CN109528782A - Ginkgo biloba p.e has the application of the drug for the treatment of or health care as synergist in preparation to sleep disturbance disease - Google Patents

Ginkgo biloba p.e has the application of the drug for the treatment of or health care as synergist in preparation to sleep disturbance disease Download PDF

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CN109528782A
CN109528782A CN201811648190.2A CN201811648190A CN109528782A CN 109528782 A CN109528782 A CN 109528782A CN 201811648190 A CN201811648190 A CN 201811648190A CN 109528782 A CN109528782 A CN 109528782A
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ginkgo biloba
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郭姣
贝伟剑
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Guangdong Pharmaceutical University
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Abstract

Preparation and application the invention discloses ginkgo biloba p.e as Insomnia therapy medicine Brain targeting synergist.Inventor has found part ginkgo biloba p.e class compound in long-term experimental research, especially ginkgo biloba p.e extract and its hydroxy derivatives, especially its glucosides, ester, ether derivative, energy invertibity Opening Blood Brain Barrier can increase considerably drug such as Schisandra chinens P.E, siberian Ginseng P.E, Herb Gynostemmae Pentaphylli extract, the Wild jujube seeds extract isoreactivity ingredient of the sleep disturbance such as treatment neurasthenia, difficulty falling asleep, insomnia through blood-brain barrier, increase in brain tissue at concentrations up to 3~20 times, there is excellent Brain targeting effect.It can be used for developing the original new drug and/or health care product of efficiently prevention and treatment sleep disturbance, increase the curative effect or health-care effect for the treatment of sleep disturbance (neurasthenia, difficulty falling asleep, insomnia etc.) drug, medication dose is reduced, periphery risk of toxicity is reduced, reduces drug side-effect and adverse reaction.

Description

Ginkgo biloba p.e as synergist preparation to sleep disturbance disease have treatment or The application of the drug of health care
Technical field
The present invention relates to a kind of new opplication of ginkgo biloba p.e and new drug composition based on the application, specially silver-colored Apricot leaf extract has the application of the drug for the treatment of or health care as synergist in preparation to sleep disturbance disease.
Background technique
Brain is vital center place, and complicated nervous system structures and function have become most valuable in human sciences' history The research topic of value, the increasingly concern by World Science man.
Cerebral blood flow velocity is most fast, however slow into the speed ratio of brain tissue into its hetero-organization after many drug Formulations for systemic administration Much, therefore the concept of blood-brain barrier is formd.Blood-brain barrier refers to the screen between blood-brain tissue between liquid and blood-cerebrospinal fluid Barrier, by blood-brain barrier (blood-brainbarrier, BBB), cerebrospinal fluid-brain barrier (cerebro-spinalfluid- ) and three barrier structures of blood-cerebrospinal fluid barrier (blood-cerebro-spinalfluidbarrier) brainbarrier At.The function of blood-brain barrier is selectively Cucumber to be prevented to enter brain tissue.Due to blood-brain tissue barrier surface Product is about 5000 times of blood-cerebrospinal fluid barrier surface product, therefore, blood-brain tissue barrier be the inside and outside source property substance of control into The main barrier of brain parenchym out facilitates the stabilization for maintaining brain tissue environment.
The sleep disturbance such as insomnia, difficulty falling asleep, neurasthenia are to seriously threaten the major disease of human health.To trouble Person, family and society cause heavy burden.But due to the presence of blood-brain barrier (BBB), limit most drugs enter brain or Effective concentration needed for treatment is not achieved in intracerebral, seriously limits the treatment of sleep disturbance.
Traditional Chinese medicine is with a long history in terms of preventing and treating sleep disturbance disease, it is significant in efficacy and have safety, low toxicity, Small side effects Etc. advantages.Such as general ginsenoside (extract), Schisandra chinens P.E, siberian Ginseng P.E, gypenosides extract, wild jujube Benevolence extract, ganoderma lucidum (lactone) extract etc. are treatment of sleep disorders medicines.But these ingredients are not easy to enter brain through blood-brain barrier Tissue plays a role.
Therefore, solve the problems, such as drug through blood-brain barrier, it has also become the key of the treatment of sleep disorders such as sleep disturbance and Research hotspot.
Summary of the invention
Have in preparation to sleep disturbance disease the purpose of the present invention is to provide ginkgo biloba p.e as synergist and controls The application of the drug for the treatment of or health care, to solve the problems mentioned in the above background technology.
It is another object of the present invention to provide one kind can effectively improve health therapy pharmaceutical activity molecule in intracerebral The new health therapy drug composition of effective concentration.
To achieve the above object, the invention provides the following technical scheme: ginkgo biloba p.e as synergist preparation pair Sleep disturbance disease has the application of the drug for the treatment of or health care, and the drug can penetrate blood-brain barrier.
Preferably, the ginkgo biloba p.e is natural ginkgo leaf extract and its hydroxy derivatives.
Preferably, the natural ginkgo leaf extract and its hydroxy derivatives are its glucosides, ester and ether.
Preferably, there is the drug for the treatment of or health care to be selected from general ginsenoside extract, Schisandra chinensis sleep disturbance disease Extract, siberian Ginseng P.E, Herb Gynostemmae Pentaphylli extract, Wild jujube seeds extract and its active constituent.
In addition, the invention also discloses the pharmaceutical composition that a kind of pair of sleep disturbance disease has treatment or health care, it is described The action ingredient of pharmaceutical composition is that ginkgo biloba p.e is made as targeting synergist and to sleep disturbance with treatment or health care Bioactive molecule.
Preferably, the ginkgo biloba p.e is selected from ginkgo biloba p.e extract, ginkgolides extract, ginkgo leaf and mentions Take object and its hydroxy derivatives.
Preferably, described pharmaceutical composition be selected from general ginsenoside extract, Schisandra chinens P.E, siberian Ginseng P.E, Gypenosides extract, Wild jujube seeds extract, Ganolactone extract and its active constituent.
Preferably, the active constituent of described pharmaceutical composition are as follows:
Ginkgo biloba p.e, general ginsenoside extract, Schisandra chinens P.E, siberian Ginseng P.E, gypenosides Extract, Wild jujube seeds extract, Ganolactone extract mass ratio be 1~10:0~60:0~60:0~50:0~60:0 ~50:0~60;
Or the mass ratio of ginkgo biloba p.e, general ginsenoside extract, Schisandra chinens P.E, Wild jujube seeds extract is 1 ~10:1~60:1~60:1~50;
Or the mass ratio of ginkgo biloba p.e, Schisandra chinens P.E, siberian Ginseng P.E, Wild jujube seeds extract is 1~10: 1~50:1~20:1~30:
Or ginkgo biloba p.e, Schisandra chinens P.E, gypenosides extract, Wild jujube seeds extract, Ganolactone The mass ratio of extract is 1~10:1~60:1~60:1~50:1~50;
Or ginkgo biloba p.e, general ginsenoside extract, Schisandra chinens P.E, siberian Ginseng P.E, gynostemma pentaphyllum total soap Glucoside extract, Wild jujube seeds extract, Ganolactone extract mass ratio be 1~10:1~60:1~60:1~50:1~50: 1~50:1~50;
Or ginkgo biloba p.e, general ginsenoside extract, siberian Ginseng P.E, Wild jujube seeds extract, Ganolactone mention The mass ratio for taking object is 1~10:1~60:1~60:1~50:1~50;
Or the mass ratio of ginkgo biloba p.e, gypenosides extract, Wild jujube seeds extract, Ganolactone extract For 1~10:1~60:1~60:1~50.
Preferably, the sleep disturbance disease is any one in insomnia, difficulty falling asleep or neurasthenia.
Compared with prior art, the beneficial effects of the present invention are: inventor during the long-term repeated research experiment, has found Part ginkgo biloba p.e class compound, especially ginkgo leaf lactone and Ginkgolides and its their hydroxy derivatives, Especially its glucosides, ester, ether derivative, can promote well to sleep disturbance have treatment or health-care effect it is other at Divide (general ginsenoside (extract), Schisandra chinens P.E, siberian Ginseng P.E, gypenosides extract, semen ziziphi spinosae extraction Object, ganoderma lucidum (lactone) extract etc. and its active constituent.) drug molecule enters in brain tissue, do not improving its blood concentration In the case of, its concentration in brain tissue is greatly improved, the curative effect of drug is effectively increased.
Composition of the invention can penetrate blood-brain barrier well, have preferably therapeutic effect to sleep disturbance, together Shi Buhui generates unnecessary side effect.
Ginkgo biloba p.e class compound, especially ginkgo biloba p.e, ginkgolides and its hydroxy derivatives, especially Its glucosides, ester, ether derivative and general ginsenoside (extract), Schisandra chinens P.E, siberian Ginseng P.E, gynostemma pentaphyllum total soap Glucoside extract, Wild jujube seeds extract, ganoderma lucidum (lactone) extract etc. and its active constituent are obvious through blood-brain barrier effect, substantially Degree improves ginsenoside, general ginsenoside (extract), Schisandra chinens P.E, siberian Ginseng P.E, gynostemma pentaphyllum total in composition The concentration of saponin extract, Wild jujube seeds extract, ganoderma lucidum (lactone) extract etc. and its active constituent etc. in brain tissue, and have Anti- sleep disturbance effect, and main active is clear, and quality is stablized, and reduces pair of the active constituent in peripheral tissues and makees With playing synergism and attenuation.Dosage is few, can be made into various control delivery formulations and is mass produced, and is a kind of Excellent natural drug and/or health food
Detailed description of the invention
Fig. 1 is ginkgolides molecular structural formula schematic diagram;
Fig. 2 is flavonols molecular structural formula schematic diagram;
Fig. 3 is the electron micrograph that ginkgo biloba p.e etc. can promote brain tissue tiny blood vessels Blood Brain Barrier (BBB) opening.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other Embodiment shall fall within the protection scope of the present invention.
Ginkgo biloba p.e and its hydroxylation derivative used in the present invention the preparation method is as follows:
Ginkgo leaf extracts 1~5 time by the C1-3 alcohol (methanol, ethyl alcohol or propyl alcohol) of 30~95 volume %, extracts every time C1-3 alcoholic solution volume is 1~15 times of quality of medicinal material, and each extraction time is 5min~5h;After C1-3 alcohol extracting, obtain C1-3 alcohol extract merges total extract, and total extract obtains concentrate after concentration, and concentrate is added on processed macropore It adsorbs on resin, macroreticular resin is polyamide resin or polystyrene weak-base anion-exchange resin, macroporous absorbent resin Amount ratio with concentrate is that 1kg macroreticular resin adds 1~5L of concentrate;Successively with the ethyl alcohol of 50~95 volume % various concentrations Elution, dosage are every 1kg macroreticular resin 5~20L ethanol solution, with the elution of 1~20ml/min flow velocity, are eluted to colourless;It receives Collect corresponding eluent, recycles ethyl alcohol, it is dry;Or recycling ethyl alcohol, it is condensed into thick paste medicine, is dried in vacuo, is crushed, is obtained and finally extract Object.
Ginkgo biloba p.e can also be bought from market.
Ginkgo biloba p.e includes the GINKGO BILOBA EXTRACT of 1~8% ginkgolides and 3~30%, wherein ginkgolides and ginkgo The structural formula difference of flavones is as depicted in figs. 1 and 2.
Ginkgo biloba p.e be nervous system, mental disease drug, to age and occur moronism phenomenon have it is unusual Curative effect is also used for treatment neuropathy, encephalopathy and myelopathy, symptom include: cacesthesia, collapses from physical exhaustion or general paresis, improper Neural reflex, muscular atrophy, muscle cramp are trembled, superficiality or depth sensitivity sexual maladjustment, headache and pain of limbs, language imbalance, Eyesight and hearing imbalance, profound dizzy, nervous disorder and shortage centrality, failure of memory and disorientation etc..Existing literature is not It data show that ginkgo biloba p.e and its hydroxy derivatives, especially its glucosides, ester, ether derivant etc. improve BBB (blood brain screen Barrier) permeability, promote drug molecule to enter the functional report of brain tissue.
Our research indicate that ginkgo biloba p.e and its hydroxy derivatives, especially its glucosides, ester, ether derivant etc. mention High BBB (blood-brain barrier) permeability promotes drug molecule to enter brain tissue.
Referring to Fig. 3, it can promote the electron micrograph of brain tissue tiny blood vessels barrier open for ginkgo biloba p.e etc., Our research indicate that ginkgo biloba p.e and its hydroxy derivatives, especially its glucosides, ester, ether derivant etc. can promote brain group Its activity is expressed and activated to the adenosine receptor for knitting tiny blood vessels endothelium, inhibits Occlaudin protein expression, reversible sexual openness blood Brain barrier improves BBB (blood-brain barrier) permeability, and drug molecule is promoted to enter brain tissue.
It is the embodiment that ginkgo biloba p.e increases sleep disturbance disease treatment ingredient Brain targeting below:
Embodiment 1
The preparation of ginkgo biloba p.e
1, the preparation of ginkgo biloba p.e 1
It takes the ginkgo leaf powder of 500kg to be broken into coarse powder, is flowed back respectively with 10 times of quality of medicinal material, 8 times and 6 times of 70% ethyl alcohol It extracts 3 times, each difference 2.0h, 1.5h and 1.5h, merges each extracting solution, vacuum decompression recycling ethyl alcohol simultaneously makes alcohol extracting moiety concentrations It is equivalent to 1g crude drug for 1ml, is added on processed macroporous absorbent resin (PD800 polystyrene weakly-basic anion exchange tree Rouge) on, the amount ratio of macroreticular resin and alcohol extract is that 1kg macroreticular resin adds alcohol extract 2.2L.Successively with 60%, 70%, 80% With 95% ethanol elution, dosage is 4.5,4,3.5,4L respectively, with the elution of 10ml/min flow velocity, collects corresponding eluent, recycles Ethyl alcohol, it is dry;Or recycling ethyl alcohol, it is condensed into thick paste medicine, is dried in vacuo, is crushed up to ginkgo biloba p.e 1 (EGB1), yield exists 2.5%;Ginkgolides content is 6.2%, kaempferia galanga phenol content is 5.6%, quercetin content be 5.8% ginkgo acid content be < 5ppm。
2, the preparation of ginkgo biloba p.e 2
It takes the ginkgo leaf powder of 500kg to be broken into coarse powder, is flowed back respectively with 70% ethyl alcohol of 10 times, 8 times and 6 times weights of quality of medicinal material It extracts 3 times, each time 2.0h, 1.5h, 1.5h, combined extract, vacuum decompression recycling ethyl alcohol simultaneously make alcohol extracting moiety concentrations respectively 1ml is equivalent to 1g crude drug, and adjusting pH value is 6.0, is added on processed macroporous absorbent resin (polyamide resin), macropore tree The amount ratio of rouge and concentrate is that 1kg macroreticular resin adds alcohol extract 2.0L.Successively washed with 60%, 70%, 80% and 95% ethyl alcohol De-, dosage is 4.5L, 5L, 3.5L, 3L respectively, is eluted with 10ml/min flow velocity, collection corresponding 70%, 80% ethanol eluate, Ethyl alcohol is recycled, it is dry;Or recycling ethyl alcohol, it is condensed into thick paste medicine, is dried in vacuo, is crushed up to ginko leaves flavone extract 2-A (EGB2-A) 2.25kg, yield is 0.45%.Wherein kaempferia galanga phenol content is 15.1%, quercetin content 16.0%, ginkgoic acid Content is < 5ppm.
Above-mentioned 60% ethyl alcohol and 95% ethanol eluate collect corresponding eluent, recycle ethyl alcohol and make alcohol extracting moiety concentrations 1ml is equivalent to 1g crude drug, and adjusting pH value is 8.0, is added on processed macroporous absorbent resin (PD800 polystyrene alkalescent yin Ion exchange resin) on, the amount ratio of macroreticular resin and alcohol extract is that 1kg macroreticular resin adds alcohol extract 2.0L.Successively use 60%, 70%, 80% and 95% ethanol elution, dosage are that 4.5L, 4L, 3.5L, 5L are received with the elution of 10ml/min flow velocity respectively Collect corresponding eluent, recycles ethyl alcohol, it is dry;Or recycling ethyl alcohol, it is condensed into thick paste medicine, is dried in vacuo, is crushed up in ginkgo leaf Ester extract 2-B (EGB2-B) 2.35kg, yield is 0.47%.Wherein ginkgolides content is 40.8%, and kaempferia galanga phenol content is 2.7%, quercetin content 2.8%, ginkgo acid content is < 5ppm.
Embodiment 2
Ginkgo biloba p.e (content flavones >=24.0%, lactone >=6.0%) 50,100g.
Active ingredient of Chinese herbs: ginsenoside Rb1 (abbreviation Rb1, content >=95%) 600g;
The above-mentioned various extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as BBXN1-1 And BXN1-2.
Effect experiment:
Processing group: suspension is made in BXN1-1 and BXN1-2, and SD rat oral gavage administration is (suitable by 100mg/kg dosage In ginsenoside Rb1 100mg/kg) 20ml/kg capacity 5 mouse of administration;
Control group: separately take ginsenoside Rb1's extract that suspension, SD rat oral gavage administration, by ginsenoside is made 5 mouse are administered in Rb1100mg/kg dosage, 20ml/kg capacity;
After 0.5hr is administered, take blood, acute execution rat takes brain tissue, be made brain homogenate, UPLC-MS detect blood and Active ingredient of Chinese herbs content in brain tissue.
NIH mouse 80 separately are taken, the BXN1 for giving solvent physiological saline respectively, being equivalent to 100mg/kg ginsenoside Rb1 Or BXN2 and ginsenoside Rb1,20ml/kg capacity gastric infusion, 20 mouse/group;After administration 2 hours, carries out yellow Jackets and sleep Using the experiment of sub-threshold dose yellow Jackets sleep derivation (yellow Jackets are injected intraperitoneally by 28mg/kg dosage in the test of dormancy time Sub-threshold dose, injection dosage are 0.1 ml/10g, and mouse righting reflex loss reaches the number of mice of 1min or more in 15min after administration Amount is sleep index, records the sleep number of cases of sub-threshold dose yellow Jackets mouse;It is slept using above threshold dose of sodium pentobarbitone Experiment (intraperitoneal injection yellow Jackets 50mg/kg, observe and record sleep time (righting reflex loss to restore when Between), record Sleep latency and the sleeping time of mouse.The sleep quality of observation comparison different dosing group mouse.
Experimental result is as shown in table 1.
The UPLC assay of table 1:BXN1 and the result for promoting saturating BBB
Note:##, P < 0.01 compared with physiological saline group;Compared with ginsenoside group,*P<0.05,**p<0.01。
The results showed that BXN1, BXN2 of dosage Rb1 and ginsenoside Rb1's administration, blood concentration difference is waited not to show It writes, but ginsenoside Rb1's content is higher than simple ginsenoside Rb1 administration rat more than 6 or 11 times in the brain tissue of BXN1, BXN2. Show that ginkgo biloba p.e is shared with ginsenoside Rb1, active constituent Rb1 can be promoted through blood-brain barrier.BXN can be significantly improved The sleep rate of sub-threshold dose yellow Jackets mouse, mouse sleep time significantly shorten, and extend above threshold dose of sodium pentobarbitone The sleeping time of mouse
Embodiment 3
Ginkgo biloba p.e extract (content >=3.0%) 10,30g.
Active ingredient of Chinese herbs: Ganolactone (content >=95%) 300g;
The above-mentioned various extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as BXN2-1 And BXN2-2.
Effect experiment:
Processing group: suspension is made in BXN2-1 and BXN2-2, and SD rat oral gavage administration is (suitable by 100m g/kg dosage 5 mouse are administered in Ganolactone 100mg/kg) 20ml/kg capacity;
Control group: separately take Ganolactone extract that suspension, SD rat oral gavage administration, by Ganolactone 100mg/ is made 5 mouse are administered in kg dosage, 20ml/kg capacity;
After 0.5hr is administered, take blood, acute execution rat takes brain tissue, be made brain homogenate, UPLC-MS detect blood and Brain tissue active ingredient of Chinese herbs Ganolactone content.
Separately take NIH mouse 80, give respectively solvent physiological saline, be equivalent to 100mg/kg Ganolactone BXN2-1 or BXN2-2 and Ganolactone, 20ml/kg capacity gastric infusion, 20 mouse/group;After administration 2 hours, when carrying out yellow Jackets sleep Between test, using sub-threshold dose yellow Jackets sleep derivation experiment (by 28mg/kg dosage intraperitoneal injection yellow Jackets threshold under Dosage, injection dosage are 0.1 ml/10g, and the mouse quantity of mouse righting reflex loss up to 1min or more are in 15min after administration Sleep index records the sleep number of cases of sub-threshold dose yellow Jackets mouse;Utilize above threshold dose of sodium pentobarbitone sleep experiments (intraperitoneal injection yellow Jackets 50mg/kg observes and records sleep time (righting reflex loss to the time restored), note Record Sleep latency and the sleeping time of mouse.The sleep quality of observation comparison different dosing group mouse.
Experimental result is as shown in table 2.
The Ganolactone UPLC assay of table 2:BXN2 and the result for promoting saturating BBB
Note:##, P < 0.01 compared with physiological saline group;Compared with ginsenoside group,*P<0.05,**p<0.01。
The results showed that waiting BXN2-1, BXN2-2 and the Ganolactone administration of dosage Ganolactone, blood concentration difference It is not significant, but Ganolactone content is 3.3/5.2 times higher than simple Ganolactone administration rat in the brain tissue of BXN2-1, BXN2-2 It is more.Show that ginkgo biloba p.e is shared with Ganolactone, active constituent Ganolactone can be promoted through blood-brain barrier.BXN can be bright The aobvious sleep rate for improving sub-threshold dose yellow Jackets mouse, mouse sleep time significantly shorten, and extend above threshold penta bar of dosage Than the sleeping time of appropriate sodium mouse.
Embodiment 4
Ginkgo biloba p.e (content >=95.0%) 10 or 50g;
Active ingredient of Chinese herbs: Schisandra chinens P.E (deoxyschizandrin content >=30%) 500g.
The above-mentioned various extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as BXN3-1 And BXN3-2.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by Schisandra chinens P.E 100mg/kg is made in BXN3-1 and BXN3-2 5 mouse are administered in dosage 20ml/kg capacity;
Control group: separately taking Schisandra chinens P.E extract that suspension is made, and SD rat oral gavage administration is extracted by Schisandra chinensis 5 mouse are administered in object 100mg/kg dosage, 20ml/kg capacity;0.5hr is administered, takes blood, acute execution rat takes brain tissue, brain is made Homogenate, UPLC-MS detect deoxyschizandrin content in blood and brain tissue.
NIH mouse 80 separately are taken, the BXN3-1 for giving solvent physiological saline respectively, being equivalent to 100mg/kg deoxyschizandrin Or BXN3-2 and deoxyschizandrin, 20ml/kg capacity gastric infusion, 20 mouse/group;After administration 2 hours, carries out yellow Jackets and sleep Using the experiment of sub-threshold dose yellow Jackets sleep derivation (yellow Jackets are injected intraperitoneally by 28mg/kg dosage in the test of dormancy time Sub-threshold dose, injection dosage are 0.1 ml/10g, and mouse righting reflex loss reaches the number of mice of 1min or more in 15min after administration Amount is sleep index, records the sleep number of cases of sub-threshold dose yellow Jackets mouse;It is slept using above threshold dose of sodium pentobarbitone Experiment (intraperitoneal injection yellow Jackets 50mg/kg, observe and record sleep time (righting reflex loss to restore when Between), record Sleep latency and the sleeping time of mouse.The sleep quality of observation comparison different dosing group mouse.
Experimental result is as shown in table 3:
The results showed that waiting BXN3-1, BXN3-2 and the deoxyschizandrin administration of dosage deoxyschizandrin, blood concentration Difference is not significant, but in the brain tissue of BXN2-1, BXN2-2 deoxyschizandrin ester content than simple deoxyschizandrin be administered rat It is high more than 5/8.2 times.Show that ginkgo biloba p.e is shared with deoxyschizandrin, active constituent deoxyschizandrin can be promoted through blood brain Barrier.BXN can significantly improve the sleep rate of sub-threshold dose yellow Jackets mouse, and mouse sleep time significantly shortens, and extend The above threshold sleeping time of dose of sodium pentobarbitone mouse.
The deoxyschizandrin UPLC assay of table 3:BXN3 and the result for promoting saturating BBB
Note:##, P < 0.01 compared with physiological saline group;Compared with ginsenoside group,*P<0.05,**p<0.01。
The results showed that waiting BXN3-1, BXN3-2 and the deoxyschizandrin administration of dosage deoxyschizandrin, blood concentration Difference is not significant, but in the brain tissue of BXN2-1, BXN2-2 deoxyschizandrin ester content than simple deoxyschizandrin be administered rat It is high more than 5/8.2 times.Show that ginkgo biloba p.e is shared with deoxyschizandrin, active constituent deoxyschizandrin can be promoted through blood brain Barrier.BXN can significantly improve the sleep rate of sub-threshold dose yellow Jackets mouse, and mouse sleep time significantly shortens, and extend The above threshold sleeping time of dose of sodium pentobarbitone mouse.
Embodiment 5
Siberian Ginseng P.E (Syringin content is 26%) 1000g;
Ginkgo biloba p.e (content is >=96.0%) 50g.
The above-mentioned two kinds of extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as BXN4.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by siberian Ginseng P.E 200mg/kg dosage is made in BXN4 5 mouse are administered in 20ml/kg capacity;
Control group: separately taking ginkgo biloba p.e derivative that suspension is made, and SD rat oral gavage administration is extracted by wilsonii 5 mouse are administered in object 200mg/kg dosage, 20ml/kg capacity;
0.5hr is administered, takes blood, acute execution rat takes brain tissue, and brain homogenate is made, and UPLC-MS detects blood and brain group Knit middle Syringin content.
Separately take NIH mouse 80, give respectively solvent physiological saline, be equivalent to 50mg/kg Syringin BXN3-1 or BXN3-2 and Syringin, 20ml/kg capacity gastric infusion, 20 mouse/group;After administration 2 hours, yellow Jackets sleep is carried out Using the experiment of sub-threshold dose yellow Jackets sleep derivation (yellow Jackets threshold is injected intraperitoneally by 28mg/kg dosage in time test Lower dosage, injection dosage are 0.1 ml/10g, and mouse righting reflex loss reaches the mouse quantity of 1min or more in 15min after administration For sleep index, the sleep number of cases of sub-threshold dose yellow Jackets mouse is recorded;It is slept using above threshold dose of sodium pentobarbitone real Test (intraperitoneal injection yellow Jackets 50mg/kg observes and records sleep time (righting reflex loss to the time restored), Record Sleep latency and the sleeping time of mouse.The sleep quality of observation comparison different dosing group mouse.
Experimental result is as shown in table 4.
The UPLC assay of the Syringin of table 4:BXN4 and the result for promoting saturating BBB
Note:##, P < 0.01 compared with physiological saline group;Compared with ginsenoside group,*P<0.05,**p<0.01。
The results showed that the BXN4-1 and Syringin of equivalent Syringin are administered, blood concentration difference is not significant, But Syringin content is higher than simple Syringin administration rat more than 5 times in the brain tissue of BXN4-1.Show that ginkgo leaf extracts Object is shared with siberian Ginseng P.E, and active constituent Syringin can be promoted through blood-brain barrier.BXN can significantly improve agent under threshold The sleep rate of yellow Jackets mouse is measured, mouse sleep time significantly shortens, and extend above threshold dose of sodium pentobarbitone mouse Sleeping time.
Embodiment 6
Gypenosides extract (content 66%) 1000g;
Ginkgo biloba p.e (content is >=96.0%) 50g.
The above-mentioned two kinds of extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as BXN5.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by gypenosides extract 100mg/kg agent is made in BXN5 It measures 20ml/kg capacity and 5 mouse is administered;
Control group: separately take Herb Gynostemmae Pentaphylli extract derivative that suspension, SD rat oral gavage administration, by gynostemma pentaphyllum total soap is made 5 mouse are administered in glucoside extract 100mg/kg dosage, 20ml/kg capacity;
0.5hr is administered, takes blood, acute execution rat takes brain tissue, and brain homogenate is made, and UPLC-MS detects blood and brain group Knit middle Herb Gynostemmae Pentaphylli extract active constituent ginsenoside Rb1's content.
NIH mouse 80 separately are taken, the BXN5-1 for giving solvent physiological saline respectively, being equivalent to 50mg/kg ginsenoside Rb1 And Herb Gynostemmae Pentaphylli extract, 20ml/kg capacity gastric infusion, 20 mouse/group;After administration 2 hours, when carrying out yellow Jackets sleep Between test, using sub-threshold dose yellow Jackets sleep derivation experiment (by 28mg/kg dosage intraperitoneal injection yellow Jackets threshold under Dosage, injection dosage 0.1ml/10g, the mouse quantity of mouse righting reflex loss up to 1min or more are in 15min after administration Sleep index records the sleep number of cases of sub-threshold dose yellow Jackets mouse;Utilize above threshold dose of sodium pentobarbitone sleep experiments (intraperitoneal injection yellow Jackets 50mg/kg observes and records sleep time (righting reflex loss to the time restored), note Record Sleep latency and the sleeping time of mouse.The sleep quality of observation comparison different dosing group mouse.
Experimental result is as shown in table 5.
The UPLC assay of the Herb Gynostemmae Pentaphylli extract of table 5:BXN4 and the result for promoting saturating BBB
Note:##, P < 0.01 compared with physiological saline group;Compared with ginsenoside group,*P<0.05,**p<0.01。
The results showed that the BXN5-1 and Herb Gynostemmae Pentaphylli extract of equivalent Herb Gynostemmae Pentaphylli extract are administered, blood concentration difference It is not significant, but ginsenoside Rb1's content is higher than simple Herb Gynostemmae Pentaphylli extract administration rat more than 4 times in the brain tissue of BXN5-1.Table Bright ginkgo biloba p.e is shared with Herb Gynostemmae Pentaphylli extract, and active constituent ginsenoside Rb1 can be promoted through blood-brain barrier.BXN5 energy Than the sleep rate that Herb Gynostemmae Pentaphylli extract significantly improves sub-threshold dose yellow Jackets mouse, mouse sleep time significantly shortens, and Extend the sleeping time of above threshold dose of sodium pentobarbitone mouse.
Embodiment 7
Wild jujube seeds extract (content 96%) 1000g;
Ginkgo biloba p.e (content is >=96.0%) 50g.
The above-mentioned two kinds of extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as BXN6.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by Wild jujube seeds extract 200mg/kg dosage is made in BXN6 5 mouse are administered in 20ml/kg capacity;
Control group: separately taking Wild jujube seeds extract derivative that suspension is made, and SD rat oral gavage administration is extracted by semen ziziphi spinosae 5 mouse are administered in object 200mg/kg dosage, 20ml/kg capacity;
Take NIH mouse 80, give respectively solvent physiological saline, be equivalent to 200mg/kg Wild jujube seeds extract BXN6 and Wild jujube seeds extract, 20ml/kg capacity gastric infusion, 20 mouse/group;After administration 2 hours, the examination of yellow Jackets sleeping time is carried out It tests, using the experiment of sub-threshold dose yellow Jackets sleep derivation (by agent under 28mg/kg dosage intraperitoneal injection yellow Jackets threshold Amount, injection dosage 0.1ml/10g, after administration in 15min mouse righting reflex loss up to 1min or more mouse quantity be into Index is slept, the sleep number of cases of sub-threshold dose yellow Jackets mouse is recorded;Utilize above threshold dose of sodium pentobarbitone sleep experiments (intraperitoneal injection yellow Jackets 50mg/kg observes and records sleep time (righting reflex loss to the time restored), note Record Sleep latency and the sleeping time of mouse.The sleep quality of observation comparison different dosing group mouse.
Experimental result is as shown in table 6.
The Wild jujube seeds extract of table 6:BXN4 promotees the result of BBB
Note:##, P < 0.01 compared with physiological saline group;Compared with ginsenoside group,*P<0.05,**p<0.01。
The results showed that waiting BXN6-1 and the Wild jujube seeds extract administration of dosage Wild jujube seeds extract, show ginkgo leaf Extract is shared with Wild jujube seeds extract.BXN6 can significantly improve the sleep rate of sub-threshold dose yellow Jackets mouse, and mouse sleeps The dormancy time significantly shortens, and extends the sleeping time of above threshold dose of sodium pentobarbitone mouse.
The therapeutic effect of BXN4, BXN5, BXN6 to sleep disturbance
1, it is diagnosed as the voluntary trier of sleep disturbance patient, totally 80.
2, treatment method
Wild jujube seeds extract capsule: (specification is 250mg/) treatment, 2 tablets/time, 3 times/d.
The Capsules group of BXN4,5,6: 250mg/, 2 tablets/time, three times a day.
Each group 5 days are 1 course for the treatment of, share medicine 10, therebetween auxiliary identical other treatment of sleep disorders drugs.
Each group assesses curative effect after treatment in 5,10 days.
3, efficacy analysis
Table 7 shows that the present invention can more efficiently improve cardinal symptom, the sign of sleep disturbance sleep disturbance, according to Generally acknowledged criterion of therapeutical effect, overall therapeutic sleep disturbance sleep disturbance have preferable clinical efficacy, and comparison among groups, BXN4,5 With BXN6 therapeutic equivalence, it is better than Wild jujube seeds extract capsule, otherness has significant (p < 0.01).
Table 7:BNX4,5,6 treatment sleep disturbance trier curative effect statistics
Note: compared with Wild jujube seeds extract capsule, * p < 0.05.
Using clinical cure, effective with effective and as the data basis that total effective rate calculates, 4 groups of Clinical efficacy comparisons, The capsule for treating group total effective rate of BXN4,5,6 is respectively 95%, and Wild jujube seeds extract capsule is 80%, and 3 groups are compared, and is had significant Sex differernce (p < 0.05).Illustrate to share with ginkgo biloba p.e, can significantly improve Wild jujube seeds extract, siberian Ginseng P.E and The curative effect of Herb Gynostemmae Pentaphylli extract treatment sleep disturbance.
Principle and implementation of the present invention are described for several specific embodiments used herein, the above implementation The explanation of example is merely used to help understand method and its core concept of the invention, meanwhile, for the general technology people of this field Member, according to the thought of the present invention, there will be changes in the specific implementation manner and application range, in conclusion this explanation The content of book embodiment should not be construed as limiting the invention.

Claims (9)

1. ginkgo biloba p.e has the application of the drug for the treatment of or health care as synergist in preparation to sleep disturbance disease, Be characterized in that: the drug can penetrate blood-brain barrier.
2. application according to claim 1, it is characterised in that: the ginkgo biloba p.e be natural ginkgo leaf extract and Its hydroxy derivatives.
3. application according to claim 2, it is characterised in that: the natural ginkgo leaf extract and its hydroxy derivatives are Its glucosides, ester and ether.
4. application according to claim 1 to 3, it is characterised in that: there is treatment to sleep disturbance disease or protect Strong drug is selected from general ginsenoside extract, Schisandra chinens P.E, siberian Ginseng P.E, Herb Gynostemmae Pentaphylli extract, semen ziziphi spinosae and mentions Take object and its active constituent.
5. the pharmaceutical composition that a kind of pair of sleep disturbance disease has treatment or health care, it is characterised in that: described pharmaceutical composition Action ingredient be ginkgo biloba p.e as targeting synergist and to sleep disturbance have treatment or health-care effect activity divide Son.
6. pharmaceutical composition according to claim 5, it is characterised in that: the ginkgo biloba p.e is extracted selected from ginkgo leaf Object extract, ginkgolides extract, ginkgo biloba p.e and its hydroxy derivatives.
7. pharmaceutical composition according to claim 5, it is characterised in that: described pharmaceutical composition is mentioned selected from general ginsenoside Take object, Schisandra chinens P.E, siberian Ginseng P.E, gypenosides extract, Wild jujube seeds extract, Ganolactone extract And its active constituent.
8. pharmaceutical composition according to claim 7, it is characterised in that: the active constituent of described pharmaceutical composition are as follows:
Ginkgo biloba p.e, general ginsenoside extract, Schisandra chinens P.E, siberian Ginseng P.E, gypenosides extract Object, Wild jujube seeds extract, Ganolactone extract mass ratio be 1~10:0~60:0~60:0~50:0~60:0~50:0 ~60;
Or the mass ratio of ginkgo biloba p.e, general ginsenoside extract, Schisandra chinens P.E, Wild jujube seeds extract is 1~10: 1~60:1~60:1~50;
Or the mass ratio of ginkgo biloba p.e, Schisandra chinens P.E, siberian Ginseng P.E, Wild jujube seeds extract be 1~10:1~ 50:1~20:1~30:
Or ginkgo biloba p.e, Schisandra chinens P.E, gypenosides extract, Wild jujube seeds extract, Ganolactone extract The mass ratio of object is 1~10:1~60:1~60:1~50:1~50;
Or ginkgo biloba p.e, general ginsenoside extract, Schisandra chinens P.E, siberian Ginseng P.E, gypenosides mention Take object, Wild jujube seeds extract, Ganolactone extract mass ratio be 1~10:1~60:1~60:1~50:1~50:1~ 50:1~50;
Or ginkgo biloba p.e, general ginsenoside extract, siberian Ginseng P.E, Wild jujube seeds extract, Ganolactone extract Mass ratio be 1~10:1~60:1~60:1~50:1~50;
Or the mass ratio of ginkgo biloba p.e, gypenosides extract, Wild jujube seeds extract, Ganolactone extract is 1 ~10:1~60:1~60:1~50.
9. the pharmaceutical composition stated according to claim 5, it is characterised in that: the sleep disturbance disease is insomnia, difficulty falling asleep Or any one in neurasthenia.
CN201811648190.2A 2018-12-30 2018-12-30 Ginkgo biloba p.e has the application of the drug for the treatment of or health care as synergist in preparation to sleep disturbance disease Pending CN109528782A (en)

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CN109833381A (en) * 2019-04-17 2019-06-04 湖南高迪信达生物科技有限公司 A kind of pure plant drug composition improving sleep
CN110251537A (en) * 2019-07-05 2019-09-20 广东药科大学 A kind of preparation and application that ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor

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CN106619613A (en) * 2016-12-22 2017-05-10 广东药科大学 Application of bilobalide serving as brain-targeting synergist to preparation of drug for preventing brain tumor
CN106727501A (en) * 2016-12-22 2017-05-31 广东药科大学 Bilobalide is preparing the application of preventing and treating Cranial nerve injury as birth trauma disease medicament as synergist
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CN101015605A (en) * 2007-01-19 2007-08-15 东北虎药业股份有限公司 Health-care food for improving sleeping and its preparing process
CN106619613A (en) * 2016-12-22 2017-05-10 广东药科大学 Application of bilobalide serving as brain-targeting synergist to preparation of drug for preventing brain tumor
CN106727501A (en) * 2016-12-22 2017-05-31 广东药科大学 Bilobalide is preparing the application of preventing and treating Cranial nerve injury as birth trauma disease medicament as synergist
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* Cited by examiner, † Cited by third party
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Application publication date: 20190329