CN100522189C - Method for preparing broad-spectrum antiviral drug of nano total acid of chickweed as well as usage and chickweed acid A - Google Patents
Method for preparing broad-spectrum antiviral drug of nano total acid of chickweed as well as usage and chickweed acid A Download PDFInfo
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- CN100522189C CN100522189C CNB021385734A CN02138573A CN100522189C CN 100522189 C CN100522189 C CN 100522189C CN B021385734 A CNB021385734 A CN B021385734A CN 02138573 A CN02138573 A CN 02138573A CN 100522189 C CN100522189 C CN 100522189C
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Abstract
A nano-class broad-spectrum activirus medicine of common stellaria acid, its preparing process, its application in suppressing HIV, hepatitis virus, influenza virus, parainfluenza virus, adenovirus, rhinovirus, etc. and the stallaria acid A are disclosed. Its advantages are high effect and no environmental pollution.
Description
One, technical field:
The present invention relates to a kind of Preparation method and use of antiviral drugs, particularly a kind of compositions is as the chemical constitution of broad-spectrum antiviral preparation method of Chinese medicine, purposes and compositions.
Two, background technology:
So far still lacking real effectively medicine aspect the many viral diseases of treatment, substantially also past medical help when particularly causing infection or mixed infection by multiple virus or variable virus both at home and abroad, this is to perplex the famous thorny difficult problem of world the world of medicine for a long time.
Because the disease that some viruses cause almost is fatal, as HIV (human immunodeficiency virus), Ebola virus, dengue virus, rabies virus etc.; The hepatitis that other viruses cause as 5 kinds of hepatitis viruss such as hepatitis A, hepatitis B; Viral myocarditis of initiation such as Coxsackie virus, influenza virus or the like can make people disability even lifelong disability, and particularly some virus still is one of major reason of cause cancer, so the disease that virus causes harm is very big.The whole world is all urgently being sought and can had powerful inhibiting broad-spectrum antiviral medicament simultaneously to RNA and DNA two big viroids in vivo now, and requires this medicine must have enough safeties.Because, only develop broad spectrum activity antiviral and safe drugs again, just might really solve variable virus and multiple viroid infects or mixed infection causes virosis; When promptly no matter which kind of virus or its variant viral can both be suppressed by medicine in vivo, this medicine could real these virus diseases of solution.
With regard to by flu: flu comprises bacterial infection and viral infection two big classes, wherein " virus flu " (comprising influenza) accounted for more than 75% of patient of flu, antibacterial and viral this two big quasi-microorganism also can alternately infect or mixed infection.The available antibiotic therapy of bacillary flu, and " virus flu " do not have real specific drug so far yet on whole world medical market.
Why the virus flu does not still have specific drug, be that four classes and other tens of kinds viruses such as rhinovirus, Echovirus such as influenza virus (A, B, C), parainfluenza virus, respiratory syncytial virus that belongs to the RNA class and some kinds of adenoviruss that belong to the DNA class are arranged because of the virus that can cause this disease, wherein influenza virus etc. is also constantly morphing., be very difficult just so look to solving this world's thorny difficult problem of medicine that causes by multiple viroid, easy variation virus with vaccine because of causing the various and easy variation of viral species of virus flu.Because the vaccine specificity is very strong, can only make human body to producing immunity in order to the virus of making this vaccine, can not can both produce immunization to other miscellaneous virus and variant thereof, and vaccine can only prevent and can not treat.When just must developing clinical treatment, this can just might really cure a world-renowned medical difficult problem-" the virus flu " that causes by multiple viroid or its variant viral to the specially good effect broad-spectrum antiviral medicament of RNA and the powerful antivirus action of the DNA two equal tools of big class cold virus, but the still untapped medicine that goes out to have this clinical usefulness in the whole world appears on the market so far, " coldrex " used always often can only symptomatic treatment, and be difficult to etiological treatment, often do not know after taking medicine to shorten the course of disease several days on earth yet, the median of its paresthesia alleviateding time needed several days etc., if the ill poison flu of patient was just taken medicine after 5～6 days, then cross 1～2 day patient and take medicine and all can be almost recovered, this can not prove the Drug therapy effect.In fact, the effective medicine of most in vitro testses, oral and behind liver first-pass effect often usefulness lower greatly or become invalid, be difficult to reach the purpose of clinical cure virus flu.So the world of medicine generally acknowledges: also not have really the specific drug of can Cure Viruses catching a cold at present, particularly when infection that causes when multiple virus or variable virus or mixed infection especially the good medicine difficulty ask.This is to perplex the famous thorny difficult problem of world the world of medicine for a long time.Therefore, The World Health Organization (WHO) wishes that my China solves this world-renowned difficult medical problem of viral influenza, but the China and even the whole world all fail really to solve so far.
Report according to the data on " Development Research Center of the State Council's Information Network ": China has 75% people to suffer from once flu at least every year approximately, promptly has every year nearly 1,000,000,000 people at least need be with a cold medicine; Influenza morbidity example time accounts for about 4%～37% of total population when influenza pandemic, even also reach every year on average more than tens million of examples time with conservative algorithm.Influenza virus not only can cause sick deterioration of patient base also can cause secondary infection, causes rheumatism, pneumonia, viral myocarditis etc., even causes death, and its harm and influence are all bigger.According to " foreign medical science social medicine fascicle " 1998.09; 15 (3): Liu 142-143 passes nanmu " 1997-1998 year U.S.'s influenza active situation " and reports once literary composition: the U.S.'s 122 city influenza pandemic, first all mortality rates have surpassed 8% (basic horizontal 7.2%).Other has the report U.S. to die from the patient of influenza every year with regard to about 20,000 people." Nanjing morning newspaper " calendar year 2001 JIUYUE " gene of cold virus changes mortality " literary composition report on the 18th: recent studies on of Univ Wisconsin-Madison USA shows, is called as PB in the influenza virus
2Specific gene generation limited variation after, viral toxicity will obviously increase, thereby becomes novel deadly virus.Influenza virus just constantly makes a variation, and will become new human killer at any time, and influenza is again modal frequently-occurring disease, and this becomes seriously with regard to making problem.
Ribavirin is synthetic broad-spectrum antiviral Western medicine, in the test cell line multiple RNA and DNA viruses is had obvious inhibition, and its mechanism of action mainly is suppress viral nucleic acid synthetic, stops virus replication.Influenza virus is truly had inhibition, is the medicine commonly used of present clinical treatment virus influenza.But its curative effect still can not make the very fast rehabilitation of patient during its clinical treatment influenza, and have the report ribavirin also have certain toxic and side effects if any gastrointestinal reaction, cause anemia etc.
" influenza vaccines " to the true tool preventive effect of influenza, but only can only prevent, and can not treat, in case influenza morbidity back just should not re-use.Its specificity that suppresses virus is also strong, can only make human body to producing immunity in order to the virus of producing vaccine, and the injection of must seeking medical advice, and price is also more expensive, and a pin just at least need be more than 50 yuan; And be difficult to judge in oneself necessity that whether is bound to infect influenza, has or not vaccinate during healthy people's vaccinate next few month, therefore use and inconvenience.According to " science abstract newspaper " 16 days January calendar year 2001 the 5th edition " mistaken ideas of health care " one literary composition introduce: " influenza vaccines " are a kind of virus in fact, make the old man produce problems such as the reaction of pathologic autoimmunity, easier cancer stricken.
According to multiple newspapers and periodicals such as " Chinese medicine Tribune ", " foreign medical science pharmacy fascicles ": at present in the world exploitation to be used for the treatment of the best medicine of influenza be Britain, U.S.'s exploitation " influenza virus neuraminidase inhibitor " class medicine, after 1999, go on the market on Australia, Europe, the United States and other places.Its major advantage can suppress A, Type B influenza virus exactly.According to " Chinese medicine Tribune " 2001.1.11 " NICE recommends Oseltamvir Zanamivir (Relenza) for a high-risk group " literary composition and " foreign medical science pharmacy fascicle " 1999.08; 26 (4): the data that 247 report and Britain Glaxo-Wellcome company deliver on the internet waits: the median time of Zanamivir treatment group remission is 5 days, shortened 1.5 days in 6.5 days than placebo group, this has been obtained maximum progress aspect the viral influenza of treatment that world the world of medicine generally acknowledges, also is real accomplishment very.But, can only suppress influenza virus A during clinical treatment virus influenza and B still is not enough, this class medicine remains following defectives and deficiency:
1, paresthesia alleviateding time needs 5 days approximately behind the clinical use medicine, and matched group is 6.5 days, but shorten the course of disease about 1.5 days, although this has been a real accomplishment very, could rehabilitation but still need stand about 5 days misery after patient's medication.
2, influenza virus neuraminidase inhibitor can only suppress influenza A, B virus, and to other virus that can cause respiratory tract infection as influenza virus C, parainfluenza virus, respiratory syncytial virus and belong to the adenovirus etc. of DNA class, also have rhinovirus, Echovirus, Coxsackie virus or the like whether also to have and suppress there is no report, so its therapeutic domain still can not really solve the virus flu that comprises influenza, is its limitation.
3, influenza virus neuraminidase inhibitor still has certain untoward reaction, for example Zanamivir has the symptom of similar influenza disease and diarrhoea, dizzy, nausea and vomiting etc., the Placenta Hominis transfer phenomena is arranged during animal experiment, thereby still difficulty is determined in the trimester of pregnancy safety of whether taking medicine, especially Ren Shen head should not take Zanamivir in three months, and doctor formula must be arranged.
4, Zanamivir etc. is not suitable for child below 12 years old, and child Geng Yi suffers from influenza.
5, the Zanamivir oral administration biaavailability has only 2%, so can not oral administration.
6, the inventor once asked someone to buy in Hong Kong Zanamivir market price 200 Hongkong dollars (25 dollars) ex hoc genus anne product Oseltamivir market price 250 Hongkong dollars (30 dollars) of a retail packaging, the price comparison height, the middle and low income patient Shang Nan of China and developing country bears.
So the world of medicine only approves that influenza virus neuraminidase inhibitors such as Zanamivir and Oseltamivir make etiological treatment virus influenza become possibility at present.
Active drug just because of do not have to suppress so multiple influenza virus simultaneously and do not see overt toxicity on the whole world medical market up to the present at all, also be difficult to solve up hill and dale with the stronger influenza vaccines of specificity comprehensively, " so influenza is taken medicine and a week is cured the spontaneous recovery in seven days of not taking medicine ".
Again with regard to generalized antiviral drugs: the ucleosides antiviral drugs " acycloguanosine " that Britain Burroghs Wellcome company developed the seventies, official name: acyclovir can have the high selectivity activity to herpes simplex and varicella zoster virus.U.S. FDA was ratified in nineteen eighty-two first in Britain listing in 1981, and China trial-produceed successfully, put into production with ＂ acycloguanosine ＂ name in 1985 in nineteen eighty-three, but ＂ acycloguanosine ＂ therapeutic domain still has limitation.
The medicine " interferon " that the also useful modern genetic engineering of antiviral drugs commonly used is clinically now produced, this is the present clinical viral hepatitis medicine preferably that is used for the treatment of, the herpes-like virus disease also there is better curative effect, but its price is more expensive, palpus long term injections administration during treatment hepatitis, medical expense is high, and the disease kind of use also has certain restricted.
Be used for the treatment of nucleic acid drug and " HAART " thereof of acquired immune deficiency syndrome (AIDS) at present, promptly treat acquired immune deficiency syndrome (AIDS) with the various combination and variation of dissimilar medicines and play a good role, obviously relief of symptoms prolongs patient's life.But, because HIV (human immunodeficiency virus) is that multiple viroid is variable again just as influenza virus, having found tens kinds of HIV (human immunodeficiency virus) in the world at least, China has also found at least 8 kinds, Here it is, and existing nucleic acid drug and vaccine thereof are insoluble.Nucleic acid drug poison pair is made comparisons greatly in addition, is subjected to certain limitation in the use, and price is also relatively more expensive, need life-time service again, the general common people are not still with rising, thus have " aids patient rich way arranged; out of funds can not " say, can be in case can not just mean death, this is extremely serious.
In a word, at present both at home and abroad on the medical market, be used for the treatment of viral disease have only some specificities stronger at the effective medicine of minority virus, these medicines or curative effect are limited, perhaps toxic and side effects is bigger, and it is convenient inadequately perhaps to use, and perhaps costs an arm and a leg or the like.So the urgent hope in the whole world can be sought a kind of safe and effective, cheap broad-spectrum antiviral medicament easily early and solve the viral disease that is caused by multiple virus and variable virus etc.
Three, summary of the invention:
1, the technical problem to be solved in the present invention: invent a kind of can broad-spectrum antiviral do not see not only obvious toxic-side effects and but also relatively inexpensive innovation Chinese medicine, plugging a gap aspect the treatment viral disease for solving world the world of medicine, and its production method and preparation thereof be provided.
2, the technical solution used in the present invention: the total acidic compound compositions that obtains with extraction separation such as nanotechnologys from plant Herba stellariae mediae Stellaria media (L.) Cyr. and congener thereof is being used aspect the treatment virus disease as antiviral natural medicine (to call " compositions " in the following text).
By retrieval the Pharmazie and the U.S. " chemical abstracts " (Chemical Abstracts) till the 134th volume, the chemical constituent of the Stellaria plant of being reported mainly is benzoic acid, ferulic acid and esters thereof, chlorogenic acid, neochlorogenic acid, caffeic acid, quininic acid, ascorbic acid class, oxalic acid and calcium oxalate, monoacyl galactose lipoid, flavone and the former class of flavonoid glycosides, Saponin and Saponin, ring peptide class, alkaloids, galactopyranose-SN-glycero class, sterols, steroid enol class or the like from nineteen twenty to calendar year 2001.Do not see research, report and the application of total acid and sulfur-bearing composition, but and this compositions is the total acidic chemical compound of Stellaria plant extract sulfur-bearing soluble in water.Relevant both at home and abroad by retrieval patent, consult National Drug Administration announces on domestic and international pertinent literature such as U.S.'s " chemical abstracts " (Chemical Abstracts), the retrieval the Internet approval clinical application catalogue etc., up to the present do not see as yet with Stellaria plant extract total acidic compound compositions is clinical and be used to prevent and treat correlational study and reports such as virus disease, also do not see the medicine made from same combination and appear on the market, so the present invention has novelty, creativeness.
The present composition comprises one of following 77 kinds the extraction with methods such as nanotechnologys with Stellaria plant Herba stellariae mediae Stellariamedia (L.) Cyr. or Stellaria plant Stellaria L. and cattle Stellaria plant Malachium Fries: Stellaria alsine Grim. Stellaria alsineGrimm., brown lobe Stellaria alsine Grim. Stellaria alsine var.phaeuspetala Hand.-Mazz., Anhui Herba stellariae mediae Stellaria anhwiensis Migo., blunt calyx Herba stellariae mediae Stellaria amblyosepalaSchrenk., apicule Herba stellariae mediae Stellaria apiculata Wils., Herba malachii aquatici Stellaria aquatica (L) Scop., the husky Herba stellariae mediae Stellaria arenaria Maxim. that gives birth to, Alishan Herba stellariae mediae Stellariaarisanensis Hayata., slender lobule Alishan Herba stellariae mediae Stellaria arisanensis var.leptophylla Hayata., north Herba stellariae mediae Stellaria borealis Bigel., short lobe Herba stellariae mediae Stellaria brachypetala Bge., long lobe Herba stellariae mediae Stellaria bungeana Fenzl., northeast Herba stellariae mediae Stellaria cherleriae (Fisch.) Will., China Herba stellariae mediae Stellaria chinensisRegel, Taiwan Herba stellariae mediae Stellaria cicrantha Hayata, thick leaf Herba stellariae mediae Stellariacrassifolia Ehrh., wrinkle leaf Herba stellariae mediae Stellaria crispate Wall., David's Herba stellariae mediae Stellariadavidii Hemsl., the Herba stellariae mediae Stellaria decumbens Edgew. that crouches lays down, the needle-like Herba stellariae mediae Stellaria decumbens var.acicularia Edgew.et Hook.f. that crouches that lays down, southwest Herba stellariae mediae Stellaria delavayi Franch., Stellaria dianthifolia Williams Stellaria dianthifoliaWilliams, forked cyme Herba stellariae mediae Stellaria dichasioides Williams, bifid Herba stellariae mediae Stellaria dichotoma L., narrow leaf bifid Herba stellariae mediae Stellaria dichotoma var.lanceolata Bge., line leaf bifid Herba stellariae mediae Stellaria dichotoma var.stephenianaWilld., Herba stellariae mediae Stellaria diffusa Wills. looses in the shop, turn over white Herba stellariae mediae Stellaria discolorTurcz., Stellaria diversiflora Maxim. Stellaria diversiflora Maxim., the different colored Herba stellariae mediae Stellariadiversiflora var.gymnandra Franch. of naked stamen, concave veins Herba stellariae mediae Stellaria depressaSchnid., Du Shi Herba stellariae mediae Stellaria duthiei Gandoger, line stem Herba stellariae mediae Stellariafilicaulis Mak., line handle Herba stellariae mediae Stellaria filipes Komar., spend more Herba stellariae mediae Stellariaflorida Fisch., standing grain leaf Herba stellariae mediae Stellaria graminea L., dredge pubescence standing grain leaf Herba stellariae mediae Stellaria graminea var.pilosula Maxim., turn green standing grain leaf Herba stellariae mediae Stellariagraminea var.viridescens Maxim., Jiangzi's Herba stellariae mediae Stellaria gyantsensisWilliams, XIACAO Herba stellariae mediae Stellaria gypsophiloides Fenzl., Stellaria henryi williams Stellaria henryi Williams, the Herba stellariae mediae Stellaria hsinganensis Kitagawa of Xingan, introversion Herba stellariae mediae Stellaria infracta Maxim., slender lobule Herba stellariae mediae Stellaria leptophyllaHance, Stellaria maximowixziana Franch. Stellaria maximowixziana Franch., Stellaria micrantha Hayata Stellariamicrantha Hayata, gentle Herba stellariae mediae Stellaria mitans Williams, goose intestinal Herba stellariae mediae Stellaria neglecta Weihe, Herba stellariae mediae Stellaria neo-palustris Kitagawa is given birth in new natural pond, eight stamen Herba stellariae mediae Stellaria octandra Fobedim., raspberry Herba stellariae mediae Stellariaoxycoccoides Komar., Herba stellariae mediae Stellaria palustris L. is given birth in the natural pond, exhibition leaf Herba stellariae mediae Stellaria patentifolia Kitagawa, handle flower Herba stellariae mediae Stellaria peduncularis Bge., Herba stellariae mediae Stellaria pilosa Franch. becomes mildewed, imitation stone is given birth to Herba stellariae mediae Stellaria pseudosaxatilisHand.-Mazz., blinks Stellaria pusilla Schmid., flint lobe Herba stellariae mediae Stellariaradians L., net arteries and veins Herba stellariae mediae Stellaria reticulivena Hayata, rock Herba stellariae mediae Stellariarupestris Hemsl., stone is given birth to Herba stellariae mediae Stellaria saxatilis Buch.-Ham., embrace stem stone and give birth to Herba stellariae mediae Stellaria saxatilis var.amplexicaulis Hand.-Mazz., accurate Ge Er Herba stellariae mediae Stellaria soongorica Roshev., Su Shi Herba stellariae mediae Stellaria souliei Williams, star hair Herba stellariae mediae Stellaria stellato-pilosa Hayata, garden calyx Herba stellariae mediae Stellariastrongylosepala Hand.-Mazz., intend umbrella flower Herba stellariae mediae Stellaria subumbellataEdgew., little fine hair Herba stellariae mediae Stellaria tomentella Ohwi, three type Herba stellariae mediae Stellariatrimorpha Nakai, Turkestan Herba stellariae mediae Stellaria turkestanica Schischk., wetland Herba stellariae mediae Stellaria uda Williams, umbrella flower Herba stellariae mediae Stellaria umbellate Turcz., LVHUA Herba stellariae mediae Stellaria virdiflora Pax et O.Hoffm., Stellaria wushanensis Williams Stellariawushanensis Williams, five Herba stellariae mediae Stellaria wutaica Hand.-Mazz., Yunnan Herba stellariae mediae Stellaria yunnanensis franch. and Caryophyllaceae cattle Stellaria MalachiumFries plant cattle Herba stellariae mediae Malachium aquaticum (L.) Fries.
According to " Chinese medicine voluminous dictionary " record " Herba stellariae mediae "
[nature and flavor]: sweet little salty, flat." not Lu ": " acid be flat nontoxic."; Compendium of Material Medica " sweet little salty ".
[function cures mainly]: blood circulation and promoting silt, stimulating milk secretion expedites the emergence of.The back stasis of blood of managing property stagnates, stomachache, and breast is few down, summer-heat vomiting, acute appendicitis, gonorrhea, malignant boil toxic swelling, traumatic injury." not Lu ": main malignant boil not for many years be healed." " middle traditional Chinese medicines are planted illustrated handbook ": leave is rubbed juice, and skin ulcer wound etc. is controlled in external.
[usage and consumption]: for oral administration: as to fry in shallow oil 1～2 liang of soup; Or smash juice.External: smash deposited; Or charred medicinal herb with its property retained is ground into powder and transfer to be applied.
3, compositions of the present invention has following physicochemical characteristics:
1). become duplicate samples to do with Rt21.76 peak in the compositions high-efficient liquid phase chromatogram (Figure 13)
13Visible δ in C NMR (DMSO D-6) spectrogram (Figure 10): 182.4 (carboxyls), 164.3 and 161.3 (carbonyls), 129.7～103.7 (olefinic carbon or phenyl ring carbon), 102.318 (alduronic acid or glucosides end group carbon), 60.956～102.318 (sugar charcoals).
2). done with above-mentioned same one-tenth duplicate samples
1Visible δ in H NMR (DMSO D-6) spectrogram (Figure 11): 13.8 (carboxylic hydroxyls), (10.2 phenolic hydroxyl group), with 9.2 (phenolic hydroxyl groups), 8.2～6.8 (fragrant hydrogen), (5.1 end proton), 4.8～4.5 (sugared hydroxyls), 4.7～4.3 (alkene hydrogen), 3.8～3.6 (saccharic) have carboxyl, carbonyl, ester, phenyl ring, phenol, hydroxyl, alkene and alditol acids or glycoside structure in the visible molecular structure.
3). above-mentioned sample adds after the heavy water exchange
1H NMR spectrogram (Figure 12): blackouts such as the carboxylic hydroxyl peak among Figure 11, phenolic hydroxyl group peak and sugared hydroxyl peak prove that it is active hydrogen entirely.
4). the mass spectrum of above-mentioned composition (Fig. 5) the as seen molecular weight of this chemical compound is 564.2.
Composing this molecular weight of undoubted proof because of above-mentioned proton nmr spectra and carbon is that 564.2 composition has carboxyl, is Herba stellariae mediae acid A so call this composition in the following text.
5). show with Herba stellariae mediae acid UV scanning that A does (Fig. 8): λ
H20 Max: 270.1 (170.27) nm and λ
H20 Max: 326.6 (154.90) nm, two maximum absorption bands and molar extinction coefficient thereof (E value) are arranged, in the prompting molecular structure just like the structure of cinnamyl and benzoyl class.
6). with Herba stellariae mediae acid A done infrared scan figure (Fig. 3) IR ν
KBr MaxCm
-1: 3400 (hydroxyls), 1653,1625 (α, β unsaturated carbonyls), 1580 and 1508 (phenyl ring) show in the molecular structure to have ester, benzene or groups such as phenol, hydroxyl.
7). according to molecular weight in the compositions is the above-mentioned spectral data that 564.2 Herba stellariae mediae acid A is done, and adds sample PYRIDIN-D
5Making solvent does
1H NMR,
13C NMR and DEPT thereof,
1H-
1H COSY,
1H-
1H NOESY,
13C-
1H COSY reaches
13C-
1Long-range relevant spectrogram and the elementary analysis of waiting of H learnt: its molecular weight is 564.2; Molecular formula should be C
26H
28O
16It is respectively δ that 2 methylene are only arranged in the molecular structure
C62.734 with δ
H3.186, δ
H3.3843 join, δ
C72.478 with δ
H3.3843, δ
H2.8444 join; 12 methine δ
C70.300,70.443,70.776,71.932,75.917,76.424,76.683,76.800,81.286,103.063,117.035,130.390 respectively with δ
H4.2496,3.559,3.2396,4.288,4.6494,4.0713,3.2147,3.2241,3.1927,5.6574,6.2894,7.6011 join, can know by inference in the molecular structure to have disaccharidase structure, wherein δ
C103.063 be sugared end group carbon; Remaining carbon is quaternary carbon and knows by inference phenol and ester structure are arranged in the carbon spectrum; Long-range relevant demonstration δ
H5.657 with δ
C(183.155 carboxyl), δ
C162.808 and δ
C103.063 relevant, can know by inference to have the alduronic acid structure; The NOESY spectrum shows δ
H2.8444 with δ
H3.3843 relevant, δ
H3.559 with δ
H3.186 and δ
H3.2147 relevant, δ
H4.0713 with δ
H4.6494 it is relevant;
1H-
1HCOSY shows δ
H4.2496 relevant with 4.0713, δ
H4.288 relevant with 4.649 or the like, tentatively judge in the Herba stellariae mediae acid A chemical constitution to should be two galacturonic acid benzoyl ene derivatives, and can form the esters of polygalacturonic acid benzoyl ene derivative.
8). the UV scanning of composition solution (Fig. 1) shows: λ
H20 Max: 271.7 (130.27) nm and λ
H20 Max: 327.4 (112.6) nm, two maximum absorption bands and molar extinction coefficient thereof (E value) are arranged, in the prompting molecular structure just like the structure of cinnamyl and benzoyl class.
9). the UV scanning of composition solution (Fig. 2) shows: λ
H20 Max273.6 (74.50) nm and λ
H20 Max321.0 (58.74) two of nm maximum absorption bands and E value thereof, in the prompting compositions molecular structure just like the structure of cinnamyl and benzoyl class.
10). carry out from each the Main Ingredients and Appearance peak to high performance liquid chromatography that compositions is done the termination of pumping scanning (Fig. 9) as seen: what be designated as " 8 ", " 17 ", " 27 ", " 36 " and " 43 " is respectively the 192nm peak of 5 peak compositions; What be designated as " 9 ", " 18 ", " 28 ", " 37 ", " 44 " then is the 202nm peak of 5 peak compositions; What be designated as that " 10 ", " 19 " " 29 ", " 38 " reach " 45 " then is the 273nm peak of 5 peak compositions; Be designated as " 11 ", " 20 ", " 30 ", " 39 ", and " 46 " then be the 327nm peak at 5 composition peaks, wherein being designated as 6 peaks of 26～31 is UV scanning spectrograms of Herba stellariae mediae acid A.Basic identical with the UV scanning of Herba stellariae mediae acid A with the UV scanning that Herba stellariae mediae acid A has similar maximal ultraviolet absorption peak, particularly compositions of the present invention because of the composition of each main peaks, as seen they have identical parent nucleus or the chromophore with the sour A of Herba stellariae mediae.
11). as seen compositions is dissolved among the mass spectrum total ion current figure (Fig. 6) that the first alcohol and water done: ESI (-) 100V m/z:149.1 is arranged in the compositions, 234.9,242.1,296.4,344.1,355.9,383.1,434.9,475.9,522.8,563.1,573.6,601.8,626.6,683.6,730.1,804.6,818.3,850.3,901.8,937.1,963.6,984.1,1013.8,1070.6,1075.3,1118.6,1157.8,1197.3,1278.1,1296.1,1348.1,1394.8,1434.6,1474.8,1521.6,1578.3,1593.8,1629.6,1691.3,1709.1,1766.1,1794.6,1819.6,1872.3,1914.1,1945.8,1955.6,2051.4,2100.1,2121.1,2146.6,2193.6,2224.1,2232.1,2296.9,2337.1,2393.9,2456.4,2497.4 etc.
12). as seen compositions is dissolved among the mass spectrum total ion current figure (Fig. 7) that the first alcohol and water done: ESI (-) 100V m/z:105.3 is arranged in the compositions, 136.6,173.1,200.4,222.9,278.1,319.6,429.6,443.9,503.4,513.8,543.1,644.6,647.6,778.3,834.1,916.6,939.1,973.8,1017.3,1051.6,1056.3,1058.1,1090.3,1127.8,1134.3,1204.3,1242.6,1300.1,1342.3,1455.6,1528.6,557.1,1657.8,1684.1,1730.3,1747.1,1755.1,1816.3,1934.6,1988.6,2040.3,2047.8,2126.4,2171.6,2186.4,2254.6,2286.4,2342.4,2399.4,2445.4,2466.6 etc.
13). it is its feature (report 2 and Figure 14) that compositions or its dark brown black partly contain elements such as more sulfur, nitrogen, calcium.
14). compositions can be adsorbed by DEAE-cellulose or weak anion exchanger etc., proved that also compositions is tart.
15). the aqueous solution of compositions is met ferric chloride reagent can show dark brown reaction.
16). can compositions further be separated into dark brown black, brownish red and foresythia three parts according to color, dark its antiviral activity of part of color and luster is stronger in the compositions.
4, compositions has following beneficial effect:
One), the intravital The acute toxicity tests of animal shows that compositions do not see overt toxicity:
1). the maximum tolerated dose (MTD) of compositions mice nasal mucosa medicine administration: 2.25g/kg;
2). the maximum tolerated dose of compositions rat nasal mucosa medicine administration: 1.125g/kg;
3). the maximum tolerated dose of compositions mouse stomach administration: 11.25g/kg;
4). the LD of compositions mouse vein administration
50: 3.406g/kg, its 95% credible being limited to: 3.069g/kg to 3.780g/kg.
Two), the animal body internal stimulus test of rat nasal mucosa medicine administration shows this product nonirritant:
1). compositions is at Cmax, maximum administration volume, and single-dose and successive administration were not seen toxic reaction after 7 days in 24 hours, put to death animal after 24 hours, separates and cuts nasal cavity open, and the perusal mucosa does not have stimulations such as red and swollen hyperemia, ulcer.Mucosa situation and normal saline matched group are as good as.
2). compositions is at Cmax, maximum administration volume, and multiple dosing and successive administration were not seen toxic reaction after 7 days in 24 hours, put to death animal after 24 hours, separates and cuts nasal cavity open, and the perusal mucosa does not have stimulations such as red and swollen hyperemia, ulcer.Mucosa situation and normal saline matched group are as good as.
Above-mentioned experimental data shows that acute toxicity test does not see that compositions of the present invention has zest or overt toxicity etc. in the animal body, so compositions is a kind of natural drug as safe as a house.
Three), compositions has broad spectrum activity, powerful preventing respiratory viruses usefulness:
1). existing test cell line proof compositions can to the adenovirus of the influenza virus, parainfluenza virus, rhinovirus, Echovirus, herpesvirus and the genus DNA class that adhere to the RNA class separately-
3, adenovirus-
7Deng two big class Respiroviruses stronger inhibitory action is arranged, particularly to influenza virus, the parainfluenza virus of adhering to the RNA class separately and the adenovirus that adheres to the DNA class separately-
3Deng very strong inhibition is arranged, show the broad-spectrum antiviral usefulness of the uniqueness that the compositions tool is very strong.
2). resisiting influenza virus FM in the compositions mice animal body
1Result of the test show: 50% mice protective rate (ED
50) be 0.51mg/kg, because of the mice collunarium after the maximum tolerated dose of nasal mucosa medicine administration (MTD) is 2250mg/kg, so the in vivo test therapeutic index (TI) of compositions mice nasal mucosa medicine administration is: TI
Compositions=MTD/ED
50=2250 ÷ 0.51=4412; The so high proof compositions of interior therapeutic index has powerful resisiting influenza virus effect.
And the ED of reference substance Chinese medicine " SHUANGHUANGLIAN KOUFUYE "
50Be 866mg/kg, according to this ED
50As can be known its dosage need approximately 1700 times of this compositions could with this compositions therapeutic equivalence;
The ED of reference substance Western medicine " ribavirin " mouse mainline
50Be about 25mg/kg; On the http//toxnet.nlm.nih.gov website, check in the median lethal dose(LD 50) (LD of its mouse mainline
50) be 900mg～1300mg/kg; By its LD
50The therapeutic index of calculating is: TI
Ribavirin=LD
50/ ED
50=900～1300 ÷ 25=36～52 only are about 1/100 of this compositions, as calculating then TI with the non-toxic of " ribavirin "
RibavirinWill be lower.
The above results has convincingly demonstrated the present composition and has had the characteristics of powerful broad spectrum influenza virus, and its performance significantly is better than " SHUANGHUANGLIAN KOUFUYE " and reaches " ribavirin " etc.
3). the clinical practice curative effect:
One of nasal drop is made in the compositions water 5ml dissolving that our personal accumulated dose is 0.4g, can cure a routine influenza patient in 2 days.Its concentration is 80mg/ml, and 120/5ml, each every nostril splashes into two, each 4, so the actual dose of each administration is about 12mg/ time/people.120 branches drip off for 30 times, and altogether collunarium is two days, and every day from 7 o'clock to 21 amounts to collunarium 15 times, and per 1 hour collunarium once.The viral influenza of clinical personal treatment has 100 many cases time over 6 years, no matter is which day in the influenza course of disease, in case thereby used this composition medicine about 1～2 two day, control clinical symptoms and cure the influenza operate as normal and learnt; Comprise in more than ten minute to 1 hour and can eliminate headache fully, then stuffy nose relieving, eliminate clear nasal mucus, tear and symptom such as pain from head to foot, brought down a fever in 48 hours at 24 hours.The early stage result of use of falling ill is good more, the fastest case once morbidity that night (headache, from head to foot pain, 39.5 ℃, drop tears, nasal mucus etc.) use medicine just before going to bed one time, only several, promptly normally gone to work the next morning.This composition medicine prevention and treatment virus flu (comprising influenza) could shorten the course of disease about 5 days, reached the specific drug degree, and the virus flu to comprise influenza etc. because of healing is become a reality!
The calculating of its theoretical dose: the ED that draws compositions according to Virology Inst., Chinese Academy of Preventive Medical Science
50=0.5mg/kg, be 0.05mg/kg divided by body surface coefficient 10, the body weight 60kg that multiply by the people is 3mg/ time/people, puts to be twice to be 6mg/ time/people, substantially match with the 12mg/ time/people of dosage of clinical everyone each administration, for clinical application provides basis and evidence.
Do not see any toxicity during clinical use present composition clinical treatment influenza patient.Because of being 2250mg/kg through the maximum tolerated dose of mice nasal mucosa medicine administration with nasal drop, do not see toxicity as yet, and everyone each dosage 6mg to 12mg, its accumulated dose also only is everyone 0.2g to 0.4g, medication only about 2 days what tangible toxicity to be arranged obviously.
So the present composition that extracts with scientific method from the Stellaria plant is safe enough and effective antiviral natural medicine.This is the beneficial effect that the present invention gives prominence to, and can really solve the famous difficult problem of " influenza " this world's medicine that World Health Organization (WHO) wishes that China solves.
Four), test cell line shows that also compositions has anti AIDS virus (HIV-
1) effect.
Five), preliminary test cell line shows that also compositions also has inhibitory action to the expression of hepatitis B virus HBsAg and HBeAg.
5, the composition of compositions and beneficial effect are provided by following 9 reports and 13 subordinate lists:
It is drug effect result of the test in the animal body of indication that table 1 provides with dead mouse, protective rate.
It is that index is calculated median effective dose that table 2 provides with mice protective rate and prolongation vital rates.
It is drug effect result of the test in the animal body of indication that table 3 has provided with the mouse lung pathological changes.
Table 4 is subordinate lists of table 3, provides with pathological changes mouse lung suspension inoculation Embryo Gallus domesticus, and detecting viral pneumonia is the interior drug effect result of the test of animal body of index.
Table 5 provides 4 test cell line results (wherein the 4th test provides " report 3 ") that compositions suppresses HIV (human immunodeficiency virus) (HIV-1), can find out that from table 5 medicine just can suppress almost all HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) in 60 μ g/ml concentration.
Table 6 provides the actual efficacy of compositions clinical treatment influenza: compositions can shorten viral influenza course of treatment more than 5 days at least, therefore, function with extraordinary prevention and treatment influenza, its commercially available other resisiting influenza virus medicine such as influenza virus neuraminidase inhibitor at present that are better than evident in efficacy can reach the specific drug degree.
Table 7 provides the actual efficacy of compositions clinical treatment herpes simplex and herpes zoster: patient is after constantly being applied in the affected part with medicine as can be seen from Table 7, actual medication 0.3g～0.6g got final product pain relieving in 1 to 3 day, thereby the bleb that disappears, incrustation reach recovery from illness, and wherein the size and the curative effect of drug concentrations and herpes area have substantial connection.
Table 8 provides the result of implementation of compositions clinical treatment infantile parotitis: as can be seen from Table 8 the clinical use of parotitis sick child contain compositions buccal tablet 0.1g * 4 slice after 6, only need can fully recover in about 2 days.
Table 9 provides the actual efficacy of compositions clinical treatment sexually transmitted disease condyloma: the combination treatment condyloma acuminatum also has better curative effect as can be seen from Table 9.
Table 10 provides the example of compositions as " disinfectant " flu-prevention, parotitis etc.
Table 11 provides the example of compositions as " health product " flu-prevention, parotitis etc.
6, the present invention has 14 width of cloth accompanying drawings:
Fig. 1: UV scanning Fig. 1 of composition solution.
Fig. 2: UV scanning Fig. 2 of composition solution.
Fig. 3: infrared scan Fig. 3 of Herba stellariae mediae acid A.
Fig. 4: the infrared scan figure of compositions.
Fig. 5: the mass spectrum of Herba stellariae mediae acid A.
Fig. 6: compositions is dissolved in the mass spectrum total ion current figure (2) that the first alcohol and water is done.
Fig. 7: compositions is dissolved in the mass spectrum total ion current figure (2) that the first alcohol and water is done.
Fig. 8: UV scanning Fig. 3 of Herba stellariae mediae acid A aqueous solution.
Fig. 9: to the termination of pumping UV scanning figure that 5 in the high-efficient liquid phase chromatogram of compositions main peak compositions carry out, sweep limits: 190nm～400nm.
Figure 10: Herba stellariae mediae acid A's
13C NMR spectrogram (DMSO D-6).
Figure 11: Herba stellariae mediae acid A's
1H NMR spectrogram (DMSO D-6).
Figure 12: above-mentioned Herba stellariae mediae acid A sample adds after the heavy water exchange
1H NMR spectrogram.
Figure 13: the high-efficient liquid phase chromatogram of compositions, its test condition is: C
18Post; The test wavelength is 360nm; Decay to 256; Chart speed is 0.25cm/min; Water and acetonitrile with variable concentrations is that mobile phase is carried out eluting respectively, and controls the Herba stellariae mediae acid A peak that retention time is long in the composition peak of two maximums and go out about Rt21min.
Figure 14: the elementary analysis figure that compositions X ray-fluorescence spectrophotometry detects.
Four, with Stellaria and a kind of plant extract present composition of cattle Stellaria embodiment:
The present composition can be made with following three kinds of methods by Herba stellariae mediae or its a kind of congener.
First method is: will the fresh dried herb of a kind of Stellaria plant clean silt, pulverize the back and extract aqueous solution, with this aqueous solution through precipitation, centrifugal or filter after obtain liquid A; With liquid A by the macroporous resin column handled well in advance to adsorb compositions composition of the present invention, wash the ethanol of reuse 5%～60% eluting compositions and collect brownish red or the dark brown-red solution that eluting obtains from the resin column.To promptly get compositions crude product of the present invention through concentrated or vacuum drying again behind this brownish red or the dark brown-red solution recovery ethanol.With the crude drug crude product with water dissolution after the refining back of methods such as centrifugal removal precipitate concentrate drying compositions (crude drug).The character of compositions and character are: a kind of have a common brown glassy or cellular glass shape thing of Chinese medicine dry extract, be ground into then to present behind the fine powder and be ground into powdered brownly as the common Chinese dry extract, general Chinese medicine abnormal smells from the patient, stable in properties, soluble in water, bitterness are slightly arranged.Crude drug again through 0.22 μ m membrane filtration or/and through cobalt 60 irradiation, heating with degerming, sterilization, make the commercially available prod.
Second method is: the back is cleaned, pulverized to the fresh dried herb of a kind of Stellaria plant extract aqueous solution, with this aqueous solution through precipitation, centrifugal or filter after obtain liquid A; With this liquid A through the anionite post, compositions class composition of the present invention is attracted on the post, the effective ingredient that will be mainly compositions of the present invention with sodium chloride solution elutes from post, again through desalting processing,, concentrate and drying after promptly get the composition material medicine crude product of compositions of the present invention.The crude drug crude product after making with extra care concentrate drying, methods such as centrifugal removal precipitate is become the compositions crude drug with water dissolution.This crude drug character and character are: a kind of have a common brown glassy or cellular glass shape thing of Chinese medicine dry extract, be ground into to present behind the fine powder and be ground into brown behind the powdery as the common Chinese dry extract, general Chinese medicine abnormal smells from the patient, stable in properties, soluble in water, slightly bitterness are arranged.Crude drug through 0.50 μ m membrane filtration or/and cobalt
60Irradiation, heating are with degerming, sterilization, promptly.
The third method is: place retort to add deionized water a kind of Stellaria plant, import microwave, make its 2,000,000,000 times/second to 3,000,000,000 times second speed do molecular motion, the temperature of controlled microwave extraction was at 35 ℃～55 ℃, 1～6 hour; Through centrifugal, obtain the dark-brown extract and under 35 ℃～55 ℃ conditions, be evaporated to small size after filtering, enter after the filtering salt of separating out, the phlegmatic temperament etc. again large tracts of land film vacuum drier 35 ℃～65 ℃ ,-0.1MPa, vacuum under foaming promptly got semifinished product in dry 5 hours; Or the above-mentioned extract that is concentrated into small size filtered out impurities after spray drying tower, carry out drying with supersonic jet, its effluxvelocity is 340 meter per second to 950 meter per seconds, and the control temperature at 35 ℃～55 ℃, pressure about 0.05MPa, make the concentrated solution wink-dry, promptly get nanometer Herba stellariae mediae total acid crude drug through exquisite, degerming again.
Five, with the embodiment of Stellaria and a kind of plant extract present composition of cattle Stellaria:
Embodiment with first method: after getting the fresh dried herb 20kg of the Herba stellariae mediae of choosing clean impurity and cleaning earth, pulverize with tap water, centrifugal, filter, extract medicinal liquid, residue discards and can resign from office and return home makes fertilizer.With medicinal liquid through precipitation, centrifugal or filter after promptly obtain liquid A, constantly by the commercially available macroporous resin column of id 10cm * 120cm, the control flow velocity is at 1ml/min to 3ml/min with this liquid A.As seen macroporous resin column from top to bottom becomes a kind of brownish red or taupe gradually and is filled medicine until pillar.Discard effusive liquid in the pillar, and earlier with the residual liquid in the clean post of tap water.Continue and clean macroporous resin column with distilled water that is about 3 times of amounts of column volume or deionized water, this routine consumption is about 25L water.Subsequently during eluting earlier with being about the 5% yellow liquid of ethanol flush away part of 2 times of amounts of column volume and discarding, this routine consumption is about the ethanol of 20L 5%; Reuse is about 60% ethanol elution of 3 times of amounts of column volume and collects the brownish red alcoholic solution, and this routine consumption is about the ethanol of 30L60%.Alcoholic solution is concentrated into thick emitting after vacuum drying apparatus reclaims ethanol, is about about 700m1, promptly get the about 49.79g of crude drug crude product after the drying.With behind the crude drug crude product usefulness 200m1 water dissolution centrifugal 5 minutes (4000r/min), discard precipitate.Supernatant in sterilized clean container, becomes the thick paste shape through concentrating under reduced pressure through 0.22 μ m membrane filtration under aseptic condition, drying gets highly finished product again.Compositions is a dark brown red, and the dark brown red that is behind the porphyrize behind the general Chinese medicine dry extract porphyrize is Powdered, and Chinese medicine fragrance is arranged.Count 48.7g, make compositions 589.2g crude drug altogether with this method, its preparation is through cobalt
60Radiation sterilization.
Embodiment with second method: get the dried herb 2.5kg of Herba stellariae mediae, clean earth with tap water after, pulverize, centrifugal, extract medicinal liquid; Residue discards, and can resign from office and return home and make fertilizer.With medicinal liquid through precipitation, centrifugal or filter after promptly obtain liquid A, with the commercially available weak anion exchange resin post of this liquid A by id 10cm * 120cm, after adsorbing compositions of the present invention, clean the weak-base anion-exchange resin post with water recently distilled that is about 3 times of column volumes or deionized water, discard from post effusively by light yellow thin out gradually until the almost colourless post liquid of washing, this routine consumption is about 30L water.To be adsorbed on the rapid eluting of compositions of the present invention on the post and collect this dark brown red eluent with 2 times of NaCl solution to the 2N of column volume concentration then, this routine consumption is the 20L saline solution.This saline solns suitably is concentrated into is placed on about 750ml in the semipermeable membrane bag, successively tap water and distilled water are dialysed until solution to AgNO
3Solution reaction is very weak or do not have till the saline taste.The back gained dark brown red solution of will dialysing is transferred in the vacuum drying apparatus drying under reduced pressure to thick, be about 150ml, transfer in the vacuum desiccator and make its foaming, keep and promptly get composition material medicine crude product of the present invention, about 57.77g more than 12 hours through 60 ℃ of vacuum dryings.With the crude drug crude product with the 250ml water dissolution after centrifugal 5 minutes (4000r/min) discard precipitate.Supernatant again through 0.50 μ m membrane filtration in sterilized clean container, under aseptic condition, become the thick paste shape through concentrating under reduced pressure, drying gets highly finished product again.Glassy for dark brown red, it is Powdered to be dark brown red behind the porphyrize, and general taste of Chinese medicine is arranged.Amount to 56.2g, make compositions 311.8g crude drug altogether with this method, its preparation heat sterilization.
Embodiment with the third method: get fresh Herba stellariae mediae herb 35kg, clean earth with tap water and be placed on and add the about 100kg submergence of water in the retort, the importing microwave extracting, and control rate is 2,000,000,000 times/second to 3,000,000,000 times seconds, 35 ℃～65 ℃, 6 hours; Through centrifugal, obtain the dark-brown extract and under 55 ℃ of conditions, be evaporated to 2000ml after filtering, the filtering precipitate, spray-dried again tower, carry out drying with supersonic jet, its effluxvelocity is 800 meter per second to 900 meter per seconds, and the control temperature at 45 ℃～65 ℃, pressure about 0.05MPa, make the concentrated solution wink-dry, obtain 71.3g nanometer Herba stellariae mediae total acid crude drug through exquisite, degerming again.
Table 12 be embodiment 1 from post during the eluting compositions concentration of alcohol change yield influenced.
The yield that table 13 provides embodiment 1 usefulness Stellaria 14 kind of plant extraction compositions compares.
Six, the present composition can have following 12 kinds of preparations and purposes at least as crude drug:
1. injection can be used for treating various viral diseases such as acquired immune deficiency syndrome (AIDS), hepatitis.
2. injectable powder can be used for treating various viral diseases such as acquired immune deficiency syndrome (AIDS), hepatitis.
3. aerosol is used for children's and treats influenza, parotitis etc., and can be used as the antiviral disinfectant of air and oral cavity, health product or antiviral functional food.
4. buccal tablet or chewable tablet are used for the treatment of parotitis etc., can be used as the antiviral disinfectant in air and oral cavity, health product or antiviral functional food.
5. capsule, the oral various viral diseases such as acquired immune deficiency syndrome (AIDS), hepatitis, influenza for the treatment of.
6. microcapsule is treated chronic viral diseases in order to slow releasing pharmaceutical.
7. nasal drop is used for the treatment of influenza etc., also can be used as the antiviral disinfectant of nasal cavity, health product etc.
8. membrane or liniment etc. are used for treating for skin disease such as herpes, condyloma acuminatum.
9. mucilage is used for the treatment of dermatosiss such as herpes.
10. water preparation is used for the clinical dermatosiss such as treatment herpes, condyloma acuminatum of directly smearing; Also can be used as disinfectant is sprayed in air and the living environment.
11. the liquid chewing gum can be used as oral cavity antiviral disinfectant, antiviral health product or functional food etc.
12. chewing gum can be used as oral cavity antiviral disinfectant, antiviral health product or functional food etc.
Seven, the preparation embodiment of various dosage forms:
1. injection: the medicine highly finished product 200g that the embodiment extraction separation is obtained with 0.9% sodium chloride injection 2000ml dissolving back with centrifugal 5 minutes of centrifuge (4000r/min), the gained supernatant of centrifugal back is filtered in sterilized clean container through the sealing of 0.22 μ m filter membrane, use in the ampoule in injection through the filling and sealing machine fill, be distributed into respectively optionally that 1ml/ props up 1000,0.1g/ prop up, 450 of propping up of 2m1/, 0.2g/ prop up, and promptly get injection through sterilization again.
2. injectable powder: the medicine highly finished product 200g that the embodiment extraction separation is obtained with distilled water 50ml dissolving after centrifugal 5 minutes of centrifuge (4000r/min), the gained supernatant of centrifugal back is filtered in sterilized clean container through the sealing of 0.22 μ m filter membrane, the spray of spray-dried machine is dried to become medicated powder, be potted in the ampoule through filling and sealing machine again, again through cobalt
60Radiation sterilization promptly can be made into the injectable powder of 2ml, amounts to 2000, and 100mg/ props up, and uses with the water for injection dissolving.
3. aerosol: get 4g medicine highly finished product add 0.9% sodium chloride injection 100ml dissolving, centrifugal, filter in the 10ml of cleaning dress aerosol bottle, promptly make 10 aerosols, 200mg/ props up.Can be used as oral cavity antiviral disinfectant, health food or antiviral functional food.
4. contain tablet: the dressing, spice, correctives etc. one of getting the medicine highly finished product 100g that makes by embodiment 1 and tablet is reinstated tablet machine and is made 1000 of buccal tablets, the 100mg/ sheet.Can be used as the antiviral disinfectant in oral cavity, health food or antiviral functional food.
5. capsule: be ground into powdered highly finished product 100g under aseptic condition after getting the medicine vacuum drying that makes by embodiment 1, fill becomes 1000 capsules, the 100mg/ capsule.Can be used for treating various virosiss, the antiviral disinfectant in oral cavity, health food or antiviral functional food.
6. microcapsule: the medicine dry powder 3g that gets the process refinement treatment that makes by embodiment 1 makes and is suspended in the 3.6g liquid Paraffin; Get I hundred glue 10g more in addition and add distilled water 200ml, boil half an hour with disruptive oxidation enzyme after waiting to dissolve, warm liquid Paraffin is injected my hundred glues, emulsifying is 1～2 minute in tissue mashing machine, makes oil in water emulsion.Get gelatin 10g again and add distilled water 200ml, place in 60 ℃ of water-baths and dissolve, and be mixed in the 1000ml beaker, keep glue, stir at a slow speed at 45 ℃～50 ℃ with above-mentioned my hundred glues.Add in the glue with freshly prepared 5% acetum 5ml, the pH value of regulator solution produces cohesion to being about 4.1.Inject distilled water 750ml behind the encystation, move in the ice bath again and cool off, be cooled to 5～10 ℃, the gelatin cyst membrane is congealed.At this moment microcapsule is spherical.Adding 37% formaldehyde 7ml again is cured.Stirred 15 minutes, and made the microcapsule typing.Regulate capsule liquid to PH about 8.0 with 20% sodium hydroxide solution then.After low temperature stirs 1 hour, filter with centrifuge, washing is to neutral formaldehydeless flavor.Add capsule again and weigh 3% magnesium stearate and make diluent, cross 16 mesh sieves behind the mix homogeneously, 50 ℃ of vacuum dryings again, the microcapsule of this medicine, yield 72.2%, meter 16.6g microcapsule, medicament contg is 180mg/g.
7. nasal drop: the medicine highly finished product 4g that will obtain by embodiment 1 extraction separation with 0.9% sodium chloride injection 100ml dissolving back with centrifugal 5 minutes of centrifuge (4000r/min), the gained supernatant of centrifugal back filtered in sterilized clean plastics eyedrops bottle through the sealing of 0.22 μ m filter membrane be distributed into 10 nasal drop, medicament contg is that 400mg/ props up.
8. membrane: get the medicine highly finished product 30g, the azone 0.3ml that make by embodiment 1 add water 100ml dissolving back centrifugal, through 0.22 μ m membrane filtration in clean container, add the suitable heated and stirred of PVA (05-88) 19.5g and make its dissolving, on plate glass, paint wide 100mm under the cleaning condition, be about the medicine film of 100mm, thick about 0.1mm.Lucifuge coating film with wide about 100mm, long 100mm, thick about 0.05mm respectively covers one deck as coating membrane at medicine film upper and lower surface again, is packaged into membrane then.Its dosage is 0.3g/cm
2, face the time spent on demand and dosage shear to use.
9. mucilage: get Pseudobulbus Bletillae (Rhizoma Bletillae) colloid (medium powder) 2g and be sub-packed in the dry glass bottle of 10 15ml, each adds glycerol 2ml and makes dispersant, after jolting is uniformly dispersed, other gets the stirring of chloroform water 100ml adding 3g medicine highly finished product and makes its dissolving, centrifugal after 0.22 μ m filter membrane filters respectively in finely dispersed Pseudobulbus Bletillae (Rhizoma Bletillae) Plexiglas's bottle, fierce jolting gets the medicine mucilage, the 200mg/ bottle.
10. water preparation: the medicine dry powder 10g that gets the refinement treatment that makes by embodiment 1 makes and is dissolved in the 250ml water, can be distributed into 25 bottles of water preparations, medicament contg 400mg/ bottle.
11. liquid chewing gum: in water preparation, add spice, correctives etc. and make the liquid chewing gum, can be used as oral cavity antiviral disinfectant, antiviral health food or functional food etc.
12. chewing gum: 100g chewing gum glue, 0.1ml Oleum menthae spice, pentose 1g make chewing gum as correctives etc. and can be used as oral cavity antiviral disinfectant, antiviral health food or functional food etc.
In sum: The World Health Organization (WHO) wishes that China can solve " viral influenza " and " senile pruritus " these two diseases, of the present inventionly can solve this world-renowned medical difficult problem of viral influenza at least as a kind of natural drug of broad-spectrum antiviral safely and effectively, and reach the specific drug degree with Herba stellariae mediae or the isolating total acidic compound compositions of a kind of Stellaria plant extract.Preliminary result of study has proved that also compositions also may be used for the treatment of the major disease of HIV (human immunodeficiency virus), hepatitis virus initiation, also has been expected therapeutic domain widely after planning the further investigation of carrying out.Therefore, the broad-spectrum antiviral medicament safe, effective, inexpensive, easy to use that natural drug of the present invention should a kind of just whole world be seek assiduously will have immeasurable important meaning to a series of viral diseases that solve world's medicine difficult problem.
Pharmaceutical preparation methodological science of the present invention, simple, safety, production process need not special installation, has successfully kept the distinctive drug effect of medicine: environment is not polluted yet.
The Herba stellariae mediae grass is a kind of weeds that growth is all arranged from all parts of the world, is used as weeds usually and removes, and the present invention is turned waste into wealth, medicinal herbs wide material sources, with low cost, and be easy to breeding and cultivation, can fully satisfy industrial mass-produced demand.
Table 5 medicine suppresses 4 test cell line results of HIV (human immunodeficiency virus) (HIV-1)
The example that the nasal drop of table 6 clinical administration 0.2g/10m1 is treated 12 routine influenza patients
The mucilage of table 7 clinical administration 0.5g/25ml is treated the example of 12 routine herpes simplexes and herpes zoster
The clinical example of giving buccal tablet 0.1g/ sheet * 4 treatment 12 routine parotitis children of table 8
Table 9 clinical administration 0.3g/cm
2The membrane example for the treatment of 7 routine condyloma acuminatum patients
Table 10 compositions is as the example of " disinfectant " flu-prevention, parotitis etc.
Table 11 compositions is as the example of " health product " flu-prevention, parotitis etc.
Among table 12 embodiment 1 from post during the eluting compositions concentration of alcohol change influence to yield
Among table 13 embodiment 1 from Stellaria not kindred plant extract compositions yield relatively
Report 1: the elementary analysis report of nitrogen, carbon and the hydrogen of dark brown black part in the medicine
Analysis report
Sample sent by: Zhu Gengxin numbered originally: KD95368
Date landed: April 12 nineteen ninety-five accession designation number: do not have
Require analysis project: N, C, H sample to contain element:
Analysis result: fusing point or boiling point:
N%:8.02; 8.05 sensitization, suction character:
C％：47.34；47.61
H％：5.47；5.51
Analyst: swallow tinkling of pieces of jade analysis time: April 13 nineteen ninety-five
The report of elements such as report 2:X ray-fluorescence spectrophotometry detection of drugs institute sulfur-bearing, calcium
The Ministry of Education of the state
Nanjing University modern analysis center
Examining report
| Sample title: Herba stellariae mediae total acid 010201 | Client: Zhu Gengxin |
| Date landed: March 07 calendar year 2001 | Test item: qualitative elementary analysis |
| Detect foundation: the analytical method general rule | Checkout equipment: VF-320 type x-ray fluorescence spectrometry instrument |
Analysis result
Report 3: medicine suppresses the test cell line report of HIV (human immunodeficiency virus)-1 (HIV-1)
Virology Inst., Chinese Academy of Preventive Medical Science
Two, result:
1, antiviral activity: the in vitro tests result shows that medicine " gram poison " (KD) has anti AIDS virus (HIV-1) and acts on result such as table 1:
Table 1 medicine KD is to the inhibition of HIV (human immunodeficiency virus) (HIV-1)
Calculate IC by statistics
50=0.174mg/ml.
Positive control drug AZT concentration is when 1 μ g/ml, and suppression ratio is 100%.
2, cytotoxicity: be the former cytotoxicity of having measured this medicine of comparative drug antiviral activity and Cytotoxic relation, the result is as showing:
The cytotoxicity of table 2 KD
Calculate TC by statistics
50=2.904mg/ml.So safety index (TC
50/ IC
50) be 16.7.
Virology Inst., China Academy of Preventive Medicine Sciences
HIV (human immunodeficiency virus) research department (official seal)
Director teaches Ceng Yi (signature)
Professor Li Zelin (signature)
On August 2nd, 1997
Report 4: medicine suppresses the test cell line report of 8 kinds of influenza virus
Conclusion:
Medicine " gram poison " (KD) handles cell with three kinds of diverse ways and Embryo Gallus domesticus is got the result that urine is surveyed hemagglutinative titer, and medicine 1mg/ml concentration is as follows to the cytopathogenic protective effect of viral infection institute:
1,, all shows very strong poison and the virus killing effect of pressing down with three kinds of methods to adenovirus-3 type.
2, to rhinovirus usefulness method 1, HSV-1 usefulness method 2 and 3 all shows the strong toxic effect that presses down, and appeal reduces by 2 titres.
3, to adenovirus type VII, usefulness method 1 and the cytopathic appearance of 2 deferrables, to the ECHO11 first method, the appearance of deferrable pathological changes.
4, can reduce by 4 times～128 times (first method can suppress virus multiplication fully, and second method can reduce by 4 times) to influenza virus, the very strong toxic effect that presses down is arranged.
5, equally all can reduce by 8 times to parainfluenza virus with two kinds of methods, the toxic effect of pressing down is arranged.
6, invalid to adenovirus-11 type.
From above interpretation of result: medicine is to several different Respiroviruses, with different processing method performances have in various degree press down poison and virus killing effect.All effective with first method, best to adenovirus-3 type and influenza virus (A3).
Microbiology teaching and research room of Nanjing Medical University (official seal)
Experiment people signature: Yao's Kun (signature)
August 2 nineteen ninety-five
Report 5: medicine suppresses the test cell line report of adenovirus-3 type virus
Medicine is to the external toxin inhibitory test of adenovirus-3 type
One, medicine: KD is a Chinese medicine extract, is provided by Zhu Gengxin.
Two, virus: adenovirus-3 type, separated evaluation strain (C in 72 years by this chamber
10Strain).
Three, cell: the human embryonic lung cell, build strain by this chamber.
Four, method:
1, (drug level mg/ml) selected in the nontoxic boundary line of medicine pair cell: medicine is non-toxic concn with 1mg/ml.
2, medicine presses down the toxic effect fruit to adenovirus-3 type: virus is with 100TCID
50Be infective dose, first infection cell monolayer added medicine after 3 hours.
Five, result: medicine can have the effect of inhibition adenovirus-3 type (C10 strain) with 1mg/ml concentration on cell in vitro is cultivated.
Microbiology teaching and research room of Nanjing Medical University (official seal)
On July 18th, 1996
Report 6: medicine also has the test cell line report of some inhibition to hepatitis B virus
Table 4, medicine restrain poison (KD) inhibition effect analysis to HbeAg and HbsAg in the 2.2.15 cell culture
Summary of Design reporter: Chen Hongshan professor
Experiment, statistics person: Teng Li technologist-in-charge
The experiment date: 2～March in 1999
Protocol preservation place: Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences Viral Laboratory
(official seal)
Human embryonic lung diploid fibroblast monolayer culture plate adds different dilution keduling medicines, and 37 ℃ discarded medicine after 24 hours, added 100TCD
50/ 0.1ml virus (VSV) is attacked, and establishes cell contrast and virus control, observation of cell pathological changes after 24 hours, and the result is as follows:
Test unit: clinical Viral Laboratory, Hubei medical college institute of viruses
Report time: on February 28th, 1992
Report 8: medicine is the laboratory report of the acute toxicity testing of doing in animal body
Animal acute toxicity test data and documents and materials
Test name: the acute toxicity test of mouse stomach administration
The acute toxicity test of mouse mainline administration
The acute toxicity test of mice intranasal administration
The acute toxicity test of rat intranasal administration
The local irritation test of rat intranasal administration
Person: Yu Shuqin (associate professor pharmacology) is responsible in test
Test participant: Li Pingping thanks to the diligent Zhang Meiying of the surplus book of positive good fortune
Date of test: March calendar year 2001～May calendar year 2001
Raw data preservation place: China Medicine University
Contact person: Yu Shuqin
Phone: 025-3271262
Test unit: China Medicine University's Pharmacology Lab (official seal)
12. conclusion
The acute toxicity tests shows: being subjected to the heal maximum tolerated dose of influenza nasal drop mouse stomach administration of reagent is 11.25g/kg, and the maximum tolerated dose of intranasal administration is 2.25g/kg.Intravenous LD
50Be 3406mg/kg, the 95% credible 3069～3779mg/kg that is limited to.More the maximum tolerated dose of influenza nasal drop extractum rat intranasal administration is 1.125g/kg.
Be subjected to reagent at Cmax, maximum administration volume, single-dose and successive administration were not seen toxic reaction after 7 days in 24 hours, put to death animal after 24 hours, separated and cut nasal cavity open, and the perusal mucosa does not have stimulations such as red and swollen hyperemia, ulcer.Mucosa situation and normal saline matched group zero difference.
Report the test of pesticide effectiveness result of 9 this product resisiting influenza virus of doing in the mice body
Conclusion
(mice) test of pesticide effectiveness proves that the influenza nasal drop medicine of healing has the effect of obvious resisiting influenza virus in body.
EXPERIMENTAL DESIGN person: Duan Shumin, Xue Fengju
Test director: Duan Shumin, Zhao new life, Wen Ruifu, Liang Yingjuan
Test period: May 12 March 2 calendar year 2001 to calendar year 2001
First revisal: Duan Shumin, Liang Yingjuan
Whole school: Duan Shumin, Liang Yingjuan
Set type: Liang Yingjuan
Raw data preservation place: Virology Inst., Chinese Academy of Preventive Medical Science diagnoses two Room
Address: No.100, Yingxin Street, Xuanwu District, Beijing City
Contact person: Duan Shumin
Phone: (010) 63535459
Postcode: 100052
Virology Inst., Chinese Academy of Preventive Medical Science's (official seal)
Diagnose two Room
Claims (15)
1, a kind of broad-spectrum antiviral compositions is characterized in that said composition prepares by following method:
Place retort to add deionized water the Stellaria plant, import microwave, make its 2,000,000,000 times/second to 3,000,000,000 times second speed do molecular motion, the temperature of controlled microwave extraction was at 35 ℃～55 ℃, 1～6 hour; Through centrifugal, obtain the dark-brown extract and under 35 ℃～55 ℃ conditions, be evaporated to small size after filtering, enter after the filtering salt of separating out, the phlegmatic temperament again large tracts of land film vacuum drier 35 ℃～65 ℃ ,-vacuum of 0.1MPa under foaming promptly got semifinished product in dry 5 hours; Or the above-mentioned extract that is concentrated into small size filtered out impurities after spray drying tower, carry out drying with supersonic jet, its effluxvelocity is 340 meter per second to 950 meter per seconds, and the control temperature at 35 ℃～55 ℃, pressure at 0.05MPa, make the concentrated solution wink-dry, promptly get nanometer Herba stellariae mediae total acid crude drug through refining, degerming again.
2, broad-spectrum antiviral compositions according to claim 1 is characterized in that containing in the compound structure element sulphur.
3, broad-spectrum antiviral compositions according to claim 1 is characterized in that nitrogenous element in the compound structure.
4, broad-spectrum antiviral compositions according to claim 1 is characterized in that its aqueous solution chance ferric chloride reagent shows dark brown reaction.
5, broad-spectrum antiviral compositions according to claim 1, it is characterized in that extracting with Caryophyllaceae Stellaria (Stellaria L.) plant Herba stellariae mediae Stellaria media (L.) Cyr., or, comprising: Stellaria alsine Grim. Stellaria alsine Grimm. with a kind of extraction in the following plants, brown lobe Stellaria alsine Grim. Stellaria alsine var.phaeuspetala Hand.-Mazz., Anhui Herba stellariae mediae Stellariaanhwiensis Migo., blunt calyx Herba stellariae mediae Stellaria amblyosepala Schrenk., apicule Herba stellariae mediae Stellaria apiculata Wils., Herba malachii aquatici Stellaria aquatica (L) Scop., the husky Herba stellariae mediae Stellaria arenaria Maxim. that gives birth to, Alishan Herba stellariae mediae Stellaria arisanensis Hayata., slender lobule Alishan Herba stellariae mediae Stellaria arisanensis var.leptophylla Hayata., north Herba stellariae mediae Stellaria borealis Bigel., short lobe Herba stellariae mediae Stellaria brachypetala Bge., long lobe Herba stellariae mediae Stellaria bungeana Fenzl., northeast Herba stellariae mediae Stellaria cherleriae (Fisch.) Will., China Herba stellariae mediae Stellaria chinensis Regel, Taiwan Herba stellariae mediae Stellaria cicrantha Hayata, thick leaf Herba stellariae mediae Stellaria crassifolia Ehrh., wrinkle leaf Herba stellariae mediae Stellaria crispate Wall., David's Herba stellariae mediae Stellaria davidii Hemsl., the Herba stellariae mediae Stellaria decumbensEdgew. that crouches lays down, the needle-like Herba stellariae mediae Stellaria decumbens var.acicularia Edgew.etHook.f. that crouches that lays down, southwest Herba stellariae mediae Stellaria delavayi Franch., Stellaria dianthifolia Williams Stellariadianthifolia Williams, forked cyme Herba stellariae mediae Stellaria dichasioides Williams, bifid Herba stellariae mediae Stellaria dichotoma L., narrow leaf bifid Herba stellariae mediae Stellaria dichotoma var.lanceolata Bge., line leaf bifid Herba stellariae mediae Stellaria dichotoma var.stephenianaWilld., Herba stellariae mediae Stellaria diffusa Wills. looses in the shop, turn over white Herba stellariae mediae Stellaria discolorTurcz., Stellaria diversiflora Maxim. Stellaria diversiflora Maxim., the different colored Herba stellariae mediae Stellariadiversiflora var.gymnandra Franch. of naked stamen, concave veins Herba stellariae mediae Stellaria depressaSchnid., Du Shi Herba stellariae mediae Stellaria duthiei Gandoger, line stem Herba stellariae mediae Stellariafilicaulis Mak., line handle Herba stellariae mediae Stellaria filipes Komar., spend more Herba stellariae mediae Stellariaflorida Fisch., standing grain leaf Herba stellariae mediae Stellaria graminea L., dredge pubescence standing grain leaf Herba stellariae mediae Stellariagraminea var.pilosula Maxim., turn green standing grain leaf Herba stellariae mediae Stellaria graminea var.viridescens Maxim., Jiangzi's Herba stellariae mediae Stellaria gyantsensis Williams, XIACAO Herba stellariae mediae Stellaria gypsophiloides Fenzl., Stellaria henryi williams Stellaria henryi Williams, the Herba stellariae mediae Stellaria hsinganensis Kitagawa of Xingan, introversion Herba stellariae mediae Stellaria infractaMaxim., slender lobule Herba stellariae mediae Stellaria leptophylla Hance, Stellaria maximowixziana Franch. Stellariamaximowixziana Franch., Stellaria micrantha Hayata Stellaria micrantha Hayata, gentle Herba stellariae mediae Stellaria mitans Williams, goose intestinal Herba stellariae mediae Stellaria neglecta Weihe, Herba stellariae mediae Stellaria neo-palustris Kitagawa is given birth in new natural pond, eight stamen Herba stellariae mediae Stellaria octandraFobedim., raspberry Herba stellariae mediae Stellaria oxycoccoides Komar., Herba stellariae mediae Stellariapalustris L. is given birth in the natural pond, exhibition leaf Herba stellariae mediae Stellaria patentifolia Kitagawa, handle flower Herba stellariae mediae Stellariapeduncularis Bge., Herba stellariae mediae Stellaria pilosa Franch. becomes mildewed, imitation stone is given birth to Herba stellariae mediae Stellaria pseudosaxatilis Hand.-Mazz., blinks Stellaria pusilla Schmid., flint lobe Herba stellariae mediae Stellaria radians L., net arteries and veins Herba stellariae mediae Stellaria reticulivena Hayata, rock Herba stellariae mediae Stellaria rupestris Hemsl., stone is given birth to Herba stellariae mediae Stellaria saxatilisBuch.-Ham., embrace stem stone and give birth to Herba stellariae mediae Stellaria saxatilis var.amplexicaulisHand.-Mazz., accurate Ge Er Herba stellariae mediae Stellaria soongorica Roshev., Su Shi Herba stellariae mediae Stellaria souliei Williams, star hair Herba stellariae mediae Stellaria stellato-pilosa Hayata, garden calyx Herba stellariae mediae Stellaria strongylosepala Hand.-Mazz., intend umbrella flower Herba stellariae mediae Stellariasubumbellata Edgew., little fine hair Herba stellariae mediae Stellaria tomentella Ohwi, three type Herba stellariae mediae Stellaria trimorpha Nakai, Turkestan Herba stellariae mediae Stellaria turkestanicaSchischk., wetland Herba stellariae mediae Stellaria uda Williams, umbrella flower Herba stellariae mediae Stellaria umbellateTurcz., LVHUA Herba stellariae mediae Stellaria virdiflora Pax et O.Hoffm., Stellaria wushanensis Williams Stellaria wushanensis Williams, five Herba stellariae mediae Stellaria wutaicaHand.-Mazz., Yunnan Herba stellariae mediae Stellaria yunnanensis franch. and Caryophyllaceae cattle Stellaria Malachium Fries plant cattle Herba stellariae mediae Malachium aquaticum (L.) Fries.
6, broad-spectrum antiviral preparation of compositions method according to claim 1, the steps include: to place retort to add deionized water a kind of Stellaria plant, import microwave, make its 2,000,000,000 times/second to 3,000,000,000 times second speed do molecular motion, the temperature of controlled microwave extraction was at 35 ℃～55 ℃, 1～6 hour; Through centrifugal, obtain the dark-brown extract and under 35 ℃～55 ℃ conditions, be evaporated to small size after filtering, enter after the filtering salt of separating out, the phlegmatic temperament again large tracts of land film vacuum drier 35 ℃～65 ℃ ,-vacuum of 0.1MPa under foaming promptly got semifinished product in dry 5 hours; Or the above-mentioned extract that is concentrated into small size filtered out impurities after spray drying tower, carry out drying with supersonic jet, its effluxvelocity is 340 meter per second to 950 meter per seconds, and the control temperature at 35 ℃～55 ℃, pressure at 0.05MPa, make the concentrated solution wink-dry, promptly get nanometer Herba stellariae mediae total acid crude drug through refining, degerming again.
7, the application of the described broad-spectrum antiviral compositions of claim 1 in preparation inhibition HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) medicine.
8, the application of the described broad-spectrum antiviral compositions of claim 1 in preparation inhibition influenza virus medicine.
9, the application of the described broad-spectrum antiviral compositions of claim 1 in preparation inhibition herpesvirus medicament.
10, the application of the described broad-spectrum antiviral compositions of claim 1 in preparation inhibition hepatitis virus medicament.
11, the application of the described broad-spectrum antiviral compositions of claim 1 in preparation inhibition mumps virus medicine.
12, the application of the described broad-spectrum antiviral compositions of claim 1 in preparation inhibition condyloma acuminate disease cytotoxic drug.
13, broad-spectrum antiviral compositions according to claim 1 is characterized in that the said composition dosage form is that injection, injectable powder, aerosol, buccal tablet, chewable tablet, capsule, microcapsule, nasal drop, membrane are coated with, membrane, mucilage or water preparation.
14, the application of the described broad-spectrum antiviral compositions of claim 1 in the disinfectant of preparation inhibition virus.
15, the described broad-spectrum antiviral compositions of claim 1 suppresses the health product of virus or the application in the functional food in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385734A CN100522189C (en) | 2002-11-11 | 2002-11-11 | Method for preparing broad-spectrum antiviral drug of nano total acid of chickweed as well as usage and chickweed acid A |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385734A CN100522189C (en) | 2002-11-11 | 2002-11-11 | Method for preparing broad-spectrum antiviral drug of nano total acid of chickweed as well as usage and chickweed acid A |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1498630A CN1498630A (en) | 2004-05-26 |
| CN100522189C true CN100522189C (en) | 2009-08-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021385734A Expired - Fee Related CN100522189C (en) | 2002-11-11 | 2002-11-11 | Method for preparing broad-spectrum antiviral drug of nano total acid of chickweed as well as usage and chickweed acid A |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100522189C (en) |
-
2002
- 2002-11-11 CN CNB021385734A patent/CN100522189C/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| Phenolic acids and flavonoids from Stellariamedia(L.)Vill.(Garyophyllaceae).. Kitanov,G.m.Pharmazie,Vol.47 No.6. 1992 |
| Phenolic acids and flavonoids from Stellariamedia(L.)Vill.(Garyophyllaceae).. Kitanov,G.m.Pharmazie,Vol.47 No.6. 1992 * |
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| Publication number | Publication date |
|---|---|
| CN1498630A (en) | 2004-05-26 |
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