medicine standard, Pharmacopoeia of People's Republic of China record.
The object of the present invention is to provide a kind of due to illness poison, Remidies for hepatitis that medicine, chemicals caused, it can transaminase lowering, resist hepatic injury, promote liver cell regeneration, recover the hepatic tissue normal configuration, promote immunity of organism to rebuild.
Another object of the present invention provides the preparation method of Remidies for hepatitis.
Solution of the present invention is based on the modern pharmacology data, reference medication experience among the people and motherland's medical science are to the understanding and the Therapeutic Principle of hepatitis, extracted, concentrated, made with extra care the natural plant that forms through modern scientific method, this medicine safety range is big, toxic and side effects is little, have significantly and protect the liver, fall enzyme, detoxifcation, enhancing immunity effect, and its medication dose is little, only be present commercially available similar Chinese patent medicine 1/3rd to sixth.
Plant amedica is actually the synergistic pharmaceutical composition of number of chemical composition.But the variation of plant chemical ingredient is quite big, is subjected to influence of various factors such as the medical material place of production, collecting season, processing technique.Therefore, the stability of assurance plant amedica therapeutical effect must at first be guaranteed the stability of medical material, crude drug chemical constituent.This drug invention claim 1,2,3 described features are exactly as starting point.The S.macrosperma chemical constituent is unusual abundant and complicated, can not all in standard, feature, be investigated all components, but its main several effective ingredient have been carried out limited investigation, just can guarantee the basicly stable of its chemical constituent, also just guaranteed the reliability of curative effect of medication.Be rich in the iridoid constituents in the medicine of the present invention, bibliographical information proves that this constituents is one of main effective ingredient of Swertia medicinal plants, but therefore this constituents guarantees that to heat, long-term illumination, long-term solution state instability the maximum of this effective constituents in preparation process keeps and the relatively stable of component ratio is the key of guaranteeing curative effect of medication.The present invention uses for reference the specification requirement that Chinese medicine is investigated chemical composition stability, adopts the main effectively method of chemical constituent relative amount feature description, guarantees that the medicament active chemical is formed and the stability of ratio.Therefore, crude drug Swertia mileensis T.N. Ho et W. L. Shi extractum, the smart powder of Swertia mileensis T.N. Ho et W. L. Shi, the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity all have identical chemical combination feature among the present invention in this analysis condition, the Chinese patent medicine preparation of being made by them is referred to as Swertia mileensis T.N. Ho et W. L. Shi, but its medication dose, route of administration are distinguished to some extent.
The main active chemical and the composition proportion of medicine of the present invention: main effective ingredient has oleanolic acid; sweroside; swertiamarin; gentiopicrin; 2 '-hydroxy benzoyl sweroside; 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside; Mengiferin; 1; 3; 5; 8-tetrahydroxy ketone (1; 3; 5; 8-tetrahydroxyxanthone); 1; 3; 5,8-tetrahydroxy ketone 1-O-β-D-glucopyanoside (1,3; 5; 8-tetrahydroxy-xanthone 1-O-β-D-glucopyranoside); 5,7,4 '-trihydroxyflavone 6-C-β-D-glucopyanoside (5; 7,4 '-trihydroxyflavone 6-C-β-D-glucopyranoside); the glucopyanoside (luteolin-7-O-β-D-glucopyransyl-(6-1) glucopyranoside) etc. of luteolin-7-O-β-D-glucopyranosyl-(6-1).
Use for reference the part specification requirement of Chinese medicine finger printing, according to high performance liquid chromatography (HPLC) figure of Swertia mileensis T.N. Ho et W. L. Shi extractum, the smart powder of Swertia mileensis T.N. Ho et W. L. Shi and the smart powder of water solublity, its main effectively chemical constituent ratio is described and is seen Table-1.
The main preferred group of active component: according to the different places of production of medical material, different collecting time, pharmaceutical chemistry component ratio scope of the present invention has following preferred group other, sees Table-2.
The main active chemical proportion of table-1 Swertia mileensis T.N. Ho et W. L. Shi
Table-1 and table-2 remarks:
| The chemical compound title | Retention time (min) | Content ratio | |
| ????I | 1,3,5,8-tetrahydroxy ketone 1-O-β-D-glucopyanoside | ????22.0 | ????1 |
| ????II | 2 '-hydroxy benzoyl sweroside | ????20.0 | ????0.06＜X＜1.5 |
| ????III | 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside | ????14.0 | ????0.05＜X＜0.75 |
| ????IV | Mengiferin | ????9.8 | ????0.04＜X＜1.5 |
| ????V | Sweroside | ????7.9 | ????0.03＜X＜0.65 |
| ????VI | Swertiamarin | ????5.5 | ????+ |
1.I ∽ VI is respectively 1,3,5,8-tetrahydroxy ketone 1-O-β-D-glucopyanoside, 2 '-hydroxy benzoyl sweroside, 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside, Mengiferin, sweroside, swertiamarin.
2. content ratio is with under this condition determination 1,3,5, and 8-tetrahydroxy ketone 1-O-β-D-glucopyanoside chromatographic peak integral area is 1, and the integral area of other chemical compound and its ratio are as its content ratio meter.
3. retention time is the physical record time, has certain fluctuation, and it can be used as the reference of the affirmation of chemical compound peak position.
4.+ number expression must detect, but does not do the content limit requirement.Other chemical compounds are bad or be difficult to detect because of separating degree under this HPLC condition determination, confirm and the component ratio requirement so do not make component.
5.HPLC the chromatographic condition instrument of analyzing: Tianjin, island LC-10AT UV-detector: SPD-10AVP chromatographic column: SHIMADZU 4.6 * 150mm flow velocity: 1ml/min mobile phase: methanol-water-formic acid (30: 70: 0.3) detects wavelength: the 237nm column temperature: 30 ℃ of chromatograph writing times: 30min chromatographic peak integrating range: 3.80min-30.00min
The main active chemical ratio of table-2 Swertia mileensis T.N. Ho et W. L. Shis preferable range group
The separation preparation of 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside, structure are identified and biological activity
| Preferred group | ????I | ????II | ????III | ????IV | ????V | ????VI |
| One | ????1.0 | ?0.20-0.75 | ?0.08-0.42 | ?0.04-0.30 | ?0.03-0.25 | ????+ |
| Two | ????1.0 | ?0.20-0.55 | ?0.10-0.45 | ?0.15-0.60 | ?0.08-0.45 | ????+ |
| Three | ????1.0 | ?0.10-0.45 | ?0.05-0.30 | ?0.15-0.60 | ?0.10-0.50 | ????+ |
| Four | ????1.0 | ?0.06-0.16 | ?0.05-0.15 | ?0.55-1.21 | ?0.03-0.27 | ????+ |
| Five | ????1.0 | ?0.08-0.38 | ?0.05-0.30 | ?0.15-0.50 | ?0.05-0.30 | ????+ |
| Six | ????1.0 | ?0.06-0.22 | ?0.08-0.40 | ?0.30-0.85 | ?0.05-0.30 | ????+ |
| Seven | ????1.0 | ?0.06-0.25 | ?0.05-0.16 | ?0.35-0.85 | ?0.08-0.40 | ????+ |
| Eight | ????1.0 | ?0.10-0.30 | ?0.06-0.28 | ?0.20-0.58 | ?0.05-0.26 | ????+ |
A key character of medicine of the present invention is wherein to contain new, efficient antihepatitic activity material---1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside (its chemical constitution is seen accompanying drawing 1), its chemical constitution is accredited as 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone 8-O-β-D-glucopyran-oside.Usually the effective ingredient that it is believed that treatment hepatitis in the Swertia plant is materials such as triterpene, iridoid, ketone.And 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside is a tetrahydrochysene ketone glycoside, and at present such material occurring in nature of bibliographical information has only in the minority plant and contains, and content is below the one thousandth.1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside content in S.macrosperma can reach 1.6%, and its specific activity oleanolic acid, gentiopicrin, swertiamarin, sweroside are all high.
The preparation method of 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside:
The smart powder 100g of method one Swertia mileensis T.N. Ho et W. L. Shi water solublity is dissolved in 100ml methanol, mixes sample with 200-300 order silica gel 300 orders, and drying is removed methanol.Taking by weighing 200-300 order silica gel 2kg and be chromatographic column by the well-established law filling, is that mobile phase is carried out chromatography to mixing sample with methanol-chloroform-water (3: 1: 0.2), collects to contain 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside fraction section, reclaims solvent, gets the 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside crude product.This crude product is that mobile phase carry out purification or with RP-18 (ODS) post with 30% methanol or 30% ethanol be mobile phase carry out purification through Sephadex LH-20 chromatographic column with 50% ethanol or 50% first by well-established law, promptly gets white or micro-yellow powder shape 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside 8.56g.
Method two is got the smart powder 20g of Swertia mileensis T.N. Ho et W. L. Shi water solublity, be dissolved in the 100ml water, is that mobile phase carry out repeatedly chromatography with RP-18 (ODS) post with 30% methanol or 30% ethanol by well-established law, collect single 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside fraction section, reclaim solvent, get white or micro-yellow powder shape 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside 1.86g.
The structure of 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside is identified: 1.
13C nuclear magnetic resoance spectrum (CD
3OD) (see accompanying drawing 2)
Attribution data: 163.2 (C-1), 100.1 (C-2), 166.1 (C-3), 95.1 (C-4), 159.1 (C-4a), 168.2 (C-4b), 67.5 (C-5), 27.4 (C-6), 27.8 (C-7), 71.4 (C-8), 117.7 (C-9b), 182.9 (C-9), 105.2 (C-9a); Glc:105.2 (C-1 '), 75.7 (C-2 '), 77.9 (C-3 '), 71.5 (C-4 '), 78.1 (C-5 '), 62.7 (C-6 ').2.
1H nuclear magnetic resoance spectrum (CD
3OD) (see accompanying drawing 3)
Attribution data: 6.32 (1H, s, H-4), 6.15 (1H, d, J=1.7Hz, H-2), 4.92 (1H, s, H-8), 4.68 (1H, J=7.8Hz, H-1 '), 4.57 (1H, dd, J=7.0,9.6Hz, H-5), (3.90 1H, q, J=2.2,11.9Hz, H-6 '), (3.71 1H, q, J=5.3,11.9Hz, H-6 '), (3.42 1H, t, J=8.8Hz, H-3 '), 3.30-3.35 (2H, m, H-4 ', 5 '), 3.18 (1H, dd, J=7.8,9.2Hz, H-2 '), 2.29 (1H, dd, J=3.2,12.6Hz, H-7), 2.08-2.10 (2H, m, H-6), 1.78 (1H, t, J=12.9Hz, H-7).
Remarks:
1H,
13Each data based HMQC of C NMR, HMBC two-dimensional correlation spectrum ownership.(3.FAB bearing)-MS (mass spectrum)
Attribution data: 425 is quasi-molecular ion peak.4.[α]
DSpecific rotation
Attribution data ([α]
D 20.0) :+3.8 ° of (MeOH, c=0.1) 5.IR (infrared spectrum) attribution data (cm
-1): 3402,1659,1623,1585,1509,1451,1369,1289,1169,1070,918,817.6. 5/8 of 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside cis relative configuration basis
1The coupling constant of each data of H NMR, NOESY confirm.
In the S.macrosperma monomer component antihepatitic activity relatively:
1. the heavy dose of D-Gal amine of principle (D-GalN) can cause serious hepatocyte injury, and low dose is injected repeatedly and can be caused hepatitis interstitialis chronica.The liver histopathology feature of this pharmacological model is very similar to human virus's hepatitis, therefore is pharmacological model commonly used in the present hepatitis medicament research.Zymetology experiment accounts for critical role in liver parenchyma infringement diagnosis, enzyme activity raises normal and liver tissue injury degree and scope are parallel relation in the serum, so serum aminotransferase activity is the sensitive indicator of hepatocellular damage.Monomer component 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside in this experiment test S.macrosperma, sweroside, swertiamarin, gentiopicrin, Mengiferin, 1; 3; 5,8-tetrahydroxy ketone 1-O-β-D-glucopyanoside is to the protective effect of D-GalN/LPS (lipopolysaccharide) induced mice acute liver damage.
2. method acute liver damage: mice (20-25g) lumbar injection D-GalN (700mg/kg)/LPS (10 μ g/kg).
Normal control group (10): respectively at experiment preceding 18 hours and 2 hours subcutaneous injection Polyethylene Glycol, intraperitoneal injection of saline during experiment.
Poisoning group (10): respectively at experiment preceding 18 hours and 2 hours subcutaneous injection Polyethylene Glycol, lumbar injection D-GalN (700mg/kg)/LPS during experiment (10 μ g/kg).
Low dose of administration group (10,25mg/kg): respectively at preceding 18 hours of experiment
With 2 hours subcutaneous injection Polyethylene Glycol dissolved drug samples, lumbar injection during experiment
D-GalN(700mg/kg)/LPS(10μg/kg)。
Heavy dose of administration group (10,50mg/kg): respectively at preceding 18 hours of experiment
With 2 hours subcutaneous injection Polyethylene Glycol dissolved drug samples, lumbar injection during experiment
D-GalN(700mg/kg)/LPS(10μg/kg)。
The mensuration of ALT: lumbar injection D-GalN (700mg/kg)/LPS (10 μ g/kg)
The back was measured mice ALT level in 8 hours.
3. result's (seeing the following form)
| Group | Mice number (only) | Dosage (mg/kg) | ALT level (U/l) | The ALT level reduces (%) |
| The normal control group | ????10 | ????- | ????55±25 | ????- |
| The poisoning group | ????10 | ????- | ????2655±850 | ????- |
| 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside | ????10 ????10 | ????25 ????50 | ????1124±410 ????619±265 | ????58 ????77 |
| Sweroside | ????10 ????10 | ????25 ????50 | ????1205±366 ????1505±282 | ????55 ????43 |
| Swertiamarin | ????10 ????10 | ????25 ????50 | ????1124±290 ????1452±350 | ????58 ????45 |
| Gentiopicrin | ????10 ????10 | ????25 ????50 | ????1350±401 ????1860±386 | ????49 ????30 |
| 2 '-(2-hydroxybenzoyl) sweroside | ????10 ????10 | ????25 ????50 | ????1244±406 ????1766±320 | ????53 ????33 |
| Mengiferin | ????10 ????10 | ????25 ????50 | ????2447±433 ????2505±431 | ????8 ????6 |
| 1,3,5,8-tetrahydroxy ketone 1-O-β-D-glucopyanoside | ????10 ????10 | ????25 ????50 | ????2506±390 ????2590±384 | ????6 ????2 |
Annotate: the p of statistical data＜0.05.
4. conclusion
Hepatic injury has significant protective effect to 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside to the D-GalN/LPS induced mice, and medicine and prevention effect are linear positive correlation.Other compositions in the S.macrosperma do not have the 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside effect obvious in this experiment, and iridoid compositions such as sweroside have showed the prevention effect of moderate strength, and ketone compositions such as Mengiferin do not have preventive and therapeutic effect substantially.Therefore, 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside is the active substance of new, the anti-hepatitis of efficiency natural.
Contain iridoid constituents such as gentiopicrin, swertiamarin in the medicine of the present invention, this constituents is except that unstable chemcial property, its flavor is extremely bitter, therefore adopts the preparation technique of modern medicinal agents to make the modern medicines dosage form that the various convenience of taking medicine, medication can guarantee the pharmaceutical chemistry stable components accurately, again.The characteristics of pharmaceutical chemistry composition according to the present invention, the preferred dosage form of medicine of the present invention are tablet, capsule and injectable powder.
The preparation method of this medicine---Swertia mileensis T.N. Ho et W. L. Shi is (process chart is seen accompanying drawing 4):
1. medical material is selected, removes impurity such as weeds, silt, is ground into 60 order fine powders.
2. add the ethanol merceration and extract 2 times, merceration is 48 hours for the first time, and merceration is 24 hours for the second time.Merge 2 times extracting solution, filter, concentrating under reduced pressure below 90 ℃ reclaims ethanol, gets Swertia mileensis T.N. Ho et W. L. Shi extractum.
3. add 8 times of water in the Swertia mileensis T.N. Ho et W. L. Shi extractum, mixing, left standstill 8 hours, and filtered, filtrate is with the n-butanol extraction first time of equal volume, with filtrate 1/2 second and third time of volume n-butanol extraction, merge the n-butanol layer extract, reclaim solvent, oven dry at concentrating under reduced pressure below 90 ℃, pulverize, get the smart powder of water solublity; Add the active carbon of its 35% weight in the water-insoluble fraction (filtering residue), add 4 times of ethanol again, refluxed 1 hour, filter, the active carbon that adds same amount in the filtrate again refluxed 1 hour, filtered, and filtrate is reclaimed solvent, oven dry is pulverized, and gets fat-soluble smart powder (main component is an oleanolic acid).Merge water solublity and fat-soluble smart powder and get the smart powder of Swertia mileensis T.N. Ho et W. L. Shi.
4. the also available adsorbent resin of the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity is prepared with chromatography in the step 3: add 8 times of water in the Swertia mileensis T.N. Ho et W. L. Shi extractum, mixing, left standstill 8 hours, and filtered, filtrate is through the macroporous resin chromatography, be that mobile phase is removed impurity such as monosaccharide, oligosaccharide with water earlier, be mobile phase again with ethanol, collect the fraction section of ethanol elution and get paste, oven dry at the recovery of concentrating under reduced pressure below 90 ℃ solvent, pulverize, get the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity.
This method can be removed impurity such as monosaccharide more completely, and is active constituent-enriched to greatest extent, compares with solvent extraction, overcome in the solvent extraction solvent dissolve each other phenomenon cause the effective ingredient extraction not exclusively, impurity separates problems such as not thorough.
5. make Chinese patent medicine preparation with the smart powder of Swertia mileensis T.N. Ho et W. L. Shi or Swertia mileensis T.N. Ho et W. L. Shi extractum or the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity.
Iridoid is an important effective constituents in the medicine of the present invention; comprise sweroside, swertiamarin, gentiopicrin, 2 '-hydroxy benzoyl sweroside etc.; it is to heat, light and long-term solution state instability; therefore; adopt merceration extraction, decompression and solvent recovery and temperature must not be higher than 90 ℃ in preparation process, the optimum temperature range of solvent recovery is preferably 50-80 ℃.
An important feature of medicine of the present invention is to have concentrated nearly all main active component (as oleanolic acid, swertiamarin, sweroside, gentiopicrin, Mengiferin etc.) in the present Swertia plant, and do not have any or two kinds of compositions have comparative advantage, these active component tool obvious synergistic effects.
According to pharmacology data, medication experience among the people and different route of administration, this medicine dosage scope is 60mg/ days to 2500mg/ days.The smart powder of its preferred dosage Swertia mileensis T.N. Ho et W. L. Shi water solublity is that 140 ± 100mg/ is big, the smart powder 360 ± 120mg/ of Swertia mileensis T.N. Ho et W. L. Shi days, Swertia mileensis T.N. Ho et W. L. Shi extractum 600 ± 240mg/ days.
Medicine The pharmacological results of the present invention shows that following advantage is arranged:
1. to select single natural plant among the people for use be raw material in the present invention, and toxic and side effects is very little, can long-term safety take.
2. dosage of the present invention is little, takes medicine conveniently, for originally the hepatitis of substance metabolism imbalance is particularly important.
3. medicine of the present invention contains multiple antihepatitic activity material, the comprehensive synergism of each active component, many target spots, polyceptor, act on patient's body at many levels, transaminase lowering, repair impaired hepatic tissue, promote liver cell regeneration, improve the hepatic region blood circulation, strengthen macrophage phagocytic activity, promote the immunologic reconstitution of body.
For showing the therapeutic effect of medicine of the present invention, its pharmacological experiment is the result be summarized as follows: 1. toxicity test
Acute toxicity: 3 groups of mices (20-25g), 10 every group, smart powder of Swertia mileensis T.N. Ho et W. L. Shi and Swertia mileensis T.N. Ho et W. L. Shi extractum is the 10g/kg gastric infusion respectively, the smart powder 10g/kg of Swertia mileensis T.N. Ho et W. L. Shi water solublity intraperitoneal injection does not have dead the generation in seven days, mice is movable normal, there is not obvious poisoning symptom, so Swertia mileensis T.N. Ho et W. L. Shi LD
50＞10g/kg.
Subacute toxicity: 5 groups of mices, 10 every group, smart powder of Swertia mileensis T.N. Ho et W. L. Shi and Swertia mileensis T.N. Ho et W. L. Shi extractum were irritated stomach respectively in 5g/kg/ days, and continuous 15 days, mice did not have dead the generation, and is movable normal, do not have obvious poisoning symptom, body weight change and matched group (filling normal saline) zero difference yet.The smart powder 5g/kg of Swertia mileensis T.N. Ho et W. L. Shi water solublity lumbar injection, continuous 15 days, mice did not have dead the generation, and is movable normal, do not have obvious poisoning symptom, body weight change and matched group (injecting normal saline) zero difference yet.
Long term toxicity: 5 groups of rats (120-150g), 8 every group, smart powder of Swertia mileensis T.N. Ho et W. L. Shi and Swertia mileensis T.N. Ho et W. L. Shi extractum were irritated stomach respectively in 5g/kg/ days, continuous 120 days, rat did not have dead the generation, and is movable normal, there is not obvious poisoning symptom, internal organs and body weight change and matched group zero differences such as the rat heart, lung, liver yet.
Conclusion: Swertia mileensis T.N. Ho et W. L. Shi (smart powder, extractum etc.) drug safety scope is big, and toxic and side effects is low.2. Swertia mileensis T.N. Ho et W. L. Shi function for protecting liver and reducing enzyme activity
A. to mice and rat CCl
4Due to the influence of hepatic injury
CCl
4Due to the mice of hepatic injury and rat is given and the smart powder of Swertia mileensis T.N. Ho et W. L. Shi 60mg/kg/ days, the administration in 120mg/kg/ days of Swertia mileensis T.N. Ho et W. L. Shi extractum, irritate stomach, continuous 7 days; 30mg/kg/ days intraperitoneal injections of the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity, continuous 7 days.Observe CCl
4Due to the hepatic injury district obviously repair: liver cytoplasm is loose, the balloon sample becomes and reduces, hepatic glycogen savings showed increased; The administration group obviously reduces than matched group SGPT value.
B. to the D-that influences of hepatic injury due to mice and the rat D-GalN (D-Gal)
The mice of hepatic injury and rat are given and the smart powder of Swertia mileensis T.N. Ho et W. L. Shi 60mg/kg/ days, the administration in 120mg/kg/ days of Swertia mileensis T.N. Ho et W. L. Shi extractum due to the GalN, irritate stomach, continuous 7 days; 30mg/kg/ days intraperitoneal injections of the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity, continuous 7 days.Observing due to the D-GalN hepatic injury district obviously repairs; The administration group obviously reduces than matched group SGPT value.
Conclusion: above description of test Swertia mileensis T.N. Ho et W. L. Shi has significant protection, repair to chemical liver injury, and the SGPT rising that chemical liver injury is caused also has significant decline effect.3. Swertia mileensis T.N. Ho et W. L. Shi is to the influence of liver detoxification function
Protective effect to the digitophyllin poisoning mice
5 groups of mices, 10 every group.Give the smart powder of mice Swertia mileensis T.N. Ho et W. L. Shi 60mg/kg/ days, Swertia mileensis T.N. Ho et W. L. Shi extractum 120mg/kg/ days, irritate stomach, for three days on end, gave and digitalin 20mg/kg in the 4th day, give for three days on end then and the smart powder of Swertia mileensis T.N. Ho et W. L. Shi 60mg/kg/ days, Swertia mileensis T.N. Ho et W. L. Shi extractum 120mg/kg/ days, irritate stomach, matched group (filling normal saline) mice 20 has 8 death as a result, and the smart powder administration group of Swertia mileensis T.N. Ho et W. L. Shi has only 4 death; 5 death of Swertia mileensis T.N. Ho et W. L. Shi extractum administration group.30mg/kg/ days lumbar injections of the smart powder of mice Swertia mileensis T.N. Ho et W. L. Shi water solublity, for three days on end, gave and digitalin 20mg/kg in the 4th day, give for three days on end then and the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity 30mg/kg/ days, lumbar injection, matched group (intraperitoneal injection of saline) dead mouse is 9 as a result, dead 5 of administration group.
Conclusion: Swertia mileensis T.N. Ho et W. L. Shi can be strengthened the mouse liver function of detoxification.4. Swertia mileensis T.N. Ho et W. L. Shi influence that colloid carbon granule in the mice blood is cleaned up speed and Kupffer cell phagocytic function
Give smart powder 60mg/kg of mice Swertia mileensis T.N. Ho et W. L. Shi and Swertia mileensis T.N. Ho et W. L. Shi extractum 120mg/kg, irritate stomach, continuous 4 days; Give the smart powder 40mg/kg of mice Swertia mileensis T.N. Ho et W. L. Shi water solublity lumbar injection, continuous 4 days.The last administration is given after 1 hour and 20% india ink (i.v.), gets hematometry after 2 and 10 minutes respectively, and the colloid carbon granule is cleaned up speed and obviously quickened than matched group in the administration group blood, the phagocytic index K of Kupffer cell and engulf the factor alpha value and obviously increase.
Conclusion: Swertia mileensis T.N. Ho et W. L. Shi has the effect of human body immunity improving function.5. pharmacological evaluation is summed up
Swertia mileensis T.N. Ho et W. L. Shi drug safety scope is big, and toxic and side effects is low.By its medicine of making obviously transaminase lowering, resist hepatic injury, improve the liver microcirculation disturbance, promote liver cell regeneration, recover the hepatic tissue normal configuration, strengthen immunity of organism and rebuild.Therefore prompting: Swertia mileensis T.N. Ho et W. L. Shi all has therapeutical effect to virus, hepatitis that medicine, chemicals caused.Can be used for hepatitis due to medicine that various acute and chronic viral hepatitis, early stage liver cirrhosis, symptomless virus carrier, medicine and chemicals cause etc. clinically.
Production method embodiment one
100kg Swertia mileensis T.N. Ho et W. L. Shi medical material is removed impurity such as weeds, silt through selected, is ground into 60 order fine powders.Add ethanol 300kg, merceration extracted 48 hours, with same amount ethanol again merceration extract for the second time merceration 24 hours.Merge 2 times extracting solution, filter, 78 ℃ of concentrating under reduced pressure reclaim ethanol, get contained humidity less than 10% Swertia mileensis T.N. Ho et W. L. Shi extractum 22.16kg (its chromatogram is seen accompanying drawing 5).Add 8 times of water (180kg) in the Swertia mileensis T.N. Ho et W. L. Shi extractum, mixing left standstill 8 hours, filtered, and filtrate is with 4 times of n-butyl alcohol (about 90kg) extraction first time of extractum amount, and second and third time extracts with 2 times of n-butyl alcohol (about 45kg) again.Merge the n-butanol layer extract, reclaim solvent at concentrating under reduced pressure below 80 ℃, oven dry is pulverized, and gets the smart powder (12.96kg) of water solublity; Water-insoluble fraction (filtering residue, 5.6kg) middle 1/3rd times of active carbons (1.8kg) that add add 4 times of ethanol (22.5kg) again, refluxed 1 hour, and placed and be cooled to room temperature, filter, the active carbon (1.8kg) that adds same amount in the filtrate again, refluxed 1 hour, and placed and be cooled to room temperature, filter, filtrate is reclaimed solvent, oven dry is pulverized, and gets fat-soluble smart powder (2.4kg).Merge water solublity and fat-soluble smart powder and get the smart powder (15.36kg) (its chromatogram is seen accompanying drawing 6) of Swertia mileensis T.N. Ho et W. L. Shi.
With the smart powder 1500g of Swertia mileensis T.N. Ho et W. L. Shi, add starch 3000g, granulate, be pressed into the 0.45g tablet, coating gets 9720 of qualified Swertia mileensis T.N. Ho et W. L. Shi sheets.This tablet is taken three times every day, each a slice.
With the smart powder 1250g of Swertia mileensis T.N. Ho et W. L. Shi, add starch 3000g, granulate, load into the 0.25g capsule, get Swertia mileensis T.N. Ho et W. L. Shi and hand over 17500 in capsule.This capsule is taken three times each two every day.
Embodiment two
Get the Swertia mileensis T.N. Ho et W. L. Shi extractum (1000g) that makes among the production method embodiment one, add starch 3000g, granulate, be pressed into the 0.4g tablet, the bag film-coat gets 9800 of qualified Swertia mileensis T.N. Ho et W. L. Shi sheets.This tablet is taken three times each two every day.
With Swertia mileensis T.N. Ho et W. L. Shi extractum 1000g, add starch 3000g, granulate, load into the 0.2g capsule, get 17650 of Swertia mileensis T.N. Ho et W. L. Shi capsules.This capsule is taken three times each four every day.
Get getting of making among the production method embodiment one and add 8 times of water (40kg) in the Swertia mileensis T.N. Ho et W. L. Shi extractum (5kg), mixing, left standstill 8 hours, and filtered, filtrate is through DM-130 macroporous resin chromatography, be that mobile phase is removed impurity such as monosaccharide, oligosaccharide with water (100 liters) earlier, be mobile phase with ethanol (120kg) again, collect the fraction section of ethanol elution and get slurry, oven dry at the recovery of concentrating under reduced pressure below 80 ℃ solvent, pulverize, get the smart powder (2.1kg) (its chromatogram is seen accompanying drawing 7) of Swertia mileensis T.N. Ho et W. L. Shi water solublity.In the gnotobasis the smart powder 1000g of Swertia mileensis T.N. Ho et W. L. Shi water solublity is dissolved in 10 liters of waters for injection, ultrafiltration membrance filter, filtrate pours in the 2ml ampoule bottle, pours into the 1ml medicinal liquid in every ampoule bottle, and lyophilization is sealed, and makes 9610 of Swertia mileensis T.N. Ho et W. L. Shi lyophilized injectable powders.This injection intramuscular injection or intravenous injection, every day secondary, each one.
Claims (10)
1. a medicine for the treatment of hepatitis---Swertia mileensis T.N. Ho et W. L. Shi is characterized in that with S.macrosperma (Swertia macrosperma C.B.Clarke) be the medicament that the effective chemical constituents of feature such as the iridoids that extracts of raw material, ketone, triterpenes are made.
2. treatment hepatitis medicament according to claim 1 is characterized in that its main active chemical proportion of composing is relatively stable, and has the special ratios scope.
3. treatment hepatitis medicament according to claim 2 is characterized in that its main active chemical proportion has eight preferred groups.
4. according to claim 1,2 described treatment hepatitis medicaments, it is characterized in that it contains new natural antihepatitic activity material-1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone-8-O-BETA-D-glucopyranoside.
5. treatment hepatitis medicament according to claim 1 is characterized in that said medicament is a said dosage form on any pharmaceutics.
6. treatment hepatitis medicament according to claim 5 is characterized in that said medicament is tablet or capsule or injectable powder.
7. treatment hepatitis medicament according to claim 1 is characterized in that its effective dosage scope is 60mg/ days to 2500mg/ days.
8. treatment hepatitis medicament according to claim 7 is characterized in that the smart powder of its medication preferred dose Swertia mileensis T.N. Ho et W. L. Shi water solublity is that 140 ± 100mg/ days, the smart powder of Swertia mileensis T.N. Ho et W. L. Shi are that 360 ± 120mg/ days, Swertia mileensis T.N. Ho et W. L. Shi extractum are 600 ± 240mg/ days.
9. treatment hepatitis medicament according to claim 1, its feature also are its exclusive extraction, preparation technology: with pulverizing medicinal materials, add the ethanol merceration and extract 2 times, merge extractive liquid, filters, and filtrate gets Swertia mileensis T.N. Ho et W. L. Shi extractum at concentrating under reduced pressure below 90 ℃.Add 8 times of water in the Swertia mileensis T.N. Ho et W. L. Shi extractum, mixing, left standstill 8 hours, and filtered, filtrate is with the n-butanol extraction first time of equal volume, second and third time of n-butanol extraction with 1/2 filtrate volume, merge the n-butanol layer extract, reclaim solvent, oven dry at concentrating under reduced pressure below 90 ℃, pulverize, get the smart powder of water solublity; 35% of its quality of adding active carbon adds 4 times of ethanol again in the water-insoluble fraction (filtering residue), refluxes 1 hour, is chilled to room temperature, filter, add the active carbon of same amount in the filtrate again, refluxed 1 hour, be chilled to room temperature, filter, filtrate is reclaimed solvent, oven dry, pulverize fat-soluble smart powder.Smart powder of water solublity and fat-soluble smart powder merge, and mixing gets the smart powder of Swertia mileensis T.N. Ho et W. L. Shi.Mix an amount of pharmaceutic adjuvant with smart powder of Swertia mileensis T.N. Ho et W. L. Shi extractum or Swertia mileensis T.N. Ho et W. L. Shi or the smart powder of water solublity and make Chinese patent medicine preparation.The also available following method preparation of the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity: add 8 times of water in the Swertia mileensis T.N. Ho et W. L. Shi extractum, mixing, leave standstill, filter, filtrate is through the macroporous resin chromatography, be that mobile phase is removed impurity such as monosaccharide, oligosaccharide with water earlier, be mobile phase again with ethanol, collect the fraction section of ethanol elution and get paste, oven dry at the recovery of concentrating under reduced pressure below 90 ℃ solvent, pulverize, get the smart powder of Swertia mileensis T.N. Ho et W. L. Shi water solublity.
10. treatment hepatitis medicament Swertia mileensis T.N. Ho et W. L. Shi preparation method according to claim 9, its feature is that also the temperature range of solvent recovery among its preparation technology is preferably 50-80 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01129401 CN1391928A (en) | 2001-06-15 | 2001-06-15 | Medicine Qingyedan for curing hepatitis and its preparing method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 01129401 CN1391928A (en) | 2001-06-15 | 2001-06-15 | Medicine Qingyedan for curing hepatitis and its preparing method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100341516C (en) * | 2004-06-03 | 2007-10-10 | 昆明聚智达医药技术有限公司 | Hepatitis treating medicine and its preparation method |
| CN101429187B (en) * | 2008-12-18 | 2012-01-25 | 重庆理工大学 | Ketone compound, preparation method and application thereof |
| CN117074595A (en) * | 2023-07-25 | 2023-11-17 | 广东一方制药有限公司 | Method for constructing characteristic spectrum of swertia Japonica Makino and application thereof |
-
2001
- 2001-06-15 CN CN 01129401 patent/CN1391928A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100341516C (en) * | 2004-06-03 | 2007-10-10 | 昆明聚智达医药技术有限公司 | Hepatitis treating medicine and its preparation method |
| CN101429187B (en) * | 2008-12-18 | 2012-01-25 | 重庆理工大学 | Ketone compound, preparation method and application thereof |
| CN117074595A (en) * | 2023-07-25 | 2023-11-17 | 广东一方制药有限公司 | Method for constructing characteristic spectrum of swertia Japonica Makino and application thereof |
| CN117074595B (en) * | 2023-07-25 | 2024-06-11 | 广东一方制药有限公司 | Method for constructing characteristic spectrum of swertia Japonica Makino and application thereof |
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