CN108635352A - Magnoflorine is in the Use and preparation method for preparing prevention insomnia antidepressant agents - Google Patents
Magnoflorine is in the Use and preparation method for preparing prevention insomnia antidepressant agents Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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Abstract
The invention discloses magnoflorines in the Use and preparation method for preparing prevention insomnia antidepressant agents, and magnoflorine is detached using high-speed countercurrent chromatography.The method provided by the invention for isolating and purifying alkaloid monomer magnoflorine, compared with the existing technology, the present invention isolate and purify monomer is efficient, preparation amount is big, loss less, product purity it is high, easy to operate, economic and environment-friendly.The alkaloid monomer magnoflorine that the present invention disposably isolates and purifies reaches 95% or more through high performance liquid chromatography (HPLC) method purity.Show that magnoflorine is significantly improved and therapeutic effect depression, insomnia disease tool through animal pharmacodynamics experimental study.
Description
Technical field
The present invention relates to one kind the invention belongs to medicine, field of health care products, is related to a kind of alkaloid active ingredient magnolia
Application and preparation method of the alkali in terms for the treatment of depression, insomnia disease.
Background technology
Depression is with the low syndrome for main clinical manifestation of notable and lasting mental state, and severe patient will appear suicide
Currently, global incidence of depression has had reached 3.3%, and it has been more than 6% in developed country with the behavior of autotomy, the whole world
Patients with depression is more than 700,000,000, and the illness rate of China's depression is between 3%-5%, with the development of society, this data also exists
Constantly continuous rise.Insomnia refer to normally being slept, specific Symptoms be toss about in bed, sleep quality
Difference, sleeping time are reduced, and severe patient may have a sleepless night all night[3].Today's society, more and more people suffer from insomnia, and insomnia is
Through seriously affecting the normal life of people, the very big mental suffering of patient is brought, thus by social extensive concern[4].Research hair
It is existing, it is closely related between insomnia and depression.Most of patients with depression are suffering from insomnia, and the depression of insomniac is sent out
Sick rate is also significantly larger than normal population.Long-term clinical test shows that depression and insomniac can produce using western medicine
Raw a large amount of side effect, such as memory loss, drug is according to lazyness, or even the state of an illness can be made to rebound, and increases degree of danger, but in use
Medicine therapeutic effect is good, few side effects, and target user is extensive, therefore treats depression with Chinese medicine and insomnia is more and more closed
Note.
It is confirmed in existing research, magnoflorine adjusts immune function and anti-oxidant etc. tool in protection cardiovascular system
There is good effect.Therefore the medicinal and health value research of magnoflorine, is increasingly becoming the popular domain studied both at home and abroad, but
Have no the new application of its drug in terms of preparing antidepression, insomnia.The prior art generally uses the tradition such as chromatogram column technique, recrystallization
Separation method separating plant in effective monomer, not only time-consuming and laborious, pollution environment, and have can not for all fixed relative samples
Inverse property suction-operated.High speed adverse current chromatogram (HSCCC) is a kind of continuous efficient, quick liquid-liquid for being not necessarily to solid support
Partition chromatography isolation technics, it is easily each by dead absorption, loss and denaturation etc. that it avoids the sample that solid state adhesion body or carrier are brought
Kind problem, foundation substance distribution coefficient in two-phase is different and is detached, point particularly suitable for natural product active ingredient
From.
Invention content
The object of the present invention is to provide a kind of alkaloid monomer ingredient magnoflorine and its applications, solve prior art moderate resistance
Blahs aypnia medicine side reaction is more, the big problem of Chinese medicine taking amount.
The method for preparing magnoflorine the second object of the present invention is to provide high speed adverse current chromatogram, this method can be from wild jujubes
Pure magnoflorine is extracted in benevolence medicinal material, extraction separation spina date seed active constituent is time-consuming and laborious, fixes to overcome in the prior art
Relative sample has the problem of irreversibility suction-operated, low yield.
The invention is realized by the following technical scheme：
Magnoflorine is preparing prevention insomnia, the purposes of antidepressant agents, and using magnoflorine as active constituent, medicine is added
It learns acceptable auxiliary material and various preparations is made, wherein the magnoflorine is alkaloids, molecular formula C20H24NO4 +, molecular structure
Formula is as follows：
The active constituent is that extraction separation is similar either by chemical synthesis process or selected from having from spina date seed
The natural drug of pharmacological action.
A kind of preparation method of magnoflorine, the described method comprises the following steps：
(1) preparation of crude extract：
Spina date seed crushes, and is sieved by 40 mesh, and after petroleum ether degreasing, the concentration expressed in percentage by volume that 6~12 mass times are added is
60%~80% ethanol water, heating and refluxing extraction 2~3 times, every time 1~3h, filtration merge extracting solution, filtrate concentration
With 2~6 times of amount water dissolutions after ethyl alcohol to no alcohol taste, with extracting n-butyl alcohol 4-6 time, extracting solution is concentrated under reduced pressure, must after recycling design
To n-butanol crude extract, i.e., sample to be separated；
(2) high-speed countercurrent chromatography is used to detach magnoflorine：
It is 1~3 to take the volume ratio of ethyl acetate, n-butanol and water:1~5:2~7, it is placed in separatory funnel and prepares two-phase
Solvent system, it is stationary phase to take phase, and lower phase is mobile phase；Stationary phase is full of to the chromatographic column of adverse current chromatogram, at 25~35 DEG C
Under, host rotates forward, and rotating speed is 300~900r/min, then enters mobile phase with the flow pump of 1.5~10ml/min, until two mix
Agent reaches equilibrium state in column；The mixing crude extract for taking step (1) to prepare, with phase, lower phase volume ratio 1:1 mixed solvent
Sample introduction after dissolving collects the efflux of magnoflorine, concentration, drying, you can respectively obtain lily magnolia respectively under UV detector
Flower alkali.
In step (2), the volume ratio of n-butanol-ethyl acetate-water is：2:3:5.
In step (2), at 25 DEG C, host rotates forward, then rotating speed 500r/min is become a mandarin with the flow pump of 7ml/min
Dynamic phase.
The beneficial effects of the invention are as follows：
The method provided by the invention for isolating and purifying alkaloid monomer magnoflorine, compared with the existing technology, the present invention point
, preparation amount efficient from purified monomer be big, loss less, product purity it is high, easy to operate, economic and environment-friendly.The present invention disposably divides
The alkaloid monomer magnoflorine obtained from purifying reaches 95% or more through high performance liquid chromatography (HPLC) method purity.
Description of the drawings
Fig. 1 is magnoflorine and Si Pi Northeys, 6 made from embodiment 1, and " '-asafoetide acyl spinosin mixes crude extract
HPLC collection of illustrative plates；
Fig. 2 is high speed adverse current chromatogram (HSCCC) figure of embodiment 1；
Fig. 3 is the HPLC collection of illustrative plates of 1 magnoflorine of compound made from embodiment 1；
Fig. 4 is magnoflorine mass spectrogram；
Fig. 5 is magnoflorine nuclear magnetic resonance spectroscopy；
Fig. 6 is the carbon-13 nmr spectra figure of magnoflorine.
Specific implementation mode
It is further illustrated the present invention below by way of specific embodiment, not limitation of the invention, according to known in this field
The prior art, embodiments of the present invention are not limited to specific embodiment.In the premise without prejudice to spirit of that invention and principle
Under, it is fallen in the scope of the present invention to inventing any modifications or changes that individual technical steps carry out.
Embodiment 1
Magnoflorine preparation method
(1) preparation of crude extract：
Spina date seed 250g is crushed, and is sieved by 40 mesh, after petroleum ether degreasing, adds 1200ml, 800ml, 600ml percentage respectively
A concentration of 70% ethanol water, heating and refluxing extraction 3 times, 1 hour every time, filtration merged extracting solution, and filtrate concentrates ethyl alcohol
With 2 times of amount water dissolutions after to no alcohol taste, with extracting n-butyl alcohol 5 times, extracting solution is concentrated under reduced pressure, and it is thick to obtain n-butanol after recycling design
Extract, i.e., sample to be separated, HPLC collection of illustrative plates are as shown in Figure 1.
(2) high-speed countercurrent chromatography separation magnoflorine and the " '-asafoetide acyl spinosin of spinosin, 6 are used：
It is 2 to take the volume ratio of n-butanol, ethyl acetate and water:3:5, it is placed in preparation two-phase solvent system in separatory funnel,
It is stationary phase to take phase, and lower phase is mobile phase；Stationary phase is full of to the chromatographic column of adverse current chromatogram, at 25 DEG C, host rotates forward, and turns
Speed is 500r/min, then enters mobile phase with the flow pump of 7ml/min, until two-phase solvent reaches equilibrium state in column；Take step
Suddenly the mixing crude extract that prepared by (1), with phase, lower phase volume ratio 1:Sample introduction after 1 mixed solvent dissolving, with wavelength 280nm's
UV detector detection efflux is shown in Fig. 2 according to high speed adverse current chromatogram figure, to 72min to 84min, 86min to 100min and
The corresponding effluxes of 176min to 202.5min merge collection, concentration, drying to constant weight, you can respectively obtain lily magnolia respectively
Flower alkali (flow point I) and " '-asafoetide acyl spinosin (flow point III) of spinosin (flow point II), 6.
(3) monomer purity measurement and structure determination
Gained monomeric compound is detected using high performance liquid chromatograph to what is obtained respectively.Chromatographic column：Agilent
TC-C18Column (4.6mm × 250mm, 5 μm)；- 0.1% aqueous acetic acid of acetonitrile, gradient elution；Run time 40min；0min
10% acetonitrile, 20% acetonitriles of 5min, 5~40min, 20%~30% acetonitriles；Flow velocity：1mL/min；Column temperature：30℃；Sample size：
20μL；Detection wavelength 280nm.The purity for measuring compound magnoflorine reaches 95.0% (Fig. 3).Through mass spectrum (MS) (Fig. 4),1H-NMR and13C-NMR is analyzed, and is compared through structure elucidation and with data in literature, gained monomeric compound is respectively magnoflorine
250mg。
Magnoflorine Structural Identification：For yellow needles, blue-fluorescence is shown under ultraviolet lamp 254nm, improves Dragendorff's reagent
Colour developing is positive.Nuclear magnetic resoance spectrum identification is carried out to it,1H-NMR (400MHz DMSO) (Fig. 5) chemical shift is as follows：
6.504 (1H, s), 6.356 (IH d, J=8.0Hz), 6.598 (IH d, J=8.0Hz)；Its13C-NMR(100MHz MeOD-
d4) (Fig. 6) chemical shift is as follows：43.5,53.8 (N-Me), 24.6 (2*Me), 56.0,56.3 (10,11-MeO), 150.8,
151.7 (2,10), comparison pertinent literature determine that compound is magnoflorine (magnoflorine), molecular formula C20H24NO4 +,
Molecular weight 342.4.
Embodiment 2
Effect experiment of the magnoflorine to CUMS blahs aypnia mouse models
1 experiment material
1.1 experimental animal
Healthy male ICR mouse (20 ± 2g of weight) is purchased from Institute of Radiation Medicine, Chinese Academy of Medical Sciences experimental animal
The heart；Raising adapts to environment in 3 days before experiment.22 ± 2 DEG C of room temperature, relative humidity 65%~70%.Day illumination 12h, free diet are taken the photograph
Water.1.2 reagents and drug：
Magnoflorine, spinosin (self-control of this laboratory)；Venlafaxine hydrochloride slow-release capsule (Chengdu Kang Hong medicine companies group
Limited liability company)
1.3 instrument
Stopwatch (Huo Yeer-Ao Lidasi factories of Switzerland)；
120 type analysis balances of AUX (Shimadzu (Hong Kong) Co., Ltd)；
ZH-YLS-1A independent activity of animals recorder (Anhui Zhenghua Biology Instrument Equipment Co., Ltd.)；
KQ-200KDB type high powers numerical control ultrasonic cleaning machine (ultrasonic instrument Co., Ltd of Fauna of Kunshan, Jiangsu city).
2 experimental methods
2.1 animal packets and administration
Mouse is randomly divided into 6 groups, every group 10, respectively blank group, model group, Western medicine positive group (Venlafaxine), in
Patent medicine positive group (resolving stagnation for tranquilization granule), decocting group, magnoflorine group.In addition to blank group, remaining each group mouse presses " 2.2 "
Method modeling；From daystart every morning 8 of modeling:00-9:00 gastric infusion continues 21 days, and dosage regimen is shown in Table 1.
1 animal packet of table and dosage regimen
The method for building up of 2.2 CUMS blahs aypnia mouse models
10 kinds of stress factors of random arrangement are pressed in 21d, arbitrary two kinds of stimulations are given once daily, to avoid mouse from generating adaptation
Mild-natured each stimulation is given 4 times.
(1) moist raising：Suitable quantity of water is added in mouse bedding and padding makes its humidity, and survive 12h in a humid environment.
(2) fasting：12h is jejunitas.
(3) prohibit water：12h cuts off the water supply.
(4) raising is tilted：Mouse cage is tilted into 45 ° of raising mouse 12h.
(5) tail is pressed from both sides：Mouse is put into fixed cage, is clamped away from lasting 1min at root of the tail 1cm with haemostatic clamp.
(6) it is raised without bedding and padding：Mouse, each 12h are raised in the mouse cage of no bedding and padding.
(7) sleep deprivation：Sleep deprivation is for 24 hours.Using chain-wales water environment method, in container bottom setting diameter 3cm, height
The platform of 2cm, periphery fill water (depth of water 0.5cm), can fall into the water if mice sleep.
(8) cold-wate swimming：Animal is placed on to (depth of water 5cm) 5min in the container for filling 10 DEG C of water.
(9) hot water is swum：Animal is placed on to (depth of water 5cm) 5min in the container for filling 45 DEG C of water.
(10) it overturns round the clock：In early 7:The cage of mouse is placed on dark space when 00 not turn on light, until evening 19:It will when 00
Mouse is placed in the room turned on light until next day early 7:When 00.
2.3 observation indexs and method
(1) weight
The changes of weight of measurement mouse during the experiment, i.e., the 1st day, the 3rd day, the 10th day, the 17th day, the 21st day body
Weight, and calculate each group mouse weight increment.
(2) tail-suspention test (TST)
Mouse tail end is attached on a horizontal waddy, waddy is liftoff to make animal in vacantly projecting shape, hangs both sides partition board
Block mouse sight.Animal is to overcome abnormal position and struggle activity, but activity is after a certain period of time, discontinuity " motionless " occurs
" disappointment " state of display.It tests and carries out 6min, the dead time after record in 4min.
(3) forced swim test (FST)
Mouse is placed individually into the transparent glass cylinder for filling deep 10cm or more, temperature 45 C water, experiment carries out 6min.It is small
Mouse is to struggle to escape to after feeling hopeless to stop struggling, only by head above water four limbs in motionless state, after record in 4min
The dead time of mouse.
(4) yellow Jackets synergistic effect experiment
Sub-threshold dose yellow Jackets, dosage 28mg/kg are injected in the 8th day gavage 0.5h pneumoretroperitoneum of zoopery.
There is the number of elements slept in record each group mouse.Above threshold dose of sodium pentobarbitone, dosage are for gavage 0.5h pneumoretroperitoneums injection in 9th day
38mg/kg.Start timing after injection, records Sleep latency and sleeping time.When starting for sleep when righting reflex loss
Between, righting reflex reverts to the sleep end time.To sleep onset time it is Sleep latency after intraperitoneal injection, incubation period is more than
15min is recorded by 15min.
3 results
3.1 each administration groups test CUMS mouse TST the influence of dead time
Model group obviously increases compared with the naive mice TST dead times.The TST dead times of magnoflorine group are low
In model group, difference has statistical significance (P ＜ 0.05)；Magnoflorine group TST dead times less hundred compared with model group
It is point more suitable than with decocting group, it the results are shown in Table 2.
Influence of the 2 each administration group of table to the CUMS blahs aypnia mouse tail suspension dead times
* the P compared with model group<0.05** P compared with model group<0.01
3.2 each administration groups test CUMS mouse FST the influence of dead time
The FST dead times of magnoflorine group are substantially reduced compared with model group, have notable significant difference (P ＜
0.01), positive drug group, decocting the group difference compared with model group have statistical significance (P ＜ 0.05).Magnoflorine group and model
It is suitable with blank group, decocting group, positive drug group that group compares FST dead times less percentage, the results are shown in Table 3.
Influence of the 3 each administration group of table to the mouse forced swimming test dead time
* the P compared with model group<0.05** P compared with model group<0.01
The influence that 3.3 each administration groups test mouse sub-threshold dose yellow Jackets
Indicate that the sleep number of elements percentage of each administration group is significantly raised compared with model group by 4 experimental result of table, wherein
Magnoflorine group sleep number of elements percentage is suitable with decocting group.
The influence that 4 each administration group of table tests mouse sub-threshold dose yellow Jackets
The influence that 3.4 each administration groups act synergistically to above threshold dose of sodium pentobarbitone
It is shown by 5 data of table, each administration group Sleep latency no difference of science of statistics.Each administration group sleeping time is longer than mould
Type group, wherein magnoflorine group sleeping time are considerably longer than model group, and difference has statistical significance (P<0.05), with Xie Yuan
Refreshing granule group and decocting group are close.
5 each administration group of table to mouse, above threshold test by dose of sodium pentobarbitone
* the P compared with model<0.05** P compared with model group<0.01
Embodiment 3
Magnoflorine is added pharmaceutically acceptable auxiliary material and various dosage forms is made according to a conventional method, as the liquid of various specifications is noted
Penetrate agent, powder needle injection, emulsion for injection, tablet, pill, capsule, paste, creme, patch, liniment, pulvis, spray,
Implant, drops, suppository, ointment, confection etc..
The administration route of magnoflorine includes various administration routes：Oral medication, drug administration by injection, drug delivery implant, intracavitary are given
Medicine, sublingual administration, anum administration, cutaneous penetration, interior external application etc..
Claims (5)
1. magnoflorine is in the purposes for preparing prevention insomnia antidepressant agents, which is characterized in that lived to be main with magnoflorine
Property ingredient, pharmaceutically acceptable auxiliary material is added and is made various preparations, the magnoflorine is alkaloids, molecular formula C20H24NO4 +, molecular structural formula is as follows：
2. magnoflorine is in the purposes for preparing prevention insomnia antidepressant agents according to claim 1, which is characterized in that institute
It is that extraction detaches either by chemical synthesis process or selected from similar medicine from spina date seed to state active constituent magnoflorine
The natural drug of reason effect.
3. a kind of preparation method of magnoflorine, which is characterized in that the described method comprises the following steps：
(1) preparation of crude extract：
Spina date seed crushes, and is sieved by 40 mesh, and after petroleum ether degreasing, the concentration expressed in percentage by volume that 6~12 mass times are added is 60%
~80% ethanol water, heating and refluxing extraction 2~3 times, every time 1~3h, filtration merge extracting solution, and filtrate concentrates ethyl alcohol
With 2~6 times of amount water dissolutions after to no alcohol taste, with extracting n-butyl alcohol 4-6 time, extracting solution reduced pressure obtains just after recycling design
Butanol crude extract, i.e., sample to be separated；
(2) high-speed countercurrent chromatography is used to detach magnoflorine：
It is 1~3 to take the volume ratio of ethyl acetate, n-butanol and water:1~5:2~7, it is placed in separatory funnel and prepares two-phase solvent
System, it is stationary phase to take phase, and lower phase is mobile phase；Stationary phase is full of to the chromatographic column of adverse current chromatogram, it is main at 25~35 DEG C
Machine rotates forward, and rotating speed is 300~900r/min, then enters mobile phase with the flow pump of 1.5~10ml/min, until two-phase solvent is in column
In reach equilibrium state；The mixing crude extract for taking step (1) to prepare, with phase, lower phase volume ratio 1:After 1 mixed solvent dissolving
Sample introduction collects the efflux of magnoflorine, concentration, drying, you can obtain magnoflorine respectively under UV detector.
4. the preparation method of magnoflorine according to claim 3, which is characterized in that in the step (2), n-butanol-second
The volume ratio of acetoacetic ester-water is：2:3:5.
5. the preparation method of magnoflorine according to claim 3, which is characterized in that in the step (2), at 25 DEG C,
Host rotates forward, then rotating speed 500r/min enters mobile phase with the flow pump of 7ml/min.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113073123A (en) * | 2021-03-29 | 2021-07-06 | 上海交通大学 | Method for improving lignin oxidation capacity of laccase by using bisphenol mediator |
| CN114129580A (en) * | 2021-12-24 | 2022-03-04 | 西安荷默奇医药科技有限公司 | Traditional Chinese medicine-based component composition and application thereof in treating depression |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113073123A (en) * | 2021-03-29 | 2021-07-06 | 上海交通大学 | Method for improving lignin oxidation capacity of laccase by using bisphenol mediator |
| CN113073123B (en) * | 2021-03-29 | 2022-11-11 | 上海交通大学 | Method for improving lignin oxidation capacity of laccase by using bisphenol mediator |
| CN114129580A (en) * | 2021-12-24 | 2022-03-04 | 西安荷默奇医药科技有限公司 | Traditional Chinese medicine-based component composition and application thereof in treating depression |
| CN114129580B (en) * | 2021-12-24 | 2024-05-10 | 海南云泽医药科技有限公司 | Traditional Chinese medicine-based component composition and application thereof in treating depression |
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