Medicine of a kind of anti-hepatic fibrosis and preparation method thereof
Technical field
The present invention relates to a kind of medicine for the treatment of hepatic fibrosis, particularly use the medicine that Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract prepare anti-hepatic fibrosis.
Background technology
Hepatic fibrosis is that hepatocyte necroses or during inflammatory stimulus, the paraplasm pathological change process of fibrous connective tissue in the liver, and various chronic hepatopathys such as viral hepatitis, alcoholic liver disease etc. all can develop into hepatic fibrosis, liver cirrhosis.Hepatitis is one of China's sickness rate disease with high, it is reported, hepatitis accounts for more than 10% of total population at the sickness rate of China.China is again the big country of drinking in the world, adds the change of environmental pollution and dietary structure, and at present, the sickness rate of hepatic fibrosis is in continuous rising, has now become one of problem that China hygiene department is concerned about, payes attention to most.In recent years, Chinese scholars has proposed a series of anti-hepatic fibrosis medicines and method to the formation mechanism of hepatic fibrosis, as the application corticoid, and treatments such as interferon, but the curative effect of these medicines can not be affirmed.Though have the treatment of Colchicum autumnale aspect anti-hepatic fibrosis to obtain certainly, it has bigger toxic and side effects, be difficult for taking for a long time.Chinese herbal medicine and preparation thereof are one of problems of domestic and international medical research unit primary study to the effect of anti-hepatic fibrosis always.In the recent period, China has begun to occur relevant compound recipe anti-hepatic fibrosis Chinese medicine preparation, as sunflower board liver-protecting tablet etc., but it is the big compound recipe crude preparation by using of Chinese medicine, and it is big to have a dose, and the cycle of taking is long, uncertain therapeutic efficacy is cut, treatment mechanism is difficult to shortcomings such as research, is difficult to deal with market anti-hepatic fibrosis patient's needs, more can't integrate with countries in the world.
Salviamiltiorrhizabung and Radix Paeoniae Rubra have certain blood circulation promoting and blood stasis dispelling, microcirculation improvement, increase liver blood flow amount, protect hepatocyte, alleviate hepatocellular degeneration, necrosis and inflammatory reaction, promote liver cell regeneration, suppress proliferation of fibrous tissue, suppress the hepatocyte lipid peroxidation, remove oxygen-derived free radicals, suppress collagenation and increase effect such as its decomposition.
The effective site Radix Salviae Miltiorrhizae extract of salviamiltiorrhizabung, it is the powder of being processed into through extraction separation by the dry root and rhizome of Labiatae Radix Salviae Miltiorrhizae (Salvia miltorrhiza Bunge), be the xanchromatic amorphous powder of a kind of palm fibre, gas is special, sour in the mouth, easily molten in water, methanol, ethanol, ethyl acetate.
Chinese medicine Radix Paeoniae Rubra is the dry rhizome of cohosh Radix Paeoniae (Paeonia lactflora Pall), the effective site Radix Paeoniae Rubra extract of Radix Paeoniae Rubra (Chishao Tiquwu) is processed into through extraction separation by the dry rhizome of Radix Paeoniae, be a kind of pale brown toner end, bitter in the mouth, easily molten in water, methanol, ethanol, ethyl acetate, insoluble in petroleum ether.
Utilize Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract to make the medicine of anti-hepatic fibrosis, yet there are no report.
Summary of the invention
The purpose of this invention is to provide a kind of medicine of using Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract preparation.
Particularly use the medicine that Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract prepare anti-hepatic fibrosis.
Technical scheme of the present invention is:
Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract prepare the medicine of anti-hepatic fibrosis, mainly the medicament of being made by following composition (composition by weight): 8~2 parts of Radix Salviae Miltiorrhizae extracts, 2~8 parts of Radix Paeoniae Rubra extracts; Preferred component proportioning is a Radix Salviae Miltiorrhizae extract: Radix Paeoniae Rubra extract=7: 3.
Radix Salviae Miltiorrhizae extract provided by the present invention and Radix Paeoniae Rubra extract prepare the medicine of anti-hepatic fibrosis, can add various pharmaceutically acceptable carriers when needing.
Radix Salviae Miltiorrhizae extract provided by the present invention and Radix Paeoniae Rubra extract prepare the medicine of anti-hepatic fibrosis, can be various peroral dosage forms, as various ways such as tablet, granule, powder, capsule, oral liquids.
Radix Salviae Miltiorrhizae extract provided by the present invention and Radix Paeoniae Rubra extract prepare the medicine of anti-hepatic fibrosis, can be capsule formulations, mainly make (composition by weight) by following component: 8~2 parts of Radix Salviae Miltiorrhizae extracts, 2~8 parts of Radix Paeoniae Rubra extracts, right amount of auxiliary materials.Adjuvant can select for use microcrystalline cellulose or corn starch or hydroxymethyl starch etc. to be fit to oral adjuvant.
The preparation method of anti-hepatic fibrosis medicines provided by the invention is as follows:
1, the preparation method of Radix Salviae Miltiorrhizae extract:
Get salvia piece, decocting boils secondary, adds doubly amount of water 10 (weight) for the first time, adds doubly amount of water 6 (weight) for the second time, and twice decoction each 1.5 hours filters respectively, discards medicinal residues, merges twice filtrate then, is concentrated into every milliliter of filtrate and contains crude drug 1.0g.Add 5% gelatin precipitation tannin in the filtrate after concentrating, placed 12 hours, filter, filtrate is concentrated into every milliliter and contains crude drug 1.5g, transfers PH2~3 with dilute hydrochloric acid, reuse equal-volume ethyl acetate extraction three times, merge ethyl acetate, the reclaim under reduced pressure ethyl acetate through 80 ℃ of vacuum dryings, promptly gets Radix Salviae Miltiorrhizae extract then.Containing radix salviae miltiorrhizae peimine in the Radix Salviae Miltiorrhizae extract must not calculate with radix salviae miltiorrhizae peimine sodium and is less than 10%; Containing the salvia-soluble total phenols must not calculate with protocatechualdehyde and is less than 60%.
2, the preparation method of Radix Paeoniae Rubra extract:
Get Radix Paeoniae Rubra and be ground into coarse powder, cross 20 mesh sieves, with 50% alcohol reflux secondary, reflux, extract, is doubly measured ethanol with 10 (weight) for the first time, reflux, extract, is doubly measured ethanol with 6 (weight) for the second time, each 1.5 hours, the extracting solution of merging secondary filtered, reduce pressure back and get ethanol, concentrated filtrate to relative density is 1.10 (60 ℃) then, adds hot water (≤90 ℃) dilution of triplication in concentrated solution, puts to add 5% gelatin water liquid after cold, making gelatin water liquid measure is 15% (w/w) of former concentrated solution, place after 24 hours, filter, (the post reducing was than 24: 1 by ZTC-1 type macroporous resin with filtrate then; Medical material is 4: 1 with the resin demand ratio; The absorption flow velocity is resin volume 2-3BV/ hour) negative with deionized water rinsing reducing sugar reaction to the eluent, reuse 40% ethanol elution, the eluent consumption is the 6BV of resin volume, the desorbing flow velocity is resin volume 1000.5-1BV/ hour, merge last twice ethanol elution, reduce pressure back once more and get ethanol, concentrate eluant to relative density is the thick extractum of 1.30~1.35 (50 ℃) then, through 80 ℃ of following vacuum dryings, promptly make Radix Paeoniae Rubra extract again.
3, Radix Salviae Miltiorrhizae extract provided by the present invention and Radix Paeoniae Rubra extract prepare the medicament capsule of anti-hepatic fibrosis, and its preparation method is:
Get Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract in proportion, add appropriate amount of auxiliary materials, mixing is sieved, and with 80% ethanol wet granulation, incapsulates promptly after the drying.
The medicine that Radix Salviae Miltiorrhizae extract provided by the present invention and Radix Paeoniae Rubra extract prepare anti-hepatic fibrosis proves through pharmaceutical research and drug effect animal experiment result of study: the effective site Radix Salviae Miltiorrhizae extract of salviamiltiorrhizabung and Radix Paeoniae Rubra and Radix Paeoniae Rubra extract be proportioning by a certain percentage, picked-up and the decomposition of liver be can obviously increase, glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT rising suppressed hyaluronic acid, laminin; The same demonstration of animal pathological section has good preventive and therapeutic effect to hepatic fibrosis.Influence result of the test shown in table 1,2,3, Radix Salviae Miltiorrhizae extract to what cause the experimental rat hepatic fibrosis with carbon tetrachloride: the anti-liver dimension chemical fibre medicine of Radix Paeoniae Rubra extract=7: 3 has than remarkable influence hyaluronic acid (HA), laminin (LN); Radix Salviae Miltiorrhizae extract: the anti-hepatic fibrosis medicines of Radix Paeoniae Rubra extract=5: 5 or 3: 7 has significant difference to glutamic oxaloacetic transaminase, GOT (AST); The Radix Salviae Miltiorrhizae extract of each dosage and Radix Paeoniae Rubra extract anti-hepatic fibrosis medicines test group have appreciable impact to glutamate pyruvate transaminase (ALT) and hepatic tissue hydroxyproline, zoopery shows that hepatic fibrosis has good preventive and therapeutic effect to experimental rat for Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract anti-hepatic fibrosis medicines.
Table 1: Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract anti-hepatic fibrosis medicines
The influence that the experimental rat liver function is detected (X ± SE)
Group | n | Glutamate pyruvate transaminase (ALT) | Glutamic oxaloacetic transaminase, GOT (AST) | Globulin (TP) | Albumin (ALB) |
Normal group | 8 | ?61.65±15.24* | 159.84±37.14* | 62.94±4.00* | 27.06±2.10* |
Model group | 9 | ?124.32±78.50 | 293.29±132.00 | 61.33±3.36 | 28.40±2.69 |
The colchicine group | 8 | ?50.58±8.30* | 202.06±57.78 | 65.66±2.97 | 26.34±1.52 |
Red 7: red 3 organize greatly | 8 | ?57.39±12.95* | 227.79±44.59 | 70,55±5.27 | 32.64±2.72 |
Red 7: red 3 groups | 9 | ?57.18±13.53* | 245.58±53.98 | 64.10±5.59 | 29.77±2.44 |
Red 5: red 5 organize greatly | 8 | ?50.28±10.54* | 163.51±38.61* | 65.10±4.00 | 29.79±2.10 |
Red 5: red 5 groups | 8 | ?45.10±15.14* | 119.06±31.29* | 60.58±5.52 | 26.29±2.91 |
Red 3: red 7 organize greatly | 8 | ?44.00±15.04* | 114.21±15.20* | 64.53±7.71 | 28.53± |
Red 3: red 7 groups | 9 | ?53.73±14.76* | 152.23±27.13* | 63.64±5.96 | 28.22±3.11 |
Compare with model group: * P<0.05
Table 2: Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract anti-hepatic fibrosis medicines
To the influence of experimental rat hepatic fibrosis index of correlation (X ± SE)
Group | n | Hyaluronic acid (HA) ng/ml | Laminin (LN) ug/l | Liver hydroxyproline ug/mgprot |
Normal group | 8 | ?79.91±18.68* | 16.77±7.37* | 1.35±0.29* |
Model group | 9 | ?155.14±57.12 | 29.92±12.20 | 2.56±0.70 |
The colchicine group | 8 | ?97.27±23.98* | 16.06±10.68* | 1.61±0.40* |
Red 7: red 3 organize greatly | 8 | ?96.14±33.34* | 15.73±6.33(#)* | 1.73±0.37* |
Red 7: red 3 groups | 9 | ?94.50±32.48* | 6.69±2.01(#)* | 1.83±0.56* |
Red 5: red 5 organize greatly | 8 | ?92.05±31.40* | 3.21±0.79(#)* | 1.78±0.70* |
Red 5: red 5 groups | 8 | ?102.08±28.31* | 8.96±4.19(#)* | 1.87±0.35* |
Red 3: red 7 organize greatly | 8 | ?111.99±37.87 | 17.93±9.46 | 1.85±0.61* |
Red 3: red 7 groups | 9 | ?93.40±27.55* | 11.87±6.96* | 1.99±0.48 |
Compare with model group: * P<0.05
Table 3: Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract anti-hepatic fibrosis medicines
To experimental rat pathological observation result
Group | Hepatic fibrosis |
0 grade | 1 grade | 2 grades | 3 grades | 4 grades | 5 grades | 6 grades |
Normal group | ???8 | ???0 | ???0 | ???0 | ???0 | ???0 | ???0 |
Model group | ???0 | ???1 | ???2 | ???4 | ???1 | ???1 | ???0 |
The colchicine group | ???0 | ???4 | ???7 | ???1 | ???0 | ???0 | ???0 |
Red 7: red 3 organize greatly | ???2 | ???2 | ???7 | ???0 | ???0 | ???0 | ???0 |
Red 7: red 3 groups | ???3 | ???6 | ???3 | ???0 | ???0 | ???0 | ???0 |
Red 5: red 5 organize greatly | ???1 | ???2 | ???7 | ???0 | ???0 | ???0 | ???0 |
Red 5: red 5 groups | ???1 | ???0 | ???9 | ???1 | ???0 | ???0 | ???0 |
Red 3: red 7 organize greatly | ???0 | ???3 | ???7 | ???1 | ???0 | ???0 | ???0 |
Red 3: red 7 groups | ???1 | ???2 | ???7 | ???0 | ???0 | ???0 | ???0 |
Learn check by statistics:
Model group: normal group x
2=11.22>x
20.001 there is the difference of highly significant (l) P<0.001 between model group and the normal group, show the modeling success.
Colchicine group: model group x
2=6.115>x
20.05 (l) P<0.05
Red red 73 organize greatly: model group x
2=6.960>x
20.01 (l) P<0.01
Red red 73 organize greatly: model group x
2=10.433>x
20.01 (l) P<0.01
Red red 55 organize greatly: model group x
2=6.110>x
20.05 (l) P<0.05
Red red 55 organize greatly: model group x
2=4.763>x
20.05 (l) P<0.05
Red red 37 organize greatly: model group x
2=4.287>x
20.05 (l) P<0.05
Red red 37 organize greatly: model group x
2=6.110>x
20.05 (l) P<0.05
This shows that each organizes medication therapy groups and Liver Fibrosis Model group, and all there were significant differences, illustrates that each dose compatibility of Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract all has the positive therapeutic effect to hepatic fibrosis.Wherein no matter red 7: red 3 big small dose group is from pathological section itself or statistical testing of business cycles, and curative effect is all more obvious.
The present invention shows through acute toxicity animal experiment result of study, the medicine of the anti-hepatic fibrosis of Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract preparation, and administration in selected dosage range has no side effect.
The invention has the advantages that: adopt effective ingredient in Chinese Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract to research and develop out the novel drugs of treatment hepatic fibrosis, hepatic fibrosis had good preventive and therapeutic effect and effect, be an extremely promising new Chinese medicine, have positive meaning safeguarding people ' s health.
Specific embodiment
The preparation of embodiment 1, Radix Salviae Miltiorrhizae extract
(1) preparation of salvia miltiorrhiza raw material and pre-treatment:
Get the salviamiltiorrhizabung that the place of production is Luoyang, Henan, require to meet pertinent regulations under Radix Salviae Miltiorrhizae item of Chinese Pharmacopoeia version in 2000.After medical material is selected, gets clean medical material 50Kg and thinly slice, standby.
(2) preparation technology:
Get salvia piece 50Kg, decocting boils secondary, adds doubly amount of water 10 (weight) for the first time, adds doubly amount of water 6 (weight) for the second time, and twice decoction each 1.5 hours filters respectively, discards medicinal residues, merges twice filtrate then, is concentrated into every milliliter of filtrate and contains crude drug 1.0g.Add 5% gelatin precipitation tannin in the filtrate after concentrating, leak and placed 12 hours, filter, filtrate is concentrated into every milliliter and contains crude drug 1.5g, transfers PH2~3 with dilute hydrochloric acid, reuse equal-volume ethyl acetate extraction three times, merge ethyl acetate, the reclaim under reduced pressure ethyl acetate through 80 ℃ of vacuum dryings, promptly gets Radix Salviae Miltiorrhizae extract 1.285Kg then.This product contains radix salviae miltiorrhizae peimine and is calculated as 12.52% with radix salviae miltiorrhizae peimine sodium; Contain the salvia-soluble total phenols and be calculated as 82.79% with protocatechualdehyde.
The preparation of embodiment 2, Radix Paeoniae Rubra extract
(1) preparation of Radix Paeoniae Rubra raw material and pre-treatment:
Getting the place of production is the Chinese medicine Radix Paeoniae Rubra of Chifeng, the Inner Mongol, requires to meet pertinent regulations under Radix Paeoniae Rubra item of Chinese Pharmacopoeia version in 2000.Pulverizing Radix Paeoniae Rubra becomes coarse powder 25Kg standby.
(2) concrete preparation technology:
Get Radix Paeoniae Rubra coarse powder 25Kg, cross 20 mesh sieves, with 50% alcohol reflux secondary, reflux, extract, is measured ethanol with 10 times for the first time, reflux, extract, is measured ethanol with 6 times for the second time, each 1.5 hours, the extracting solution of merging secondary filtered, reduce pressure back and get ethanol, concentrated filtrate to relative density is 1.10 (60 ℃) then, adds hot water (≤90 ℃) dilution of triplication in concentrated solution, puts to add 5% gelatin water liquid after cold, making gelatin water liquid measure is 15% (w/w) of former concentrated solution, place after 24 hours, filter when reaching below 10 ℃, (the post reducing was than 24: 1 by ZTC-1 type macroporous resin with filtrate then; Medical material is 4: 1 with the resin demand ratio; The absorption flow velocity is resin volume 2-3BV/ hour) negative with deionized water rinsing reducing sugar reaction to the eluent, reuse 40% ethanol elution, the eluent consumption is the 6BV of resin volume, the desorbing flow velocity is resin volume 1000.5-1BV/ hour, merge last twice ethanol elution, reduce pressure back once more and get ethanol, concentrate eluant to relative density is the thick extractum of 1.30~1.35 (50 ℃) then, through 80 ℃ of following vacuum dryings, promptly make Radix Paeoniae Rubra extract 0.962Kg again.This product contains peoniflorin 54.26%; Contain the Radix Paeoniae Rubra phenolic acid and be calculated as 8.39% with gallic acid.
Embodiment 3, Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract prepare the anti-hepatic fibrosis medicines capsule
(1) component proportioning:
Radix Salviae Miltiorrhizae extract 77g
Radix Paeoniae Rubra extract 33g
Microcrystalline cellulose 140g
Make 1000 of capsules altogether.
(2) component proportioning:
Above-mentioned prescription raw material blending is sieved,, incapsulate after the drying and get final product with 80% ethanol wet granulation.
Embodiment 4, Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract prepare the anti-hepatic fibrosis medicines capsule
(1) component proportioning:
Radix Salviae Miltiorrhizae extract 55g
Radix Paeoniae Rubra extract 55g
Corn starch 140g
Make 1000 of capsules altogether.
(2) preparation method: with embodiment 3.
Embodiment 5, Radix Salviae Miltiorrhizae extract and Radix Paeoniae Rubra extract prepare the anti-hepatic fibrosis medicines capsule
(1) component proportioning:
Radix Salviae Miltiorrhizae extract 33g
Radix Paeoniae Rubra extract 77g
Hydroxymethyl starch 140g
Make 1000 of capsules altogether.
(2) preparation method: with embodiment 3.