CN103242419A - Friedelane triterpenoid and preparation method as well as application thereof - Google Patents
Friedelane triterpenoid and preparation method as well as application thereof Download PDFInfo
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Abstract
The invention relates to a 3,4-seco-friedelolactone triterpenoid. The molecular structure of the compound is shown in the formula (I) in the specification. The compound is obtained by carrying out ethanol reflux extraction, organic solvent extraction and column chromatography separation and purification on viola diffusa ging. The compound has anti-HBV (hepatitis B virus) activity and can be used for preparing medicines for preventing and treating hepatitis B.
Description
Technical field
The present invention relates to Oxygenic heterocyclic compounds, be specifically related to 3,4-driffractive ring friedelane type triterpene compound.
Background technology
Driffractive ring friedelane compounds is few in distributed in nature, nineteen sixty-eight from the leaf of Calophylum lanigerum plant Calophyllum apetalum, separate obtained first 3,4 driffractive ring friedelane compounds apetalactone(Govindachari TR that rupture and become lactone, Prakash D, Viswanathan N.Apetalactone, a New Triterpene Lactone from Calophyllum Species.J Chem Soc (C), 1968,1323-1324).From congener Calophyllum tomentosum, Calophyllum moonii, also separate subsequently and obtained this compound (Dharmaratne HRW, Sotheeswaran S, Balasubramaniam S.Triterpenes and Neoflavonoids of Calophyllum Lankaensis and Calophyllum Thwaitesii.Phytochemistry, 1984,23 (11): 2601-2603; Bandara BMR, Dharmaratne HRW, Sotheeswaran S, Balasubramaniam S.Phytochemistry, 1986,25 (2): 425-428).Another driffractive ring friedelane compounds lithocarpic lactone in 1975 separates from the leaf of Lithocarpus zitchioides and Lithocarpus irwinii and obtains (Hui WH, Li MM, Lee YC.Structure of Lithocarpic Lactone, a New Triterpenoid from Two Lithocarpus Species of Hong Kong.J Chem Soc (Perkin I), 1975:617-619).From the bark of Itoa orientalis and withe, separated in 2009 and obtained another new driffractive ring friedelane compounds Itoaic acid, and find that this compound has better inhibited activity (Chai XY to COX-2, Xu ZR, Bai CC, Zhou FR, Tu PF.A New Seco-friedelolactone Acid from the Bark and Twigs of Itoa orientalis.Fitoterapia, 2009,80:408-410).There is research group that Calophyllum flavoramulu has been carried out separation under the active guidance recently, therefrom also isolate apetalactone, and its activity that suppresses AGEs carried out estimating (Ferchichi L, Derbre S, Mahmood K, Toure K, Guilet D, Litaudon M, Awang K, Hadi AHA, Ray AML, Richomme P.Bioguided Fractionation and Isolation of Natural Inhibitors of Advanced Glycation End-products (AGEs) from Calophyllum flavoramulu.Phytochemistry, 2012,78:98-106).In sum, the at present relevant bioactive report of driffractive ring friedelane compounds is few, only suppresses the research report of COX-2 and AGEs activity relevant for this compounds.
Herba Violae Diffusae (Viola diffusa Ging) is the annual or per nnial herb of Violaceae (Violaceae) Viola (Viola), has another name called seven-star lotus, viola diffusa etc., is distributed in each province on the south the Changjiang river, district and Shaanxi, Gansu, and the various places, Fujian are common.Be born in the roadside, field, spacious ground or roadside, hillside also see the moistening place of opening more.All herbal medicine has clearing heat and detoxicatingly, and dissipating blood stasis for subsidence of swelling is removed necrosis and promoted granulation, the effect of removing heat from the lung to relieve cough, and bright product are mashed external application or dry product levigation damping external application (" Fujian flora " (Volume Four).Foochow: Fujian science tech publishing house, nineteen ninety).Little hardship, cold; Has clearing heat and detoxicating effect.Cure mainly hepatitis, pleuritis, binding film inflammation, venomous snake bite, malignant boil, carbuncle.(" Fujian medicine will " (second volume. revised edition).Foochow: Fujian science tech publishing house, 1994).
The chemical research report of relevant this plant is seldom put down in writing the contained chemical ingredients of this plant according to " Chinese Plants will " and is mainly flavones, carbohydrate and phlegmatic temperament (" Chinese Plants will ".Beijing: Science Press, 1991).The compound that separates from Herba Violae Diffusae at present and identify has paulownia sterol (clersterol), palmitinic acid (Peng Yuangui such as (palmitic acid), Zhao Zhenping, Wang Xiaoshu. the effective constituent of Herba Violae Diffusae (hundred grass) leukocyte increasing. herbal medicine, 1990,9:426).Author Hu Dan and Ding Xuliang have reported in violet (Viola verecunda) in " bulletin of Chinese materia medica " the 12nd the 06th phase of volume in 1987 and have isolated a kind of 3-suberone, and finish structure and identify.Subsequently, report suberone such as He Lan have anti-inflammatory activity and suppress fungal growth effect (He Lan etc. the suberone chemical structure is modified and anti-inflammatory activity. applied chemistry, 1996,13 (5): 67).
Summary of the invention
It is a kind of 3 that the technical problem to be solved in the present invention provides, 4-driffractive ring friedelane type triterpene compound, and this compound has the effect of anti-hepatitis B virus.
The technical scheme that the present invention will address the above problem is:
A kind of 3,4-driffractive ring friedelane type triterpene compound, its molecular structure is suc as formula shown in the I:
Of the present invention 3, the molecular formula of 4-driffractive ring friedelane type triterpene compound is C
30H
48O
5, HR-ESI-MS m/z511.3393[M+Na]
+, chemistry 2 beta-hydroxies-3 by name, 4-splits friedelane-27-carboxylic acid, English 2 β by name-hydroxy-3,4-seco-friedelolactone-27-oic acid.
Of the present invention 3,4-driffractive ring friedelane type triterpene compound can be by the method for chemosynthesis.Those skilled in the art can determine synthesis step and processing condition by the knowledge of this area.Of the present invention 3,4-driffractive ring friedelane type triterpene compound can also separate from Herba Violae Diffusae (Viola diffusa Ging) and obtains, and concrete separation method is made up of step down:
(1) get Herba Violae Diffusae, (volume that is ethanol is the multiple of Herba Violae Diffusae weight to use 12,10 and 8 times successively.If described volume unit is L, described weight unit is kg; If described volume unit is ml, described weight unit then is g) concentration be 95% alcohol reflux Herba Violae Diffusae herb 2h, merge ethanol extract, reclaim ethanol and also be evaporated to and do not have the alcohol flavor, get total medicinal extract;
(2) total medicinal extract is dissolved in the water, then, uses sherwood oil, vinyl acetic monomer and water saturated n-butanol extraction successively, get butanol extraction liquid, concentrating under reduced pressure, desolventizing gets n-butyl alcohol extract;
(3) n-butyl alcohol extract is dissolved in the water, crosses D-101 type macroporous resin column, water, concentration are that 10% ethanol, concentration are that 30% ethanol, concentration are that 60% ethanol, concentration are that 90% ethanol, concentration are 95% ethanol elution successively; Collecting concentration and be 95% ethanol eluate and cross 200～300 purpose silicagel columns, be solvent by Shi You Mi ︰ vinyl acetic monomer with sherwood oil-vinyl acetic monomer is that the gradient of 250 ︰, 1～2 ︰ 1 is carried out wash-out; Collection Shi You Mi ︰ vinyl acetic monomer is that the elutriant of 2 ︰ 1 is crossed the silica gel H post, is the eluent wash-out with the vinyl acetic monomer, collects the vinyl acetic monomer elutriant, obtains green plate crystal after concentrating;
(4) green plate crystal being crossed the SephdexLH-20 post, is the eluent wash-out with methyl alcohol, collects meoh eluate, obtains white, needle-shaped crystals after concentrating and gets final product.
Concentration of ethanol described in the above-mentioned separation method is volumetric concentration.
Herba Violae Diffusae described in the above-mentioned separation method is Violaceae (Violaceae) Viola (Viola) per nnial herb.
Cork alkyl-type triterpenoids of the present invention has the effect of anti-hepatitis B virus, can be used for preparing the medicine of prevention and treatment hepatitis B.Described medicine is by shown in (I) formula 3,4-driffractive ring friedelane type triterpene compound and the formulation commonly used formed of acceptable auxiliary material pharmaceutically, as, injection, tablet or capsule etc.The weight percentage of the compound shown in (I) formula is 10%～50% in the described preparation.
Prove shown in (I) formula 3 below by experiment, the technique effect that 4-driffractive ring friedelane type triterpene compound has.Adopt the human liver cancer cell HepG2.2.15 of hepatitis B virogene transfection, the research compound is to the influence of HBV surface antigen (HBsAg), HBV cAg (HBeAg) secretory volume in the HepG2.2.15 cell culture fluid supernatant, investigate the anti-HBV effect of compound of the present invention, concrete experimental technique is as described below.
(1) preparation of pastille nutrient solution
With following embodiment 1 resulting compound 2 beta-hydroxies-3,4-splits friedelane-27-carboxylic acid respectively with the mother liquor that is mixed with 100mmol/L after the DMSO dissolving, again with the high sugared nutrient solution of DMEM (being perfect medium: contain 10% foetal calf serum, 150 μ g/mLG418, penicillin 100 μ g/mL, 100 μ g/mL Streptomycin sulphates and 0.3g/L glutamine) dilution, be mixed with 100 respectively, 50,25,12.5,6.25 3.125 μ mol/L are the pastille nutrient solution of totally 6 concentration gradients.
(2) experimental technique
1. cytotoxicity experiment
Mtt assay: with 0.25% trypsinase and 2 ‰ EDTA1:1 mixture slaking single-layer culturing cells, after stopping to digest, add PBS liquid, blow and beat cell dispersion repeatedly with the elbow suction pipe, in the centrifugal 3min of 1000rpm.Supernatant discarded, adding 5mLDMEM is high, and sugared nutrient solution is resuspended, is made into the individual cells suspension behind the piping and druming cell dispersion, with 3 * 10
5Individual/mL is inoculated in 96 well culture plates, every pore volume 100 μ L.Culture plate is put into 37 ℃, 5%CO
2Incubator in cultivate 24h, after treating that cell is adherent fully, add the pastille nutrient solution (experimental group) of different concns, normal nutrient solution (blank group), 1 ‰ DMSO solution (DMSO control group), experimental group, blank group and DMSO control group are established 4 multiple holes for every group, the medicine control group is (acellular, the pastille nutrient solution that only adds different concns) establish 1 multiple hole, each group is cultivated 3d simultaneously.Supernatant liquor is removed in suction, and every hole adds 5g/L MTT20 μ L, hatches 4h for 37 ℃, inhales and abandons supernatant liquor, and every hole adds DMSO150 μ L, culture plate is placed shake 10min on the oscillator, and crystallisate is fully dissolved.Survey each hole OD value in microplate reader, measure wavelength 570nm, the record result calculates cell survival rate and half toxic concentration (TC
50).
Cell survival rate (%)=(OD
Experimental group/ OD
The blank group) * 100%
Half toxic concentration (TC
50Inhibition percentage * the C of the inhibition percentage of)=Anti log[logB+ (50-B)/(A-B)] (A ≧ inhibition 50% drug level, B ≦ inhibition 50% drug level, C=log extension rate), with reference to the Reed-Muench method.
2. the inhibition of HBeAg, HBsAg is tested
Euzymelinked immunosorbent assay (ELISA): getting cell conditioned medium liquid, adopt euzymelinked immunosorbent assay (ELISA), with hepatitis B surface antigen and the operation of e antigen detecting agent box by specification, serves as to detect wavelength to measure each hole OD value with 630nm as reference wavelength, 490nm on microplate reader.Calculate antigen inhibiting rate and medicine to the half-inhibition concentration (IC of antigen
50).
Medicine is to inhibiting rate (%)=(1-OD of antigen
Experimental group/ OD
The blank group) * 100%
Medicine is to the half-inhibition concentration (IC of antigen
50Inhibition percentage * the C of the inhibition percentage of)=Anti log[logB+ (50-B)/(A-B)] (A ≧ inhibition 50% drug level, B ≦ inhibition 50% drug level, C=log extension rate), with reference to the Reed-Muench method.
3. statistical analysis
Experimental data with
(mean ± standard deviation) expression, the SPSS13.0 statistical software is adopted in statistical study.The OD value of same compound between the different concns group carried out one-way analysis of variance (One-way ANOVA): adopt the check of LSD method when variance is neat behind the variance test of homogeneity; Adopt Dunnett ' s T3 method during heterogeneity of variance.Significance level is got α=0.05, with P＜0.05 o'clock, judges that group difference has statistical significance.
4. calculate therapeutic index
Secretion to HBeAg or HBsAg has obvious restraining effect, and inhibiting rate and drug level be the compound of typical amount effect relationship, and its external anti-HBV effect therapeutic index (TI) is estimated.
Therapeutic index (TI)=TC
50/ IC
50, wherein TI ≧ 2 are effective low toxicity; 1＜TI＜2 are that poor efficiency is poisonous; TI ≦ 1 is toxicity.TI numerical value more large compound is more safe.
(3) experimental result and discussion
With experimental data after above-mentioned statistical procedures the result shown in following table 1～3.
Table 1 cytotoxicity experiment result
*: P＜0.05 when comparing with the blank group
The inhibition experimental result of table 2 couple HBeAg, HBsAg
*: P＜0.05 when comparing with the blank group
Table 3 TC
50, IC
50With the TI value
Above-mentioned experimental result shows 2 beta-hydroxies-3 of the present invention, and 4-splits friedelane-27-carboxylic acid and has anti-HBV activity, and the TI of HBeAg greater than 2, but is respectively 1.16,0.8 to the TI of HBsAg, can be used for preparing treatment and the prophylactic agent of hepatitis B.
Description of drawings
Fig. 1 compound of the present invention
1H-NMR schemes (500MHz).
Fig. 2 compound of the present invention
13C-NMR schemes (150MHz).
The DEPT figure of Fig. 3 compound of the present invention.
The HSQC NMR figure of Fig. 4 compound of the present invention.
The HMBC NMR figure of Fig. 5 compound of the present invention.
The NOE NMR figure of Fig. 6 compound of the present invention.
Embodiment
Following experiment is picked up from Fujian Province's Yongchun County with Herba Violae Diffusae (Viola diffusa Ging) herb.
Example 1:
One, the preparation of compound
(1) get dry Herba Violae Diffusae herb 10kg, use 120L successively, 100L and 80L concentration are 95% alcohol reflux Herba Violae Diffusae herb 2h, merge ethanol extract, reclaim ethanol and are evaporated to and do not have the alcohol flavor, get total medicinal extract;
(2) total medicinal extract is dissolved in the water, then, uses the water saturated n-butanol extraction of 1.4L sherwood oil, 3L vinyl acetic monomer and 3L 3 times successively, get butanol extraction liquid, the concentrating under reduced pressure desolventizing gets n-butyl alcohol extract 168g;
(3) get n-butyl alcohol extract 84g and be dissolved in the 600ml water, cross D-101 type macroporous resin column, water, concentration are that 10% ethanol, concentration are that 30% ethanol, concentration are that 60% ethanol, concentration are that 90% ethanol and concentration are 95% ethanol elution successively; Collecting concentration and be 95% ethanol eluate and cross 200～300 purpose silicagel columns, be solvent by Shi You Mi ︰ vinyl acetic monomer with sherwood oil-vinyl acetic monomer is that the gradient of 250 ︰, 1～2 ︰ 1 is carried out wash-out; Collection Shi You Mi ︰ vinyl acetic monomer is that the elutriant of 2 ︰ 1 is crossed 200～300 order silicagel columns, is the eluent wash-out with the vinyl acetic monomer, collects the vinyl acetic monomer elutriant, obtains green plate crystal after concentrating;
(4) green plate crystal being crossed the SephdexLH-20 post, is the eluent wash-out with methyl alcohol, collects meoh eluate, obtains white, needle-shaped crystals 29mg after concentrating.
Two, the evaluation of compound
Resulting white, needle-shaped crystals is soluble in chloroform, is insoluble in methyl alcohol.HR-ESI-MS m/z511.3393[M+Na]
+(calculated value 511.3398) determines that its molecular formula is C
30H
48O
5, degree of unsaturation is 7.After testing, its
1H-NMR,
13The C-NMR data are as follows:
1H-NMR（500MHz，CDCl
3）δ/ppm:4.34(1H,dd,J=12.0,2.0Hz,H-2)，4.23(1H,q,J=6.5Hz,H-4)，1.23(3H,d,J=6.5Hz,CH
3-23)，0.87(3H,s,CH
3-24)，0.87(3H,s,CH
3-25)，1.12(3H,s,CH
3-26)，1.21(3H,s,CH
3-28)，0.99(3H,s,CH
3-29)，0.93(3H,s,CH
3-30)。
13C-NMR(125MHz，CDCl
3)δ/ppm:29.5(C-l)，69.3(C-2)，177.0(C-3)，84.9(C-4)，40.2(C-5)，37.8(C-6)，18.3(C-7)，52.6(C-8)，38.2(C-9)，60.4(C-10)，37.9(C-11)，27.7(C-12)，54.5(C-13)，39.1(C-14)，33.0(C-15)，35.6(C-16)，30.7(C-17)，43.2(C-18)，36.1(C-19)，28.4(C-20)，32.3(C-21)，38.5(C-22)，16.2(C-23)，13.5(C-24)，18.4(C-25)，22.7(C-26)，181.6(C-27)，30.9(C-28)，30.3(C-29)，35.5(C-30)。
Referring to Fig. 1～6,
1Show 7 methyl among the H-NMR, comprise 4 unimodal [δ of angular methyl(group)
H: 0.87 (3H, s, CH
3-24), 0.87 (3H, s, CH
3-25), 1.12 (3H, s, CH
3-26), 1.21 (3H, s, CH
3-28)], 2 unimodal [δ of gem-dimethyl
H: 0.99 (3H, s, CH
3-29), 0.93 (3H, s, CH
3-30)] and the bimodal δ of methyl
H1.23 (3H, d, J=6.5Hz, CH
3-23); And at δ
H: there are 2 even oxygen proton [δ in 4～5 zones
H: 4.23 (q, J=6.5Hz, H-4), 4.34 (dd, J=12.0,2.0Hz, H-2)].By
13C-NMR and DEPT spectrum is determined to contain 7 methyl, 10 methylene radical and 5 methynes in the molecule, wherein 2 (δ that link to each other with oxygen
C: 84.9,69.3), 8 quaternary carbons (comprise 2 carbonyl carbon δ
C: 177.0,181.6), infer tentatively that by above-mentioned feature this structure is triterpene compound.
In the HMBC spectrum, contain oxygen proton δ
H4.23 (1H, q, J=6.5Hz, H-4) and δ
C16.2 relevant, by HSQC as can be known, this is the bimodal δ of methyl
H1.23 (J=6.5Hz) carbon on is contained the coupling constant of oxygen proton and methyl proton and is split branch by this and can release and contain oxygen methyne and CH for 3H, d
3Link to each other carbonyl δ in HMBC
C177.0 with H-1, H-2 and H-4 coherent signal is arranged, in addition, also has H-10 and C-1, C-2; H-4 and C-10; H-24 is to long-range coherent signals such as C-4, C-5, C-10, and by above nuclear magnetic data and long-range relevant deducibility, this new compound is one 3, and 4-splits the cork alkane type triterpenoid.Consult document [Patra A, Chaudhuri S K, Acharyya A K.Applications of Two-Dimensional NMR in Spectral Assignments of Some Friedelanes and Secofriendelanes.Magnetic Resonance in Chemistry, 1990,28:85-92] find, new compound is compared with the carbon spectrum of 2 α-hydroxyfriedelolactone, many carbonyl signal δ 181.6, and lacked a methyl signals δ 18.5, simultaneously the C-13 of new compound to low mobile (+15.3ppm), C-12 moves (2.9ppm) to High-Field, the molecular weight more than 458 30 of molecular weight 488 to the 2 α-hydroxyfriedelolactone of new compound, the above-mentioned data of analysis-by-synthesis infer that tentatively new compound is the product that the C-27 methyl of 2 α-hydroxyfriedelolactone is oxidized to carboxyl.
Compare with compound 2 α-hydroxyfriedelolactone, the C-1 of new compound to low mobile (+4.3ppm), and C-2 moves to High-Field and (infers that 3.2ppm), new compound C-2 configuration is opposite with 2 α-hydroxyfriedelolactone.Observing H-2 and H-4 and H-10 from NOESY has tangible NOESY effect, and the prompting three is positioned at the same side, and confirmation C-2-OH is beta comfiguration.In addition, H-26 and H-25 and H-28 all have tangible NOESY effect, determine 25,26,28-CH
3Be beta comfiguration.According to document [Baas W J.Naturally occurring seco-ring-A-triterpenoids and their possible biological significance.Phytochemistry1985,24 (9): 1875-89] and source of students relation, determine that C-27-COOH is positioned at C-13 α position.Identify the structural formula of the friedelane that the present invention prepares thus for shown in (I) formula, its name is called 2 beta-hydroxies-3, and 4-splits friedelane-27-carboxylic acid, and English name is 2 β-hydroxy-3,4-seco-friedelolactone-27-oic acid.
Example 2:(injection)
Get the compound 1000mg that adopts above-described embodiment 1 described method to obtain, add the water for injection of 1000ml, with yellow soda ash adjust pH to 7～7.5, stirring makes dissolving, and degerming filters, embedding, through 100 ℃ of 15 minutes flowing steam sterilizations, the injection liquid of making every 2mg/2ml uses for injection.
Example 3:(capsule)
Getting the compound 5000mg that adopts above-described embodiment 1 described method to obtain fully mixes with auxiliary materials such as 4000mg Microcrystalline Cellulose, 500mg sodium starch glycolate, 400mg sodium lauryl sulphate, adopt roll-in method to carry out dry granulation, again with an amount of Magnesium Stearate mixing, be packed into the 3# Capsules, make specification and be the capsule of 100mg/ grain for orally using.
Example 4:(tablet)
Getting the compound 5000mg and 4000mg starch, 200mg cross-linked pvp, the 300mg sodium starch glycolate that adopt above-described embodiment 1 described method to obtain mixes, with 75% ethanolic soln of 5%PVP as tackiness agent, softwood processed, granulate with 18 mesh sieves, 60 ℃ of dry back 1h, the whole grain of 20 orders back adds an amount of talcum powder, mixing, compressing tablet is made specification and is the tablet of 100mg/ sheet for orally using.
Claims (5)
1. one kind 3,4-driffractive ring friedelane type triterpene compound, shown in the following formula I of its molecular structure:
2. claim 1 is described 3, the preparation method of 4-driffractive ring friedelane type triterpene compound, and this method is made up of step down:
(1) getting Herba Violae Diffusae, is 95% alcohol reflux 2h successively with 12,10 and 8 times concentration, merges ethanol extract, reclaims ethanol and also is evaporated to and does not have the alcohol flavor, gets total medicinal extract;
(2) total medicinal extract is dissolved in the water, then, uses sherwood oil, vinyl acetic monomer and water saturated n-butanol extraction successively, get butanol extraction liquid, concentrating under reduced pressure, desolventizing gets n-butyl alcohol extract;
(3) n-butyl alcohol extract is dissolved in the water, crosses D-101 type macroporous resin column, water, concentration are that 10% ethanol, concentration are that 30% ethanol, concentration are that 60% ethanol, concentration are that 90% ethanol and concentration are 95% ethanol elution successively; Collecting concentration and be 95% ethanol eluate and cross 200～300 purpose silicagel columns, be solvent by Shi You Mi ︰ vinyl acetic monomer with sherwood oil-vinyl acetic monomer is that the gradient of 250 ︰, 1～2 ︰ 1 is carried out wash-out; Collection Shi You Mi ︰ vinyl acetic monomer is that the elutriant of 2 ︰ 1 is crossed the silica gel H post, is the eluent wash-out with the vinyl acetic monomer, collects the vinyl acetic monomer elutriant, obtains green plate crystal after concentrating;
(4) green plate crystal being crossed the SephdexLH-20 post, is the eluent wash-out with methyl alcohol, collects meoh eluate, obtains white, needle-shaped crystals after concentrating and gets final product.
3. claim 1 is described 3, the application of 4-driffractive ring friedelane type triterpene compound in the medicine of preparation prevention and treatment hepatitis B.
One kind the prevention and the treatment hepatitis B medicine, this medicine is by claim 1 described 3,4-driffractive ring friedelane type triterpene compound and pharmaceutically the acceptable auxiliary material form, wherein said 3, the weight percentage of 4-driffractive ring friedelane type triterpene compound is 10%～50%.
5. the medicine of prevention according to claim 4 and treatment hepatitis B is characterized in that described medicine is injection, oral tablet or capsule.
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| CN109010524A (en) * | 2018-09-29 | 2018-12-18 | 宁夏医科大学 | Application of the n-butanol portion of viola mandshurica ethanol extract as epidemic prevention liver injury medicament |
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| CN109010524B (en) * | 2018-09-29 | 2021-04-27 | 宁夏医科大学 | Application of n-butanol fraction of herba Violae ethanol extract as medicine for preventing immunological liver injury |
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