CN104693265A - Preparation method of cyclovirobuxine D and novel application of medicine - Google Patents
Preparation method of cyclovirobuxine D and novel application of medicine Download PDFInfo
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Abstract
The invention discloses cyclovirobuxine D extracted from buxus microphylla SieB.et Zucc.var.sinica Rehd.etWils. and congeners, and a composition. The cyclovirobuxine D and the composition have the action of preventing and treating senile dementia. Enzymology and animal experiments prove that the cyclovirobuxine D and the composition have good action of preventing and treating senile dementia. Further research proves that the cyclovirobuxine D is higher than the composition in activity, which illustrates that the cyclovirobuxine D is a main pharmacodynamic material.
Description
Technical field
The invention relates to the cyclovirobuxinum D that extracts from little leaf boxwood and congener and take cyclovirobuxinum D as the composition of main component has in the medicine of control senile dementia application in preparation.Also relate to the pharmaceutical preparation of this medicine, the invention belongs to medical art.
Background technology
Senile dementia is a kind of nervus centralis decline property disease.Progressive symmetric erythrokeratodermia memory impairment and mental loss is had, dysmnesia, abstract thinking obstacle, language energy during being mainly manifested in person in middle and old age
power is lostoften, the symptom such as behavior and direction obstacle.Its pathogeny is not fully aware of, is a kind of very complicated nerve and cellular senescence process.Gu the prevention and therapy of this senile dementia is still a world-famous puzzle at present.Prevent to be take pathological characters as point of penetration substantially to senile dementia at present, Kang β – amyloid beta deposition medicine can be divided into, cholinomimetic thing, short acetic acid choline release medicine, cell growth factor promotor, medicine for improving brain function etc.The medicine gone on the market or entering clinical study has acetylcarnitine, tacrine, ties up (volume 8 phase herbal medicine calendar year 2001 32 attached 4-5) such as that crin, silymarin, Physostigmine, selagine and timosaponins.The medicine toxic side effect of having gone on the market is all larger.So research and development toxic side effect is little, anti senile dementia drug is significant safely and effectively.
Little leaf boxwood Buxus micr ophylla Sieb.et Zucc.var.sinica Rehd.et Wils. system Buxaceae Buxus plant, originates in each provinces and regions on the south the Qinling Mountains.Buxus plant is at me
domestic17 kinds and several subspecies and mutation, be rich in alkaloid, be called as buxus alkaloids (Buxus Alkaloids), belongs to derivatives of pregnane.Record according to Chinese medicine voluminous dictionary: Chinese medicine Chinese littleleaf box property is put down, bitter is nontoxic.Function cures mainly: wind-damp dispelling, regulates the flow of vital energy, pain relieving.Dispelling the wind and dampness pathogens pain, chest abdominal distension gas, toothache, pain, wound.Oneself have developed Buxine (cyclovirobuxinum D) and hat peace sheet from Buxus plant at present, is mainly used in cardiovascular disorder.But up to the present, there is not yet the cyclovirobuxinum D extracted from little leaf boxwood at home and abroad and take cyclovirobuxinum D as the report of composition for prevention and therapy senile dementia of main component.The present invention is with a wide range of applications.
The structural formula of cyclovirobuxinum D (cyclovirobuxine D)
Summary of the invention
An object of the present invention is to provide cyclovirobuxinum D and is that the composition of main component is in the application for the treatment of and in prevention senile dementia with cyclovirobuxinum D.Cyclovirobuxinum D and take cyclovirobuxinum D as the novelty teabag of composition for the preparation of control medicine for senile dementia of main component specifically.Cyclovirobuxinum D and be that the composition of main component shows all have the activity of obvious acetylcholine esterase inhibition through enzymology with cyclovirobuxinum D; Prove through animal experiment, equal tool is significantly improved dementia mice learning and memory function, and can significantly improve the activity of SOD, reduces the content of MDA, improves the effect of brain coefficient.Further research shows, cyclovirobuxinum D has stronger pharmacologically active compared with the composition taking cyclovirobuxinum D as main component.
Another object of the present invention is, providing with cyclovirobuxinum D is the composition of main component has in control medicine for senile dementia application in preparation, and composition is mainly containing cyclovirobuxinum D, cycloprotobuxine A, the former buxine C of ring, Cyclovirobuxine C.More precisely, cyclovirobuxinum D accounts for 50-90%, and cycloprotobuxine A accounts for 1-5%, and the former buxine C of ring accounts for 2-10%, and Cyclovirobuxine C accounts for 1-5%, and in composition, the content of cyclovirobuxinum D is not less than 80%.
The present invention adopts large pores cation exchange resin to be separated buxus alkaloids composition first, do not utilize the organic reagent separation and purification buxus alkaloids composition that trichloromethane, benzene, ether, methyl alcohol etc. are poisonous, just utilize acidic ethanol extraction, resin isolation, can prepare in a large number, and workable, little to the pollution of environment, only apply a small amount of trichloromethane when preparing cyclovirobuxinum D monomer, there is obvious technical progress and innovation.
Outstanding contributions of the present invention are: the unexpected discovery of the present invention, and cyclovirobuxinum D has the effect of very strong control senile dementia.The preparation being main raw material due to cyclovirobuxinum D records in Chinese Pharmacopoeia, has had the applicating history of two more than ten years, proves without any side effects, so the present invention has the superiority being developed to control senile dementia new drug.
Present invention also offers cyclovirobuxinum D and take cyclovirobuxinum D as the pharmaceutical preparation of composition of main component.Mainly oral preparations, is mainly selected from any one in tablet, capsule, pill, granule, suspensoid, oral preparations.
Another object of the present invention there is provided cyclovirobuxinum D and take cyclovirobuxinum D as the preparation method of composition of main component, it is characterized in that:
(1) the 60-95% alcohol reflux 3 time of little leaf boxwood meal containing glacial acetic acid or formic acid, each 2-3 hour, united extraction liquid, add medicine liquid volume 0.1%-1% gac, stir, filter, decompression filtrate recycling ethanol obtains medicinal extract, be dissolved in water, make every 1ml containing 1g medicinal material, centrifugal, get supernatant liquor, by D001-CC macroporous type storng-acid cation exchange resin, first enter with 10-30% ethanol elution 3-5 times of resin volume, use 50-90% ammonia ethanol ammonia wash-out 4-7 times of resin volume again, collect ammonia ethanol eluate, recycling design, drying under reduced pressure, namely the composition that cyclovirobuxinum D is main component is able to.
(2) getting with cyclovirobuxinum D is the composition of main component, utilize water dissolution, adjust pH most 7, utilize trichloromethane jolting to extract 3-5 time, water layer adjusts pH to be 10 with ammoniacal liquor again, extract 2-5 time with trichloromethane jolting, anhydrous sodium sulfate dehydration, trichloromethane liquid passes through neutral alumina column, recycling design, drying, recrystallization, obtains cyclovirobuxinum D.
In order to realize above technical scheme, the content of cyclovirobuxinum D measures by the following method:
Chromatographic condition: chromatographic column: ZORBAX SB C18 post (250mm*4.6mm, 35 μm); Column temperature: 30 DEG C; Moving phase: methyl alcohol: water (83:17); Flow velocity: 1.0mL/min, determined wavelength: 242nm; Sample size: 10 μ L.
The preparation of reference substance solution: it is appropriate that precision takes Control of Cyclovirobuxine D, add trichloromethane and dissolve, constant volume, is made into the solution of 0.2mg/mL.
The preparation of need testing solution: test sample is about 10mg, accurately weighed, put in 50ml measuring bottle, add the molten and constant volume of trichloromethane.
Pre-column derivatization and mensuration: precision measures cyclovirobuxinum D contrast solution or each 2mL of need testing solution, add phenylcarbimide test solution and (get phenylcarbimide 20 μ L, add trichloromethane 10mL to shake up and get final product), room temperature reaction 30min, add methanol dilution and be settled to 50mL, filter, sample introduction measures, and calculates.
Cyclovirobuxinum D and take cyclovirobuxinum D as the effect that the composition (abbreviation composition) of main component has prevention and therapy senile dementia disease, these pharmacological actions, are confirmed by following pharmacodynamics test example.
Cyclovirobuxinum D and be that the composition of main component provides by Jilin Academy of Chinese Medicine Sciences with cyclovirobuxinum D; Positive control drug E 2020 manufactures (140322A) by Pharmaceutical Co., Ltd. of health material.Acetylcholinesterase produces (>=200U/g) by Yuan Ye bio tech ltd, Shanghai.
1, cyclovirobuxinum D and be that the composition of main component is to inhibiting activity of acetylcholinesterase, with cyclovirobuxinum D
The preparation of the Tris-HCl damping fluid of 0.05M (pH=7.8): the accurate 6.0501gTris alkali that claims is in 1L beaker, add about 800mL distilled water to dissolve, connect pH meter, constantly add a little concentrated hydrochloric acid, measure pH value after abundant stirring, be finally adjusted to pH=7.80 and be then transferred in 1L volumetric flask, beaker and glass stick a little distilled water wash 3 times, together proceed in volumetric flask, be finally settled to 1L.
The Na of 0.2M
2hPO
4solution: claim Na
2hPO
412H
2o altogether 7.164g is dissolved in water to 100mL.
The NaH of 0.2M
2pO
4solution: claim NaH
2pO
42H
2o altogether 3.121g is dissolved in water to 100mL.
The PBS of the pH=7.0 of 0.1M: get 39mL0.2M NaH
2pO
4the Na of solution and 61mL 0.2M
2hPO
4, fully mixing is the PBS of 0.2M PH=7.0, this liquid is diluted 1 times, is the PBS of 0.1M pH7.0.
The PBS of the pH=8.0 of 0.1M: get 5.3mL 0.2M NaH
2pO
4solution and 94.7mL0.2M Na
2hPO
4solution, fully mixing is the PBS of 0.2M PH=8.0, this liquid is diluted 1 times, is the PBS of 0.1M pH=8.0.
The acetylcholinesterase of the preparation of acetylcholinesterase (AChE) solution: 100U is dissolved in the Tris-HCl (0.05M of 50mL, pH=7.8) in damping fluid, add the bovin serum albumin stabilized enzyme liquid of 50mg again, obtain the enzyme solution of 2U/mL.The PBS of the enzyme liquid pH=8.0 of 2U/mL is diluted to the enzyme liquid of 0.5U/mL for Ellman method.
The preparation of 2mM DTNB: 3.96mg DTNB first uses the anhydrous alcohol solution of 500 μ L, then adds 1.5mg NaHCO
3, then use the PBS constant volume of pH=7.0 to 5mL.
The preparation of 15mM ATCI: 21.67mg ATCI adding distil water dissolves and is settled to 5mL.4 DEG C of Refrigerator stores.
The E 2020 of the configuration of E 2020 solution: 10mg is dissolved in the PBS of the pH=8.0 of 5mL, abundant concussion is made into the solution of 2mg/mL, is then diluted to the stand-by solution of 0.025mg/mL, 0.05mg/mL, 0.1mg/mL, 0.25mg/mL, 0.5mg/mL, 1.0mg/mL successively with the PBS of pH=8.0.
Treat the configuration of sample measuring liquid: get correct amount sample appropriate, being made into concentration with the PBS solution dissolving of pH=8.0 is 2mgmL
-1solution, be then diluted to the stand-by solution of 0.001mg/mL, 0.025mg/mL, 0.05mg/mL 0.1mg/mL, 0.25mg/mL, 0.5mg/mL, 1.0mg/mL with the PBS of pH=8.0.
Sample well: add 140 μ L PBS damping fluid (0.1M, pH=8.0) in enzyme plate aperture, 20 μ L testing sample solutions and 15 μ L enzyme solution, preserve 20min at 4 DEG C after mixing.Taking-up adds 10 μ L DTNB (2mM) and 10 μ L ATChI (15mM), can read absorbance after 37 DEG C of reaction 20min at 405nm.
Sample Background control wells: replace 15 μ L enzyme solution with 15 μ L PBS damping fluids, other condition is constant.
Blank control wells: replace 20 μ L testing sample solutions with 20 μ L PBS damping fluids, other condition is constant.
Experimental result is shown in
figure1-3.According to suppression curve, cyclovirobuxinum D and be that the composition of main component has stronger inhibit activities compared with positive control drug E 2020 with cyclovirobuxinum D.The IC of positive control drug E 2020
50for 0.187mg/mL, cyclovirobuxine IC
50for 0.0106mg/mL, the IC of composition
50for 0.0179mg/mL.
Accompanying drawing explanation
figure1 is that positive control drug acetylcholine esterase inhibition suppresses curve
figure.
figure2 is that cyclovirobuxinum D acetylcholine esterase inhibition suppresses curve
figure.
figure3 is that composition acetylcholine esterase inhibition suppresses curve
figure
2, cyclovirobuxinum D and composition cause the impact of memory deficits in mice to AlCl3
Get mouse 90, be divided into 9 groups at random, press
table 1grouping.1st day to the 7th day, control group subcutaneous injection every day physiological saline, all the other respectively organized mouse subcutaneous injection AlCl350mg/kg.Medication group difference gavage successive administration 2 weeks.Carry out keeping away dark test, in record 3min, mouse enters darkroom
mistakenumber of times, after 24h with
mistakenumber of times and
mistakepercentage test Memory result.Experimental result is shown in
table 1.
table 1, cyclovirobuxinum D and composition cause the impact (n=10, X ± S) of memory deficits in mice to AlCl3
* compare with normal group, * P<0.05, * * P<0.01; △ compares with model group, △ P<0.05, △ △ P<0.0l
Illustrate that cyclovirobuxinum D metering different from composition causes dysmnesia to AlCl3 and all have antagonism effect in various degree.Minimizing mouse
mistakefrequency and
mistakeincidence.Under same dose condition, ring dimension yellow star D comparatively composition has good activity.
3, cyclovirobuxinum D and composition cause the impact of memory deficits in mice to Scopolamine
Get mouse 90, be divided into 9 groups at random, press
table 2grouping.1st day to the 7th day, control group and model group, to distilled water, were pressed for all the other each group
table 2administration.Once a day, continuous 7 days, after last administration 1h, normal group was to physiological saline 0.1ml/10g, and all the other each group, to scopolamine hydrobromide 3mg/kg, is carried out Jumping test after 10min, carried out test result after training 3min, 24h.The results are shown in
table 2.
table 2, cyclovirobuxinum D and composition cause the impact (n=10, X ± S) of memory deficits in mice to Scopolamine
* compare with normal group, * P<0.05, * * P<0.01; △ compares with model group, △ P<0.05, △ △ P<0.0l
Scopolamine hydrobromide group mouse
mistakenumber of times compared with normal group significantly increases, and medication group considerably reduces mouse
mistakenumber of times, has obvious antagonistic action to the memory deficits in mice caused by scopolamine hydrobromide group.Obvious minimizing mouse
mistakefrequency and
mistakeincidence.Under same dose condition, ring dimension yellow star D comparatively composition has good activity.
4, cyclovirobuxinum D and composition cause the impact of memory deficits in mice to 30% ethanol
Get mouse 90, be divided into 9 groups at random, press
table 3grouping.1st day to the 7th day, control group and model group, to distilled water, were pressed for all the other each group
table 3administration.Once a day, continuous 7 days, after last administration 1h, normal group was to physiological saline 0.1ml/10g, and all the other each group, to 30% ethanol, is carried out Jumping test after 15min, mouse every in test record 5min
mistakenumber of times.The results are shown in
table 3.
table 3, cyclovirobuxinum D and composition cause the impact (n=10, X ± S) of memory deficits in mice to 30% ethanol
* compare with normal group, * P<0.05, * * P<0.01; △ compares with model group, △ P<0.05, △ △ P<0.0l
30% ethanol group mouse
mistakenumber of times compared with normal group significantly increases, and medication group is except low dose of total flavones, and all the other each group has obvious antagonistic action to the memory deficits in mice caused by 30% ethanol.Under same dose condition, D is stronger to the memory deficits in mice antagonistic action caused by 30% ethanol compared with composition for ring dimension yellow star.
5, cyclovirobuxinum D and composition are on the impact of Senlie dementia model mouse brain SOD2 SOD activity, mda (MDA) content and brain coefficient.
Get mouse 90, be divided into Normal group and model group at random.Model group is to A1C1
3solution, starts to press 400mg/kg/d gavage in 70 days, uses 2g/L A1C1 later always
3solution is drunk; The distilled water of Normal group gavage equivalent.Model group is divided into 8 groups at random, presses
table 4shown in, gastric infusion 60 days, Normal group Model of Dementia group is filled with the distilled water of amount.Whole experimentation is avoided contacting with aluminum products.Put to death mouse, in ice bath, take out cerebral tissue rapidly, and accurately take, measure SOD, MDA and calculating brain coefficient respectively.Experimental result is shown in
table 4.
table 4, cyclovirobuxinum D and composition, MDA content active on Senlie dementia model mouse brain SOD and brain coefficient impact (n=10, X ± S)
* compare with normal group, * P<0.05, * * P<0.01; △ compares with model group, △ P<0.05, △ △ P<0.0l
Model control group brain SOD activity reduces, and MDA content increases, and brain coefficient reduces (P<0.05).Compare with model group, the high, medium and low dosage group SOD activity of cyclovirobuxinum D raises, MDA content reduces, combination object height, middle dosage group SOD activity raise, MDA content reduces (P<0.05 or P<0.01), illustrate that cyclovirobuxinum D and composition have obvious antioxygenation, improve free radical excess metabolism in vivo.Increase SOD content, strengthen resistance of oxidation, accelerate the removing of free radical, suppress peroxidation, suppress Peroxidation Product MDA to produce and remove the effect of excessive MDA, cyclovirobuxinum D comparatively composition increases significantly brain coefficient, thus the effect with stronger anti-encephalatrophy is described.
6, cyclovirobuxinum D and composition are on the impact of Senlie dementia model acetyl choline content.
Get mouse 90, be divided into Normal group and model group at random.Model group is to A1C1
3solution, starts to press 400mg/kg/d gavage in 70 days, uses 2g/L A1C1 later always
3solution is drunk; The distilled water that Normal group gavage etc. are held.Model group is divided into 8 groups at random, presses
table 5shown in, gastric infusion 60 days, Normal group Model of Dementia group is filled with isopyknic distilled water.Whole experimentation is avoided contacting with aluminum products.Rat sacrificed by decapitation, open rapidly cranium and peel off cerebral tissue (removal cerebellar tissue), get rinsing in Brain tissue physiology salt solution, removing blood, filter paper is wiped dry, adds cold saline and puts into homogenate tube and fully grind at ice bath, make the brain homogenate of 10%, centrifugal, get supernatant colorimetric method for determining cerebral tissue enzyme acetylcholine content.Experimental result is shown in
table 5.
table 5, cyclovirobuxinum D and composition be on the impact (n=10, X ± S) of Senlie dementia model acetyl choline content
* compare with normal group, * P<0.05, * * P<0.01; △ compares with model group, △ P<0.05, △ △ P<0.0l
Each treatment group and model group compare, and acetyl choline content reduces, and has significant difference.Under same dose, cyclovirobuxinum D is more remarkable compared with the content influence of composition to vagusstoff.
The present invention is achieved (confirmation) by following embodiment
embodiment 1, composition extraction preparation
Little leaf boxwood 5kg is ground into meal, with 80% alcohol reflux 3 times containing 2% glacial acetic acid, each 2 hours, united extraction liquid, add medicine liquid volume 0.2% gac, stir, filter, decompression filtrate recycling ethanol obtains medicinal extract, be dissolved in water, make every 1ml containing 1g medicinal material, centrifugal, get supernatant liquor, by D001-CC macroporous type storng-acid cation exchange resin, first use 15% ethanol elution, 5 times of resin volumes, be 70% ethanol elution, 5 times of resin volumes of 11 again with ammoniacal liquor tune pH, collect ammonia ethanol eluate, recycling design, drying under reduced pressure, namely the composition that cyclovirobuxinum D is main component is able to.In composition, cyclovirobuxinum D content is 83.5%.
embodiment 2, cyclovirobuxinum D preparation
Getting with cyclovirobuxinum D is the composition 50mg of main component, uses 500ml water dissolution, adjusts pH most 7, first extract 4 times with trichloromethane jolting, each 100ml, water layer adjusts pH to be 10 with ammoniacal liquor again, extract 5, each 100ml with trichloromethane jolting, collect trichloromethane liquid, after anhydrous sodium sulfate dehydration, directly by neutral alumina column, recycling design, dry, acetone recrystallization, obtains cyclovirobuxinum D.
Claims (6)
1. the cyclovirobuxinum D extracted from Buxus plant has the application in control medicine for senile dementia in preparation.
2. extract from Buxus plant with cyclovirobuxinum D be main component composition preparation have control medicine for senile dementia in application.
3. be the composition of main component has in control medicine for senile dementia application in preparation according to claim 2 with cyclovirobuxinum D, it is characterized in that: composition is mainly containing cyclovirobuxinum D, cycloprotobuxine A, the former buxine C of ring, Cyclovirobuxine C.
4. be the composition of main component according to claim 3 with cyclovirobuxinum D, it is characterized in that: by weight percentage: cyclovirobuxinum D accounts for 50-90%, cycloprotobuxine A accounts for 1-5%, the former buxine C of ring accounts for 2-10%, Cyclovirobuxine C accounts for 1-5%, and in composition, the content of cyclovirobuxinum D is not less than 80%.
5. cyclovirobuxinum D according to claims 1 to 4 and take cyclovirobuxinum D as the preparation method of composition of main component, is characterized in that:
(1) the 60-95% alcohol reflux 3 time of little leaf boxwood meal containing glacial acetic acid or formic acid, each 2-3 hour, united extraction liquid, add medicine liquid volume 0.1%-1% gac, stir, filter, decompression filtrate recycling ethanol obtains medicinal extract, be dissolved in water, make every 1ml containing 1g medicinal material, centrifugal, get supernatant liquor, by D001-CC macroporous type storng-acid cation exchange resin, first enter with 10-30% ethanol elution 3-5 times of resin volume, use 50-90% ammonia ethanol ammonia wash-out 4-7 times of resin volume again, collect ammonia ethanol eluate, recycling design, drying under reduced pressure, namely the composition that cyclovirobuxinum D is main component is able to,
(2) getting with cyclovirobuxinum D is the composition of main component, by water dissolution, adjust pH most 7, extract 3-5 time with trichloromethane jolting, water layer adjusts pH to be 10 with ammoniacal liquor again, extract 2-5 time with trichloromethane jolting, anhydrous sodium sulfate dehydration, trichloromethane liquid passes through neutral alumina column, recycling design, drying, recrystallization, obtains cyclovirobuxinum D.
6. cyclovirobuxinum D and take cyclovirobuxinum D as the composition of main component according to claim 1-5, it is characterized in that: can oral preparations be made, be selected from any one in the middle of tablet, capsule, soft capsule, granule, pill, suspensoid, dripping pill, oral liquid.
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| CN105601697A (en) * | 2016-03-26 | 2016-05-25 | 吉林省中医药科学院 | Preparation method and new medical use of cyclovirobuxine D derivatives |
| CN105601697B (en) * | 2016-03-26 | 2018-01-30 | 吉林省中医药科学院 | New cyclovirobuxine D derivatives and medical usage |
| CN107233347A (en) * | 2017-06-07 | 2017-10-10 | 新乡医学院 | A kind of pharmaceutical composition for treating Alzheimer formula syndrome and its application |
| CN109078002A (en) * | 2018-09-23 | 2018-12-25 | 吉林省中医药科学院（吉林省中医药科学院第临床医院） | Cyclovimbuxine D solid dispersions preparation method and its new medical use |
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Application publication date: 20150610 |