CN104356138A - Vasicine R-type optical isomer as well as preparation method and application thereof - Google Patents

Vasicine R-type optical isomer as well as preparation method and application thereof Download PDF

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Publication number
CN104356138A
CN104356138A CN201410581998.9A CN201410581998A CN104356138A CN 104356138 A CN104356138 A CN 104356138A CN 201410581998 A CN201410581998 A CN 201410581998A CN 104356138 A CN104356138 A CN 104356138A
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vasicine
acid
optical isomer
type optical
type
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王长虹
程雪梅
王峥涛
刘伟
杨雅迪
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Shanghai University of Traditional Chinese Medicine
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Shanghai University of Traditional Chinese Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a vasicine R-type optical isomer as well as a preparation method and application thereof. The chemical structural formula of the vasicine R-type optical isomer is as shown in the specification. The preparation method comprises the following steps: preparing vasicine despinner into an ethanol saturated solution; by using a high performance liquid chromatograph and by taking a mixed solution prepared from ethanol and diethylamine in a volume ratio of 100:0.1 as a flow phase, separating by using a chiral chromatographic column at the column temperature of 25 DEG C under the ultraviolet detection wave length of 210nm at the flowing speed of 0.5mL/minute; collecting the fraction of which the retention time is within 8.8-10.8 minutes in a chromatogram; concentrating and recrystallizing, so as to obtain the vasicine R-type optical isomer. The experiment shows that the pure vasicine R-type optical isomer has relatively high anti-AChE activity and anti-BChE activity when being compared with those of S-type vasicine, particularly has remarkable anti-BChE activity, and can be used for preparing cholinesterase inhibitors and medicines for treating senile dementia.

Description

A kind of vasicine R type optical isomer and its production and use
Technical field
The present invention relates to a kind of vasicine R type optical isomer and its production and use, belongs to natural medicine technical field.
Background technology
The senile dementia that alzheimer's disease (Alzheimer's disease is called for short AD) is namely usually said is a kind of chronic degenerative disease.Modern medicine study finds: the neurobiology change of AD brain in patients is mainly cholinergic function and weakens, the extensive region such as Cerebral cortex and hippocampus vagusstoff (Acetylcholine, be called for short ACh) reduction of level and activity, cholinergic neuron and fibrosis, necrosis or lack.Active and the ACh content of CAT in brain (Choline acetyltransferase is called for short ChAT) reduces that to be recognized be the key character of AD.The disappearance of ACh is the feature of AD, also attempts adopting multi-medicament to improve the level of ACh in patient's brain to compensate its cholinergic disappearance in clinical, reaches the object for the treatment of AD.Method that is the most ripe and successful treatment AD adopts acetylcholinesterase (Acetylcholine Esterase is called for short AChE) inhibitor exactly at present.Up to now, the U.S. FDA approved medicines of four kinds of AChE inhibitor as AD.These medicines comprise E2020 (Donepezil, Aricept tM), bright (Rivastigmine, the Exelon of Li Fansi tM), lycoremine (Galantamine, Reminyl tM) and tacrine (Tacrine, Cognex tM).
AChE inhibitor is the hydrolysis by suppressing synaptic cleft place ACh, improves the content of ACh, finally reaches the object for the treatment of AD.In normal brain, the ACh level in brain is mainly through the performance regulating effect of AChE, and the effect that butyrylcholine esterase (Butyrylcholinesterase is called for short BChE) plays is very little; And in patient's AD brain the activity of AChE constant or decline, but the activity of BChE rise.Therefore, exploitation has the inhibiting material of AChE and BChE simultaneously or conbined usage has AChE or BChE restraining effect material, treatment for AD is more effective (see document: Greig N H, et al.Current Medical Research and Opinion, 2001,17 (3): 159 ~ 165).
Vasicine is a kind of pyrrolo-(2, the 1b)-quinazoline alkaloid being separated acquisition from the plants such as Acanthaceae (Acanthaceae) plant Adhatoda vasica Nees (Adhatoda vasica Nees) and zygophyllaceae (Zygophyllaceae) plant Herba pegani harmalae (Peganum harmala Linn).Although there is bibliographical information vasicine to have vagusstoff and butyrylcholine esterase restraining effect, about the drug efficacy study of its optical isomer so far there are no relevant report.
Summary of the invention
The object of this invention is to provide a kind of vasicine R type optical isomer and its production and use, to utilize the pharmaceutical use of vasicine better.
Vasicine R type optical isomer of the present invention, has following chemical structural formula:
The preparation method of described vasicine R type optical isomer, comprises the steps:
A) by vasicine raceme dissolve with ethanol, alcohol saturated solution is made;
B) above-mentioned alcohol saturated solution is injected high performance liquid chromatograph, the mixing solutions formed for 100:0.1 by volume with ethanol and diethylamine is for moving phase, use chiral chromatographic column column temperature be 25 DEG C, ultraviolet detection wavelength is 210nm, flow velocity for 0.5mL/ minute under be separated, collecting retention time in color atlas is the cut within the scope of 8.8 ~ 10.8 minutes;
C) solvent in concentrated dry collected cut, obtains crude product;
D) carry out drying after recrystallization process being carried out to crude product with the mixed solvent that methyl alcohol and ethyl acetate are formed for 1:1 by volume, obtain vasicine R type optical isomer.
Preferably, described chiral chromatographic column selects the Chiralpak AY-H chromatographic column that column length is 150mm, column internal diameter is 4.6mm, filling agent particle diameter is 5.0 μm.
Preferably, steps d) in drying be vacuum-drying at 35 ~ 45 DEG C.
Vasicine R type optical isomer of the present invention can be used for preparing anticholinesterase, and described anticholinesterase comprises acetylcholinesterase depressant or/and butyrylcholinesterase inhibitor.
Vasicine R type optical isomer of the present invention can be used for the medicine preparing treatment senile dementia.
Medicine of the present invention can be various different formulation and uses for patient, as various normal oral solid preparation (tablet, capsule, particle etc.), and other formulation such as sustained-release and controlled release, injection.
Vasicine R type optical isomer of the present invention can free alkali form or apply with the addition salt form that acid is formed, and described acid can be mineral acid, such as: sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid etc.; Also can be organic acid, such as: acetic acid, oxalic acid, citric acid, gluconic acid, succsinic acid, tartrate, tosic acid, methylsulfonic acid, phenylformic acid, lactic acid, toxilic acid etc.
Compared with prior art, the present invention has following beneficial effect:
Experiment proves: it is active that pure vasicine R type optical isomer (referred to as R type vasicine) has the anti-AChE stronger than vasicine S type optical isomer (referred to as S type vasicine) and anti-BChE, especially there is significant anti-BChE active, be 33.7 times of S type vasicine activity.The present invention has important value to evident in efficacy, that security the is good anticholinesterase of screening.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of embodiment vasicine raceme used.
Fig. 2 is the HPLC collection of illustrative plates that embodiment is separated the S type vasicine obtained.
Fig. 3 is the HPLC collection of illustrative plates that embodiment is separated the R type vasicine obtained.
Embodiment
Do to illustrate in detail, intactly further to the present invention below in conjunction with embodiment; The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.
Embodiment 1: be separated preparation R type vasicine and S type vasicine by vasicine raceme
A) by 300mg vasicine raceme at 30 DEG C with dissolve with ethanol, make alcohol saturated solution (concentration is 50mg/mL);
B) above-mentioned alcohol saturated solution is injected high performance liquid chromatograph, be that the mixing solutions that formed of 100 ﹕ 0.1 is for moving phase by volume with ethanol and diethylamine, the Chiralpak AY-H chiral chromatographic column that use column length is 150mm, column internal diameter is 4.6mm, filling agent particle diameter is 5.0 μm, it is 25 DEG C at column temperature, flow rate of mobile phase is 0.5mL/ minute, ultraviolet detection wavelength is be separated under the condition of 210nm, and collecting retention time in color atlas is respectively the fraction A within the scope of 5.8 ~ 7.3 minutes and the fraction B within the scope of 8.8 ~ 10.8 minutes;
C) concentrate the solvent in dry collected fraction A and fraction B respectively, obtain S type vasicine crude product and R type vasicine crude product.
D) be that the mixed solvent that 1 ﹕ 1 is formed carries out recrystallization process to S type vasicine crude product and R type vasicine crude product respectively by volume by methyl alcohol and ethyl acetate, then at 40 DEG C, carry out vacuum-drying to constant weight, namely separablely obtain S type vasicine and R type vasicine.
Detect through optical purity: the equal >99% of HPLC purity being separated S type vasicine and the R type vasicine obtained.
Fig. 1 is the HPLC collection of illustrative plates of vasicine raceme used, and Fig. 2 is the HPLC collection of illustrative plates being separated the S type vasicine obtained, and Fig. 3 is the HPLC collection of illustrative plates being separated the R type vasicine obtained.
Anticholinesterase activity is tested:
Experiment purpose: investigation R type vasicine, S type vasicine, different ratios R type compare the inhibit activities of acetylcholinesterase (AChE) and butyrylcholine esterase (BChE) respectively with S type vasicine mixture, vasicine raceme.
Experimental principle: vagusstoff (ACh) or BuCh (BCh) can be hydrolyzed and generate acetic acid or butyric acid and choline under AChE or BChE effect, therefore can determine the activity of AChE or BChE by the growing amount measuring choline.When adding the material with AChE or BChE inhibit activities, choline growing amount being caused to reduce, by measuring the growing amount of choline, just can calculate the inhibiting rate of determinand.
Materials and methods:
Tested material: R type vasicine, S type vasicine, vasicine raceme, for subsequent use with methyl alcohol preparation desired concn storing solution before test.
Main reagent and material: acetylcholinesterase (AChE) comes from Electrophorus electricus, butyrylcholine esterase (BChE) comes from horse serum, Ovisot (ACh), chlorination BuCh (BCh), choline chloride 60 (Ch), interior mark choline dichloride (IS), lycoremine equal purchased from American Sigma-Aldrich company, vasicine, hplc grade methanol and acetonitrile equal purchased from American Fisher Co., chromatographic grade formic acid purchased from American Tedia Inc., ultrapure water is obtained by Milli-Q Academic System, other reagent are commercially available AG.
Key instrument: the Waters-ACQUITYTM UPLC system that water generation u s company produces, the Micromass Quattro Premier XE that water generation UK corporation produces connects triple level Four bar mass spectrum, refrigerated centrifuge, micropipet that German Eppendorf company produces.
Preparation of reagents:
Volumetric molar concentration is the Na of 1mol/L 2hPO 4solution: take 12 hydration Na 2hPO 4358.14g is dissolved in the ultrapure water of 1L;
Volumetric molar concentration is the NaH of 1mol/L 2pO 4solution: take two hydration NaH 2pO 4156.01g is dissolved in the ultrapure water of 1L;
Volumetric molar concentration is 1mol/L, the phosphate buffered saline buffer of pH value 7.6: get the Na that 84.5mL volumetric molar concentration is 1mol/L 2hPO 4solution and 15.5mL volumetric molar concentration are the NaH of 1mol/L 2pO 4be diluted to 1000mL after solution mixing and get final product;
Volumetric molar concentration is 20mmol/L, the phosphate buffered saline buffer of pH value 7.6: get the Na that 100mL volumetric molar concentration is 0.02mol/L 2hPO 4solution adds the NaH that a certain amount of volumetric molar concentration is 0.02mol/L 2pO 4after solution mixing pH value is adjusted to 7.6 and get final product;
Standardized solution and quality-control sample preparation: get the volumetric flask that appropriate Ch and IS is placed in 25mL, add dissolve with methanol and be mixed with the storage liquid that volumetric molar concentration is 5.386mmol/L and 2.012mmol/L respectively, initial flow is used to obtain working fluid and quality-control sample by a series of dilution mutually, use methanol dilution obtains the IS working fluid that volumetric molar concentration is 1.899 μm of ol/L, all solution is all stored in 4 DEG C, uses after placing room temperature;
The preparation of sample solution: use volumetric molar concentration is 20mmol/L, the phosphate buffered saline of pH value 7.6 obtains AChE and the BChE mother liquor that concentration is 3.470unit/mL, is stored in-80 DEG C; Use volumetric molar concentration is 20mmol/L, the phosphoric acid buffer of pH value 7.6 is prepared respectively and obtained ACh and the BCh substrate solution that volumetric molar concentration is 11.011 μm of ol/L and 14.305 μm ol/L; Use concentration of volume percent be 0.2% the appropriate testing sample preparation of dmso solution to obtain volumetric molar concentration be 20mmol/L mother liquor, and use the testing sample solution that volumetric molar concentration is 20mmol/L, the dilution of the phosphoric acid buffer of pH value 7.6 obtains a series of concentration, as shown in Table 1 below, wherein: RS is vasicine raceme; S is S type vasicine; R is R type vasicine.
Table 1, testing sample composition and testing sample solution volumetric molar concentration
Testing sample forms Testing sample solution volumetric molar concentration (μm ol/L)
Lycoremine 5,2,1,0.5,0.2,0.1,0.05,0.02,0.01
RS 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S 100,20,4,0.8,0.16,0.032,0.0064,0.00128
R 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝10﹕1 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝8﹕1 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝6﹕1 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝4﹕1 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝2﹕1 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝1﹕2 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝1﹕4 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝1﹕6 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝1﹕8 100,20,4,0.8,0.16,0.032,0.0064,0.00128
S﹕R＝1﹕10 100,20,4,0.8,0.16,0.032,0.0064,0.00128
AChE and BChE inhibition test:
AChE inhibition test: the testing sample solution first getting 10 μ L, then the AChE enzyme solution mixing that 40 μ L concentration are 0.0035unit/mL is added, place after 15 minutes and add the ACh substrate solution that 50 μ L volumetric molar concentrations are 5.505 μm of ol/L, 25 DEG C of reactions are after 20 minutes, be 0 DEG C by 300 μ L, temperature, be the IS-ice acetonitrile solution termination reaction of 1.899 μm of ol/L containing volumetric molar concentration immediately, with the centrifuge 10 minutes of 15000 revs/min, get supernatant liquor for analyzing.
BChE inhibition test: the testing sample solution getting 10 μ L, then the BChE enzyme solution mixing that 40 μ L concentration are 0.008unit/mL is added, place after 15 minutes and add the BCh substrate solution that 50 μ L volumetric molar concentrations are 7.152 μm of ol/L, 25 DEG C of reactions were 0 DEG C by 300 μ L, temperature, are the IS-ice acetonitrile solution termination reaction of 1.899 μm of ol/L containing volumetric molar concentration after 20 minutes, with the centrifuge 10 minutes of 15000 revs/min, get supernatant liquor for analyzing.
Sample analysis:
Use Waters-ACQUITYTM UPLC system systematic position, chromatographic column uses the ACQUITY UPLC HSS T3 chromatographic column of column length 100mm, column internal diameter 2.1mm, filling agent particle diameter 1.8 μm, column temperature is 40 DEG C, moving phase is the mixing solutions that 98 ﹕ 2 are formed by volume by the aqueous formic acid of 0.1vol% and methyl alcohol, flow rate of mobile phase is 0.3mL/ minute, Gradient elution, sample size is 5 μ L.
Micromass Quattro Premier XE is used to connect triple level Four bar mass spectrograph associating electron spray(ES) as analyzing and testing instrument, adopt multiple-reaction monitoring pattern in the positive-ion mode, mass spectrometry parameters is: capillary voltage 3.00kV, extraction voltage 3.00V, ion source temperature 120 DEG C, desolventizing temperature 400 DEG C, desolventizing gas is the nitrogen of flow 550L/ hour, taper hole gas is flow is 50L/ hour, purity is the nitrogen of 99.9%, collision gas is the argon gas of purity 99.999%, and data acquisition and procession is completed by MassLynx 4.1 software.
Data processing:
The inhibiting rate of each testing sample to AChE and BChE is calculated by following form with measuring the result obtained:
Inhibiting rate=(negative control sample-testing sample)/negative control sample × 100%.
Carry out nonlinear dependence by using Prism software and analyze matching acquisition IC 50value, as shown in Table 2 below.
Table 2, tested material are to the inhibit activities of AChE and BChE
From table 2 result: tested material becomes positive correlation to the inhibit activities of AChE with BChE with R type vasicine proportion in tested material, that is: R type vasicine proportion its activity larger is stronger; It is active that pure R type vasicine has the anti-AChE stronger than S type vasicine and anti-BChE, especially has significant anti-BChE active, be 33.7 times of S type vasicine activity.R type vasicine can be used for preparing anticholinesterase medicine, and described anticholinesterase medicine can be acetylcholine esterase inhibitor medication, butyrylcholinesterase inhibitor medicine, acetylcholinesterase depressant and butyrylcholinesterase inhibitor medicine.Furtherly, R type vasicine can be used for the medicine preparing treatment senile dementia, has pharmaceutical use.
The preparation of embodiment 2:R type vasicine tablet
A) 1000 tablet recipes are prepared:
Raw material Weight (g)
R type vasicine 15.0
Starch 122.0
Sodium starch glycolate 7.5
30 POVIDONE K 30 BP/USP 30 2.5
Talcum powder 3.0
B) preparation method: get R type vasicine 15.0g, starch 122.0g, cross 80 mesh sieves, add sodium starch glycolate 7.5g by inside and outside addition, mix, the volume by volume concentration added containing 2.5g PVP K30 be 10% ethanolic soln make softwood, make particle with 20 mesh sieves, wet granular after drying, adds talcum powder 3.0g under 60 ~ 80 DEG C of conditions, mix, cross the whole grain of 16 mesh sieve, be pressed into 1000, obtain final product.
The preparation of embodiment 3:R type vasicine injection
A) prescription:
Raw material Weight (g)
R type vasicine 10.0
Lactic acid 1.0
Sodium-chlor 18.0
S-WAT 2.0
0.1mol/L Citric Acid Regulate PH to 2.0 ~ 5.0
Water for injection 2000mL
B) preparation method: take R type vasicine 10.0g, lactic acid 1.0g, sodium-chlor 18.0g, be placed in preparation container, add the water for injection of 2/3 recipe quantity, stirring adds 0.1M Citric Acid to be made main ingredient dissolve and regulates PH2.0 ~ 5.0, then adds antioxidant S-WAT 2.0g, mends water for injection to 2000mL full dose, stir about 30 minutes, add medicinal carbon absorption 15 ~ 20 minutes, the amount of carbo medicinalis used is about 0.03%, and after filtering, namely sterile filling, sterilizing obtain injection.
In sum: R type vasicine provided by the invention has the inhibit activities than S type vasicine and stronger AChE and BChE of vasicine raceme, free alkali form or the addition salt form formed with acid and pharmaceutical excipient can prepare anticholinesterase and treat the various pharmaceutical dosage forms of senile dementia, as various normal oral solid preparation (tablet, capsule, particle etc.), similar drugs compared to existing technology, have evident in efficacy, the advantages such as consumption is little, the incidence of untoward reaction can be reduced by high degree, there is the pharmaceutical use of significance.
Finally be necessary described herein: above content is only for being described in further details technical solution of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.

Claims (10)

1. a vasicine R type optical isomer, is characterized in that, has following chemical structural formula:
2. prepare a method for vasicine R type optical isomer according to claim 1, it is characterized in that, comprise the steps:
A) by vasicine raceme dissolve with ethanol, alcohol saturated solution is made;
B) above-mentioned alcohol saturated solution is injected high performance liquid chromatograph, the mixing solutions formed for 100:0.1 by volume with ethanol and diethylamine is for moving phase, use chiral chromatographic column column temperature be 25 DEG C, ultraviolet detection wavelength is 210nm, flow velocity for 0.5mL/ minute under be separated, collecting retention time in color atlas is the cut within the scope of 8.8 ~ 10.8 minutes;
C) solvent in concentrated dry collected cut, obtains crude product;
D) carry out drying after recrystallization process being carried out to crude product with the mixed solvent that methyl alcohol and ethyl acetate are formed for 1:1 by volume, obtain vasicine R type optical isomer.
3. method as claimed in claim 2, is characterized in that: described chiral chromatographic column selects the Chiralpak AY-H chromatographic column that column length is 150mm, column internal diameter is 4.6mm, filling agent particle diameter is 5.0 μm.
4. vasicine R type optical isomer according to claim 1 is for preparing the pharmaceutical use of anticholinesterase.
5. the anticholinesterase described in claim 4 comprises acetylcholinesterase depressant or/and butyrylcholinesterase inhibitor.
6. vasicine R type optical isomer according to claim 1 is for preparing the pharmaceutical use for the treatment of senile dementia.
7. the addition salt form that the vasicine R type optical isomer described in claim 4 or 6 is free alkali form or is formed with acid.
8. the acid described in claim 7 is mineral acid or organic acid.
9. the mineral acid described in claim 8 is sulfuric acid, hydrochloric acid, Hydrogen bromide or phosphoric acid.
10. the organic acid described in claim 8 is acetic acid, oxalic acid, citric acid, gluconic acid, succsinic acid, tartrate, tosic acid, methylsulfonic acid, phenylformic acid, lactic acid or toxilic acid.
CN201410581998.9A 2014-10-27 2014-10-27 Vasicine R-type optical isomer as well as preparation method and application thereof Pending CN104356138A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107233371A (en) * 2017-07-27 2017-10-10 广州中医药大学 The big application for refuting bone in the medicine for preparing prevention and/or treatment nerve degenerative diseases and medicine
CN108226319A (en) * 2016-12-22 2018-06-29 亚宝药业集团股份有限公司 A kind of method for detecting optical isomer in Rivastigmine patch

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CN101433565A (en) * 2008-11-26 2009-05-20 上海中医药大学 Total alkaloid extract of seeds of harmel genus and effective monomer component thereof, and preparation and use thereof
CN103626773A (en) * 2012-08-25 2014-03-12 上海壹志医药科技有限公司 Salt of vasicine derivative

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US20030180392A1 (en) * 2002-03-21 2003-09-25 Chattopadhyay Sunil Kumar Process for the production of vasicine
CN101433565A (en) * 2008-11-26 2009-05-20 上海中医药大学 Total alkaloid extract of seeds of harmel genus and effective monomer component thereof, and preparation and use thereof
CN103626773A (en) * 2012-08-25 2014-03-12 上海壹志医药科技有限公司 Salt of vasicine derivative

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108226319A (en) * 2016-12-22 2018-06-29 亚宝药业集团股份有限公司 A kind of method for detecting optical isomer in Rivastigmine patch
CN107233371A (en) * 2017-07-27 2017-10-10 广州中医药大学 The big application for refuting bone in the medicine for preparing prevention and/or treatment nerve degenerative diseases and medicine

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Application publication date: 20150218