CN102499916A - Application of 1 beta-hydroxy alantolactone in preparation of medicine for preventing and curing rheumatoid arthritis - Google Patents
Application of 1 beta-hydroxy alantolactone in preparation of medicine for preventing and curing rheumatoid arthritis Download PDFInfo
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Abstract
The invention provides application of 1 beta-hydroxy alantolactone in preparation of medicine for preventing and curing rheumatoid arthritis. The structural formula of the 1 beta-hydroxy alantolactone is as follows: the 1 beta-hydroxy alantolactone is used for carrying out animal pharmaceutical effect tests, and results show that the 1 beta-hydroxy alantolactone obviously suppresses attack severity and morbidity of CIA (collagen-induced arthritis). TNF-alpha (tumor necrosis factors alpha), IL-17 (interleukin 17) and IFN-gamma (interferon gamma) in supernate of splenocyte can be reduced, secretion of proinflammatory cytokine TNF-alpha, IFN-gamma and IL-17 is suppressed, and accordingly CIA diseases are prevented. Accordingly, the application can be used for preparing medicine for treating rheumatoid arthritis. Medicine composition in the invention is prepared by the 1 beta-hydroxy alantolactone used as active ingredients and conventional medicine carriers and can be prepared into tablets, dispersible tablets, lozenge, orally disintegrating tablets, sustained-release tablets, capsules, soft capsules, dropping pills, granular formulation, injection, powder injection or aerosol and the like. The application has great clinical application values.
Description
Technical field
The present invention relates to Chinese medicine, be specifically related to the application of 1 beta-hydroxy alantolactone in the medicine of preparation control rheumatoid arthritis.
Background technology
(Rheumatoid Arthritis is the not clear as yet chronic systemic inflammatory property disease of a kind of cause of disease RA) to rheumatoid arthritis, is main clinical manifestation with pathological changes outside chronic, symmetry, many synovial jointss inflammation and the joint, belongs to the autoimmune inflammatory diseases.This disease is sent out well in little joints such as hands, wrist, foots, is prone to outbreak repeatedly, and is the symmetry distribution.Ill have joint red and swollen heat pain and dysfunction to show in early days, and when arriving late period, stiff deformity in various degree can appear in the joint, and with bone and skeletal muscle atrophy, very easily disables.From the angle of pathological change, rheumatoid arthritis is a kind of synovium of joint (can feed through to articular cartilage, osseous tissue, articular ligament and flesh key later on) that mainly involves, and is the popularity diseases associated with inflammation of connective tissues such as serous coat, the heart, lung and eye secondly.The general performance of rheumatoid arthritis also has heating, fatigue and weak, pericarditis, subcutaneous nodule, pleuritis, arteritis, peripheral neuropathy etc. except that arthropathy.But rheumatoid arthritis does not still have specific short so far, still is in the treatment stage to inflammation and sequela.
Inula (Inula L.) plant is that one in the Compositae (Compositae) belongs to, and the whole world has 100 kinds approximately, respectively at Asia, Europe And Africa, is main with Mediterranean Region.In kind surplus state-owned 20, the normal hyoscine of this genus various plants can be used as like Radix Inulae (I.helenium) and to be good for the stomach, diuresis, to eliminate the phlegm and anthelmintic; Inula Britannica (I.britannica) has effects such as expectorant, the therapeutic method to keep the adverse QI flowing downwards, softening the hard mass, row water.Sesquiterpenoids is the characteristic chemical constituent of this platymiscium, is main with eudesmane-type, germacrane type and guainane type, also comprises pseudo-guainane type, driffractive ring eudesmane-type, olive alkane type, xanthane type and a spot of acyclic sesquiterpene and sesquiterpene dimers.Research shows that the sesquiterpenoids in this platymiscium has anthelmintic parasite killing, antibiotic antitumor, antiviral, immunosuppressant effect.
Flos Inulae (Inula japonica) has another name called Jin Fohua, Herba Inulae (Jiangsu and Zhejiang Provinces), chrysanthemum in June (Hebei).Perennial herb.Root stock is short, horizontally walks or tiltedly gives birth to, and sturdy fibrous root is arranged.Be distributed in ground such as NORTH CHINA, northeast, middle part, east, Sichuan, Guangdong, but hyoscine.The root of Flos Inulae and leaf can be treated the knife injury furunculosis; The decoction antitussive of can relievining asthma; Its flower is the expectorant that is good for the stomach, and treats also in the heart that painful abdominal mass is vexed, stomach expansion, belch, cough, vomiting etc. (" Jiangsu Province's medical material will ").Flos Inulae ancient prescription for eliminate the phlegm, dehumidify, sharp intestinal, be the bullate main medicine of harnessing the river again.The inventor has carried out the chemical constitution study of system to the Flos Inulae that picks up from Haozhou, Chinese Anhui; In the hope of clear and definite its chemical constituent; Find that the extract 1 beta-hydroxy alantolactone of Flos Inulae has the excellent activity of treatment rheumatoid arthritis, suitable further research and development new drug.
Summary of the invention
Technical problem to be solved by this invention is the application of extract 1 beta-hydroxy alantolactone in preparation treatment medicine for treating rheumatoid arthritis of research design Flos Inulae.
The invention provides the application of 1 beta-hydroxy alantolactone in the medicine of preparation control rheumatoid arthritis.
The structural formula of 1 beta-hydroxy alantolactone is following:
1 beta-hydroxy alantolactone according to the invention prepares through following method:
Aerial parts (comprise stem, Ye Hehua picks up from the Haozhou, the Anhui) powder of exsiccant Flos Inulae (I.japonica) is pure, under the room temperature with 95% ethanol, respectively with 24,12, extraction in 12 hours 3 times.After the gained crude extract added suitable quantity of water dilution, use petroleum ether successively, dichloromethane, ethyl acetate, n-butanol extraction.Dichloromethane extract is separated with 200-300 purpose thin layer silica gel, carry out gradient elution with methylene chloride-methanol.Thin layer chromatography detects; Collect the component that wherein contains 1 beta-hydroxy alantolactone respectively; Adopt SephadexLH-20 to separate again, carry out eluting, obtain mixture with methylene chloride-methanol; The colour developing of vanillin concentrated sulphuric acid is sesquiterpenoids, adopts HPLC to separate at last and obtains 1 beta-hydroxy alantolactone.
The 1 beta-hydroxy alantolactone that the present invention will extract carries out the animal test of pesticide effectiveness; The result shows that 1 beta-hydroxy alantolactone can suppress CIA (Collagen-Induced Arthritis; Collagen-induced arthritis) clinical onset has obviously suppressed the morbidity order of severity and the sickness rate of CIA.And can reduce TNF-α (tumor necrosis factor) in the splenocyte supernatant, IL-17 (interleukin-17), IFN-γ (interferon gamma), suppress the secretion of proinflammatory cytokine TNF-α, IFN-γ and IL-17, thereby the CIA disease is had protective effect.TNF-α and IFN-γ play an important role in the RA pathogenesis.TNF-α is induced protein hydrolytic enzyme synthetic directly, the destruction of causing matrix structure.Experimental result shows that also 1 beta-hydroxy alantolactone can reduce spleen cell TNF secretion-α largely.Obtained good effect in treatment on the RA with anti-TNF-α therapy, not only stoped bone destruction but also suppressed the generation of IL-17.1 beta-hydroxy alantolactone is to the control of inflammation and maybe be relevant with its reduction TNF-alpha content to the protection of joint tissue.IFN-γ is mainly by soaking at the partial CD4 of focus
+T emiocytosis, it can activating macrophage, and activatory macrophage is expressed multiple inflammatory factor subsequently, participates in and the exacerbate inflammation reaction; IFN-γ also can induce the expression of MIP-1 α, MIP-1 β and IP-10, and these chemotactic factors are participated in the process of lymphocyte to the focus migration.In the experiment of the present invention, 1 beta-hydroxy alantolactone has obviously reduced the level of IFN-γ in vivo, might be with to have blocked lymphocytic follow-up migration relevant.The research report is arranged; But TNF-α and IFN-γ are in the generation of external common stimulation fibroblast and human microvascular endothelial cell (mvec) co-induction chemotactic factor CXCL10; The expression of a large amount of CXCL10 causes the infiltration of activating Th 1 cell and natural killer cell in patient's RA synovial fluid, and tissue is caused damage.(1、Ueno?A，Yamamura?M，Iwahashi?M，Okamoto?A，Aita?T，Ogawa?N，Makino?H.The?production?of?CXCR3-agonistic?chemokines?by?synovial?fibroblasts?from?patients?with?rheumatoid?arthritis.Rheumatol?Int.2005?Jun；25(5)：361-7。2、Bedard?PA，Golds?EE：Cytokine-induced?expression?of?mRNAsfor?chemotactic?factors?in?human?synovial?cells?and?fibroblasts.J?Cell?Physiol?1993，154：433-441)。
The IL-15 that in the model of rheumatoid arthritis, raises can bring into play the characteristic of its pro-inflammatory cytokine through inducing IL-17, and IL-15 possibly cause the IL-17 excessive secretion in the joint through cyclosporin A and the responsive approach of steroid.IL-17 discharges the various inflammatory mediators except stimulating the synovial cell, also can combine with RANK through stimulating RANKL, stimulates bone resorption, is one of most important cytokine in rheumatoid arthritis osteoclasia pathology of recognizing at present.(M?I?Koenders，L?A?B?Joosten，W?B?van?den?BergPotential?new?targets?in?arthritis?therapy：interleukin(IL)-17and?its?relation?to?tumour?necrosis?factor?and?IL-1in?experimental?arthritis.Ann?Rheum?Dis?2006；65：1129-1133)。
Above-mentioned explanation, 1 beta-hydroxy alantolactone has the curative effect that shows notes to CIA, can obviously suppress the CIA clinical onset, suppresses the generation of IL-17, reduces the secretion of inflammatory cytokine TNF-α and IFN-γ, therefore, can be used for preparing the medicine of treating rheumatoid arthritis.
The pharmaceutical composition of the medicine that 1 beta-hydroxy alantolactone according to the invention is prevented and treated rheumatoid arthritis in preparation for processing as active component and conventional pharmaceutical carrier by 1 beta-hydroxy alantolactone.Said pharmaceutical composition can be tablet, dispersible tablet, buccal tablet, oral cavity disintegration tablet, slow releasing tablet, capsule, soft capsule, drop pill, granule, injection, injectable powder or aerosol etc.Bigger clinical value is arranged.
Description of drawings
Figure 11 beta-hydroxy alantolactone clinical score figure
Figure
model group
group
1β-hydroxy alantolactone 1mg/kg
1β-hydroxy alantolactone 5mg/kg
1β-hydroxy alantolactone 10mg/kg
Fig. 2 splenocyte supernatant cytokine TNF-α testing result figure; Post 1: blank control group post 2: model group post 3: methotrexate group post 4:1 beta-hydroxy alantolactone 0.2mg/kg post 5:1 beta-hydroxy alantolactone 1mg/kg post 6:1 beta-hydroxy alantolactone 2mg/kg * P＜0.05 * * P＜0.01
Fig. 3 splenocyte supernatant cytokine IL-17 testing result figure; Post 1: blank control group post 2: model group post 3: methotrexate group post 4:1 beta-hydroxy alantolactone 0.2mg/kg post 5:1 beta-hydroxy alantolactone 1mg/kg post 6:1 beta-hydroxy alantolactone 2mg/kg * P＜0.05 * * P＜0.01
Fig. 4 splenocyte supernatant cytokine IFN-γ testing result figure; Post 1: blank control group post 2: model group post 3: methotrexate group post 4:1 beta-hydroxy alantolactone 0.2mg/kg post 5:1 beta-hydroxy alantolactone 1mg/kg post 6:1 beta-hydroxy alantolactone 2mg/kg * P＜0.05 * * P＜0.01
The specific embodiment
The preparation of embodiment 11 beta-hydroxy alantolactones
Exsiccant Flos Inulae (I.japonica) aerial parts (comprise stem, leaf, flower, pick up from the Haozhou, Anhui) 10.0kg powder is pure, and room temperature (25 ℃ of temperature) is descended the ethanol extraction 3 times (each 100L) with 95%, and the time spent is 24,12,12 hours respectively at every turn.After gained crude extract 427.5g added in right amount the dilution of (10L) water, use petroleum ether (dividing each 40L four times) successively, dichloromethane (dividing each 40L four times), ethyl acetate (dividing four times, at every turn 40L), n-butanol extraction (dividing four times, at every turn 40L).The dichloromethane extract 50.5g that wherein obtains is separated with 200-300 purpose thin layer silica gel, with methylene chloride-methanol (100: 0,50: 1,20: 1,10: 1,5: 1,2: 1) carry out gradient elution.Thin layer chromatography detects (2010 editions Chinese Pharmacopoeia appendix VI B thin layer chromatography); Collect the component that wherein contains 1 beta-hydroxy alantolactone respectively, adopt Sephadex LH-20 to separate again, carry out eluting with methylene chloride-methanol (1: 1); Obtain mixture; The colour developing of vanillin concentrated sulphuric acid is sesquiterpenoids, and this mixture adopts preparation HPLC separation, and (adopting octadecyl silane is the chromatographic column of filler, is at 50: 50 developing solvent with methanol-water;) (chemical compound that obtains adopts mass spectroscopy molecular weight 248, molecular formula C earlier to obtain 1 beta-hydroxy alantolactone 95mg
15H
20O
3, carry out nuclear magnetic resonance spectroscopy again and obtain carbon spectrum, hydrogen spectrum and two-dimensional spectrum data, carry out structure elucidation, with the data consistent of known compound 1 beta-hydroxy alantolactone).
The embodiment 21 beta-hydroxy alantolactone animal tests of pesticide effectiveness
One, experiment material
Medicine and reagent
1 beta-hydroxy alantolactone: embodiment 1 makes, and the CMC-Na with 3 ‰ (sodium carboxymethyl cellulose) solution is dissolved into the solution of 1mg/ml.During administration according to the different volume of the weight of animals lumbar injection.
Chicken II Collagen Type VI (C II): Chondrex, Redmond, WA 98052, USA;
Incomplete Freund's complete adjuvant (IFA) Difco Laboratories, Detroit, MI;
PBS (PBS): prepare voluntarily: in the 800ml distilled water, dissolve 8gNaCl, 0.2g KCl, 1.44g Na by this laboratory
2HPO
4With 0.24g KH
2PO
4Transfer PH to 7.4 with hydrochloric acid, add water and be settled to 1L, use after the filtration sterilization;
The DMSO dimethyl sulfoxide (Dimethyl sulfoxide, DMSO): be the sigma Company products;
1640 culture medium: lucky promise biological medicine technology company limited;
Calf serum: people's marine growth company limited;
96 hole flat undersides, CORNING company; 70 μ m cells grind filter screen, BD Falcon company; 15ml, 50ml centrifuge tube, BD Falcon company; 0.22 μ m filter, Millipore company; 1ml revolves a mouthful syringe, BD company; The bright threeway of shellfish, German Bei Lang company;
Methotrexate sheet: Shanghai Pharmaceutical (Group) Co., Ltd. letter friendship pharmacy head factory (080605) animal
DBI/I type mice, male, in 6-8 week, credit number is provided by Shanghai Slac Experimental Animal Co., Ltd.: SCXK (Shanghai) 2007-0005, raise in The 2nd Army Medical College Experimental Animal Center cleaning level environment.
Instrument and equipment
High speed tabletop centrifuge, Eppendorf; The desk-top refrigerated centrifuge of high speed, HITACHI company; Inverted microscope, Nikon company; Super-clean bench, the safe and sound manufactured of Su Jing group; The electric heating constant temperature air dry oven, the grand experimental facilities company limited of last Nereid; Humidity CO
2Incubator, Heraus company; Thermostat water bath, Shanghai state China Electrical Appliances Co., Ltd.
Two, experimental technique
The foundation of model
Experiment is prepared
The preparation of complete Freund's adjuvant (CFA): in incomplete Freund's adjuvant, add heat-inactivated Mycobacterium tuberculosis to final concentration 4mg/ml, abundant mixing before using.
0.01M the glacial acetic acid preparation: 11.43 μ l glacial acetic acids are dissolved in the 20ml deionized water, filter, 4 ℃ subsequent use.
C II preparation: C II is dissolved in the 0.01M glacial acetic acid to final concentration 4mg/ml, 4 ℃ of preservations.
Antigenic emulsifying: connect two glass needle tubings with tee T; PBS, complete Freund's adjuvant and antigens c II are added (per 100 μ l emulsions contain 200 μ g C II and 50 μ l complete Freund's adjuvants) in the needle tubing respectively; After getting rid of the interior bubble of needle tubing; Promote needle tubing back and forth about 500 times, each composition in the needle tubing fully is mixed into emulsified state.
Inducing of CIA model
The 0th day, mouse tail root 2-3 centimeters gave 100 a μ l/ emulsifying good C II antigen subcutaneous injection immunity; The 21st day, booster immunization: 50 μ l CII and the abundant mixing of 150 μ l PBS, 150ul/ lumbar injection; Normal group is injected with method with normal saline.
Three, experiment is divided into groups and dosage regimen
Mice is divided into 6 groups at random, 12 every group, is respectively normal group, CIA model group, positive controls (methotrexate 2mg/kg); 1 beta-hydroxy alantolactone component is high, medium and low three dose groups, and its dosage is respectively 10mg/kg, 5mg/kg, 1mg/kg.Press 10mg/kg, 5mg/kg, the continuous gastric infusion of 1mg/kg in secondary immunity the previous day (the 20th day) respectively to the 34th day 1 beta-hydroxy alantolactone group, the methotrexate group was pressed the 2mg/kg administration in per two days, and normal group and model group give drinking water by 10ml/kg.
1, polyarthritis index (arthritis index, AI) scoring
Behind the secondary immunity, periodic logging mice whole body arthropathy situation by 3 grades of point system evaluations, is calculated sickness rate and average disease index.Concrete standards of grading are: 0 minute-joint is normal; 1 minute-joint is slightly red and swollen; 2 minutes-redness and swelling of joints is serious, involves whole joint, limitation of activity; 3 minutes-claw or joint function disturbance, ankylosis.The summation of extremity is the scoring of mice, is up to 12 fens.
2, the preparation of lymph and spleen mononuclearcell (MNC) suspension
Mice is put to death, and is fixing, cuts off skin of abdomen, gets the both sides inguinal lymph nodes; After open the abdominal cavity, take out spleen, put into immediately 1640 15ml centrifuge tube be housed, place on ice; The cell of spleen being poured into 70 μ m grinds in the filter screen, fully grinds with 1ml syringe nook closing member, makes it into cell suspension; The collecting cell suspension, 4 ℃, 1000rpm, centrifugal 8min, centrifugal back supernatant discarded; Break up cell, add 0.83% ammonium chloride water (about 1.0ml/ spleen), cracking 5min; The PBS that adds 3 times of volumes stops lytic response, and removes the floccule in the cell suspension with glass pipette; 4 ℃, 1000rpm, centrifugal 8min, centrifugal back supernatant discarded; Break up cell, add 1ml 1640 (containing calf serum), count behind the mixing, in 96 orifice plates, cultivate 5 * 10 with 1640 complete mediums (containing calf serum)
6The every hole 100ul of/ml, adherent 2 hours.
3, splenocyte NO measures
Every hole adds 5 * 106/ml spleen MNC100ul in the flat round bottom plate in 96 holes, every group 4 multiple hole; After adherent 2 hours, change liquid DMEM culture medium (commercially available, as to replenish the manufacturer, available from the beautiful minister bio tech ltd in Shanghai), every hole adds LPS (lipopolysaccharide) (final concentration 1ug/ml), cell is placed 37 ℃, 5%CO
2Cultivate in the incubator and take out supernatant detection NO after 18 hours.
4, spleen, lymphocyte increment are measured
In the flat round bottom plate in 96 holes, add 5 * 10 respectively
6/ ml spleen and lymph MNC100ul, every group 4 multiple hole; After adherent 2 hours, add C II (100ug/ml), cell is placed 37 ℃, 5%CO
2Cultivate in the incubator to take out after 72 hours and add MTS (tetramethyl azo azoles salt) survey increment.
5, splenocyte cytokine assay
In the flat round bottom plate in 96 holes, add 5 * 10
6/ ml spleen MNC100ul, every group 4 multiple hole; After adherent 2 hours, add C II (100ug/ml), cell is placed 37 ℃, 5%CO
2Cultivate in the incubator and get supernatant detection cytokine after 48 hours.
Four, result
1,1 beta-hydroxy alantolactone can suppress the clinical onset of CIA
In the experiment of this CIA (rheumatoid arthritis), induce the CIA model with C II, initial immunity is the 0th day, mice is divided into 6 groups at random behind the 21st day booster immunization: matched group and three group of 1 beta-hydroxy alantolactone group.Began in the 20th day to, positive controls gave methotrexate medicine 2mg/kg in per two days, 1 beta-hydroxy alantolactone high dose group gives 10mg/kg, middle dose groups is 5mg/kg, low dose group is 1mg/kg, successive administration 14 days finishes up to experiment.Observe mice every day and give every mice scoring according to standards of grading.
C II induces CIA, and morbidity appears in mice successively behind the booster immunization, and matched group and medication group do not have notable difference on disease time.After the morbidity, the model group group mouse disease order of severity increases the weight of comparatively fast, after immunity, peaked in the 37th day, and disease progression relaxes (Fig. 1) than control group mice behind the administration group mouse invasion.From sickness rate, model group is 90%, and matched group is that high, medium and low three dose groups of 73%, 1 beta-hydroxy alantolactone are respectively 68%, 70% and 71%.This shows that 1 beta-hydroxy alantolactone does not obviously influence the CIA disease time, but obviously suppressed the morbidity order of severity and the sickness rate of CIA, explain that 1 beta-hydroxy alantolactone has the significant protection effect to CIA.
2,1 beta-hydroxy alantolactone can be reduced TNF-α in the splenocyte supernatant, IL-17, IFN-γ
Give in vivo in the experiment of Drug therapy CIA, disease is put to death mice after reaching plateau, takes out spleen cell, processes single cell suspension, every hole 1.5 * 10
6Individual cell bed board stimulates at the antigens c II of external use 20 μ g/ml, cultivates and collects supernatant after 48 hours, measures the concentration of cytokine TNF-α, IFN-γ with ELISA method elisa method.
Like Fig. 2,3, shown in 4, after CII stimulated, TNF-α, IFN-γ and IL-17 all were higher than each drug treating group in the model group cell conditioned medium, compare with positive controls and 1 beta-hydroxy alantolactone group, have significant difference (p＜0.05).Explain give Drug therapy in the body after, can suppress the secretion of proinflammatory cytokine TNF-α, IFN-γ and IL-17, thus and can have protective effect to the CIA disease.
Tablet:
Method for preparing: 1 beta-hydroxy alantolactone, lactose and starch are mixed, and water is evenly moistening, sieves the mixture after moistening and drying; After sieve, add magnesium stearate, then with the mixture tabletting; Every heavy 300mg, 1 beta-hydroxy alantolactone content is 25mg.
Embodiment 4:
Injection: 1 beta-hydroxy alantolactone 5g
Glucose 50g
Method for preparing: 1 beta-hydroxy alantolactone and glucose are dissolved in the proper amount of water for injection, filter gained solution, in the infusion bottle of under aseptic condition, packing into, every bottle contains 1 beta-hydroxy alantolactone 5mg.
Embodiment 5:
Freeze-dried powder injection: 1 beta-hydroxy alantolactone 10g
Mannitol 30g
Method for preparing: 1 beta-hydroxy alantolactone and mannitol are dissolved in the proper amount of water for injection, filter gained solution, in the cillin bottle of under aseptic condition, packing into, lyophilizing, every contains 1 beta-hydroxy alantolactone 10mg.
Claims (5)
1.1 the application of beta-hydroxy alantolactone in preparation prophylactic treatment medicine for treating rheumatoid arthritis is characterized in that the structural formula of said 1 beta-hydroxy alantolactone is following:
2. application according to claim 1 is characterized in that, said 1 beta-hydroxy alantolactone prepares through following method:
With the aerial parts of exsiccant Flos Inulae, comprise that stem, leaf, pollen are pure, under the room temperature with 95% ethanol, respectively with 24; Extracted in 12,12 hours 3 times, the gained crude extract is added the suitable quantity of water dilution after, use petroleum ether successively; Dichloromethane, ethyl acetate, n-butanol extraction; Dichloromethane extract is separated with 200-300 purpose thin layer silica gel, carry out gradient elution with methylene chloride-methanol, thin layer chromatography detects; Collect the component that wherein contains 1 beta-hydroxy alantolactone respectively, adopt Sephadex LH-20 to separate again, carry out eluting with methylene chloride-methanol; Obtain mixture, the colour developing of vanillin concentrated sulphuric acid is sesquiterpenoids, adopts HPLC to separate at last and obtains 1 beta-hydroxy alantolactone.
3. application according to claim 1 is characterized in that the pharmaceutical composition of said medicine for being processed as active component and pharmaceutical carrier by 1 beta-hydroxy alantolactone.
4. application according to claim 3 is characterized in that said pharmaceutical composition is tablet, dispersible tablet, buccal tablet, oral cavity disintegration tablet, slow releasing tablet, capsule, soft capsule, drop pill, granule, injection, injectable powder or aerosol.
5. application according to claim 3, it is 5mg-25mg that the single dose that it is characterized in that said pharmaceutical composition contains 1 beta-hydroxy alantolactone.
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| CN201110388307XA CN102499916A (en) | 2011-11-29 | 2011-11-29 | Application of 1 beta-hydroxy alantolactone in preparation of medicine for preventing and curing rheumatoid arthritis |
| PCT/CN2012/001410 WO2013078764A1 (en) | 2011-11-29 | 2012-10-22 | Applications of 1β-hydroxy isoalantolactone in preparing medicines against rheumatoid arthritis |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013078764A1 (en) * | 2011-11-29 | 2013-06-06 | 中国人民解放军第二军医大学 | Applications of 1β-hydroxy isoalantolactone in preparing medicines against rheumatoid arthritis |
| CN103251667A (en) * | 2013-05-07 | 2013-08-21 | 中国人民解放军第二军医大学 | Application of general inula helenium sesquiterpene lactone in preparation of medicine for treating rheumatoid arthritis |
| CN105311015A (en) * | 2014-07-31 | 2016-02-10 | 中国人民解放军第二军医大学 | Application of 1 beta-hydroxyl costus lactone in preparation of deubiquitinase agent |
| CN108864015A (en) * | 2018-08-28 | 2018-11-23 | 青海大学 | It is a kind of to have effects that treat the compound and pharmaceutical composition of neurodegenerative disease |
| WO2019011285A1 (en) * | 2017-07-14 | 2019-01-17 | 孙青� | Tetrahydronaphtho[1,2-b]furan-2(3h)-one derivative and preparation and use thereof in pharmaceuticals |
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| CN102499916A (en) * | 2011-11-29 | 2012-06-20 | 中国人民解放军第二军医大学 | Application of 1 beta-hydroxy alantolactone in preparation of medicine for preventing and curing rheumatoid arthritis |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013078764A1 (en) * | 2011-11-29 | 2013-06-06 | 中国人民解放军第二军医大学 | Applications of 1β-hydroxy isoalantolactone in preparing medicines against rheumatoid arthritis |
| CN103251667A (en) * | 2013-05-07 | 2013-08-21 | 中国人民解放军第二军医大学 | Application of general inula helenium sesquiterpene lactone in preparation of medicine for treating rheumatoid arthritis |
| CN103251667B (en) * | 2013-05-07 | 2015-07-15 | 中国人民解放军第二军医大学 | Application of general inula helenium sesquiterpene lactone in preparation of medicine for treating rheumatoid arthritis |
| CN105311015A (en) * | 2014-07-31 | 2016-02-10 | 中国人民解放军第二军医大学 | Application of 1 beta-hydroxyl costus lactone in preparation of deubiquitinase agent |
| WO2019011285A1 (en) * | 2017-07-14 | 2019-01-17 | 孙青� | Tetrahydronaphtho[1,2-b]furan-2(3h)-one derivative and preparation and use thereof in pharmaceuticals |
| JP2020528079A (en) * | 2017-07-14 | 2020-09-17 | 上海青東生物科技有限公司Ｓｈａｎｇｈａｉ Ｑｉｎｇｄｏｎｇ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ． | Tetrahydronaphtho [1,2-b] furan-2 (3H) -ketone derivative, its production, and its use in pharmaceutical production |
| JP7158060B2 (en) | 2017-07-14 | 2022-10-21 | 上海青東生物科技有限公司 | Tetrahydronaphtho[1,2-b]furan-2(3H)-ketone derivatives, their manufacture and their use in pharmaceutical manufacture |
| CN108864015A (en) * | 2018-08-28 | 2018-11-23 | 青海大学 | It is a kind of to have effects that treat the compound and pharmaceutical composition of neurodegenerative disease |
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| WO2013078764A1 (en) | 2013-06-06 |
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