CN1660106A - Combination of inhibiting activity of acetylcholinesterase, preparation method and application - Google Patents
Combination of inhibiting activity of acetylcholinesterase, preparation method and application Download PDFInfo
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- CN1660106A CN1660106A CN 200510200023 CN200510200023A CN1660106A CN 1660106 A CN1660106 A CN 1660106A CN 200510200023 CN200510200023 CN 200510200023 CN 200510200023 A CN200510200023 A CN 200510200023A CN 1660106 A CN1660106 A CN 1660106A
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- dehydroevodiamine
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Abstract
A composition with the activity for suppressing the acetylcholinesterase for preparing the medicines to prevent and treat senile dementia, vascular dementia, apoplexy and memory disfunction is prepared from dehydroevodiamine or its salt and berberine or its salt.
Description
Technical field: the present invention is a kind of combination of inhibiting activity of acetylcholinesterase, and its production and application that has, and belongs to the technical field of medicine.
Background technology: have the material of inhibiting activity of acetylcholinesterase,, promptly acetylcholinesteraseinhibitors inhibitors (AchEI) can reduce the degraded of neurotransmitter acetylcholine, is the strongest cholinergic reinforcing agent of generally acknowledging at present; Acetylcholinesteraseinhibitors inhibitors is by suppressing the degraded of acetylcholine in the synaptic space; increase the concentration of M-ChR and nicotine receptor place acetylcholine; thereby raising cognitive competence; in addition; acetylcholine has neuroprotective to the excitement of M-ChR and nicotine receptor, and most acetylcholinesteraseinhibitors inhibitors all can improve cognitive function.
Senile dementia (Alzheimer ' sDisease, AD) among the patient, the forfeiture of learning and memory ability, the decline with acetylcholine function of nervous system that is to say, with the height direct correlation of acetyl choline content.Therefore improve the acetyl choline content in AD patient's brain, promote the medicine of cholinergic function, be the alternative medicine of treatment senile dementia, as tacrine (Tacrine), donepezil (Donepezil), galantamine (Galanthanmine), Rivastigmine etc., account for listing and be used for the treatment of 70% of senile dementia disease drug.Vascular dementia, apoplexy etc. are the disordered brain function disease, with cognitive dysfunction, and the Learning and Memory ability drop.By seeking novel acetylcholinesteraseinhibitors inhibitors, increase the content of acetylcholine in patient's brain, improve the cholinergic nerve function, improve disordered brain function, improve ability of learning and memory, be an effective way of prevention and diseases such as treatment senile dementia, apoplexy.
Foreign study is found: and the dehydroevodiamine of one of chemical constituent (amine) in the Fructus Evodiae (dehydroevodiamine, DHED) external have a strong anti-acetylcholinesterase effect (Park CH; Kim SH; Choi W; Lee YJ; Kim JS; Kang SS; Suh YH; Novel anticholinesterase and antiamnesic activities ofdehydroevodiamine; a constituent of Evodia rutaecarpa.; Planta Med.; 1996; 62:405-409); can strengthen cerebral blood flow (Akira Haji; Yasumori Momose; Ryuji Takeda; SuehiroNakanishi; Increase Feline Cerebral Blood Flow Induced by DehydroecodiamineHydrochlorideFromEvodia Rutaecarp); dehydroevodiamine can recover the dysmnesia that scopolamine causes significantly; the damage that can protect cerebral ischemia that neurocyte is caused; promote the effect of nerve growth factor; and improve the inductive amnesia (Wang of amyloid-beta; H.H.; Chou; C.J.; Liao, J.F., and Chen; C.F.Dehydroevodiamine attenuates beta-amyloid peptide-induced amnesia in mice; European JournalofPharmacology, 2001,413 (2-3): 221-225).Aspect anti-senile dementia, it is also better than Tacrine in the body effect.Dehydroevodiamine can be repaired the effect that brain cell reaches the treatment apoplexy in addition, and therefore, dehydroevodiamine is expected to develop into the medicine of a class novel anti senile dementia and apoplexy.
Berberine (Berberine) is present in the various plants, connect Radix Berberidis Amurensis, Japanese Mahonia fortunei (Lindl.) Fedde as Berberidaceae plant Japan Radix Berberidis Amurensis, nine, the bloodroot Herba Chelidonii, menispermaceous plants headdress flower Radix Stephaniae Japonicae, the cohosh Rhizoma Coptidis, rutaceae Cortex Phellodendri etc., have antimicrobial and protozoon, blood pressure lowering, function of gallbladder promoting, calm, analgesic, effect such as brighten, be mainly used in treatment bacillary dysentery, typhoid fever, pulmonary tuberculosis, routine cerebrospinal meningitis, pulmonary abscess, hypertension, acute tonsillitis etc. clinically, it is quite safe to take therapeutic dose, takes for a long time and does not see any toxic and side effects.Research report is arranged: berberine low dosage have the effect that strengthens acetylcholine (open to emit and continue, Journal of physiology, 1963,19 (1): 12), high dose then has inhibitory action; Berberine can strengthen the inductive PC12 cell axon growth of nerve growth factor NGF and strengthen NGF induces the differentiation (ShigetaK. of neurocyte, Otaki K., Tatemoto H., et al., Potential of nerve growth factor-inducedneurite outgrowth in PC12 cells by a Coptidis Rhizoma extract and protoberberinealkaloids[J] .Biosci Biotechnol Biochem, 2002,66 (11): 2491-2494); Discover that recently berberine hydrochloride is the specific agonist of m receptor, can cause the blood vessel endothelium expansion, can improve (Wang Wenya, Chen Kemin, Guan Yongyuan such as AD symptom, berberine hydrochloride is to the effect [J] of muscarinic receptor. Acta Pharmaceutica Sinica, 1999,34 (4) 260-263).In addition, berberine can improve memory maintenance (Guo Shuren, the Luo Weifang that scopolamine causes the mouse memory acquired disturbance and promotes normal mouse, Liu Tianpei, berberine is to the influence of learning and memory of little mouse and prologue behavior, Pharmacology and Clinics of Chinese Materia Medica [J] .1997,13 (2): 17-20).Therefore, berberine reaches the improvement effect of improvement to brain function by strengthening acetylcholine.
Summary of the invention: when we have the research of anti-senile dementia disease material base in carrying out ethnic drug multiple medical material has been carried out research, experiment, screening, screening 100 surplus in kind of birth canal ground, the Guizhou Province Miao Ethnomedicine material total ethanol extract of Fructus Evodiae and Rhizoma Coptidis have inhibiting activity of acetylcholinesterase, preferably, through segment processing, follow the tracks of in conjunction with active, extracted active component and be respectively the material of dehydroevodiamine and berberine, this result is consistent with above-mentioned bibliographical information; Discover that further dehydroevodiamine and berberine have collaborative anti-acetylcholinesterase effect.
For this reason, the present invention is in order to reach following purpose:
1, provides a kind of compositions, i.e. dehydroevodiamine and berberine prescription, and prescription such as their hydrochlorate, sulfate, phosphate, the compositions of formation with inhibiting activity of acetylcholinesterase.
2, provide the method for preparing raw material that adopts in the compositions, i.e. synthetic or separation and purification obtains from plant (as the Chinese medicine Fructus Evodiae) dehydroevodiamine (and salt); From plants such as Chinese medicine such as Rhizoma Coptidis, obtain berberine and salt thereof and be combined into compositions by a certain percentage.
3, the combined method of compositions is provided, promptly even by mechanical agitation, also can be water, ethanol, the dissolving of ethyl acetate equal solvent after, remove the homogeneous mixture that solvent obtains.
4, the application of the compositions with inhibiting activity of acetylcholinesterase, is provided, promptly is applied in the medicine of diseases such as preparation prevention and treatment senile dementia, vascular dementia, damage in learning and memory, apoplexy.
The present invention constitutes like this: the compositions with inhibiting activity of acetylcholinesterase,, dehydroevodiamine (dehydroevodiamine) and berberine (berberine) prescription, and prescription such as their hydrochlorate, sulfate, phosphate, the compositions of formation.According to weight ratio: dehydroevodiamine or its salt 0.5～99.5 are mixed with berberine or its salt 99.5～0.5 and form.Its preparation method: synthetic or from plant, as separation and purification from Chinese medicine Fructus Evodiae, Rhizoma Coptidis etc., the dehydroevodiamine for preparing and salt and berberine and salt thereof, after the dehydroevodiamine that obtains and salt thereof and berberine and salt thereof taked churned mechanically method or water, ethanol, the dissolving of ethyl acetate equal solvent, the method preparation of removing the homogeneous mixture that solvent obtains had combination of inhibiting activity of acetylcholinesterase.The concrete grammar of preparation said composition raw material from Chinese crude drug: the dry almost ripe fruit of Chinese medicine Fructus Evodiae is through alcohol reflux, remove and desolvate, obtain crude extract, crude extract to be that eluant carries out gradient elution with the chloroform-methanol, obtains being rich in the position of dehydroevodiamine again through silica gel column chromatography, this position is again behind medium pressure column chromatography (silica gel), obtain the crude product that height contains dehydroevodiamine, behind recrystallization, the pure product dehydroevodiamine that gets final product; After the tuber powder essence with Rhizoma Coptidis, extract with ethanol heat, the extract diluted hydrochloric acid dissolution that obtains, the mother solution after the remove impurity: the sour water layer is after alkalization, separate out precipitation, filtering-depositing is after the washing, recrystallization can get pure product berberine again, can make the salt of berberine in corresponding acid with salify; With feed hydrogen rutaecarpin or its salt and berberine or its salt difference powder essence, cross 80～120 eye mesh screens, after desired proportions is carried out the mechanical agitation uniform mixing, add adjuvant in case of necessity, be prepared into suitable form of administration: capsule, tablet, injection, injection etc.; After also can using dissolvings such as aqueous solvent, ethanol or ethyl acetate, remove the uniform mixing raw material that solvent obtains, add adjuvant in case of necessity, be prepared into suitable form of administration.Application with combination of inhibiting activity of acetylcholinesterase: this compositions has significant inhibition active to acetylcholinesterase.Specifically: be applied in the medicine of diseases such as preparation prevention and treatment senile dementia, vascular dementia, apoplexy, damage in learning and memory.
In the present invention: can also adopt the method for synthetic to prepare dehydroevodiamine and salt thereof
Artificial synthesis: Jan Bergman reference literature i), Solveig Bergman, Studies ofRutaecarpine and Related Quinazolinocarboline Alkaloids, J.Org.Chem., 1985,50:1246～1255; Ii) Tatsuo Nakasato, Shozo Asada and Keiko Marui, Dehydroevodiamine, Main Alkaloid from the Leaves of Evodia rutaecarpa Hookerfil.Et Thomson, Yakugaku Zasshi, 1962,82:619 ~ 626 obtain following technical scheme:
Synthetic route is:
Isotoic anhydride (1) is dissolved in the pyridine, adds trifluoroacetic anhydride, is chilled to room temperature after the backflow, adds tryptamines, after back flow reaction finishes, adds the processing of acetic acid and hydrochloric acid mixed solution and can get intermediate (2).Intermediate (2) obtains rutaecarpine (3) under alkaline effect.Rutaecarpine (3) methylates through nitrogen can get dehydroevodiamine (4), its salt (4 ') be with corresponding reaction after obtain.
The inhibiting activity of acetylcholinesterase, test of compositions
The compositions that obtains by technical method of the present invention is carried out biological activity test.
(1) method:
A. medicine and reagent: acetylcholine is a Fluka company product, and acetylcholinesterase and tacrine are SIGMA company product, 5, and the two nitrobenzoic acids (DTNB) of 5-two sulfur are ACROS company product, other reagent are analytical pure.
B. experimental apparatus: Bio-RAD 550 microplate reader are Bio Rad Laboratories's product
C. sample is added and contain in the system of enzyme and DTNB, hatch a period of time for 37 ℃.Add acetylcholine, hatch a period of time again for 37 ℃.Add dodecyl sodium sulfate (SDS) cessation reaction.Measure optical density value at the 450nm place.Test is provided with blank, standard control, positive control, color sample contrast simultaneously.Be calculated as follows suppression ratio:
Suppression ratio=(standard control optical density value-sample optical density value)/standard control optical density value * 100
(2) sample number into spectrum and ratio
A: dehydroevodiamine; B: berberine; C: berberine hydrochloride
Ab11: a/b=1: 1 (weight ratio); Ab12: a/b=1: 2 (weight ratios);
Ab15: a/b=1: 5 (weight ratios); Ab110: a/b=1: 10 (weight ratios);
Ab21: a/b=2: 1 (weight ratio); Ab51: a/b=5: 1 (weight ratio);
Ac11: a/c=1: 1 (weight ratio); Ac31: a/b=3: 1 (weight ratio);
(3) result: by discovering to inhibiting activity of acetylcholinesterase,, the compositions that obtains according to technology provided by the invention has significant activity (the results are shown in Table 1), show: i) compare with the constitutive material dehydroevodiamine (a) of compositions, the activity of all compositionss is all than its height (IC
50Value is 2～5 times).The ii) IC of the IC50 value of compositions ab11, ab12, ab15, ab110, ab21 and ac11 and berberine (b)
50Value is suitable, and the inhibition activity of compositions ab51 and ac31 is than Radix Berberidis Amurensis alkaline error (about 2 times); Iii) the external inhibiting activity of acetylcholinesterase, of the constitutive material of all compositionss and compositions thereof is all low than positive control Tacrine.
Table 1 different proportion compositions is to the inhibition effect (3 meansigma methodss) of acetylcholinesterase
| Sample number into spectrum | IC 50(mg/ml) | Sample number into spectrum | IC 50(mg/ml?) |
| ab11 | ????0.0043 | ab21 | 0.0043 |
| ab12 | ????0.0045 | ab51 | 0.0069 |
| ab15 | ????0.0030 | ac11 | 0.0044 |
| ab110 | ????0.0031 | ac31 | 0.0070 |
| a | ????0.0157 | b | 0.0034 |
| Tacrine | ????0.0009 |
Prove by experiment: compositions provided by the invention has significant inhibiting activity of acetylcholinesterase,, the specific activity of all compositionss is formed the active height of the raw material dehydroevodiamine (a) of compositions, the activity of the activity of most of compositions and berberine quite, particularly in the ab11 compositions, dosage has reduced half, and its activity is 4 times of constitutive material dehydroevodiamine (a).Though the external inhibiting activity of acetylcholinesterase, of compositions provided by the invention, constitutive material dehydroevodiamine (a) and berberine (b) does not have positive control Tacrine strong, but the anti-senile dementia disease effect that has proved dehydroevodiamine (a) in the body zoopery is better than Tacrine, so compositions provided by the invention can be applicable to the preparation prevention and treats in the medicine of diseases such as senile dementia, vascular dementia, learning memory disorder, children mental retardation, apoplexy.
Compared with prior art, beneficial effect of the present invention is:
1) the invention provides a kind of new compositions.
2) constitutive material of compositions provided by the invention source is abundant, and preparation technology is reasonable, feasible, is suitable for the expansion scale, is easy to realize the purpose of industrialization.
3) compositions provided by the invention has significant inhibiting activity of acetylcholinesterase,, between its component synergism is arranged, and this result of study is not being appeared in the newspapers before this as yet; This compositions can be used in the preparation prevention and treat in the medicine of diseases such as senile dementia, vascular dementia, apoplexy, damage in learning and memory.
The specific embodiment:
The present invention further illustrates by following examples, but is not limited to content of the present invention.
Embodiments of the invention 1:
The preparation of dehydroevodiamine and salt thereof
1, synthetic:
Isotoic anhydride (1) (580mg, 3.56mmol) be dissolved in the 15mL pyridine, stir and drip trifluoroacetic anhydride 1.5g (7.12mmol) down, behind the backflow 15min, be cooled to room temperature, add tryptamines 570mg (3.56mmol), at backflow 30min, reaction finishes back (TLC follows the tracks of reaction process), and removal of solvent under reduced pressure gets residue, in residue, add acetic acid (12mL) and concentrated hydrochloric acid (2mL) mixed solution, backflow 30min, acid solution is removed in decompression, adds suitable quantity of water and distributes, use ethyl acetate extraction, ethyl acetate layer behind anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, (eluant is a chloroform: methanol 40: 1) purification obtains intermediate (2) 1.2g (94%) to the crude product that obtains through silica gel column chromatography.
Get intermediate (2) 500mg and be dissolved in KOH (0.8g), in the solution that water (3mL) and ethanol (10mL) are formed, behind the backflow 30min, pressurize out and desolvate, after adding water dispenser, obtain crude product through ethyl acetate extraction, (eluant is a chloroform to crude product: required thing rutaecarpine (3) 332mg (79.3%) diethylamine 100: 1) through silica gel column chromatography.
30mg rutaecarpine (3) is placed the 25ml reaction bulb, add the dissolving of 15ml benzene, after adding 0.3ml dimethyl sulfate backflow 6h, add the 0.2ml dimethyl sulfate again, at backflow 12h (TLC follows the tracks of reaction process), removal of solvent under reduced pressure, the crude product that obtains, through the PTLC purification, get product dehydroevodiamine (4) 20mg (63%).
In methanol or ethanol, dissolve dehydroevodiamine (4), feed hydrochloric acid vapour, can make the hydrochlorate (4 ') of dehydroevodiamine (4); Other salt can be with reference to this method preparation.
2, separation and purification from Fructus Evodiae:
The dry almost ripe fruit of Chinese medicine Fructus Evodiae (5kg) is through 85% alcohol reflux (3 times), removal of solvent under reduced pressure, obtain crude extract (300g), crude extract is again through silica gel column chromatography, with chloroform/methanol 20: 1,10: 1,5: 1 was that eluant carries out gradient elution, obtain being rich in the position of dehydroevodiamine, (eluant is for being petroleum ether: acetone: diethylamine=5: 1: 0.1) through medium pressure column chromatography (silica gel) again at this position, obtain the crude product that height contains dehydroevodiamine, after recrystallizing methanol, the pure product dehydroevodiamine (4g) that gets final product.
The embodiment of the invention 2:
The preparation of berberine and salt raw material thereof
After 5kg Rhizoma Coptidis (tuber) powder essence, extract with 75% ethanol heat, the extract diluted hydrochloric acid dissolution that obtains, the mother solution after the remove impurity (sour water layer) is separated out precipitation after alkalization, and filtering-depositing after the washing, again through ethyl alcohol recrystallization, can get pure product berberine.Berberine can make the salt (recrystallization is solvent with 70%) of berberine with salify in corresponding acid.
The embodiment of the invention 3: with raw material dehydroevodiamine and berberine powder essence respectively, cross 80 eye mesh screens, carry out the mechanical agitation uniform mixing in 0.5 kilogram of ratio of dehydroevodiamine with 99.5 kilograms of berberine after, promptly get compositions, be prepared into conventional tablet.Oral, three times on the one, each 2.
The embodiment of the invention 4: with the salt of the salt of raw material dehydroevodiamine and berberine powder essence respectively, cross 120 eye mesh screens, carry out the mechanical agitation uniform mixing in the ratio of 0.5 kilogram of the salt of 99.5 kilograms of the salt of dehydroevodiamine and berberine after, promptly get compositions; Add adjuvant commonly used, be prepared into injection.
The embodiment of the invention 5: with raw material dehydroevodiamine and berberine difference powder essence, cross 100 eye mesh screens, after dissolving with ethanol (also can use the ethyl acetate equal solvent) in 50 kilograms of the dehydroevodiamines and the ratios of 50 kilograms of berberine, remove the uniform mixing raw material that solvent obtains, be compositions, directly fill, be prepared into capsule.
The embodiment of the invention 6: the salt of raw material dehydroevodiamine and the salt of berberine are distinguished powder essence, cross 90 eye mesh screens, after ratio water (or ethanol) dissolving in 30 kilograms of the salt of 70 kilograms of the salt of dehydroevodiamine and berberine, remove the uniform mixing raw material that solvent obtains, it is compositions, add conventional adjuvant, be prepared into lyophilized injectable powder.
Claims (6)
1. compositions with inhibiting activity of acetylcholinesterase,, it is characterized in that: dehydroevodiamine (dehydroevodiamine) and berberine (berberine) prescription, and prescription such as their hydrochlorate, sulfate, phosphate, the compositions of formation.
2. according to the described compositions with inhibiting activity of acetylcholinesterase, of claim 1, it is characterized in that: according to weight ratio, dehydroevodiamine or its salt 0.5 ~ 99.5 are mixed with berberine or its salt 99.5 ~ 0.5 and form.
3. the preparation method that described in claim 1 or 2, has combination of inhibiting activity of acetylcholinesterase,, it is characterized in that: synthetic or from plant as separation and purification Chinese medicine Fructus Evodiae, the Rhizoma Coptidis, the dehydroevodiamine for preparing and salt thereof and berberine and salt thereof, after the dehydroevodiamine that obtains and salt thereof and berberine and salt thereof taked churned mechanically method or water, ethanol, the dissolving of ethyl acetate equal solvent, the method preparation of removing the homogeneous mixture that solvent obtains had combination of inhibiting activity of acetylcholinesterase.
4. according to the preparation method that has combination of inhibiting activity of acetylcholinesterase, described in the claim 3, it is characterized in that: the dry almost ripe fruit of Chinese medicine Fructus Evodiae is through alcohol reflux, remove and desolvate, obtain crude extract, crude extract is again through silica gel column chromatography, with the chloroform-methanol is that eluant carries out gradient elution, obtain being rich in the position of dehydroevodiamine, this position is again behind medium pressure column chromatography (silica gel), obtain the crude product that height contains dehydroevodiamine, behind recrystallization, the pure product dehydroevodiamine that gets final product; After the tuber powder essence with Rhizoma Coptidis, extract with ethanol heat, the extract diluted hydrochloric acid dissolution that obtains, the mother solution after the remove impurity: the sour water layer is after alkalization, separate out precipitation, filtering-depositing is after the washing, recrystallization can get pure product berberine again, can make the salt of berberine in corresponding acid with salify; With feed hydrogen rutaecarpin or its salt and berberine or its salt difference powder essence, cross 80 ~ 120 eye mesh screens, after desired proportions is carried out the mechanical agitation uniform mixing, add adjuvant in case of necessity, be prepared into suitable form of administration: capsule, tablet, injection, injection etc.; After also can using dissolvings such as aqueous solvent, ethanol or ethyl acetate, remove the uniform mixing raw material that solvent obtains, add adjuvant in case of necessity, be prepared into suitable form of administration.
5. have the application of combination of inhibiting activity of acetylcholinesterase, described in claim 1 or 2, it is characterized in that: this compositions has significant inhibition active to acetylcholinesterase.
6. according to the described application of claim 5, it is characterized in that: be applied in the medicine of diseases such as preparation prevention and treatment senile dementia, vascular dementia, apoplexy, damage in learning and memory with combination of inhibiting activity of acetylcholinesterase.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017128291A1 (en) * | 2016-01-29 | 2017-08-03 | 深圳市人民医院 | Use of berberine to prevent and treat alzheimer's disease |
| CN109369650A (en) * | 2018-12-17 | 2019-02-22 | 苏州汇通色谱分离纯化有限公司 | The middle method for suppressing standby chromatography and purifying high-purity rutaecarpin and Rutaecarpine |
| CN110179859A (en) * | 2019-06-27 | 2019-08-30 | 香港科技大学深圳研究院 | The application of Radix Stephaniae Tetrandrae extract and fangchinoline in pharmacy |
| CN110384680A (en) * | 2018-04-17 | 2019-10-29 | 成都医学院 | A kind of temperature/pH responsiveness is double to carry medicine composite nanoparticle and its preparation method and application |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07330623A (en) * | 1994-06-10 | 1995-12-19 | Tsumura & Co | Suppressant for neuron death |
| KR100203456B1 (en) * | 1995-06-20 | 1999-06-15 | 한승수 | Therapeutic agent for dimentia caused by alzheimer disease containing dihydroevodiamine-hcl as an active component |
| WO2003006018A1 (en) * | 2001-07-10 | 2003-01-23 | Regen Biotech, Inc. | A composition for the protection and regeneration of nerve cells containing berberine derivatives |
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2005
- 2005-01-12 CN CNB2005102000238A patent/CN1309389C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017128291A1 (en) * | 2016-01-29 | 2017-08-03 | 深圳市人民医院 | Use of berberine to prevent and treat alzheimer's disease |
| CN110384680A (en) * | 2018-04-17 | 2019-10-29 | 成都医学院 | A kind of temperature/pH responsiveness is double to carry medicine composite nanoparticle and its preparation method and application |
| CN110384680B (en) * | 2018-04-17 | 2021-07-30 | 成都医学院 | temperature/pH responsive double-drug-loading composite nanoparticle and preparation method and application thereof |
| CN109369650A (en) * | 2018-12-17 | 2019-02-22 | 苏州汇通色谱分离纯化有限公司 | The middle method for suppressing standby chromatography and purifying high-purity rutaecarpin and Rutaecarpine |
| CN110179859A (en) * | 2019-06-27 | 2019-08-30 | 香港科技大学深圳研究院 | The application of Radix Stephaniae Tetrandrae extract and fangchinoline in pharmacy |
| CN110179859B (en) * | 2019-06-27 | 2021-09-24 | 香港科技大学深圳研究院 | Application of radix Stephaniae Tetrandrae extract and fangchinoline in pharmacy |
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