CN104116752A - Application of aucubin to preparation of medicines for treating renal interstitial fibrosis - Google Patents
Application of aucubin to preparation of medicines for treating renal interstitial fibrosis Download PDFInfo
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- CN104116752A CN104116752A CN201410376559.4A CN201410376559A CN104116752A CN 104116752 A CN104116752 A CN 104116752A CN 201410376559 A CN201410376559 A CN 201410376559A CN 104116752 A CN104116752 A CN 104116752A
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Abstract
The invention relates to the field of applications of traditional Chinese medicine extracts and in particular provides an application of aucubin to preparation of medicines for treating renal interstitial fibrosis. Aucubin is preferably the eucommia ulmoides samara extract, wherein the purity of aucubin is above 98%.
Description
Technical field
The invention belongs to Chinese medicine extract purposes field, be specifically related to the new purposes of aucubin.
Background technology
Renal fibrosis is a kind of pathophysiological change, be the function of kidney by health to damage, then to damaging, until the progressive process of afunction.Consequently the irreversible infringement of carrying out property of renal function, brings huge threat to human health.Kidney region fibrosis is the common pathological characters that kidney disease advances to renal failure in whole latter stage due to a variety of causes.Clinical and pathological data show in a large number, and the Chronic Renal Injury that a variety of causes causes and the order of severity of kidney region fibrosis change to compared with glomerulopathy closely.Therefore, in order to slow down and reverse the process of chronic renal disease, improve renal function, find and the active drug that finds treatment renal fibrosis for guiding clinical treatment, to improve nephrotic quality of life significant.
Aucubin (aucubin, AU) belongs to iridoid glycosides, and molecular formula is C
15h
22o
9, molecular weight 346.33,181 ℃ of fusing points, soluble in water, methanol and ethanol isopolarity 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 plants 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, have that protecting liver and detoxication, antiinflammatory, antioxidation, promotion collagen are synthetic, numerous pharmacologically actives such as 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, its medicinal history is long, clinical, has a wide range of applications.Eucommia is the side-product of Cortex Eucommiae industry, contains gutta-percha, oils and fats, protein, iridoid etc., and wherein aucubin (aucubin, AU) content is up to 7%-11%.Aucubin has the pharmacologically actives such as antiinflammatory, antioxidation, removing toxic substances protect the liver, anti-bacteria and anti-virus, osteoporosis, because its character is active, biological activity obviously but be difficult for obtaining, be called as " star molecule ", have exploitation and be worth.Be showed no at present the report of aucubin to kidney region fibrosis effect both at home and abroad.
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, " a kind of process of extracting aucubin from Cortex Eucommiae fruit " disclosed, 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 of rapidly and efficiently preparing aucubin monomer from the Cortex Eucommiae ", and the method can make aucubin through extraction-crystallization two steps, but yield is lower, serious waste of resources.Chinese patent CN 101863938 A disclose " a kind of method of preparing high-purity aucubin ", the method is carried out the separated aucubin that obtains 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 new purposes of aucubin.We study and find that aucubin has preventive and therapeutic effect to kidney region fibrosis, can be used for the medicine of preparation treatment kidney region fibrosis.
For achieving the above object, technical scheme of the present invention is:
The application of aucubin in preparation treatment kidney region fibrosis medicine.
Described aucubin is preferably Eucommia extract, and wherein aucubin purity is more than 98%.
Described aucubin further preferably be take Eucommia as raw material, by Eucommia, shells, and kernel is pulverized, warp
Cross defat with petroleum ether, ethanol extraction, adds acetone crystallisation by cooling, then through silicagel column purification, obtains aucubin monomer.
Further preferred, described aucubin obtains by following preparation method, comprises the following steps:
1. defat: by the dry Cortex Eucommiae kernel that really shells to obtain, kernel is pulverized, and defat with petroleum ether, obtains defat coarse fodder; Described petroleum ether consumption is that the 6-10 of Cortex Eucommiae fruit kernel quality doubly measures, and defat number of times is 2-4 time, and degreasing time is 1.5-4 hour;
2. extract: add ethanol to extract described defat coarse fodder, filter, merge extractive liquid,, 40 ℃ of-60 ℃ of 1/5-1/12 that are concentrated into extracting liquid volume, obtain concentrated extracting solution; Described ethanol consumption is that the 6-12 of Cortex Eucommiae fruit quality doubly measures, and extraction time is 3-5 time, and each extraction time is 2-5 hour;
3. crystallization: described concentrated extracting solution is added to the saturated dissolving of acetone, and crystallisation by cooling, obtains aucubin coarse crystal;
4. silica gel column chromatography: described aucubin coarse crystal is added to the saturated dissolving of ethyl acetate, add again silica gel column chromatography, wherein silica gel for chromatography and aucubin roughly the mass ratio of crystal be 6:1-11:1, the solution then forming with ethyl acetate and methanol is eluting successively, 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: by described eluent 40 ℃-60 ℃ concentrated, lyophilization, obtains aucubin monomer product.Preferred version: be 40-50 order after suddenly pulverizing described in 1..
Preferred version: step 1. PetroChina Company Limited.'s ether consumption is that the 8-9 of Cortex Eucommiae fruit kernel doubly measures, and defat number of times is 3-4 time, and degreasing time is 2-3 hour.
Preferred version: the step 8-10 that 2. middle ethanol consumption is raw material doubly measures, 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, by lysate be placed in 4-10 ℃ cooling, crystallization 12-72 hour.
Preferred version: step 4. in silica gel for chromatography and aucubin roughly the mass ratio of crystal be 8:1-10:1.
Preferred version: step in 4. with the solution of ethyl acetate and the methanol composition successively order of eluting 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 is further explained and is illustrated.
Aucubin of the present invention is preferably Eucommia extract, can be selected from pulverizing by employing, squeezes, calcines, grinds, sieves, percolation, extraction, water extraction, alcohol extraction, water precipitating, precipitate with ethanol, ester are carried, the method such as ketone is carried, chromatography, filtration obtains.Take this extract can be made into pharmaceutical preparation as active substance, and described extract can be the material of extractum form, can be that dry extract can be also fluid extract, can be powdered substance, according to the difference of preparation, need to make different states.
The present invention also mentions that aucubin is through the pharmaceutical preparation of applicable any unit dosage form of taking 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, while needing, can make slow releasing preparation, enteric coated preparation.
Aucubin of the present invention, when being prepared into pharmaceutical preparation, can add medicine acceptable carrier, 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 Eucommia being processed through extraction or other modes, being made pharmaceutically active substance, subsequently, take this active substance as raw material, while needing, add medicine acceptable carrier, according to the routine techniques of galenic pharmacy, make pharmaceutical preparation.
The specific embodiment
Below by embodiment, the present invention will be further explained, and percentage composition described in embodiment is quality percentage composition.
The preparation of embodiment 1 Eucommia extract aucubin
By Eucommia shelling, kernel powder is broken to 40 orders, gets 10kg and drops into extraction pot, adds 60L defat with petroleum ether, defat 2 times, and each 3 hours, leaching medicinal residues was defat coarse fodder.Add 80L ethanol to defat coarse fodder supersound extraction 2 hours, extract merge extractive liquid, 3 times.40 ℃ of extracting solution be evaporated to original volume 1/8 and reclaim ethanol.Concentrated solution adds the saturated dissolving of acetone, 7 ℃ of crystallizations 48 hours, and coarse crystal adds the saturated dissolving of ethyl acetate.Get 10L silica gel dress post, saturated solution is added to silicagel column, (quality is than ethyl acetate: methanol=1:0) to use successively 3BV ethyl acetate, (quality is than ethyl acetate: methanol=10:1) for 4BV10:1 ethyl acetate/methanol, (quality is than ethyl acetate: methanol=6:1) for 5BV6:1 ethyl acetate/methanol, (quality is than ethyl acetate: methanol=4:1) for 4BV4:1 ethyl acetate/methanol eluant solution, by thin layer chromatography, detect simultaneously, collect aucubin flow point, merge eluent, 40 ℃ of concentrating under reduced pressure, lyophilization, obtain aucubin monomer 410g, through HPLC method, measure, its content reaches 98.7%.
The preparation of embodiment 2 Eucommia extract aucubins
By Eucommia shelling, kernel powder is broken to 50 orders, gets 10kg and drops into extraction pot, adds 80L defat with petroleum ether, defat 3 times, and each 4 hours, leaching medicinal residues was defat coarse fodder.Add 100L ethanol to defat coarse fodder supersound extraction 4 hours, extract merge extractive liquid, 5 times.40 ℃ of extracting solution be evaporated to original volume 1/10 and reclaim ethanol.Concentrated solution adds the saturated dissolving of acetone, 4 ℃ of crystallizations 72 hours, and coarse crystal adds the saturated dissolving of ethyl acetate.Get 10L silica gel dress post, saturated solution is added to silicagel column, (quality is than ethyl acetate: methanol=1:0) to use successively 3BV ethyl acetate, (quality is than ethyl acetate: methanol=10:1) for 4BV10:1 ethyl acetate/methanol, (quality is than ethyl acetate: methanol=6:1) for 5BV6:1 ethyl acetate/methanol, (quality is than ethyl acetate: methanol=4:1) for 4BV4:1 ethyl acetate/methanol eluant solution, , by thin layer chromatography, detect simultaneously, collect aucubin flow point, merge eluent, 40 ℃ of concentrating under reduced pressure, lyophilization, obtain aucubin monomer 480g, through HPLC method, measure, its content reaches 99.2%.
Embodiment 3
The research of the Protection to kidney region fibrosis by embodiment 1 and the resulting aucubin of embodiment 2 and commercially available aucubin (being purchased from Yuan Ye bio tech ltd, Shanghai) for embodiment 3.
1. experimental technique
1.1 dosage design and groupings
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 Fluorofenidone positive controls (10mg/kg).
Table 1 test grouping and dosage design
1.2 experimental procedure
Healthy 70 of male SD rats (body weight 250～300g), randomly draw 60 for experimental group, lumbar injection streptozotocin (STZ, 55mg/kg are dissolved in the aseptic citrate buffer solution of 0.1mol/L, and concentration is 2%, and pH value is 4.5).Remaining 10 is Normal group, the citrate buffer solution of lumbar injection same volume.72 hours and the 7th day tail venous blood sampling survey random blood sugar after administration, glucose in urine biochemical indicator.Twice blood glucose all >=16.7mmol/L, glucose in urine +++～++++be defined as diabetes rat model.To be specified to 60 diabetes rats of mould, be divided at random model group (B group), the basic, normal, high dosage group of aucubin (C, D, E group), commercially available aucubin group (F group), Fluorofenidone positive controls (G group).By aucubin for distilled water, Fluorofenidone with 0.5% Carboxymethyl cellulose sodium be according to dosage mixed with respective concentration before experiment every day, now with the current, by 10mL/kg gastric infusion, and 1 times/day, continuous 15 days.A group and B group give isopyknic distilled water.Experimental session rat freely drinks water, and feed (standard diet), is not used insulin and other hypoglycemic medicine.Put to death rat the 8th weekend after experiment beginning administration.Slaughter the previous day and collect twenty-four-hour urine liquid with single metabolic cage, survey urine amount, 3000rpm leaves and takes supernatant in-20 ℃ of preservations, for the mensuration of 24h microdose urine protein after centrifugal 5 minutes.Before execution, weigh, rat is put to death in femoral artery blood-letting, leaves and takes blood specimen, 3000rpm after centrifugal 5 minutes, get serum in-20 ℃ frozen, the biochemical indicators such as blood glucose to be measured, blood urea nitrogen (BUN), serum creatinine (Scr).After opening abdominal cavity, cut rapidly two kidneys, remove after two kidney tunicles blot bloodstain with filter paper and weigh; Left kidney is placed in 4% paraformaldehyde and fixes, and treats light Microscopic observation nephridial tissue morphological changes of various tissue components
1.3 detect index
Kidney morphologic observation: getting respectively rat kidney, to be placed in 4% paraformaldehyde fixing, and conventional dehydration, embedding, section, HE dyeing, carry out histopathologic examination.Pathology integration standard: tubulointerstitial injury is marked, and the random selection of each specimen does not repeat 10 visuals field, comprises cortex, medullary substance, skin marrow intersection, comprises 6 specific targets: (1) tubular ectasia; (2) renal tubules atrophy; (3) renal cells cavity forms; (4) renal cells cavity forms; (5) kidney region fibrosis; (6) kidney interstitial inflammatory cell infiltration, the focal type cell infiltration of kidney interstitial is mild damage; The inflammatory cell infiltration that diffusivity is dispersed in is moderate infringement; The intensive inflammatory cell infiltration of diffusivity is severe infringement.Each project is divided into 0 minute according to the degree of pathological lesion: normal; 1 minute: mild damage's (pathological changes is less than 20%); 2 minutes: moderate infringement (pathological changes 20%～40%); 3 minutes: severe infringement (pathological changes is greater than 40%).
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 check normality and homogeneity of variance.If meet normality and homogeneity of variance, with one factor analysis of variance (One-way ANOVA) and post Hoc LSD, carry out statistical analysis; If do not meet normality and heterogeneity of variance, check with Kruskal-Wallis.If Kruskal-Wallis check has statistical significance (P<0.05), use Dunnett ' s Test (nonparametric technique) to compare analysis.During evaluation, consider significant difference and biological significance.
2 experimental results
The impact of aucubin on nephropathy Neo-Confucianism
With Normal group comparison, there is tubular ectasia, atrophy in model group rat kidney, and renal cells is downright bad, the inflammatory cell infiltration that kidney region fibrosis and diffusivity are intensive.From the statistical result of average pathology integration, can find out, model group pathology integration is significantly higher than Normal group, prompting renal fibrosis model modeling success.After administration 15 days, aucubin high dose group, commercially available aucubin and Fluorofenidone positive controls are compared and are all occurred significant difference with model group, and there is a change for the better for kidney region fibrosis.
Table 2 aucubin is on the pathological impact of kidney region fibrosis
Note: with Normal group comparison, ++ P<0.01, with model group comparison, * P<0.05.
3 experiment brief summaries
The above results shows, aucubin high dose group, commercially available aucubin group can significantly be improved tubular ectasia, the atrophy of kidney region fibrosis model, and the symptoms such as kidney interstitial inflammatory cell infiltration, have some improvement to kidney region fibrosis.
Claims (10)
1. the application of aucubin in preparation treatment kidney region fibrosis medicine.
2. application according to claim 1, is characterized in that, described aucubin is Eucommia extract, and wherein aucubin purity is more than 98%.
3. according to application described in claim 1 or 2, it is characterized in that, described aucubin is to take Eucommia as raw material, by Eucommia, shells, kernel is pulverized, through defat with petroleum ether, and ethanol extraction, add acetone crystallisation by cooling, then through silicagel column purification, obtain aucubin monomer.
4. application according to claim 3, is characterized in that, the preparation method of described aucubin comprises the following steps:
1. defat: by the dry Cortex Eucommiae kernel that really shells to obtain, kernel is pulverized, and defat with petroleum ether, obtains defat coarse fodder; Described petroleum ether consumption is that the 6-10 of Cortex Eucommiae fruit kernel quality doubly measures, and defat number of times is 2-4 time, and degreasing time is 1.5-4 hour;
2. extract: add ethanol to extract described defat coarse fodder, filter, merge extractive liquid,, 40 ℃ of-60 ℃ of 1/5-1/12 that are concentrated into extracting liquid volume, obtain concentrated extracting solution; Described ethanol consumption is that the 6-12 of Cortex Eucommiae fruit quality doubly measures, and extraction time is 3-5 time, and each extraction time is 2-5 hour;
3. crystallization: described concentrated extracting solution is added to the saturated dissolving of acetone, and crystallisation by cooling, obtains aucubin coarse crystal;
4. silica gel column chromatography: described aucubin coarse crystal is added to the saturated dissolving of ethyl acetate, add again silica gel column chromatography, wherein silica gel for chromatography and aucubin roughly the mass ratio of crystal be 6:1-11:1, the solution then forming with ethyl acetate and methanol is eluting successively, 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: by described eluent 40 ℃-60 ℃ concentrated, lyophilization, obtains aucubin monomer product.
5. application according to claim 4, is characterized in that, step is 40-50 order after pulverizing described in 1..
6. application according to claim 4, is characterized in that, step 1. PetroChina Company Limited.'s ether consumption is that the 8-9 of Cortex Eucommiae fruit kernel doubly measures, and defat number of times is 3-4 time, and degreasing time is 2-3 hour.
7. application according to claim 4, is characterized in that, the step 8-10 that 2. middle ethanol consumption is raw material doubly measures, and extraction time is 3-4 time, and each extraction time is 3-4 hour.
8. application according to claim 4, is characterized in that, step 3. in after the saturated dissolving of ethyl acetate, by lysate be placed in 4-10 ℃ cooling, crystallization 12-72 hour.
9. application according to claim 4, is characterized in that, step 4. in silica gel for chromatography and aucubin roughly the mass ratio of crystal be 8:1-10:1.
10. application according to claim 4, it is characterized in that, step in 4. with the solution of ethyl acetate and the methanol composition successively order of eluting 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107198696A (en) * | 2017-06-22 | 2017-09-26 | 南方医科大学 | Application of the woodruff thuja acid in treatment kidney fibrosis medicine is prepared |
| CN110538189A (en) * | 2019-09-22 | 2019-12-06 | 江西普正制药股份有限公司 | Eucommia ulmoides extract composition for treating renal fibrosis and application thereof |
Citations (1)
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| CN102911222A (en) * | 2012-10-30 | 2013-02-06 | 薛宏宇 | Extraction method of aucubin and application of aucubin |
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2014
- 2014-08-01 CN CN201410376559.4A patent/CN104116752B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102911222A (en) * | 2012-10-30 | 2013-02-06 | 薛宏宇 | Extraction method of aucubin and application of aucubin |
Non-Patent Citations (1)
| Title |
|---|
| 王伟铭等: "糖对人肾成纤维细胞增殖及纤维连结蛋白分泌的影响", 《上海医学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107198696A (en) * | 2017-06-22 | 2017-09-26 | 南方医科大学 | Application of the woodruff thuja acid in treatment kidney fibrosis medicine is prepared |
| CN107198696B (en) * | 2017-06-22 | 2020-05-29 | 南方医科大学 | Application of asperuloside in preparation of medicine for treating renal fibrosis |
| CN110538189A (en) * | 2019-09-22 | 2019-12-06 | 江西普正制药股份有限公司 | Eucommia ulmoides extract composition for treating renal fibrosis and application thereof |
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Address after: Room 601, building c8-c10, jinruilugu science and Technology Park, No.28 Lutian Road, high tech Development Zone, Changsha City, Hunan Province, 410000 Patentee after: Changsha Duzheng Biotechnology Co., Ltd Address before: 411000 Hunan province Changsha high tech Development Zone, Lu Tin Road No. 28, No. 601, C8-C10 building science and Technology Park Lugu Patentee before: CHANGSHA DUXACT BIOTECH Co.,Ltd. |