CN105853479A - Pharmaceutical composition for treating depression - Google Patents
Pharmaceutical composition for treating depression Download PDFInfo
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- CN105853479A CN105853479A CN201610268990.6A CN201610268990A CN105853479A CN 105853479 A CN105853479 A CN 105853479A CN 201610268990 A CN201610268990 A CN 201610268990A CN 105853479 A CN105853479 A CN 105853479A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
Abstract
The invention provides a pharmaceutical composition which is prepared from 20-80% of hypericum perforatum extract and the balance of ginkgo leaf extract based on the weight of the pharmaceutical composition. The invention also provides a pharmaceutical preparation containing the pharmaceutical composition. In addition, the invention also provides application of the pharmaceutical composition and the pharmaceutical preparation in preparation of a medicine for treating depression. Pharmaceutical tests show that the pharmaceutical composition provided by the invention has an obvious curative effect on depression, thereby providing a new choice for clinically treating depression.
Description
Technical field
The invention belongs to medical science and pharmaceutical field, be specifically related to a kind of new medicine group for treating depression
Compound.
Background technology
Depression, also known as depressive disorder, with significantly and persistently (more than at least 2 weeks, the even up to several years)
Mental state low for main clinical characteristics, be the main Types of mood disorders.Clinical visible mental state low with
Its situation is unbecoming, and the downhearted of emotion can be from depressed to extremely grieved, depression of feeling oneself inferior, even sad
See world-weary, can have suicidal attempt or behavior；Even occur numb；Some cases has obvious anxiety and fortune
Dynamic property is intense；Severe patient may occur in which the psychotic symptoms such as hallucination, vain hope.
Depression is a kind of high prevalence, high Disease Spectrum, high relapse rate, high disability rate, high homicide rate
Chronic mental illness.Adding up according to World Health Organization (WHO), whole world depression rate is about 11%, the whole world
There are about 3.4 hundred million patients with depression.Serious patient have 15% suicide can be selected to carry out end lives, 2/3
Patient once had the thought committed suiside, and was up to 1,000,000 because of the Population size estimation of depression committed suicide every year.When
Front depression has become as the fourth-largest disease in the world, it is contemplated that may will become to the year two thousand twenty and be only second to heart disease
The second largest illness of the mankind.The investigation of China's depression disease condition on a large scale is not the most carried out, and simply exists
The prevalence survey of depression has been carried out in different areas.Existing data show China's depression prevalence
The comparison in difference of each department is big, between 1.6%-4.1%.In view of the low consultation rate of China's patients with depression,
The rate of actually occurring should be higher.
Increasing research shows, physical disease such as tumor, diabetes, arthritis, chronic pain,
The chronic diseases such as cardiovascular disease, with depression risk factor each other, have the risk of co-morbid.Such as joint
Scorching, have a back ache, to suffer from depression risk be 1.9 to 3.2 times of general population to the patient of headache, patients with depression
Occur tumor, cardiovascular disease, apoplexy risk the highest.Therefore, the preventing and treating of depression becomes medicine
The study hotspot in field.
Along with genomics, brain iconography, the going deep into of Neuroscience Research, " naturally " magazine in 2010
It is brain development disease that chief editor Philip Campbel proposes depression, and so far, depression belongs to function
The idea of property disease is thoroughly corrected, and therefore, Drug therapy remains the primary hand of current treating depression
Section.Since the eighties in 20th century, the research for the treatment of depression achieves significant progress, particularly
The birth of the 3rd generation antidepressants serotonin reuptake inhibitor, opens the new page for the treatment of depression,
Within 10 years subsequently, in succession develop the 4th generation 5-hydroxy tryptamine and Norepinephrine dual pathways reuptake inhibitor
(SNRI class, such as venlafaxine), 5-hydroxy tryptamine and Norepinephrine dual pathways regulator (NaSSa class,
Such as mirtazapine), work out personalized therapy program for doctor to patient and provide safer, more effective, more
Medicament selection.Although the 3rd, 4 generation antidepressants have higher treatment remission rate, more preferable toleration and
Become a line antidepressant drug, and centering, major depressive disorder also have a good curative effect, but current one
The cure rate of line antidepressant drug is only 30%, and onset time 2-4 (Wang Zuxin. the medicine of depression is controlled
Treat [J]. CHINESE JOURNAL OF INTERNAL MEDICINE, 1998,37 (11): 783).In recent years, the chlorine of the up-to-date focus of drug research
Amine ketone has the feature of quick acting.Research shows ketamine to treat depression 4～72h treated effect
And cure rate average out to 77% and 43%, but maintain curative effect time shorter (Murrough J W, et al.R
apid and longer-term antidepressant effects of repeated ketamine infusions in
Treatment-resistant major depression [J] .Biol Psychiatry, 2013,74 (4): 250
-256).
Except classical chemicals Research idea, pharmaceuticals researcher and mechanism are also actively working to from include
Medical herbs finds more efficient and safe anti-depression drug in number of ways such as interior natural drugs.
Prior art has occurred in that such pharmaceutical composition.As publication number CN102961452A is (public
Open on March 2013 day 13), invention entitled " a kind of for alleviate depression pharmaceutical composition and
Preparation method " Chinese invention patent application, disclose a kind of by 5-HTP (5-hydroxyryptophan) 20 parts,
Hydrochloric acid vitamin B615 parts, Herba Hyperici perforati extract 30 parts and the medicine group of slips extract 30 parts composition
Compound.And for example publication number CN102847050A (publication date on January 2nd, 2013), invention entitled " one
Kind for treating the Chinese medicinal effective-part composition of depression " Chinese invention patent application, disclose one
Including the Herba Hyperici perforati extract with Herba Hyperici perforati total flavones as effective site, with curcumin as effective site
Rhizoma Curcumae Longae extract, the Chinese medicinal effective-part composition of Radix Ginseng extract with ginsenoside as effective site.
For another example publication number CN104147090A (publication date on November 19th, 2014), denomination of invention " one
The pharmaceutical composition for the treatment of depression " open a kind of by Folium Stevlae Rebaudianae 100～300 parts, Cortex Albiziae 100～200
Part, Saussurea lappa Clarke 100～150 parts and Folium Ginkgo 60～100 parts be the pharmaceutical composition of raw material.
Although there being appearing on the market of new drug, but it is clear that the treatment means of depression is also far from meeting patient's convection potential
Effect and the expectation for the treatment of final result.
Summary of the invention
For the problems referred to above, it is an object of the present invention to provide a kind of pharmaceutical composition.Test of pesticide effectiveness table
Bright, said composition has significant curative effect to depression, such that it is able to provide a kind for the treatment of for clinician and patient
Depression the newly selected.
In order to realize foregoing invention purpose, present invention employs following technical scheme:
A kind of pharmaceutical composition, is made up of Herba Hyperici perforati extract and Folium Ginkgo extract.
Preferably, on the basis of the weight of described pharmaceutical composition, described Herba Hyperici perforati extract accounts for
20%～80%, surplus is described Folium Ginkgo extract.
It is furthermore preferred that on the basis of the weight of described pharmaceutical composition, described Herba Hyperici perforati extract accounts for
20%～60%, surplus is Folium Ginkgo extract.
Even more preferably, on the basis of the weight of described pharmaceutical composition, described Herba Hyperici perforati extract
Accounting for 40%～60%, surplus is Folium Ginkgo extract.
Most preferably, on the basis of the weight of described pharmaceutical composition, described Herba Hyperici perforati extract accounts for
60%, described Folium Ginkgo extract accounts for 40%.
Preferably, in aforementioned pharmaceutical compositions, described Herba Hyperici perforati extract summary and discussion is no less than 0.30%,
Hyperforine is no less than 3.0%.
Preferably, in aforementioned pharmaceutical compositions, described Folium Ginkgo extract total flavonoids is no less than 24.0%,
Containing terpene lactone in terms of the total amount of bilobalide, ginkalide A, ginkalide B and ginkalide C many
In 6.0%.
A kind of pharmaceutical preparation containing aforementioned pharmaceutical compositions of offer is provided.
Described pharmaceutical preparation can be containing can also not containing pharmaceutically acceptable adjuvant.
Described pharmaceutical preparation is oral formulations, includes but not limited to tablet, capsule, soft capsule, effervescent
Sheet, oral quick-dissolving film preparation, oral cavity disintegration tablet, oral liquid.
It is also an object of the present invention to provide the preparation method of said medicine preparation, including by said medicine
Compositions and the pharmaceutically mixing of acceptable adjuvant, be conventionally prepared as acceptable clinically
Preparation.
Additionally, it is also an object of the present invention to provide aforementioned pharmaceutical compositions and described pharmaceutical preparation in system
Application in the medicine of standby treatment depression.
Pharmaceutically acceptable adjuvant of the present invention, including (1) diluent (also known as filler),
Such as starch, sucrose, dextrin, calcium carbonate, calcium sulfate, light magnesium oxide, microcrystalline cellulose, mannitol, breast
Sugar, pregelatinized Starch；(2) disintegrating agent, such as dried starch, carboxymethyl starch sodium, low substituted hydroxy-propyl fiber
Element, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, gas-producing disintegrant etc.；(3) wetting agent, such as distillation
Water, ethanol etc.；(4) binding agent, such as Icing Sugar and syrup, starch slurry, polyvinylpyrrolidone, cellulose
Derivant, rubber cement, dextrin etc.；(5) lubricant, such as stearic acid, magnesium stearate, calcium stearate, micropowder
Silica gel, hydrogenated vegetable oil, Polyethylene Glycol；And the coloring agent of necessity, aromatic and sweeting agent etc..
Adult to body weight 60 kilograms, the quantity scope of the pharmaceutical composition that the present invention provides is oral
600～1200mg/ days, preferably 900mg/ day.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
Fig. 1 illustrates rat body weight change curve in test example 1, whereinRepresent blank group,
Represent model group,Represent positive group,Represent medicine I group,Represent medicine II group,Represent medicine III group,Represent medicine IV group,Represent medicine V group,
Represent medicine VI group.
Fig. 2 is illustrated that the CUMS depression model impact on rat sucrose solution preference in test example 1, wherein 1
For blank group, 2 is model group.
Fig. 3 is illustrated that in test example 1 the assay result of NO in each rats in test groups blood plasma；Wherein,
Fig. 3 A is the assay result of NO-1 in each rats in test groups blood plasma, and Fig. 3 B is each rats in test groups blood
The assay result of NO-2 in slurry.In figure, 1 is blank group, and 2 is model group, and 3 is positive group, and 4 are
Medicine I group, 5 is medicine II group, and 6 is medicine III group, and 7 is medicine IV group, and 8 is medicine V group, 9
It it is medicine VI group.
Fig. 4 is illustrated that in test example 1 the assay result of CORT in each rats in test groups blood plasma；Wherein,
Fig. 4 A is the assay result of CORT-1 in each rats in test groups blood plasma, and Fig. 4 B is each rats in test groups
The assay result of CORT-2 in blood plasma.In figure, 1 is blank group, and 2 is model group, and 3 is positive group,
4 is medicine I group, and 5 is medicine II group, and 6 is medicine III group, and 7 is medicine IV group, and 8 is medicine V group,
9 is medicine VI group.
Fig. 5 is illustrated that the result of each rats in test groups ASP flooding test in test example 1, and wherein Fig. 5 A is level
Motion measurement result, Fig. 5 B is vertical movement measurement result.In figure, 1 is blank group, and 2 is model group, 3
Being positive group, 4 is medicine I group, and 5 is medicine II group, and 6 is medicine III group, and 7 is medicine IV group, 8
Being medicine V group, 9 is medicine VI group.
Fig. 6 is illustrated that in test example 1 measurement result of 5-HT content in each rats in test groups hippocampal tissue.
In figure, 1 is blank group, and 2 is model group, and 3 is positive group, and 4 is medicine I group, and 5 is medicine II group, 6
Being medicine III group, 7 is medicine IV group, and 8 is medicine V group, and 9 is medicine VI group.
Fig. 7 is illustrated that in test example 1 measurement result of NE content in each rats in test groups hippocampal tissue.Figure
In, 1 is blank group, and 2 is model group, and 3 is positive group, and 4 is medicine I group, and 5 is medicine II group, and 6 are
Medicine III group, 7 is medicine IV group, and 8 is medicine V group, and 9 is medicine VI group.
Fig. 8 is illustrated that in test example 1 measurement result of BDNF content in each rats in test groups hippocampal tissue.
In figure, 1 is blank group, and 2 is model group, and 3 is positive group, and 4 is medicine I group, and 5 is medicine II group, 6
Being medicine III group, 7 is medicine IV group, and 8 is medicine V group, and 9 is medicine VI group.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these are real
Executing example and be merely to illustrate the present invention, it limits the scope of the present invention never in any form.
Experimental technique in following embodiment, if no special instructions, is conventional method.Following embodiment
In used medicinal raw material, reagent material etc., if no special instructions, be commercially available purchase product, wherein,
Herba Hyperici perforati extract sheet, trade nameThe every dry extract 300mg Han Herba Hyperici perforati；
Dr Willmar Schwabe produces, import drugs registration certificate number: Z20090005；
Herba Hyperici perforati extract: containing hyperforine 3.0%, summary and discussion 0.30%；High purchased from Chongqing
Core bio tech ltd；
Folium Ginkgo extract contain total flavonoids 24.0%, terpene lactone (with bilobalide, ginkalide A,
The total amount meter of ginkalide B and ginkalide C) 6.0%；Purchased from Gao Ren bio tech ltd, Chongqing.
Embodiment 1A kind of pharmaceutical composition
Consisting of of described pharmaceutical composition:
Herba Hyperici perforati extract 40g, Folium Ginkgo extract 10g.
By said extracted thing mix homogeneously, to obtain final product.
Embodiment 2A kind of pharmaceutical composition
Consisting of of described pharmaceutical composition:
Herba Hyperici perforati extract 30g, Folium Ginkgo extract 20g.
By said extracted thing mix homogeneously, to obtain final product.
Embodiment 3A kind of pharmaceutical composition
Consisting of of described pharmaceutical composition:
Herba Hyperici perforati extract 20g, Folium Ginkgo extract 30g.
By said extracted thing mix homogeneously, to obtain final product.
Embodiment 4A kind of pharmaceutical composition
Consisting of of described pharmaceutical composition:
Herba Hyperici perforati extract 10g, Folium Ginkgo extract 40g.
By said extracted thing mix homogeneously, to obtain final product.
Test example 1The antidepressant effect research of pharmaceutical composition of the present invention
Laboratory animal and experimental drug
1. laboratory animal: SD rat, male, 130-170g, it is purchased from Hunan Si Laike scape and reaches laboratory animal and have
Limit company, credit number: SCXK (Hunan) 2013-0004.
2. experimental drug:
Herba Hyperici perforati extract sheet, trade nameThe every dry extract 300mg Han Herba Hyperici perforati；
Dr Willmar Schwabe produces, import drugs registration certificate number: Z20090005；
Herba Hyperici perforati extract: containing hyperforine 3.0%, summary and discussion 0.30%；High purchased from Chongqing
Core bio tech ltd；
Folium Ginkgo extract contain total flavonoids 24.0%, terpene lactone (with bilobalide, ginkalide A,
The total amount meter of ginkalide B and ginkalide C) 6.0%；Purchased from Gao Ren bio tech ltd, Chongqing.
Animal feeding:
Indoor temperature (18 DEG C～24 DEG C), (10g/100g body weight d), drinking-water (changes weekly water 2～3 to food-intake
Secondary).
Laboratory animal packet and dosage regimen
1. animal packet: experimental rat is randomly divided into 9 groups, often 12 rats of group, often organize 2 cages by 6/cage:
1. blank group: normal saline, gavage, 1ml/100g body weight sky
2. model group: with " blank group "
3. positive drug group: Herba Hyperici perforati extract sheet
4. medicine I group: Herba Hyperici perforati extract: Folium Ginkgo extract=1:0,
5. medicine II group: Herba Hyperici perforati extract: Folium Ginkgo extract=4:1 (compositions of embodiment 1),
6. medicine III group: Herba Hyperici perforati extract: Folium Ginkgo extract=3:2 (compositions of embodiment 2),
7. medicine IV group: Herba Hyperici perforati extract: Folium Ginkgo extract=2:3 (compositions of embodiment 3),
8. medicine V group: Herba Hyperici perforati extract: Folium Ginkgo extract=1:4 (compositions of embodiment 4),
9. medicine VI group: Herba Hyperici perforati extract: Folium Ginkgo extract=0:1.
2. dosage:
The every 300mg Han Herba Hyperici perforati extract, be grown up 3/d；If adult's body weight presses 60kg
Meter, according to adult/rat conversion scale, the rat amount of being given daily is:
900mg/60 × 6.3kg d=94.5mg/kg d
The dosage that is given daily of each medicine group is also 94.5mg/kg d.
3. drug solution preparing:
1. the preparation of normal saline: weigh 9g sodium chloride, is settled in 1000ml volumetric flask with distilled water.
2. the preparation of positive drug medicinal liquid: takeSheet 4, removes coating, is crushed to powder, weigh 0.945g
Powder, uses a small amount of physiological saline solution, is settled in 100ml volumetric flask, is configured to the solution of 9.45mg/ml.
According to described method, with joining.
3. the preparation of medicine group medicinal liquid: take Herba Hyperici perforati extract, embodiment 1～the combination of embodiment 4 respectively
Thing and each 0.945g of Folium Ginkgo extract, use a small amount of physiological saline solution, be settled to 100ml volumetric flask
In, it is configured to the solution of 9.45mg/ml.According to described method, with joining.
4. dosage regimen:
Modeling starts to be administered on the 15th day, and medicine group gavage gives corresponding medicinal liquid, model group and blank group gavage and gives
Give equal-volume normal saline, every day 1 time, continuous 4 weeks
Laboratory animal modeling: chronic gentle unpredictable stress stimulus (CUMS)
By utilizing the unpredictable stimulation of a series of light, moderate strength (moist bedding and padding, to be placed in sky cage, incline
Tiltedly mouse cage, light and shade be reverse, high light stimulation, the higher-order of oscillation, cold-wate swimming, fasting, taboo water etc.) mode
Enforcement continuous to rat 6 weeks, every day, random 1-2 kind stimulated, and caused the rat depression model of CUMS.
Experimentation and result:
1. body weight rate of increase
1) experimental technique: modeling the 1st day, the 7th day, the 14th day, the 21st day, the 28th day, the 35th
My god, within the 42nd day, measure all each experimental group rat body weights.
2) result: be shown in Table 1 and Fig. 1.
Table 1 each rats in test groups body weight
*: compare with blank group, p < 0.05；#: compare with model group, p < 0.05.
3) conclusion:
Enforcement stress after, each modeling group rat body weight increasess slowly, test the 14th day, 21 days, 28 days,
35 days, 42 days, comparing with blank group, model group, positive drug group, each medicine group rat body weight significantly subtract
Gently (P < 0.05)；After Drug therapy, modeling rat body weight increased, test the 28th day, the 35th day,
42nd day, compare with model group, positive drug group, medicine I group, medicine II group, medicine III group rat body
Weight average dramatically increases (P < 0.05)；Comparing with positive drug group, medicine I～VI group rat body weight there was no significant difference.
2. sucrose solution consumption experiment
1) experimental technique: after modeling gives rat stimulation on the 14th day, by blank group rat and model group rats
Carrying out only cage raising, make the sugary drinking-water of rat adaptability 1 day under conditions of environment quiet, water 24 is prohibited in fasting
After hour, every cage places 1 bottle of pure water, 1 bottle of 1.5% each 50ml of sucrose water, and 2 bottles of positions are put at random, and 12
Measure pure water and the consumption of sucrose solution after hour, be following calculate sucrose solution preference rate.
Sucrose solution preference rate=sucrose solution consumption/(pure water consumption+sucrose solution consumption) × 100%
2) experimental result: be shown in Table 2 and Fig. 2.
The impact on rat sucrose solution preference of table 2 depression model
*: compare with blank group, p < 0.05.
3) data analysis: after modeling 2 weeks, compares with blank group, and the sucrose solution preference rate of model group rats is notable
Decline (P < 0.05)；Show that model group rats sugary drinking-water after modeling reduces, anhedonia.Modeling is described
Success.
3. corticosterone (CORT) and NO assay in blood plasma
1) experimental technique: after modeling gives rat stimulation for the 14th day, the 42nd day, each group of rat is carried out eye
Socket of the eye takes blood (blood plasma), and after taking blood, rat is normally raised and is administered；Taken blood is stood 1 hour, centrifugal
(3000r/min, 20min), takes supernatant and is placed in EP pipe, and cryopreservation is to be measured.By blood plasma sample during mensuration
This at room temperature thaws, and uses the content of CORT and NO in ELISA method detection blood plasma.
2) experimental result: be shown in Table 3 and table 4, and Fig. 3 and Fig. 4 respectively.Wherein, each rats in test groups
In blood plasma, the assay result of NO-1 is shown in Fig. 3 A, the assay of NO-2 in each rats in test groups blood plasma
Result is shown in Fig. 3 B, and in each rats in test groups blood plasma, the assay result of CORT-1 is shown in Fig. 4 A, each test group
In rat plasma, the assay result of CORT-2 is shown in Fig. 4 B.
The impact of table 3 each rats in test groups contents of plasma NO
*: compare with blank group, p < 0.05；#: compare with model group, p < 0.05；&: compare with positive drug group, P < 0.05.
The impact of CORT content in table 4 each rats in test groups blood plasma
*: compare with blank group, p < 0.05.
3) data analysis:
1. after modeling 2 weeks, comparing with blank group, in each modeling rat plasma, NO content is significantly raised
(P<0.05)；After modeling terminates for 6 weeks, in each modeling rat plasma, NO content persistently raises, with blank group
Relatively there is significant difference (p < 0.05).Comparing with model group, in medicine II～VI group rat plasma, NO contains
Amount significantly reduces (p < 0.05).Compare with positive drug group, NO in medicine III, V and VI group rat plasma
Content significantly reduces (p < 0.05).
2. after modeling 2 weeks, CORT content no significant difference in each group rat plasma；After modeling terminates for 6 weeks,
Comparing with model group, in positive drug group, medicine I～IV group rat plasma, CORT content substantially reduces (P < 0.05)；
Compare with positive drug group, CORT content no significant difference in rat plasma between each administration group.
The most spacious field experiment (horizontal movement number of times, move vertically number of times)
1) experimental technique:
After modeling gives rat stimulation on the 42nd day, carry out the experiment of spacious field, rat is positioned over 25 lattice uncovereds
The center of square chest, observation rat was 3 minutes interior active situation at once, measured rat horizontal movement with vertical
Motion scores: it is horizontal anomalous movement score that rat passes through number of squares, passing through 1 lattice (more than three-jaw striding into) is 1 time；
Upright number of times (two liftoff more than the 1cm of forelimb) is Vertical movements score, and every rat only carries out 1 time, often
Secondary 3min.After every rat test terminates, in time rat Excreta is removed clean, in order to avoid impact is next
Experiment.
2) experimental result: be shown in Table 5 and Fig. 5.
The each rats in test groups of table 5 spacious field measuring result)
*: compare with blank group, p < 0.05；#: compare with model group, p < 0.05.
3) data analysis:
After CUMS modeling terminates, model group rats horizontal movement and vertical movement number of times all significantly reduce
(P<0.05)；After Drug therapy, compare with model group, positive drug group, medicine I～VI group rat level fortune
Dynamic and vertical movement number of times all dramatically increases (P < 0.05)；Compare with positive drug group, each administration group rat level
Motion and vertical movement number of times no significant difference.
5. the mensuration of each neurotransmitter content in Rat hippocampus
1) experimental technique:
After modeling gives rat stimulation on the 42nd day, each group of rat cervical dislocation is put to death, takes brain, on ice platform,
Separation weighs hippocampal tissue, puts in Potter-Elvehjem Tissue Grinders, adds 9 times of PBS (pH7.4) homogenate, makes 10%
Hippocampal homogenates liquid, inserts homogenate in centrifuge tube, with 3000r/min centrifugation under the conditions of 4 DEG C
20min, carefully collects supernatant after standing, be placed in 1.5mlEP pipe ,-70 DEG C of preservations, uses ELISA
5-HT (5-hydroxy tryptamine), NE (norepinephrine), BDNF (brain source property nutrition in method detection hypothalamus
The factor) content.
2) experimental result: be shown in Table 6 and Fig. 6～8.
Neurotransmitter assay result in table 6 each rats in test groups hippocampal tissue
*: compare with blank group, p < 0.05；#: compare with model group, p < 0.05；&: compare with positive drug group, P < 0.05.
3) data analysis:
1. monoamine neurotransmitter in 5-HT is brain, there are some researches show that depression is that 5-HT releases in brain
Putting minimizing, synaptic space 5-HT content declines the result caused.After modeling 42 days, model group rats Hippocampus
Tissue 5-HT content significantly reduces, and comparing with blank group has significant difference (P < 0.05)；Compare with model group,
Positive drug group, medicine I～VI group rat hippocampus 5-HT content dramatically increase (P < 0.05)；With positive drug group ratio
Relatively, each medicine group rat hippocampus 5-HT content no significant difference, but the 5-HT level of medicine III group is higher than
Property of medicine medicine group.It is compared to each other between each medicine group, medicine III group (Herba Hyperici perforati extract/Folium Ginkgo extract
=3:2) all there is significant difference with other each group.
2. NE is the neurotransmitter generated through tyrosine hydroxylase effect by dopamine, has theory to think depressed
Disease is that in central nervous system, norepinephrine synthesis and release minimizing cause.After modeling 42 days, model
Group Rat hippocampus NE content significantly reduces, and comparing with blank group has significant difference (P < 0.05)；With mould
Type group compares, and positive drug group, medicine I～IV group rat hippocampus 5-HT content dramatically increase (P < 0.05)；With
Positive drug group compares, each medicine group rat hippocampus NE content no significant difference, but the NE of medicine III group
Level is higher than property of medicine medicine group.It is compared to each other between each medicine group, medicine III group (Herba Hyperici perforati extract/Semen Ginkgo
Leaf extract=3:2) all there is significant difference with other each group.
3. BDNF can stimulate the growth of newborn neuron projection, promotes growth and the maturation of newborn neuron；
At the initial stage of stress damage, neuronal cell death or apoptosis can be reduced by the calcium concentration in regulation neurocyte,
Neuron is shielded.BDNF is not only by promoting aixs cylinder and the growth of dendron, reconstructing and prominent
Touch and formed, the structure plasticity that regulation is neural, it is also possible to change synapse by presynaptic and postsynaptic mechanisms and pass
Pass, the function plasticity that impact is neural.After modeling 42 days, model group rats hippocampal tissue BDNF content is bright
Aobvious minimizing, compares with blank group and has significant difference (P < 0.05)；Compare with model group, medicine III～VI group
Rat hippocampus BDNF content dramatically increases (P < 0.05), although positive drug can improve the level of BDNF,
But compare with model group and there is no significant difference (P ＞ 0.05)；Comparing with positive drug group, medicine VI group is big
Mus Hippocampus BDNF content dramatically increases (P < 0.05).It is compared to each other between each medicine group, medicine V and VI group
Significant difference is had with other each group.
Interpretation of result:
1. pair rat give continuously gently, the unpredictable stimulation of moderate strength 7 days time just it is observed that rat body
Heavily significantly reduce, when 14 days the sucrose solution consumption of rat substantially reduce, 42 days time rat horizontal movement number of times
All substantially reduce with vertical movement number of times, modeling success is described.
2. medicine II group (compositions of embodiment 1) and III group (compositions of embodiment 2) can show
Write the body weight of raising depression rat, improve its behavioristics, effect and positive drugQuite.
3. in blood plasma, NO level is too high, tissue and cell can be caused damage.The NO-2 water of rat model
Putting down and be significantly higher than blank group, the compositions of the present invention can significantly reduce NO-2 level, positive drug group
Although NO-2 level has declined, but compare with model group and be not significantly different from.The combination of the prompting present invention
Tissue and cell can be played a protective role by thing, and effect is better than positive control.
4. research thinks that depression is because related neurotransmitters in brain, as 5-HT, NE, BDNF etc. close
Become and the minimizing of release.The rat model of this test in i.e. showing brain above-mentioned neurotransmitter levels significantly reduce
(comparing with blank group).The compositions (medicine II～V group) of embodiment of the present invention 1-4 can significantly improve and press down
Compositions (the medicine III of the level of 5-HT, NE, BDNF in strongly fragrant rat cerebral tissue, especially embodiment 2
Group), it is better than positive drug group in the effect improving the horizontal aspect of 5-HT and NE.
Compbined test measurement result is seen, it is every that the compositions of the present invention can significantly correct the rat that depression causes
The compositions of the exception of indication, wherein Herba Hyperici perforati extract: Folium Ginkgo extract=3:2,2:3 and 1:4 is made
With more excellent.Especially Herba Hyperici perforati extract: Folium Ginkgo extract=3:2, with positive drugRelatively,
Effect of the reuptake of this preferred compositions existing 5-HT and NE monoamine neurotransmitter, again can patron saint
Through cell, improve function of nervous system's plasticity.
Test example 2The anti-reserpine of pharmaceutical composition of the present invention causes the pharmacodynamic study that mice is depressed
Laboratory animal and experimental drug
1. laboratory animal: SPF level ICR mice, male, 150, body weight 18-21g, this Lay of Hunan
Ke Jingda laboratory animal company limited provides, credit number: SCXK (Hunan) 2011-0003.
2. experimental drug
Herba Hyperici perforati extract: containing hyperforine 3.0%, summary and discussion 0.30%；High purchased from Chongqing
Core bio tech ltd；
Folium Ginkgo extract contain total flavonoids 24.0%, terpene lactone (with bilobalide, ginkalide A,
The total amount meter of ginkalide B and ginkalide C) 6.0%；Purchased from Gao Ren bio tech ltd, Chongqing.
Clomipramine Hydrochloride: purchased from purchased from Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, lot number: 22150401.
Reserpine: purchased from Chengdu Puffy moral Bioisystech Co., Ltd, lot number: 150314.
Animal feeding:
Indoor temperature (18 DEG C～24 DEG C), (10g/100g body weight d), drinking-water (changes weekly water 2～3 to food-intake
Secondary).
Laboratory animal packet and dosage regimen
1. animal packet and dosage: experiment mice is randomly divided into 6 groups, often 10 mices of group, 5/
Cage, often organizes 2 cages:
1. blank group: normal saline (NaCl 9g/L), gavage, 1ml/100g body weight sky
2. model group: with " blank group "
3. positive controls: Clomipramine Hydrochloride, 40mg kg-1·d-1
4. high dose group: Herba Hyperici perforati extract+Folium Ginkgo extract (mass ratio 3:2),
272.16mg·kg-1·d-1
Middle dosage group: Herba Hyperici perforati extract+Folium Ginkgo extract (mass ratio 3:2),
136.08mg·kg-1·d-1
6. low dose group: Herba Hyperici perforati extract+Folium Ginkgo extract (mass ratio 3:2),
68.04mg·kg-1·d-1
2. drug solution preparing:
1. the preparation of reserpine solution: dosage is 4mg kg-1, take 0.04g reserpine powder, with a small amount of
Physiological saline solution, is settled in 100ml volumetric flask, and configuration concentration is 0.4mg ml-1。
2. the preparation of normal saline: weigh 9g sodium chloride, is settled in 1000ml volumetric flask with distilled water.
3. the preparation of positive drug medicinal liquid: take Clomipramine Hydrochloride, remove coating, be crushed to powder, weigh 0.2667g
Powder, uses a small amount of physiological saline solution, is settled in 100ml volumetric flask, and configuration concentration is 2.667mg ml-1。
4. the preparation of high dose group medicinal liquid: take Herba Hyperici perforati extract 1.0887g, Semen Ginkgo extrac 0.7257g,
Mixing, uses a small amount of physiological saline solution, is settled in 100ml volumetric flask.
The preparation of middle dosage group medicinal liquid: take Herba Hyperici perforati extract 0.5443g, Semen Ginkgo extrac 0.3692g,
Mixing, uses a small amount of physiological saline solution, is settled in 100ml volumetric flask.
6. the preparation of low dose group medicinal liquid: take Herba Hyperici perforati extract 0.2721g, Semen Ginkgo extrac 0.1815g,
Mixing, uses a small amount of physiological saline solution, is settled in 100ml volumetric flask.
4. dosage regimen
Each group gavage gives medicine or normal saline, every day 1 time, and successive administration 7d (is administered volume all to press
0.015mL·g-1·d-1)；After last is administered, in addition to blank group, other respectively organizes lumbar injection 4mg kg-1
Reserpine, intraperitoneal injection volume presses 0.01ml g-1·d-1。
Experimentation and result:
1. the observation of temperature decline:
Last is administered after 4h and thermometer probe is inserted mice anal, the degree of depth with thermometer probe completely into
Anus is as the criterion, and maintains at least 2min.Record each group of data, compare the difference of body temperature in administration group and matched group.
Concrete outcome is shown in Table 7.
Body temperature measurement result respectively organized by table 7
Note: comparing with blank group, * represents that P < 0.05, * * represents P < 0.01；Compare with model group,▲Represent P < 0.05,▲▲Represent P < 0.01
Data analysis: after model group mouse peritoneal injection reserpine, body temperature compares reduction highly significant with blank group
(P < 0.01), shows that reserpine causes depression model modeling success；Positive controls and middle dosage group and model group
More all there is significant difference (P < 0.05), but both raise the effect phase of the temperature decline caused because of reserpine
When, there was no significant difference.
2. the mensuration of 5-HT content in NE in mice serum, DA and cerebral tissue
8h after last is administered, plucks eyeball and takes blood, and taken blood is stood 1 hour, centrifugal
(3000r/min, 20min), takes supernatant and is placed in EP pipe, and cryopreservation is to be measured.After taking blood, at broken end
Dead animal, peels off brain on ice pan, removes cerebellum and olfactory bulb, retain remaining whole brain tissue, use tinfoil paper
Paper bag is wrapped up in ,-70 DEG C of preservations.Add 9 times of PBS (PH7.4) homogenate, make 10% brain tissue homogenate's liquid, by even
Serosity is inserted in centrifuge tube, with 3000r/min centrifugation 20min under the conditions of 4 DEG C, carefully receives after standing
Collection supernatant, is placed in 2mlEP pipe, and-70 DEG C of preservations are to be measured.
Use NE, DA in ELISA method detection mice serum, and the content of cerebral tissue 5-HT.Result is shown in
Table 8.
The assay result of neurotransmitter in table 8 mice serum and cerebral tissue
Note: comparing with blank group, * represents that P < 0.05, * * represents P < 0.01；Compare with model group,▲Represent P < 0.05,▲▲Represent P < 0.01
Data analysis:
1) in model group mice serum, DA content significantly reduces, and compares with blank group and has pole significant difference
(P < 0.01), shows that reserpine causes depression model modeling success；Compare with model group, positive drug group and each dosage
In group mice serum, DA content all dramatically increases (P < 0.01), illustrates that the pharmaceutical composition of the present invention is high, normal, basic
Dosage all can significantly raise DA content in depressed mice serum；Comparing with positive drug group, each dosage group is little
In Mus serum, DA content is without significant difference.
2) in model group mice serum, NE content significantly reduces, and compares with blank group and has pole significant difference
(P < 0.01), shows that reserpine causes depression model modeling success；Compare with model group, positive drug group and each dosage
Group mice serum in NE content all dramatically increase (P < 0.01), illustrate the present invention pharmaceutical composition height, in,
Low dosage all has can significantly improve the content of NE in serum；Comparing with positive drug group, each administration group all has significantly
Sex differernce (P ＜ 0.05).
3) in model group Mice brain tissues, 5-HT content significantly reduces, and compares with blank group and has pole significance
Difference (P < 0.01), shows that reserpine causes depression model modeling success；Compare with model group, positive drug group and in
In low dose group Mice brain tissues, 5-HT content all dramatically increases, and illustrates in the pharmaceutical composition of the present invention low dose
Amount all can significantly raise 5-HT content in depressed Mice brain tissues；Comparing with positive drug group, low dose group is little
In murine brain, 5-HT content is the most suitable.
Experiment conclusion
Caused by reserpine, depressed mice all shows as exception in every physical signs, as body temperature significantly reduce, blood
Related neurotransmitters level in cleer and peaceful cerebral tissue significantly reduces.Herba Hyperici perforati extract and Semen Ginkgo extrac with
The pharmaceutical composition of mass ratio 3:2 composition, it is possible to reverse above-mentioned abnormal physical signs, demonstrate for depression
There is good drug effect, and effect is the most suitable with positive drug；Particularly, the pharmaceutical composition of the present invention three
Dosage group raises the effect of NE level in depressed mice serum and is better than positive control drug.Therefore, summary medicine
Effect experimental result, the effect of the medicine composite for curing depression of the present invention is better than Clomipramine Hydrochloride.
In a word, the invention provides a kind of new pharmaceutical composition that may be used for treatment depression, by passing through leaf even
Stick up extract and Folium Ginkgo extract composition.Pharmacodynamics test shows, the pharmaceutical composition of the present invention is to depression
Animal pattern has significant curative effect, especially Herba Hyperici perforati extract: Folium Ginkgo extract=3:2 (weight ratio)
Pharmaceutical composition, regulation related biochemical indicator and neurotransmitter in terms of, effect be better than prior art And Clomipramine Hydrochloride.
Specific description of embodiments of the present invention above is not limiting as the present invention, and those skilled in the art are permissible
Make various change or deformation according to the present invention, without departing from the spirit of the present invention, the present invention all should be belonged to
Scope of the following claims.
Claims (10)
1. a pharmaceutical composition, is made up of Herba Hyperici perforati extract and Folium Ginkgo extract.
Pharmaceutical composition the most according to claim 1, it is characterised in that with described medicine group
On the basis of the weight of compound, described Herba Hyperici perforati extract accounts for 20%～80%, and surplus is described Semen Ginkgo
Leaf extract.
Pharmaceutical composition the most according to claim 1 and 2, it is characterised in that with described medicine
On the basis of the weight of compositions, described Herba Hyperici perforati extract accounts for 20%～60%, and surplus is Semen Ginkgo
Leaf extract；
Preferably, on the basis of the weight of described pharmaceutical composition, described Herba Hyperici perforati extract accounts for
40%～60%, surplus is Folium Ginkgo extract.
Pharmaceutical composition the most according to claim 1, it is characterised in that with described medicine group
On the basis of the weight of compound, described Herba Hyperici perforati extract accounts for 60%, and described Folium Ginkgo extract accounts for
40%.
Pharmaceutical composition the most according to any one of claim 1 to 4, it is characterised in that
Described Herba Hyperici perforati extract summary and discussion is no less than 0.30%, and hyperforine is no less than 3.0%.
Pharmaceutical composition the most according to any one of claim 1 to 5, it is characterised in that
Described Folium Ginkgo extract total flavonoids is no less than 24.0%, containing terpene lactone with bilobalide, Semen Ginkgo
The total amount meter of lactone A, ginkalide B and ginkalide C is no less than 6.0%.
7. one kind contains the pharmaceutical preparation of pharmaceutical composition according to any one of claim 1 to 6；
Preferably, described pharmaceutical preparation contains or not contain pharmaceutically acceptable adjuvant.
Pharmaceutical preparation the most according to claim 7, it is characterised in that described pharmaceutical preparation is mouth
Formulation, selected from tablet, capsule, soft capsule, effervescent tablet, oral quick-dissolving film preparation, Orally disintegrating
One or more in sheet and oral liquid.
9. the preparation method of the pharmaceutical preparation described in claim 7 or 8, combines including by said medicine
Thing and the pharmaceutically mixing of acceptable adjuvant, be conventionally prepared as acceptable system clinically
Agent.
10. described in pharmaceutical composition according to any one of claim 1 to 6 and claim 7 or 8
Pharmaceutical preparation preparation treatment depression medicine in application.
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| CN2016100184362 | 2016-01-12 | ||
| CN201610018436 | 2016-01-12 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108283674A (en) * | 2018-03-06 | 2018-07-17 | 深圳市蓝能健康科技有限公司 | For treating the drug for adjusting depression and the product for preparing the drug |
| WO2019128499A1 (en) * | 2017-12-29 | 2019-07-04 | 江苏康缘药业股份有限公司 | Ginkgo diterpene lactone composition |
| CN112843221A (en) * | 2021-02-01 | 2021-05-28 | 宁夏杞肽科技有限公司 | Application of pharmaceutical composition in preparation of medicine for treating subliminal depression |
-
2016
- 2016-04-27 CN CN201610268990.6A patent/CN105853479A/en active Pending
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| Title |
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| 党海霞等: "抗抑郁中药研究进展 ", 《中国现代中药》 * |
| 王连芝等: "中药抗抑郁活性成分研究进展 ", 《时珍国医国药》 * |
| 贾竑晓: "抑郁症的中西医结合实验研究", 《中国中西医结合杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019128499A1 (en) * | 2017-12-29 | 2019-07-04 | 江苏康缘药业股份有限公司 | Ginkgo diterpene lactone composition |
| US11524041B2 (en) | 2017-12-29 | 2022-12-13 | Jiangsu Kanion Pharmaceutical Co., Ltd | Ginkgo diterpene lactone composition |
| CN108283674A (en) * | 2018-03-06 | 2018-07-17 | 深圳市蓝能健康科技有限公司 | For treating the drug for adjusting depression and the product for preparing the drug |
| CN112843221A (en) * | 2021-02-01 | 2021-05-28 | 宁夏杞肽科技有限公司 | Application of pharmaceutical composition in preparation of medicine for treating subliminal depression |
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Application publication date: 20160817 |