CN104116753B - The application of aucubin in preparation treatment idiopathic pulmonary fibrosis medicine - Google Patents
The application of aucubin in preparation treatment idiopathic pulmonary fibrosis medicine Download PDFInfo
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- CN104116753B CN104116753B CN201410377002.2A CN201410377002A CN104116753B CN 104116753 B CN104116753 B CN 104116753B CN 201410377002 A CN201410377002 A CN 201410377002A CN 104116753 B CN104116753 B CN 104116753B
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Abstract
The present invention relates to Chinese medicine extract purposes field, specifically provide the application of aucubin in preparation treatment idiopathic pulmonary fibrosis medicine.Described aucubin is preferably Eucommia extract, and wherein aucubin purity is more than 98%.
Description
Technical field
The invention belongs to Chinese medicine extract purposes field, be specifically related to the novelty teabag of aucubin.
Background technology
Idiopathic pulmonary fibrosis (Idiopathic Pulmonary Fibrosis, IPF) is a kind of specific type of chronic fibro voltinism interstitial pneumonia, and pathogenic factor is still not clear.The potential paathogenic factor of generally acknowledging at present comprises smoking, the exposure of environment occupational factor, infected by microbes, gastroesophageal reflux and inherited genetic factors etc.Idiopathic pulmonary fibrosis is the development of a kind of chronic progressive external, substantially irreversible pathological change, and pathological changes is confined to pulmonary, and histopathology and high-resolution ct are shown as plain edition interstitial pneumonia type feature.Idiopathic pulmonary fibrosis often occurs in old people, but each age level is all visible clinically, and its sickness rate presents the trend of increase with advancing age.The poor prognosis of idiopathic pulmonary fibrosis, makes a definite diagnosis rear median survival interval only 3-5, and within 5 years, survival rate is less than 50%.Clinical trial medicine at present for idiopathic pulmonary fibrosis comprises glucocorticoid, colchicine, ciclosporin A, acetyl cysteine, anticoagulant, pirfenidone, sldenafil and imatinib etc., but the therapeutic response of idiopathic pulmonary fibrosis to hormone and various medicine is generally poor, there is no the medicine effectively improving the final prognosis of patient at present.It is just lung transplantation that the state of an illness is uniquely effectively treated late period.Therefore study the mechanism of idiopathic pulmonary fibrosis and inquire into the focus that new effective means of prevention is current basis and clinical concern.
Aucubin (aucubin, AU) belongs to iridoid glycosides, and molecular formula is C
15h
22o
9, molecular weight 346.33, fusing point 181 DEG C, soluble in water, methanol and ethanol polar solvent, be dissolved in the weak polar solvents such as chloroform, ether and petroleum ether hardly.This compound is mainly present in Cortex Eucommiae Eucommia ulmoides Oliver, Cornaceae plant peach jaurel belongs in the plant such as (Aucubachinensis), Plantaginaceae plant Plantago (Plantago), be one of medium-height grass the effective elements of the medicines such as the Cortex Eucommiae, Herba Plantaginis, Radix Rehmanniae, there is numerous pharmacologically actives such as protecting liver and detoxication, antiinflammatory, antioxidation, promotion collage synthesis, osteoporosis and trophic nerve unit cell.Aucubin structural formula is as follows:
The Cortex Eucommiae is the dry bark of the Eucommiaceae plant Cortex Eucommiae, is Chinese famous and precious tonic herb.Tool invigorating the liver and kidney, bone and muscle strengthening, blood pressure lowering, many effects such as antiabortive, it is Chinese peculiar medical material, and its medicinal history is long, has a wide range of applications clinical.Eucommia is the side-product of Cortex Eucommiae industry, and containing gutta-percha, oils and fats, protein, iridoid etc., wherein aucubin (aucubin, AU) content is up to 7%-11%.Aucubin has antiinflammatory, antioxidation, removing toxic substances protect the liver, the pharmacologically active such as anti-bacteria and anti-virus, osteoporosis, because its character is active, biological activity obviously but not easily obtain, be called as " star molecule ", have Development volue.Be showed no the report of aucubin to idiopathic pulmonary fibrosis effect both at home and abroad at present.
Aucubin has the preparation method of multiple maturation in the prior art, but at present, the process research of extracting aucubin from Eucommia is less.Chinese patent 201010297478.7, disclose " a kind of from Cortex Eucommiae fruit, extract the process of aucubin ", mainly comprise flash or supersound extraction, macroporous resin adsorption purification, but this technique obtains aucubin purity only 50%, and reagent consumption is large, complex operation, industrialization produce that the production cycle is long, cost is high, is unfavorable for suitability for industrialized production and the exploitation of aucubin monomer.Chinese patent 201310028642.8 discloses " a kind of method rapidly and efficiently preparing aucubin monomer from the Cortex Eucommiae ", and the method can obtain aucubin through extraction-crystallization two step, but yield is lower, serious waste of resources.Chinese patent CN 101863938 A discloses " a kind of method preparing high-purity aucubin ", the method is separated obtains aucubin with polymer carrier immobile phase chromatographic column, silica gel column chromatography, recrystallization, and step is many, product yield is lower, the production cycle is longer.
Summary of the invention
Object of the present invention aims to provide a kind of novelty teabag of aucubin.We study and find that aucubin has preventive and therapeutic effect to idiopathic pulmonary fibrosis, can be used for the medicine preparing treatment idiopathic pulmonary fibrosis.
For achieving the above object, technical scheme of the present invention is:
The application of aucubin in preparation treatment idiopathic pulmonary fibrosis medicine.
Described aucubin is preferably Eucommia extract, and wherein aucubin purity is more than 98%.
It is raw material that described aucubin is preferably further with Eucommia, is shelled by Eucommia, and kernel is pulverized, and through defat with petroleum ether, ethanol extraction, adds acetone crystallisation by cooling, then through silica column purification, obtains aucubin monomer.
Further preferred, described aucubin is obtained by following preparation method, comprises the following steps:
1. defat: shell the Cortex Eucommiae of drying fruit to obtain kernel, and kernel is pulverized, and defat with petroleum ether, obtains defat coarse fodder; Described petroleum ether consumption is the 6-10 times amount of Cortex Eucommiae fruit kernel quality, and defat number of times is 2-4 time, and degreasing time is 1.5-4 hour;
2. extract: described defat coarse fodder is added ethanol and extracts, filter, merge extractive liquid, 40 DEG C-60 DEG C 1/5-1/12 being concentrated into extracting liquid volume, obtain concentrated extracting solution; Described ethanol consumption is the 6-12 times amount of Cortex Eucommiae fruit quality, and extraction time is 3-5 time, and each extraction time is 2-5 hour;
3. crystallization: described concentrated extracting solution is added the saturated dissolving of acetone, crystallisation by cooling, obtain aucubin coarse crystal;
4. silica gel column chromatography: described aucubin coarse crystal is added the saturated dissolving of ethyl acetate, add silica gel column chromatography again, wherein the mass ratio of silica gel for chromatography and aucubin crystal is roughly 6:1-11:1, then with the solution eluting successively of ethyl acetate and methanol composition, collects eluent; In the solution that during described eluting successively, ethyl acetate used and methanol form, the concentration of ethyl acetate reduces from high to low gradually;
5. concentrate drying: concentrated at 40 DEG C-60 DEG C by described eluent, lyophilization, obtains aucubin monomer product.Preferred version: rapid 1. described in pulverize after be 40-50 order.
Preferred version: step 1. PetroChina Company Limited.'s ether consumption is the 8-9 times amount of Cortex Eucommiae fruit kernel, and defat number of times is 3-4 time, and degreasing time is 2-3 hour.
Preferred version: step 2. middle ethanol consumption is the 8-10 times amount of raw material, and extraction time is 3-4 time, and each extraction time is 3-4 hour.
Preferred version: step 3. in after the saturated dissolving of ethyl acetate, lysate is placed in 4-10 DEG C of cooling, crystallization 12-72 hour.
Preferred version: step 4. in the mass ratio of silica gel for chromatography and aucubin crystal be roughly 8:1-10:1.
Preferred version: the order of the step 4. solution eluting successively of middle ethyl acetate and methanol composition is: routine ethyl acetate is the order eluting of 1:0,10:1,6:1,4:1 than methanol in mass ratio successively, and consumption is respectively 3-5BV, 3-6BV, 4-6BV, 3-5BV.
Below the present invention be further explained and illustrate.
Aucubin of the present invention is preferably Eucommia extract, can be selected from pulverizing, squeeze, calcine, grind, sieve, percolation, extraction, water extraction, alcohol extraction, water precipitating, precipitate with ethanol, ester are carried, the method such as ketone is carried, chromatography, filtration obtains by employing.With this extract for active substance can be made into pharmaceutical preparation, described extract can be the material of extractum form, can be dry extract also can be fluid extract, can be powdered substance, need to make different states according to the difference of preparation.
The present invention also mentions the pharmaceutical preparation of aucubin through the applicable any unit dosage form taken of processing preparation, these pharmaceutical preparatioies are selected from following dosage form: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, suppository, ointment, plaster, cream, spray, drop, patch, can make slow releasing preparation, enteric coated preparation when needing.
Aucubin of the present invention, medicine acceptable carrier can be added when being prepared into pharmaceutical preparation, described medicine acceptable carrier is selected from: antioxidant, intercalating agent surfactant filler disintegrating agent wetting agent dispersant lubricant solvent slow release material enteric material pH adjusting agent, correctives, pigment etc., conventional carrier is as mannitol, dextran, lactose, glucose, sorbitol, mannitol, xylitol, sodium chloride, silicon derivative, cellulose and cellulose derivative, sodium sulfite, sodium pyrosulfite, alginate, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
The pharmaceutical preparation of aucubin of the present invention is by being processed through extraction or other modes by Eucommia, making pharmaceutically active substance, subsequently, with this active substance for raw material, when needing, add medicine acceptable carrier, make pharmaceutical preparation according to the routine techniques of galenic pharmacy.
Detailed description of the invention
Below by embodiment, the present invention will be further explained, and described in embodiment, percentage composition is mass percentage.
The preparation of embodiment 1 Eucommia extract aucubin
Shelled by Eucommia, kernel powder is broken to 40 orders, and get 10kg and drop into extraction pot, add 60L defat with petroleum ether, defat 2 times, each 3 hours, leaching medicinal residues is defat coarse fodder.Add 80L ethanol to defat coarse fodder supersound extraction 2 hours, extract 3 times, merge extractive liquid.Extracting solution 40 DEG C is evaporated to 1/8 of original volume and reclaims ethanol.Concentrated solution adds the saturated dissolving of acetone, and 7 DEG C of crystallizations 48 hours, coarse crystal adds the saturated dissolving of ethyl acetate.Get 10L silica gel dress post, saturated solution is added silicagel column, use 3BV ethyl acetate (quality is than ethyl acetate: methanol=1:0) successively, 4BV10:1 ethyl acetate/methanol (quality is than ethyl acetate: methanol=10:1), 5BV6:1 ethyl acetate/methanol (quality is than ethyl acetate: methanol=6:1), 4BV4:1 ethyl acetate/methanol eluant solution (quality is than ethyl acetate: methanol=4:1), detect by thin layer chromatography simultaneously, collect aucubin flow point, merge eluent, 40 DEG C of concentrating under reduced pressure, lyophilization, obtain aucubin monomer 410g, measure through HPLC method, its content reaches 98.7%.
The preparation of embodiment 2 Eucommia extract aucubin
Shelled by Eucommia, kernel powder is broken to 50 orders, and get 10kg and drop into extraction pot, add 80L defat with petroleum ether, defat 3 times, each 4 hours, leaching medicinal residues is defat coarse fodder.Add 100L ethanol to defat coarse fodder supersound extraction 4 hours, extract 5 times, merge extractive liquid.Extracting solution 40 DEG C is evaporated to 1/10 of original volume and reclaims ethanol.Concentrated solution adds the saturated dissolving of acetone, and 4 DEG C of crystallizations 72 hours, coarse crystal adds the saturated dissolving of ethyl acetate.Get 10L silica gel dress post, saturated solution is added silicagel column, use 3BV ethyl acetate (quality is than ethyl acetate: methanol=1:0) successively, 4BV10:1 ethyl acetate/methanol (quality is than ethyl acetate: methanol=10:1), 5BV6:1 ethyl acetate/methanol (quality is than ethyl acetate: methanol=6:1), 4BV4:1 ethyl acetate/methanol eluant solution (quality is than ethyl acetate: methanol=4:1), detect by thin layer chromatography simultaneously, collect aucubin flow point, merge eluent, 40 DEG C of concentrating under reduced pressure, lyophilization, obtain aucubin monomer 480g, measure through HPLC method, its content reaches 99.2%.
Embodiment 3
The aucubin obtain embodiment 1 and embodiment 2 and commercially available aucubin (being purchased from Yuan Ye bio tech ltd, Shanghai) are studied for the Protection to idiopathic pulmonary fibrosis of embodiment 3.
1. experimental technique
1.1 dose design and grouping
Experiment is divided into Normal group, model group, aucubin low dose group (1mg/kg), middle dosage group (5mg/kg), high dose group (10mg/kg), commercially available aucubin (10mg/kg) and pirfenidone positive controls (10mg/kg).
Table 1 tests grouping and dose design
1.2 experimental procedure
Healthy male SD rat 70 (body weight 250 ~ 300g), be divided into 7 groups at random: as Normal group (A group), bleomycin group (B group), the basic, normal, high dosage group of aucubin (C, D, E group), commercially available aucubin group (F group), pirfenidone positive controls (G group).B group rats by intraperitoneal injection 3% pentobarbital sodium (30mg/kg), lie on the back after anesthesia and be fixed on Mus platform, routine disinfection drape after cervical region preserved skin, after cutting skin, successively blunt separation exposes trachea, thrusts tracheal strips, fast injection bleomycin solution 0.2-0.3ml in lung with the syringe diagonal of 1mL, hold up Mus plate immediately, roll 2 minutes, make medicinal liquid be evenly distributed in two lungs, after skin of again sterilizing, close wound.The normal saline of A group injection same volume.C, D, E, F, G group rat molding method, with B group, starts in trachea injection bleomycin second day the aucubin and the pirfenidone solution that give lumbar injection basic, normal, high dosage every day.Aucubin distilled water, Fluorofenidone 0.5% Carboxymethyl cellulose sodium are according to dosage mixed with respective concentration before experiment by every day, now with the current, by 10mL/kg gastric infusion.A group and B group start to give isopyknic distilled water at operation second day.Experimental session rat freely drinks water, feed (standard diet).Measure rat body weight once weekly.Within the 4th week after experiment starts administration, put to death rat.Adopt femoral artery depletion method, after pentobarbital sodium anesthesia, rat is lain on the back and is fixed on Mus platform, open breast and appear cardiopulmonary, repeatedly clean with normal saline after taking off lungs, electronic balance weighing body weight and lung weight, calculate paragonimus cyst (lung weight/body weight × 100%).4% formaldehyde fixes right upper lung, lower-left lung, and conventional dehydration embedding, makes 5 μm of thick paraffin sections, dye in order to HE.
1.3 Testing index
Pulmonary morphology is observed: get lungs respectively and be placed in 4% formaldehyde and fix, conventional dehydration, embedding, section, HE dyeing.According to the method that Szapiel etc. provides, determine alveolitis and pulmonary fibrosis degree, carry out pathology semi-quantitative analysis.
Alveolitis classification:
0 grade: without alveolitis;
1 grade: slight alveolitis, extent of disease is confined to full lung less than 20%;
2 grades: moderate alveolitis, extent of disease accounts for full lung 20%-50%;
3 grades: Diffuse alveolar is scorching, and extent of disease is greater than 50%.
Interstitial pulmonary fibrosis classification:
0 grade: without interstitial pulmonary fibrosis;
1 grade: slight interstitial pulmonary fibrosis, extent of disease is confined to full lung less than 20%;
2 grades: moderate interstitial pulmonary fibrosis, extent of disease accounts for full lung 20%-50%;
3 grades: severe interstitial pulmonary fibrosis, extent of disease is greater than 50%, fusion of pulmonary alveoli, pulmonary parenchyma structure disturbance.
Utilize microimage analysing system, carry out alveolitis and fibrosis is measured automatically to pathological section, the pathological section that dyeed by lung tissue HE is divided into following three regions and analyzes:
(1) without dye district: be alveolar space area occupied.
(2) engrain district: be nucleus area occupied.
(3) understain district: be interstitial lung fibrous connective tissue area occupied.
The degree of alveolitis and pulmonary fibrosis can be determined by the difference of above three region area occupied.During alveolitis, interstitial lung inflammatory cell infiltration increases, and showing as engrain district area increases, and during fibrosis, alveolar mostly subsides or disappears, and a large amount of collagen fiber appear in interstitial, show as to reduce without dye district area, and understain district area increases.Represent nucleus area occupied with engrain district, i.e. alveolar inflammation area, understain district represents fibrous connective tissue and collagen fiber area occupied, and without dye, district represents alveolar space area.Under pathological section being placed in image analyzer microscope, under the 10x visual field, often open section by left-to-right, choose 10 visuals field from top to bottom successively and carry out graphical analysis, measure the area value (pixel/visual field) in corresponding each district, and be converted into (um
2/ the visual field), average.
1.4 statistical method:
Adopt SPSS16.0 to carry out statistical analysis, the level set of statistical significance is P<0.05.Adopt mean ± standard deviation
by Leven ' s test method inspection normality and homogeneity of variance.If meet normality and homogeneity of variance, carry out statistical analysis with one factor analysis of variance (One-way ANOVA) and post Hoc LSD; If do not meet normality and heterogeneity of variance, then check with Kruskal-Wallis.If Kruskal-Wallis inspection has statistical significance (P<0.05), then Dunnett ' s Test (nonparametric technique) is used to compare analysis.Significant difference and biological significance is considered during evaluation.
2 experimental results
Aucubin is on the impact of pathologic
Compare with Normal group, model group rats presents severe alveolitis, and there is more hemorrhagic focus local, and alveolar septum is broadening, inflammatory cell infiltration, and macrophage activation is obvious: volume increases, and containing a large amount of granule in cell, most of macrophage is that foam sample changes; The fibroblast that lamellar assembles activation is closely adjacent, and alveolar septum and areas of inflammation are shown in the collagen fiber of lamellar hypertrophy, and fibrosis obviously increases.As can be seen from the statistical result of average pathology integration, model group pathology integration is significantly higher than sham operated rats, prompting renal fibrosis model modeling success.Administration is after 15 days, and aucubin high dose group and Fluorofenidone positive controls, commercially available aucubin all occur significant difference compared with model group, and there is a change for the better for kidney region fibrosis.
Table 2 aucubin is on the impact of each group of induced lung coefficient
Note: compare with Normal group,
++p<0.01, compares with model group,
*p<0.05.
3 experiment brief summaries
The above results shows, the symptoms such as aucubin high dose group, commercially available aucubin group significantly can improve the alveolitis of idiopathic pulmonary fibrosis model, macrophage foam cell formation sample changes, fibrocyte activation and collagen fiber hyperplasia, have some improvement to idiopathic pulmonary fibrosis.
Claims (10)
1. the application of aucubin in preparation treatment idiopathic pulmonary fibrosis medicine.
2. apply according to claim 1, it is characterized in that, described aucubin is Eucommia extract, and wherein aucubin purity is more than 98%.
3. apply according to claim 1 or 2, it is characterized in that, described aucubin is raw material with Eucommia, shelled by Eucommia, kernel is pulverized, through defat with petroleum ether, and ethanol extraction, add acetone crystallisation by cooling, then through silica column purification, obtain aucubin monomer.
4. apply according to claim 3, it is characterized in that, the preparation method of described aucubin comprises the following steps:
1. defat: shell the Cortex Eucommiae of drying fruit to obtain kernel, and kernel is pulverized, and defat with petroleum ether, obtains defat coarse fodder; Described petroleum ether consumption is the 6-10 times amount of Cortex Eucommiae fruit kernel quality, and defat number of times is 2-4 time, and degreasing time is 1.5-4 hour;
2. extract: described defat coarse fodder is added ethanol and extracts, filter, merge extractive liquid, 40 DEG C-60 DEG C 1/5-1/12 being concentrated into extracting liquid volume, obtain concentrated extracting solution; Described ethanol consumption is the 6-12 times amount of Cortex Eucommiae fruit quality, and extraction time is 3-5 time, and each extraction time is 2-5 hour;
3. crystallization: described concentrated extracting solution is added the saturated dissolving of acetone, crystallisation by cooling, obtain aucubin coarse crystal;
4. silica gel column chromatography: described aucubin coarse crystal is added the saturated dissolving of ethyl acetate, add silica gel column chromatography again, wherein the mass ratio of silica gel for chromatography and aucubin coarse crystal is 6:1-11:1, then with the solution eluting successively that ethyl acetate and methanol form, collects eluent; In the solution that during described eluting successively, ethyl acetate used and methanol form, the concentration of ethyl acetate reduces from high to low gradually;
5. concentrate drying: concentrated at 40 DEG C-60 DEG C by described eluent, lyophilization, obtains aucubin monomer product.
5. apply according to claim 4, it is characterized in that, step 1. described in pulverize after be 40-50 order.
6. apply according to claim 4, it is characterized in that, step 1. PetroChina Company Limited.'s ether consumption is the 8-9 times amount of Cortex Eucommiae fruit kernel, and defat number of times is 3-4 time, and degreasing time is 2-3 hour.
7. apply according to claim 4, it is characterized in that, step 2. middle ethanol consumption is the 8-10 times amount of raw material, and extraction time is 3-4 time, and each extraction time is 3-4 hour.
8. apply according to claim 4, it is characterized in that, step 3. in after the saturated dissolving of ethyl acetate, lysate is placed in 4-10 DEG C of cooling, crystallization 12-72 hour.
9. apply according to claim 4, it is characterized in that, step 4. in the mass ratio of silica gel for chromatography and aucubin coarse crystal be 8:1-10:1.
10. apply according to claim 4, it is characterized in that, the order of the step 4. solution eluting successively of middle ethyl acetate and methanol composition is: routine ethyl acetate is the order eluting of 1:0,10:1,6:1,4:1 than methanol in mass ratio successively, and consumption is respectively 3-5BV, 3-6BV, 4-6BV, 3-5BV.
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Denomination of invention: Application of aucubin in the preparation of drugs for idiopathic pulmonary fibrosis Effective date of registration: 20200928 Granted publication date: 20150909 Pledgee: Bank of Changsha Limited by Share Ltd. science and Technology Branch Pledgor: Changsha Duzheng Biotechnology Co., Ltd Registration number: Y2020430000014 |
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