CN110251537A - A kind of preparation and application that ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor - Google Patents
A kind of preparation and application that ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor Download PDFInfo
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Abstract
The invention discloses preparations and application that a kind of ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor, for natural products ginkgo biloba p.e as the application that there is the drug for the treatment of or health-care effect to pass through blood-brain barrier preparation brain tumor disease is promoted, natural products ginkgo biloba p.e (ginkgolides summation flavones) and its hydroxy derivatives are its glucosides, ester and ether.During the present invention is by research experiment repeatedly, it was found that part ginkgo biloba p.e class compound, especially ginkgo biloba p.e and its hydroxy derivatives, especially its glucosides, ester, ether derivative, drug molecule prevent and treat brain tumor or health-care effect can be promoted to enter in brain tissue well, without increasing its blood concentration, greatly improve its concentration in brain tissue, composition of the invention, brain tumor prevention and treatment or health-care effect drug molecule can be promoted through blood-brain barrier well, there is preferably therapeutic effect to brain tumor disease, it mitigates or reduces simultaneously and generates unnecessary side effect.
Description
Technical field
The invention belongs to the technical fields that ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor, specially
A kind of preparation and application that ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor.
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, is made of three blood-brain barrier, cerebrospinal fluid-brain barrier and blood-cerebrospinal fluid barrier barriers.The function of blood-brain barrier exists
Enter brain tissue in selectively prevention Cucumber.Since blood-brain tissue barrier surface area is about blood-cerebrospinal fluid screen
Hinder 5000 times of surface area, therefore, blood-brain tissue barrier is the main barrier of the inside and outside source property substance disengaging brain parenchym of control,
Facilitate the stabilization of maintenance brain tissue environment.
Malignant glioblastoma, Alzheimer cells tumor, hemangioblastoma, malignant lymphoma and sarcoma, marrow are female thin
The brain tumors such as born of the same parents' tumor or neuroblastoma are the major diseases for threatening human health.Caused to patient, family and society
Heavy burden.But it due to the presence of blood-brain barrier (BBB), limits most drugs and enters brain or treatment institute is not achieved in intracerebral
The effective concentration needed, seriously limits the treatment of brain diseases.
Traditional Chinese medicine is with a long history in terms of preventing and treating tumor disease, significant in efficacy and have safety, low toxicity, Small side effects etc. excellent
Gesture.If ginsenoside extract, kuh-seng alkali extract, Ganolactone, black uncle's toxin (extract) are treatment brain tumor diseases
Important natural drug, however their active constituent matrine, ginsenoside Rb3, Ganolactone, black uncle's toxin, elemene,
Oleic acid, octadecenic acid.Temozolomide (TMZ), nitroso ureas, Gleevec, Imatinib, Conmana, replace Ni Bo at taxol
The cytotoxic agents such as glucoside, Dacarbazine (dacarbazine), nitrate, anti-angiogenic medicaments promote cell differentiation class drug, are anti-
It invades drug and cell signalling regulator is treatment of brain tumor medicine.These ingredients are not easy to enter brain tissue through blood-brain barrier
It plays a role.
Therefore, solve the problems, such as drug through BBB, it has also become the key and research hotspot of brain diseases treatment.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the existing defects, provides a kind of ginkgo biloba p.e as Brain targeting
The preparation and application high temperature resistant aeroge composite material and preparation method that synergist is prevented and treated in brain tumor, can effectively solve
The problems in background technique.
To achieve the above object, the invention provides the following technical scheme: a kind of ginkgo biloba p.e is as Brain targeting synergy
The preparation and application that agent is prevented and treated in brain tumor, it is characterised in that: natural products ginkgo biloba p.e is swollen to brain as promoting
The application that there is tumor disease the drug for the treatment of or health-care effect to pass through blood-brain barrier preparation.
As a preferred technical solution of the present invention, the natural products ginkgo biloba p.e and its hydroxyl are derivative
Object.
As a preferred technical solution of the present invention, natural products ginkgo biloba p.e (ginkgolides total content 0.1~
99%) and its hydroxy derivatives are its glucosides, ester and ether.
As a preferred technical solution of the present invention, there is the drug for the treatment of or health-care effect to select brain tumor disease
From general ginsenoside (extract), matrine (extract), Ganolactone (extract), ganoderma lucidum (extract) and, black uncle's toxin
(extract) and treatment of brain tumor chemical drug (Gleevec, Imatinib, Conmana, Teniposide, Dacarbazine (nitrence miaow
Amine), nitrate).
As a preferred technical solution of the present invention, the composition action ingredient of said medicine is ginkgo biloba p.e work
There is the bioactive molecule for the treatment of or health-care effect for targeting synergist and to brain tumor disease.
As a preferred technical solution of the present invention, ginkgo biloba p.e is selected from ginkgo biloba p.e (extract), silver
Apricot lactone extract, ginkgo biloba p.e and its hydroxy derivatives.
As a preferred technical solution of the present invention, there is the drug for the treatment of or health-care effect to select brain tumor disease
From treatment of brain tumor medicine general ginsenoside (extract), matrine (extract), Ganolactone (extract), ganoderma lucidum (extract)
(add cytotoxic agent with black uncle's toxin (extract) and treatment of brain tumor medicine, anti-angiogenic medicaments, promote cell differentiation class medicine
Object, anti-invasion drug and cell signalling regulator, such as elemene, oleic acid, octadecenic acid, Temozolomide (TMZ), nitroso
Urea, taxol, Gleevec, Imatinib, Conmana, Teniposide, Dacarbazine (dacarbazine), nitrate).
As a preferred technical solution of the present invention, the active constituent of above-mentioned composition are as follows:
Ginkgo biloba p.e, kushenin, ginsenoside Rb3, Ganolactone mass ratio be 1~10:1~30:1~30；
1~30 or ginkgo biloba p.e extract: general ginsenoside extract: the quality of kuh-seng extract, Ganolactone extract
Than for 1~10:0.6~60:0.5~50:0.4~40；
Or ginkgo biloba p.e (extract), general ginsenoside extract, kushenin and Ganolactone mass ratio be 1
~10:1~30:1~20:1~30；
Or ginkgo biloba p.e (extract), general ginsenoside (extract), black uncle's toxin (extract), Ganolactone
The mass ratio of (extract) is 1~10:1~50:1~20；: 1~30:1~50:
Or ginkgo biloba p.e (extract), general ginsenoside extract, crow uncle's toxin (extract), Ganolactone (mention
Take object) mass ratio be 1~10:1~50:1~20；: 1~30；
Or ginkgo biloba p.e (extract), general ginsenoside extract, crow uncle's toxin (extract), lucidum spore powder
Mass ratio is 1~10:1~50:1~20:1~30；
Or the mass ratio of ginkgo biloba p.e extract, ginsenoside Rb3, matrine, Ganolactone be 1~10:1~
50:1~20:1~30；Or ginkgo biloba p.e extract, ginsenoside Rb3, matrine, Ganolactone, elemene/oleic acid/
The mass ratio of octadecenic acid is 1~10:1~50:1~20:1~30；1~30；
Or mass ratio is the ginkgo biloba p.e and Imatinib of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e of 1~10:2~50 and angstrom gram replaces；
Or mass ratio is the ginkgo biloba p.e and Teniposide of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e and Dacarbazine (dacarbazine) of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e and nitrate of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e and Temozolomide (TMZ)/nitroso ureas/taxol of 1~10:2~50.
As a preferred technical solution of the present invention, there is treatment or health-care effect composition to select brain tumor disease
From brain tumor disease such as malignant glioblastoma, Alzheimer cells tumor, hemangioblastoma, malignant lymphoma and sarcoma,
Medulloblastoma or neuroblastoma etc..
Beneficial effects of the present invention: the present invention passes through during prolonged and repeated research experiment, and discovery part ginkgo leaf extracts
Species compound, especially ginkgo biloba p.e and its hydroxy derivatives, especially its glucosides, ester, ether derivative, can be very
Promote there is the drug molecule for the treatment of or health-care effect to enter in brain tissue brain diseases well, is not improving its blood concentration
In the case where, its concentration in brain tissue is greatly improved, effectively increases the curative effect of drug, composition of the invention can
To penetrate blood-brain barrier well, there is preferably therapeutic effect to brain diseases, while unnecessary side effect will not be generated.
Detailed description of the invention
Fig. 1 is the influence that ginkgo biloba p.e penetrates in vitro blood-brain barrier model NaF；
Fig. 2 is that ginkgo biloba p.e etc. can promote brain tissue tiny blood vessels endothelial tight to connect the electronic display of reversible sexual openness
Micro mirror ultra microstructure figure；
Fig. 3 is the influence of the A1R protein expression of EBG on rat brain tiny blood vessels endothelium；
Fig. 4: influence of the ginkgo biloba p.e in vitro blood-brain barrier model resistance.
In figure: SCH:A2a adenosine receptor inhibitor；SCH+: adenosine receptor inhibitor+EGb；The suppression of DPCPX:A1 adenosine receptor
Preparation；DPCPX+: adenosine receptor inhibitor+EGb.
Specific embodiment
The present invention is further illustrated by the following examples, but these embodiments must not be used to explain to the present invention
The limitation of protection scope.
Embodiment one:
A kind of preparation and application that ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor, ginkgo leaf pass through
The C1-3 alcohol (methanol, ethyl alcohol or propyl alcohol) of 30~95 volume % extracts 1~5 time, and the C1-3 alcoholic solution volume extracted every time is medicine
1~15 times of material amount, each extraction time are 5min~5h；After C1-3 alcohol extracting, C1-3 alcohol extract is obtained, merges total extract
Object, total extract obtain concentrate after concentration, and concentrate is added on processed macroporous absorbent resin, and macroreticular resin is
The amount ratio of polyamide resin or polystyrene weak-base anion-exchange resin, macroporous absorbent resin and concentrate is 1kg
Macroreticular resin adds 1~5L of concentrate；Successively with the ethanol elution of 50~95 volume % various concentrations, dosage is every 1kg macropore tree
Rouge 5~20L ethanol solution is eluted to colourless with the elution of 1~20ml/min flow velocity；Corresponding eluent is collected, ethyl alcohol is recycled,
It is dry；Or recycling ethyl alcohol, it is condensed into thick paste medicine, is dried in vacuo, crushes, obtains final extract.
Ginkgo biloba p.e includes the GINKGO BILOBA EXTRACT of 1~8% ginkgolides and 3~30%:
Ginkgolides (A) and flavonols (B) molecular structural formula
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 permeability,
Drug molecule is promoted to enter the functional report of brain tissue.
Ginkgo biloba p.e and its hydroxy derivatives, especially its glucosides, ester, ether derivant etc. improve BBB permeability, promote
Enter brain tissue into drug molecule.
Ginkgo biloba p.e and its hydroxy derivatives, especially its glucosides, ester, ether derivant etc. can promote brain tissue small
The adenosine receptor of blood vessel endothelium is expressed, and OCCLAUDIN protein expression is inhibited, and invertibity Opening Blood Brain Barrier, raising BBB are penetrating
Property, promote drug molecule to enter brain tissue.
Shown compared with normal group according to Fig. 1-4, EGB dramatically increases the osmotic concentration of fluorescein sodium, and amplification is up to 70%；
Giving the osmotic concentration of fluorescein sodium after A2a adenosine receptor inhibitor SCH, also conspicuousness increases (< 0.05).
Embodiment two
Ginkgo biloba p.e (content flavones >=24.0%, lactone >=6.0%) 50,100g.
Active ingredient of Chinese herbs: ginsenoside Rb3 (abbreviation Rb3, 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 EGbRb3-
1 and EGbRb3-2.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by 100mg/kg dosage is made in EGbRb3-1 and EGbRb31-2
5 mouse are administered in 20ml/kg capacity；Control group: separately taking ginsenoside Rb3 extract that suspension is made, and SD rat oral gavage administration is pressed
5 mouse are administered in ginsenoside Rb3 100mg/kg dosage, 20ml/kg capacity；After 0.5hr is administered, blood is taken, acute execution rat takes brain
Tissue, is made brain homogenate, and UPLC-MS detects active ingredient of Chinese herbs content in blood and brain tissue.
Another preparation glioma Naked mouse 40, the EGbRb3- for giving solvent physiological saline respectively, being equivalent to 100mg/kg
1 or EGbRb3-2 and ginsenoside Rb3,20ml/kg capacity gastric infusion, 10 mouse/group；Administration put to death animal after 28 days, observed
Tumor control rate.Experimental result is as shown in table 1.
The UPLC assay of 1 EGbRb3 of table and the result for promoting saturating BBB
The results showed that EGbRb3-1, EGbRb3-2 and ginsenoside Rb3 of equivalent EGbRb3Rb3 are administered, blood medicine is dense
It is not significant to spend difference, but ginsenoside Rb3 content is given than simple ginsenoside Rb3 in the brain tissue of EGbRb3-1, EGbRb3-2
Medicine rat is 10~23 times high.
Show that ginkgo biloba p.e is shared with ginsenoside Rb3, active constituent Rb3 can be promoted through blood-brain barrier.
Inhibiting rate ratio Rb3 high 28.5~60.0%. of the EGbRb3 to neuroglial tumor
Embodiment three:
Based on embodiment 1, and it is different from:
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 EGbLZ-1
And EGbLZ-2.
Effect experiment:
Processing group: suspension is made in EGbLZ-1 and EGbLZ-2, and SD rat oral gavage administration is (suitable by 10mg/kg dosage
In Ganolactone 96.77 or 90.91mg/kg) 20ml/kg capacity 5 mouse of administration；Control group: separately Ganolactone extract is taken to be made
Suspension, SD rat oral gavage administration, by Ganolactone 100mg/kg dosage, 5 mouse are administered in 20ml/kg capacity；After 0.5hr is administered,
Blood is taken, acute execution rat takes brain tissue, and brain homogenate is made, and UPLC-MS detects active ingredient of Chinese herbs people in blood and brain tissue
Join saponin(e Rg1 content.
Another preparation glioma Naked mouse 40, gives EGbLZ1, EGbLZ2 of solvent physiological saline, 100mg/kg respectively
Or Ganolactone 20ml/kg capacity gastric infusion, 10 mouse/group；Animal is put to death in administration after 28 days, observe tumor control rate.Experiment
The results are shown in Table 2.
The result of the UPLC assay of Ganolactone and the saturating BBB of rush in 2 EGbLZ of table
The results showed that the EGbLZ and Ganolactone with agent are administered, Ganolactone blood concentration difference is not significant, but
Ganolactone content is 3 times and more than 6.2 times higher than simple Ganolactone administration rat in the brain tissue of EGbLZ1, EGbLZ-2.Show
Ginkgo biloba p.e is shared with Ganolactone, and active constituent Ganolactone can be promoted through blood-brain barrier, and improves brain tumor suppression
Rate effect processed.
Example IV:
Based on embodiment 1, and it is different from:
Ginkgo biloba p.e (content >=95.0%) 10 or 50g；
Active ingredient of Chinese herbs: shrubby sophora extract (matrine content >=50%) 500g.
The above-mentioned various extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as EGbKS-1
And EGbKS-2.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by 100mg/kg dosage (20ml/ is made in EGbKS-1 and EGbKS-2
Kg) 5 mouse are administered in capacity；
Control group: separately take shrubby sophora extract that suspension, SD rat oral gavage administration, by shrubby sophora extract glycosides 100mg/ is made
5 mouse are administered in kg dosage, 20ml/kg capacity；0.5hr is administered, takes blood, acute execution rat takes brain tissue, brain homogenate is made,
UPLC-MS detects matrine content in blood and brain tissue, another to prepare glioma Naked mouse 40, gives solvent physiology respectively
Salt water, the EGbKS for being equivalent to matrine 100mg/kg or matrine 20ml/kg capacity gastric infusion, 10 mouse/group；Administration 28 days
After put to death animal, observe tumor control rate.
As a result as shown in 3 table of table:
Table 3, BXN2 UPLC assay and and promote the result of saturating BBB
The results showed that EGbKS-1, EGbKS2 and shrubby sophora extract extract with dosage shrubby sophora extract are administered,
Blood concentration difference is not significant, but in the brain tissue of EGbKS-1, EGbKS/2 shrubby sophora extract content than simple shrubby sophora extract
Glycosides administration rat is high more than 2.0/7.4 times.Active constituent can be promoted by showing that ginkgo biloba p.e derivative and shrubby sophora extract share
Shrubby sophora extract glycosides penetrates blood-brain barrier, has Brain targeting effect, and can improve the anti-brain tumor drug effect of significant shrubby sophora extract glycosides and reach
32.8% and 56.7%.
Embodiment five:
Based on embodiment 1, and it is different from:
Ganodenna Lucidum P.E (content 96%) 1000g；
Ginkgo biloba p.e (content is >=96.0%) 150g.
The above-mentioned two kinds of extracts of recipe quantity are weighed, are uniformly mixed by equal increments method, obtained mixture is denoted as EGbLZE.
Effect experiment:
Processing group: suspension is made in EGbLZE, and SD rat oral gavage administration is administered by 100mg/kg dosage 20ml/kg capacity
5 mouse；
Control group: separately take ginkgo biloba p.e derivative that suspension, SD rat oral gavage administration, by Ganodenna Lucidum P.E is made
5 mouse are administered in 100 mg/kg dosage, 20ml/kg capacity；0.5hr is administered, takes blood, acute execution rat takes brain tissue, brain is made
Homogenate, UPLC-MS detect Ganodenna Lucidum P.E content in blood and brain tissue.
Another preparation glioma Naked mouse 40, give solvent physiological saline respectively, give solvent physiological saline and
The BXN4 and Ganodenna Lucidum P.E of 100mg/kg, 20ml/kg capacity gastric infusion, 10 mouse/group；Administration put to death animal after 28 days, saw
Brain tumor inhibiting rate is examined, as a result as shown in 4 table of table.
The result of the UPLC assay of ganoderma lucidum polysaccharide and the saturating BBB of rush in 4 EGbLZ of table
From the data in table 4 it is found that waiting dosage BXN4 and Ganodenna Lucidum P.E to be administered, Ganodenna Lucidum P.E blood concentration difference is not
Significantly, ganoderma polyoses content is higher than simple Ganodenna Lucidum P.E administration rat more than 9 times but in the brain tissue of EGbLZE, and brain tumor inhibits
Rate significantly improves 38.6%.Show that ginkgo biloba p.e class class compound shares with Ganodenna Lucidum P.E and active constituent can be promoted to penetrate
Blood-brain barrier has Brain targeting effect, and can improve brain tumor inhibiting rate.
Embodiment six:
Based on embodiment 1, and it is different from:
BRL-1: commercially available ginkgo biloba p.e extract (content >=6%), general ginsenoside extract (content >=60%),
Ganodenna Lucidum P.E (content >=50%) is formed by the parts by weight of 5:10:5.
BRL-2: commercially available ginkgo biloba p.e extract (content >=95%), general ginsenoside extract (content >=
90%), Ganodenna Lucidum P.E (content >=60%) is formed by the parts by weight of 10:10:10.
RSLZ: general ginsenoside extract (content >=90%), Ganodenna Lucidum P.E (content >=60%) press the weight of 10:10
Part composition.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by 100mg/kg dosage, 20ml/ is made in BRL-1, BRL-2, RSLZ
Kg capacity distinguishes 5 mouse of each administration；Control group: separately take general ginsenoside extract (content >=90%) that suspension, SD rat is made
Gastric infusion, by 50mg/kg dosage, 5 mouse are administered in 20ml/kg capacity；0.5hr is administered, takes blood, acute execution rat takes brain group
It knits, brain homogenate is made, UPLC-MS detects active component content in blood and brain tissue.
Another preparation glioma Naked mouse 40 gives solvent physiological saline respectively, 100mg/kg gives solvent respectively
BLZ-1, BRL-2 and RSLZ Ganodenna Lucidum P.E of physiological saline and 100mg/kg, 20ml/kg capacity gastric infusion, 10 mouse/group；
Animal is put to death in administration after 28 days, observe brain tumor inhibiting rate.
Experimental result is as illustrated in tables 5-7:
Active component content (μ g/ml) in blood when table 5, different components administration 1.0h
Active component content (ng/ml) in table 6, different components administration 1.0h tissues following MCAO in rats
Compared with RSLZ group, * * P < 0.01.
It is each in blood by the data of table 5~7 it is found that the different components of dosage general ginsenoside and Ganolactone is waited to be administered
Ginsenoside and Ganolactone content difference are unobvious, but after combining with ginkgo biloba p.e class, each ginsenoside in brain tissue
It increases substantially with Ganolactone content up to more than 6~10 times.
Hindbrain tumor protection effect in 14 days is administered in the dosage such as table 7, different components rat
| Drug | Physiological saline | RS total saposins | RSLV | EGbRL-1 | EGbRL-2 |
| Survival prolongation rate | 0.5 | 49.1±8.1## | 56.5±8.9## | 127.3±9.8** | 185.1±10.3** |
| Tumor control rate | 0 | 63.8±8.5 | 65.1±9.3 | 85.1±12.1** | 93.2±13.3** |
Evaluating drug effect shows after BXN5-1 and BXN5-2 administration 14 days, reduces brain tumor volume, life span extension.Drug effect ratio
Simple general ginsenoside or RSLZ are stronger.Ginkgo biloba p.e class compound, which has, promotes active ingredient of Chinese herbs to penetrate blood-brain barrier,
Improve anti-brain tumor function.
Embodiment seven:
Based on embodiment 1, and it is different from:
EGbEK: commercially available ginkgo biloba p.e extract (content >=60%), Conmana are formed by the parts by weight of 3:30.
EGbEMT: commercially available ginkgo biloba p.e (content >=98%), Imatinib are formed by the parts by weight of 5:40.
Effect experiment:
Processing group:: suspension, SD rat oral gavage administration, by 100mg/kg dosage, 20ml/kg is made in EGbEK, EGbEMT
Capacity distinguishes 5 mouse of each administration；Control group: separately taking Conmana or Imatinib that suspension is made, and SD rat oral gavage administration is pressed
5 mouse are administered in 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 active component content.
Another preparation glioma Naked mouse 40 gives solvent physiological saline respectively, 100mg/kg gives solvent respectively
The EGbEK of physiological saline and 100mg/kg EGbEMT and Conmana or Imatinib, 20ml/kg capacity gastric infusion, 10
Mouse/group；Animal is put to death in administration after 28 days, observe brain tumor inhibiting rate.
Experimental result is as shown in table 8~9:
Table 8, different components administration 1h when blood and brain tissue in Conmana content and antitumous effect
Table 8 the result shows that, wait the different components of dosage Conmana or Imatinib to be administered, Conmana content in blood
Difference is unobvious, but after combining with ginkgo biloba p.e class, Conmana content is increased substantially up to more than 6 times in brain tissue.Band
Tumor survival day significantly extends 33.2%, and antitumous effect dramatically increases 34.4%.
Table 9, different components administration 1h when blood and brain tissue in Imatinib content and antitumous effect
Table 9 the result shows that, wait the different components of dosage Imatinib to be administered, Imatinib content difference is unknown in blood
It is aobvious, but after being combined with ginkgo biloba p.e class, Conmana or imatinib content are increased substantially up to more than 4.5 times in brain tissue.
Band tumor survival day significantly extends 35.6%, and antitumous effect dramatically increases 29.8%.
Evaluating drug effect shows that EGbEK, EGbEMT are administered 28 days, tumor control rate up to 90% or more, band tumour life span
It is more stronger than simple Conmana or Imatinib to improve rat action drug effect for obvious growth.Ginkgo biloba p.e class compound has
Promote Conmana or Imatinib bar to penetrate blood-brain barrier, improves its drug action to neuroglial tumor.
Embodiment eight:
Based on embodiment 1, and it is different from:
EGbDKQ: commercially available ginkgo biloba p.e extract (content >=60%), Dacarbazine mustard, the parts by weight by 3:14.0
Composition.
EGbNJ: commercially available ginkgo biloba p.e (content >=98%), nitrate are formed by the parts by weight of 3:16.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by Dacarbazine or Buddhist nun's nitrogen 100mg/ is made in EGbDKQ, EGbNJ
Kg dosage, 20ml/kg capacity distinguish 5 mouse of each administration；Control group: separately take Dacarbazine or nitrate that suspension, SD rat is made
Stomach-filling administration, by 100mg/kg dosage, 5 mouse are administered in 20ml/kg capacity；1__hr is administered, takes blood, acute execution rat takes brain
Tissue, is made brain homogenate, and UPLC-MS detects active component content in blood and brain tissue.
Another preparation glioma Naked mouse 40 gives solvent physiological saline respectively, 100mg/kg gives solvent respectively
EGbDKQ, EGbNJ of physiological saline and 100mg/kg and, Dacarbazine or nitrate, 20ml/kg capacity gastric infusion, 10
Mouse/group；Animal is put to death in administration after 28 days, observe brain tumor inhibiting rate.
Experimental result is as shown in table 10~11:
Table 10, different components administration 1h when blood and brain tissue in Dacarbazine content and antitumous effect
Table 11, different components administration 1h when blood and brain tissue in nitrate content and antitumous effect
Table 10,11 the result shows that, the different components for waiting dosage up to EGbDKQ, EGbNJ are administered, Dacarbazine or Buddhist nun in blood
Mustargen content difference is unobvious, but after combining with ginkgo biloba p.e class, and Dacarbazine or nitrate content be substantially in brain tissue
Degree is improved up to more than 3~5 times.
Evaluating drug effect shows that EGbDKQ, EGbNJ are administered 15 days, and tumor control rate is obvious up to 80%, band tumour life span
Growth improves rat action.Drug effect is more stronger than simple Dacarbazine or nitrate.Ginkgo biloba p.e class compound has promotion to reach
Carbazine or nitrate penetrate blood-brain barrier, improve its drug action to neuroglial tumor.
Embodiment nine:
Based on embodiment 1, and it is different from:
EGbTMZ: commercially available ginkgo biloba p.e extract (content >=60%), Temozolomide press the parts by weight group of 4:18.0
At.EGbZSC: commercially available ginkgo biloba p.e (content >=98%), taxol is pressed: 20 parts by weight composition.
Effect experiment:
Processing group: suspension, SD rat oral gavage administration, by Temozolomide or taxol is made in EGbTMZ, EGbZSC
100mg/kg dosage, 20ml/kg capacity distinguish 5 mouse of each administration；Control group: separately take Dacca Muzolimine or taxol that suspension is made
Liquid, SD rat oral gavage administration, by 100mg/kg dosage, 5 mouse are administered in 20ml/kg capacity；0.5hr is administered, takes blood, acute execution
Rat takes brain tissue, and brain homogenate is made, and UPLC-MS detects active component content in blood and brain tissue.
Another preparation glioma Naked mouse 40 gives solvent physiological saline respectively, 100mg/kg gives solvent respectively
EGbTMZ, EGbZSC of physiological saline and 100mg/kg and, the capacity gastric infusion such as Temozolomide 20ml/kg or taxol, 10
Mouse/group；Animal is put to death in administration after 28 days, observe brain tumor inhibiting rate.
Experimental result is as shown in table 12~13:
Table 12 the result shows that, wait the different components of dosage Temozolomide to be administered, Temozolomide content difference is unknown in blood
It is aobvious, but after being combined with ginkgo biloba p.e class, Temozolomide content is increased substantially up to more than 6 times in brain tissue.
Evaluating drug effect shows that EGbTMZ is administered 15 days, and tumor control rate is obviously grown up to 90%, band tumour life span, changes
Kind rat is slow in action.Drug effect is more stronger up to Temozolomide than merely.Ginkgo biloba p.e class compound, which has, promotes Temozolomide saturating
Blood-brain barrier is crossed, improves it to the drug action of neuroglial tumor up to 29.2%.
Table 12, different components administration 1h when blood and brain tissue in Temozolomide content and antitumous effect
Table 13 the result shows that, wait the different components of dosage taxol to be administered, content of taxol difference is unobvious in blood, but
After combining with ginkgo biloba p.e class, content of taxol is increased substantially up to more than 5.2 times in brain tissue.
Table 13, different components administration 1h when blood and brain tissue in Temozolomide content and antitumous effect
Evaluating drug effect shows that EGbZSC is administered 15 days, and tumor control rate is obviously grown up to 90, band tumour life span, improves
Rat is slow in action.Drug effect is higher than simple taxol by 31.3%.Ginkgo biloba p.e class compound, which has, promotes taxol to penetrate
Blood-brain barrier improves its drug action to neuroglial tumor.
Embodiment ten
Based on embodiment 1, Temozolomide capsule, EGbTMZ test the therapeutic effect of neuroglial tumor
(1) clinical data and method are the same.
(2) it is diagnosed as the voluntary trier of neuroglial tumor patient.Totally 25.
(3) treatment method
Temozolomide capsule: (specification is 100mg/) treatment, 1 tablet/time, 1 time/d.
EGbTMZ Capsules group: 100mg/, 1 tablet/time, once a day.
5 days each moons were 1 course for the treatment of, were discontinued 25 days, shared medicine 9 months, therebetween auxiliary identical other treatment of brain tumor drugs.
Each group assesses curative effect after treatment in 1,3,6,12 month.
(4) observation index is the same.
(5) statistical method is the same.
(6), efficacy analysis
Table 14 shows that the present invention can more efficiently improve cardinal symptom, the sign of neuroglial tumor, according to generally acknowledged
Criterion of therapeutical effect, overall therapeutic neuroglial tumor has preferable clinical efficacy, and comparison among groups, and BXN9 and BXN10 are treated
Effect quite, is better than Dacarbazine capsule, and otherness has significant (p < 0.01).
Table 14, two kind of Temozolomide preparation neuroglial tumor trier's curative effect statistics
Using clinical cure, effective with effective and as the data basis that total effective rate calculates, 2 groups of Clinical efficacy comparisons,
EGbTMZ capsule for treating group total effective rate is respectively 92%, and Temozolomide control group is 80%, and 2 groups are compared, and has conspicuousness poor
Different (p < 0.05).
B. daily life satisfaction (LSIB) scores: after treating, curative effect BXN9 capsule is better than Dacarbazine, and difference has
Significance,statistical meaning (p < 0.05), (p < 0.05).
Table 15, two kind of Temozolomide preparation neuroglial tumor try out pretherapy and post-treatment daily life satisfaction (LSIB) scoring
Scale integral variation (x ± s)
The present invention is spread out by ginkgo biloba p.e class compound, especially ginkgo biloba p.e, ginkgolides and its hydroxyl
Biology, especially its glucosides, ester, ether derivative and ginsenoside, kushenin, ginsenoside Rb3, Ganolactone, black uncle's poison
Element, Imatinib, Conmana, Teniposide, according to Shandong replace Buddhist nun, Rui Gefeini, Tarceva, Pa Boxini, Dacarbazine (nitrogen
Alkene miaow amine), nitrate, Temozolomide (TMZ), nitroso ureas, taxol isoreactivity ingredient be when sharing, promote these active Chinese drug components
Ingredient or cytotoxic drug, promote cell differentiation class drug, anti-invasion drug and cell signalling tune at anti-angiogenic medicaments
It is obvious through blood-brain barrier effect to save the anti-tumor drugs such as agent, increases substantially ginsenoside in composition, kushenin, ginseng soap
Glycosides Rb3, it Ganolactone, black uncle's toxin, Imatinib, Conmana, Teniposide, Dacarbazine (dacarbazine), replaces according to Shandong
Buddhist nun, Rui Gefeini, Tarceva, Pa Boxini, nitrate, Temozolomide (TMZ), nitroso ureas, taxol, cytotoxicity
Drug, anti-angiogenic medicaments, rush cell differentiation class drug, anti-invasion drug and cell signalling regulator etc. are in brain tissue
In concentration, and there is anti-brain tumor to act on, and main active is clear, quality is stablized, and reduces active constituent in periphery group
Side effect in knitting, plays synergism and attenuation.Dosage is few, can be made into various control delivery formulations and is given birth on a large scale
It produces, is a kind of excellent natural drug and/or health food.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (9)
1. preparation and application that a kind of ginkgo biloba p.e is prevented and treated as Brain targeting synergist in brain tumor, it is characterised in that:
Natural products ginkgo biloba p.e passes through blood brain screen as the drug promoted to brain tumor disease with treatment or health-care effect
Hinder the application of preparation.
2. the preparation that a kind of ginkgo biloba p.e according to claim 1 is prevented and treated as Brain targeting synergist in brain tumor
And application, it is characterised in that: the natural products ginkgo biloba p.e and its hydroxy derivatives.
3. the preparation that a kind of ginkgo biloba p.e according to claim 2 is prevented and treated as Brain targeting synergist in brain tumor
And application, it is characterised in that: natural products ginkgo biloba p.e (ginkgolides total content 0.1~99%) and its hydroxy derivatives
For its glucosides, ester and ether.
4. a kind of ginkgo biloba p.e described in any one claim is as Brain targeting synergist according to claim 1~3
In the preparation and application of brain tumor prevention and treatment, it is characterised in that: have the drug for the treatment of or health-care effect to brain tumor disease
Selected from general ginsenoside (extract), matrine (extract), Ganolactone (extract), ganoderma lucidum (extract) and, black uncle (mother's brother) poison
Plain (extract) and brain tumor chemotherapeutic (Gleevec, Imatinib, Conmana, Teniposide, Dacarbazine (nitrence miaow
Amine), nitrate).
5. the preparation that a kind of ginkgo biloba p.e according to claim 4 is prevented and treated as Brain targeting synergist in brain tumor
And application, it is characterised in that: the composition action ingredient is ginkgo biloba p.e as targeting synergist and to brain tumor disease
Disease has the bioactive molecule for the treatment of or health-care effect.
6. the preparation that a kind of ginkgo biloba p.e according to claim 5 is prevented and treated as Brain targeting synergist in brain tumor
And application, it is characterised in that: ginkgo biloba p.e is selected from ginkgo biloba p.e (extract), ginkgolides extract, ginkgo leaf
Extract and its hydroxy derivatives.
What 7. a kind of ginkgo biloba p.e according to claim 5 or 6 was prevented and treated as Brain targeting synergist in brain tumor
Preparation and application, it is characterised in that: there is treatment or health-care effect composition to be selected from treatment of brain tumor medicine brain tumor disease
General ginsenoside (extract), matrine (extract), Ganolactone (extract), ganoderma lucidum (extract) and, black uncle's toxin (mentions
Take object) and treatment of brain tumor chemicals (cytotoxic drug, anti-angiogenic medicaments, rush cell differentiation class drug, anti-invasion
Drug and cell signalling regulator, such as elemene, oleic acid, octadecenic acid, Temozolomide (TMZ), nitroso ureas, Japanese yew
Alcohol, Gleevec, Imatinib, Conmana, Teniposide, Dacarbazine (dacarbazine), nitrate).
8. the preparation that a kind of ginkgo biloba p.e according to claim 7 is prevented and treated as Brain targeting synergist in brain tumor
And application, it is characterised in that: the active constituent to brain tumor disease with treatment or health-care effect composition are as follows:
Ginkgo biloba p.e, kushenin, ginsenoside Rb3, Ganolactone mass ratio be 1~10:1~30:1~30；1~30
Or ginkgo biloba p.e extract: general ginsenoside extract: kuh-seng extract, Ganolactone extract mass ratio be 1
~10:0.6~60:0.5~50:0.4~40；
Or ginkgo biloba p.e (extract), general ginsenoside extract, kushenin and Ganolactone mass ratio be 1~10:1
~30:1~20:1~30；
Or ginkgo biloba p.e (extract), general ginsenoside (extract), black uncle's toxin (extract), Ganolactone (extraction
Object) mass ratio be 1~10:1~50:1~20；: 1~30:1~50:
Or ginkgo biloba p.e (extract), general ginsenoside extract, black uncle's toxin (extract), Ganolactone (extract)
Mass ratio be 1~10:1~50:1~20；: 1~30；
Or the quality of ginkgo biloba p.e (extract), general ginsenoside extract, crow uncle's toxin (extract), lucidum spore powder
Than for 1~10:1~50:1~20:1~30；
Or the mass ratio of ginkgo biloba p.e extract, ginsenoside Rb3, matrine, Ganolactone be 1~10:1~50:1~
20:1~30；Or ginkgo biloba p.e extract, ginsenoside Rb3, matrine, Ganolactone, elemene/oleic acid/octadecylene
The mass ratio of acid is 1~10:1~50:1~20:1~30；1~30；
Or mass ratio is the ginkgo biloba p.e and Imatinib of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e of 1~10:2~50 and angstrom gram replaces；
Or mass ratio is the ginkgo biloba p.e and Teniposide of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e and Dacarbazine (dacarbazine) of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e and nitrate of 1~10:2~50；
Or mass ratio is the ginkgo biloba p.e and Temozolomide (TMZ)/nitroso ureas/taxol of 1~10:2~50.
9. the preparation that a kind of ginkgo biloba p.e according to claim 7 is prevented and treated as Brain targeting synergist in brain tumor
And application, which is characterized in that there is treatment or health-care effect composition to be selected from brain tumor disease brain tumor disease for example pernicious
Glioblastoma, Alzheimer cells tumor, hemangioblastoma, malignant lymphoma and sarcoma, medulloblastoma or nerve are female
Cytoma etc..
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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 |
| CN109528782A (en) * | 2018-12-30 | 2019-03-29 | 广东药科大学 | 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 |
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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 |
| CN109528782A (en) * | 2018-12-30 | 2019-03-29 | 广东药科大学 | 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 |
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| CN111718352A (en) * | 2020-02-19 | 2020-09-29 | 杭州普施康生物科技有限公司 | Novel compound and pharmaceutically acceptable salt thereof |
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Application publication date: 20190920 |