CN1977840A - Gingko total terpene lactone compounded medicinal composition, and its preparing method and use - Google Patents
Gingko total terpene lactone compounded medicinal composition, and its preparing method and use Download PDFInfo
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Abstract
The present invention relates to a new-type high-effective safety medicine for resisting depression-biolobalide combined medicine composition. It is made up by using five terpene lactone compounds of GJ, GC,BB, GA and GB and mixing them according to a certain mixing ratio. Said five terpene lactone compounds are oblained by using ginkgo biloba L. or other portions of said plant, suchas ginkgo nut, root bark and branch through the processes of extraction, separation and purification, in which the GJ content is 3%-15% of total lactone, GC content is 8%-30% of total lactone, BB content is 20%-65% of total lactone, GA content is 15%-50% of total lactone and GB content is 3%-40% of total lactone. Said invention also relates to preparation method of bilobalide, its application and medicine composition.
Description
Technical field
The present invention relates to fields such as pharmaceutical chemistry, particularly, the present invention relates to gingko total terpene lactone compounded medicinal composition and its production and use.
Background technology
Dysthymia is listed as the 5th in the whole world ten big diseases, expects the year two thousand twenty and will rise to second, and the numeral of WHO shows: the patients with depression in the current whole world has 8,500 ten thousand crowd, expects 2005, and the sickness rate of depression will reach 10% of total population; And the annual suicidal thought that also has 1,000 ten thousand-2,000 ten thousand people, although depression seriousness is so big, but do not obtain treatment fully among this class patient, only have 53% patient once to heal with medicine, the patient of existing depression obtains appropriate amount of drug therapist less than 10%.Fluorine west fourth, Sertraline, paroxetine etc. are SSRI class medicine, be the first-selected active drugs of many countries as the treatment depression, but the unusual sickness rate of sexual function is up to 43%, main adverse reaction is sexual dysfunction and ahedonia, and part patient is not good to its reaction, and multiple side effect and contraindication are arranged, patient can not be tolerated, be difficult to reach satisfactory effect, the relapse rate height, and also various antidepressants all might bring out manic.Withdraw from rate according to nearest investigation SSRI and be about 11% common patient practitioner.Over nearly 10 years, the goal of the invention of new antidepressants is to increase therapeutic effect, improves toleration, reduces drug interaction, reduces untoward reaction.
It is flavone and ginkgolide compound that Semen Ginkgo (Ginkgo biloba L.) mainly contains effective constituent, is used for the treatment of cerebrovascular circulation and peripheral circulation disorders, as angina pectoris, coronary heart disease, cerebral infarction, apoplexy etc.(Wu Chunfu such as Wu Chunfu, the trip pine, Liu Wen etc., ". bilobalide and Semen Ginkgo extrac are to the influence of striatum and limbic system dopamine and metabolite content thereof ", " Chinese herbal medicine ", 1995,16 (5): 253～254,262) carried out bilobalide and Folium Ginkgo extract to striatum and limbic system dopamine and metabolite content thereof research, prompting bilobalide and Folium Ginkgo extract have certain inhibitory action to rat striatum and limbic system DA metabolism, and infer that at Folium Ginkgo extract to central dopamine in the metabolic influence, bilobalide may play an important role.But bilobalide is not seen the research of anti-zoopery depression of sex so far as yet.We screen and further investigate the depressed effective site of Folium Ginkgo, we have compared four kinds of Folium Ginkgo extract antidepressant effect intensity such as mixture of bilobalide, total lactone composition, high activity extract, ginkalide A, B, discover, the mixture of total lactone composition, GA and GB, high-activity ginkgo leaf extract and BB all have antidepressant effect to rat and mice, and having confirmed that total lactone composition is that the effect of antidepressant pharmacology is the strongest, is the active substance group of extract of ginkgo biloba for treating depression; And confirm that further total lactone composition is more effective than monomer lactone, be very reasonably compatibility of monomer lactone, and have certain proportionate relationship between the monomer lactone that a better ratio is arranged.Finished the present invention thus.
Summary of the invention
Antidepressant drug one gingko total terpene lactone compounded medicinal composition that the purpose of this invention is to provide a kind of new and effective, safety, non-evident effect;
Another object of the present invention provides the preparation method of gingko total terpene lactone compounded medicinal composition;
Another object of the present invention provides the purposes that gingko total terpene lactone compounded medicinal composition is used to prepare the medicine for the treatment of depression;
Another object of the present invention provides a kind of antidepressant gingko total terpene lactone compounded medicinal composition.
The terpene lactones of Folium Ginkgo total lactones system of the present invention extraction from Folium Ginkgo (Ginkgo biloba L.) or other positions of this plant (as Semen Ginkgo, root bark, stem branch etc.) wherein mainly contains 5 kinds of terpene lactones chemical compounds, ginkalide A (Ginkgolide A; (15291-75-5) BN-52020; C
20H
24O
9), ginkalide B (Ginkgolide B; (15291-77-7) BN-52021; C
20H
24O
10), ginkalide C (GinkgolideC; (15291-76-6) BN-52022; C
20H
24O
11), bilobalide J (Ginkgolide J; (107438-79-9) BN-52024; C
20H
24O
10) and bilobalide (Bilobalide, C
15H
18O
8) (following GA, GB, GC, GJ and the BB of being called for short respectively).The content of each lactone in total lactone, wherein GJ accounts for total lactone 3%-15%, and GC accounts for total lactone 8%-30%, and BB accounts for total lactone 20%-65%, and GA accounts for total lactone 15%-50%, and GB accounts for total lactone 3%-40%.The Folium Ginkgo total lactones that the inventor obtains extraction is further purified and is obtained GA, GB, GC, GJ and BB monomer, again according to certain ratio with they compatibilities, make and have good antidepressant drugs compositions.
The preparation method of ginkgo biloba leaf total terpene lactone extract of the present invention is:
The Folium Ginkgo coarse powder, 70%～80% (v/v) ethanol extraction reclaims solvent, last macroporous adsorptive resins, the washing decontamination is behind 10%～15% (v/v) ethanol elution decontamination, use 60%～70% (v/v) ethanol elution instead, collect alcohol eluen, reclaim ethanol, last polyamide column, water elution, collect water elution liquid, concentrate ethyl acetate extraction.Reclaim solvent, or recrystallization, vacuum drying gets ginkgo biloba leaf total terpene lactone extract.
Ginkgolide monomer compounds process for production thereof of the present invention is:
Getting ginkgo biloba leaf total terpene lactone extract adopts silica gel column chromatography to separate, with petroleum ether-acetone solvent system gradient elution, fraction collection, TLC detects, and the part of identical component merges, and concentrates, crystallization is separated out in placement, recrystallization repeatedly can obtain five of BB, GA, GB, GC, GJ respectively, and purity is at the internal ester monomer compound more than 98%.
The gingko total terpene lactone compounded preparation method of composition of the present invention is:
Get the ginkgolide monomer chemical compound according to a certain percentage with they compatibilities, mix homogeneously is made gingko total terpene lactone compounded compositions.
The present invention from Folium Ginkgo, extract the method for terpene lactones with other and the product that obtains different, its distinguishing feature is: the present invention has adopted macroporous adsorbent resin and polyamide column series connection method to extract and has handled.If single macroporous adsorbent resin of using, except total lactone that can't reach high-load (＞75%), more can't remove the flavone part in the Folium Ginkgo extract, not only and this flavone part does not have the antidepressant activity, on the contrary, also present antagonism and the effect of obvious suppression appetite.The present invention adopts macroporous adsorbent resin and polyamide column series connection method to extract and handles, polyamide column firmly is adsorbed on the chromocor compound that macroporous adsorptive resins elutes on the post, and terpene lactones is easy to be got off by water elution, thereby reach complete isolating purpose, prepare ginkgo biloba leaf total terpene lactone extract of the present invention.Although (Li Xingang such as Li Xingang, Wei Wei, Chen Wei. be rich in the Folium Ginkgo dry extract preparation technology of bilobalide. Chinese Medicine technology magazine, 1998,29 (1): 8) also adopted macroporous adsorbent resin and polyamide column series connection method, but the purpose fundamental difference of connecting with inventor's polyamide column, they are intended to remove tannin, so macroporous adsorbent resin 95% ethanol elution effluent, directly go up polyamide column without reclaiming ethanol, this is to adopt the macroporous adsorbent resin key point different with the polyamide column series connection method with the present invention, as a result in the effluent terpene lactones and the flavone component while by eluting, the product flavones content 27.4% that obtains, bilobalide content 10.6%; Two of difference: inventor's polyamide column adopts water elution, and Li Xingang etc. adopt 95% ethanol elution; Three of difference: the inventor adopts polyamide column water elution liquid to concentrate, and the purification of ethyl acetate extraction and process for refining have only by this step to reach total lactone content＞75% target; And Li Xingang etc. do not design this step.Therefore the product that obtains of employing macroporous adsorbent resin such as Li Xingang and polyamide column series connection method has been said nothing of activity intensity with ginkgo biloba leaf total terpene lactone extract depression.The ginkgo biloba leaf total terpene lactone extract that the employing said method obtains is behind recrystallization, and the purity of total lactone has guaranteed the effect of silica gel column chromatography separating monomer lactone therefrom more than 90%, and the content that makes chemical compound is more than 98%.
The ginkgolide monomer chemical compound that preparation in accordance with the present invention prepares, GJ, GC, BB, GA and GB carry out compatibility by a certain percentage, and the gingko total terpene lactone compounded medicinal composition that obtains is very useful to antidepressant effect of the present invention.
In the gingko total terpene lactone compounded medicinal composition that the present invention prepares, the weight content of each lactone in total lactone: wherein the content of GJ is 3%-15%, and the content of GC is 8%-30%, and the content of BB is 20%-65%, the content of GA is 15%-50%, and the content of GB is 3%-40%;
The preferred gingko total terpene lactone compounded medicinal composition of the present invention is, the weight content of each lactone in total lactone: wherein the content of GJ is 3%-10%, and the content of GC is 10%-20%, and the content of BB is 38%-55%, the content of GA is 18%-30%, and the content of GB is 4%-15%;
The preferred bilobalide pharmaceutical composition of the present invention is, the weight content of each lactone in total lactone: wherein the content of GJ is 3%-5%, and the content of GC is 12%-20%, and the content of BB is 40%-52%, the content of GA is 20%-30%, and the content of GB is 5%-15%.
Gingko total terpene lactone compounded medicinal composition of the present invention has good antidepressant effect, can be used to prepare the medicine for the treatment of depression.
The present invention discovers, gingko total terpene lactone compounded medicinal composition (hereinafter to be referred as: total lactone composition), the mixture of GA and GB (purity 〉=98%, GA content is a little more than GB), BB (purity 〉=98%) and high-activity ginkgo leaf extract (wherein total lactone 12%, total flavones 48%) rat and mice all there is antidepressant effect, and total lactone (gastric infusion dosage: mice 7.2mg/kg, rat 3.6mg/kg) pharmacological action and other 3 kinds more all have significant difference P＜0.01, and with imipramine (gastric infusion dosage: mice 50mg/kg, rat 25mg/kg) more then there is not significant difference (P＞0.05).Their pharmacological action intensity: mixture=high-activity ginkgo leaf extract of total lactone composition＞GA and GB＞BB.Gingko total terpene lactone compounded medicinal composition of the present invention is all very effective to multiple depression animal model, can reduce outstanding tail mice dead time, reduce the forced swimming mice dead time, can increase due to shocking by electricity the success of depressed rat the number of times of runing away, act on similar to imipramine.The mixture of GA and GB can increase the weight of the anxiety of rat, and BB then has angst resistance effect.The total lactone composition that the present invention prepares is equivalent to the compound preparation of Folium Ginkgo terpene lactones, wherein BB has angst resistance effect, help anxiety-depression patient's treatment, simultaneously antagonism GA and GB mixture increase the weight of the side effect of anxiety again, this shows, in the gingko total terpene lactone compounded medicinal composition that the present invention prepares, each lactone proportioning is to the antidepressant effect significance, and the terpene lactones compatibility is very reasonable.Contain total lactone 12% in the high-activity ginkgo leaf extract, though total lactone amount wherein equates with the gingko total terpene lactone compounded medicinal composition dosage that the present invention prepares, but the former obviously is not so good as gingko total terpene lactone compounded medicinal composition of the present invention by antidepressant effect, from principal component analysis, high-activity ginkgo leaf extract is than the main flavone of the manying part of total lactone composition, infer that thus not only the flavone in the high-activity ginkgo leaf extract does not partly have the antidepressant activity, on the contrary, as if also present antagonism, in addition, the part of the flavone in the high-activity ginkgo leaf extract still has the effect of obvious suppression appetite.So terpene lactones is best effective site in the Folium Ginkgo extract, though and prove that further monomeric compounds such as BB, GA and GB have antidepressant activity, but intensity is all not as total lactone composition, also different side effect can appear simultaneously, they combine the synergism that but presents drug effect in the source of students ratio, side effect then presents antagonism, and side effect obviously reduces, i.e. efficacy enhancing and toxicity reducing.The advantage of total lactone composition be effective dose low (for imipramine 1/7), safety is big, side effect is little, significantly do not cause anxiety and cause numb effect as GA and GB mixture, not significantly as the effect of high-activity ginkgo leaf extract appetite-suppressing, more do not have the appetite effect of imipramine severe inhibition and cause the disequilibrium effect, under the situation that especially is subjected to shocking by electricity repeatedly, the general situation of total lactone composition treated animal is better than other each group.
In addition, 3 kinds of extracts of total lactone composition, GA and GB mixture and high-activity ginkgo leaf extract have facilitation to memory acquisition, memory maintenance and the reproduction of rat locus, and BB then acts on not remarkable.4 kinds of extracts of Folium Ginkgo all have sedation, but do not influence the activity such as motion, feed of animal.
Gingko total terpene lactone compounded medicinal composition of the present invention can make up with pharmaceutically acceptable auxiliaries, is made into pharmaceutical composition, is used for the treatment of depression.This pharmaceutical composition can be forms such as tablet, capsule, granule, drop pill, injection, oral cavity rapid release preparation, sustained-release preparation.
The specific embodiment
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.In addition, in the present invention, (v/v) expression volume by volume concentration or volume ratio; (w/w) expression weight ratio concentration or weight ratio; (w/v) expression weight/volume specific concentration or by weight/volume, its corresponding unit is (grams per milliliter); (rpm) expression per minute revolution (rev/min); (d) expression day, (h) expression hour, (min) expression minute, (s) expression second.Except as otherwise noted, percent of the present invention is percetage by weight.
Embodiment 1: the preparation of ginkgo biloba leaf total terpene lactone extract of the present invention
Get Folium Ginkgo coarse powder 2kg; add 20 liters of 60% ethanol; reflux, extraction 2 times each 3 hours, are reclaimed ethanol; last DM-130 macroporous adsorbent resin (production of resin subsidiary factory of Lukang Medical Co., Ltd., Shandong) post; 60% ethanol Xian takes off, and collects ethanol elution, reclaims ethanol; last polyamide column (column chromatography; Shanghai chemical reagents corporation produces), water elution is collected water elution liquid; be evaporated to an amount of; use ethyl acetate extraction, reclaim solvent, 80 ℃ of vacuum dryings; get Folium Ginkgo total lactones 3.8g, total lactone content 83.38%.The content of each lactone in total lactone, wherein the content of GJ is 3.62%, and the content of GC is 12.70%, and the content of BB is 49.59%, and the content of GA is 27.27%, the content of GB is 6.83%.
Embodiment 2: the preparation of ginkgo biloba leaf total terpene lactone extract of the present invention
Get Folium Ginkgo coarse powder 2kg, add 24 liters of 70% ethanol, reflux; extract 2 times; each 3 hours, reclaim ethanol, last DM-130 macroporous adsorbent resin (production of resin subsidiary factory of Lukang Medical Co., Ltd., Shandong) post; behind the 10% ethanol flush away impurity, change 70% ethanol Xian and take off, collect 70% ethanol elution; reclaim ethanol; last polyamide column (column chromatography, Shanghai chemical reagents corporation produces), water elution; collect water elution liquid; be evaporated in right amount, use ethyl acetate extraction, washing ethyl acetate extraction liquid; anhydrous sodium sulfate dehydration; reclaim solvent, recrystallization, 80 ℃ of vacuum dryings; get Folium Ginkgo total lactones 3.10g, total lactone content 93.13%.The content of each lactone in total lactone, wherein the content of GJ is 4.11%, and the content of GC is 15.08%, and the content of BB is 45.64%, and the content of GA is 25.14%, the content of GB is 10.03%.
Embodiment 3: the preparation of high-activity ginkgo leaf extract of the present invention
Get Folium Ginkgo coarse powder 2kg; add 24 liters of 70% ethanol, reflux, extraction 2 times, each 3 hours; reclaim ethanol; last DM-130 macroporous adsorbent resin (production of resin subsidiary factory of Lukang Medical Co., Ltd., Shandong) post, 70% ethanol Xian takes off, and collects ethanol elution; reclaim ethanol; last polyamide column (column chromatography, Shanghai chemical reagents corporation produces), water elution; collect water elution liquid; be evaporated in right amount, use ethyl acetate extraction, reclaim solvent; 80 ℃ of vacuum dryings; get ginkgo biloba leaf total terpene lactone extract 4.5g, total lactone content 87.13%, standby.Polyamide column behind the water elution, behind 10% ethanol flush away impurity, with rare pure eluting, vacuum concentration, spray drying gets Folium Ginkgo total flavones extract 13.7g, general flavone content 55.87% adds the ginkgo biloba leaf total terpene lactone extract 2.2g of front gained, mix homogeneously, get high-activity ginkgo leaf extract 15.9g, wherein total lactone content 12.05%, the content of each lactone in total lactone, wherein the content of GJ is 3.62%, the content of GC is 14.67%, the content of BB is 45.68%, and the content of GA is 26.04%, and the content of GB is 9.99%; General flavone content 48.04%.
Embodiment 4: the preparation of ginkgolide monomer chemical compound of the present invention
The ginkgo biloba leaf total terpene lactone extract of getting embodiment 2 preparations adopts silica gel column chromatography to separate, with petroleum ether-acetone solvent system gradient elution, fraction collection, TLC detects, and the part of identical component merges, concentrate, crystallization is separated out in placement, recrystallization repeatedly, vacuum drying, porphyrize obtains BB, GA, GB, GC, five monomers of GJ respectively.Through spectral data analyses such as fusing point, infrared, mass spectrum, nuclear magnetic resonance, NMR, and and standard control, compound structure identified one by one; Adopt the HPLC method to record internal ester monomer compound purity more than 98%.
Embodiment 5: the preparation of gingko total terpene lactone compounded medicinal composition of the present invention
Get each ginkgolide monomer chemical compound of embodiment 4 preparations respectively, (wherein the content of GJ is 3.62% by the content of each lactone in the high-activity ginkgo leaf extract among the embodiment 3 in total lactone, the content of GC is 14.67%, the content of BB is 45.68%, the content of GA is 26.04%-, and the content of GB is 9.99%) prescription, be mixed with gingko total terpene lactone compounded medicinal composition, mixing, promptly.
Embodiment 6: the preparation of gingko total terpene lactone compounded medicinal composition of the present invention
Get each ginkgolide monomer chemical compound of embodiment 4 preparations respectively, by the content of each lactone in total lactone, wherein the content of GJ is 4.66%, the content of GC is 18.21%, the content of BB is 38.32%, and the content of GA is 27.57%, and the content of GB is 11.24% to fill a prescription into gingko total terpene lactone compounded medicinal composition, mixing, promptly.
Embodiment 7: bilobalide GA of the present invention: the preparation of GB mixture
Get the ginkgolide monomer chemical compound GA of embodiment 4 preparations respectively, GB, by (GA: GB=57: 43) mix homogeneously, promptly.
Embodiment 8: gingko total terpene lactone compounded medicinal composition antidepressant effect research of the present invention
Material
Bilobalide (BB): purity is 〉=99% (being by embodiment 4 preparations)
Gingko total terpene lactone compounded medicinal composition: by embodiment 5 preparations; Hereinafter to be referred as: total lactone composition
Lactone GA: GB (57: 43) mixture: purity is 〉=98% (mixture of the slightly high GB of the ratio of GA is by embodiment 7 preparations); Hereinafter to be referred as: GA: GB
High-activity ginkgo leaf extract: by embodiment 3 preparations; Hereinafter to be referred as: high activity.
With distilled water respectively
In orderWith above-mentioned Folium Ginkgo extract melt into 0.675mg.ml
-1, 1.15mg.ml
-1, 0.675mg.ml
-1, 8.2mg.ml
-1The medicine liquid irrigation stomach use;
Imipramine hydrochloride 25mg/ sheet is produced by Shanghai nine good fortune Pharma Inc.s, lot number 990409, same melt into 12.5mg.ml
-1And 5mg.ml
-1The medicine liquid irrigation stomach use;
SD rat, Kunming mouse.
Method and result
1. mouse tail suspension test
Choose 60 of the male mices of body weight 20～24g, be divided into 6 groups at random, be i.e. normal saline matched group (NS), imipramine hydrochloride group, BB group, total lactone composition group, GA: GB group and high activity group, 10 every group by body weight.By body weight gastric infusion respectively, dosage sees Table 1, and the normal saline group such as gavages at the capacity normal saline, once a day, and totally 5 days.30 minutes begin to test after the 5th administration.Position with mice tail end 2cm during experiment is attached on the waddy, makes animal become reversal of the natural order of things state, the overhead about 5cm of its head.Both sides separate the animal sight line with plate, the dead time of back 3min in the record animal 6min.Test is 1 time before the administration, and administration was tested once after 5 days.Calculate the difference of twice dead time of animal self and after 1g (X+86) conversion, carry out statistical analysis, the results are shown in Table 1.
Mouse tail suspension dead time and NS group prolongs more to some extent after 4 kinds of Folium Ginkgo extract medications, find through the F check analysis, the difference of dead time and NS group relatively has significant difference before and after the medication of 4 medication treated animals, P＜0.01, promptly these 4 kinds of Folium Ginkgo extract have antidepressant effect on this model.
The influence that four kinds of Folium Ginkgo extract of table 1 are tested mouse tail suspension (n=10,
| Group | Medicine (mgkg -1) | Dead time (s) | Difference 1g (X+86) | |
| Before the medication | After the medication | |||
| NS BB total lactone composition GA: GB high activity imipramine | 5.0 7.2 5.0 60.0 50.0 | 81.4±32.8 81.9±19.1 79.1±27.8 76.5±15.8 86.7±38.4 90.2±32.8 | 65.1±30.8 45.1±15.3 37.5±17.3 60.0±18.7 59.5±28.9 31.7±16.3 | 1.826±0.645 2.082±0.080 2.122±0.061 2.008±0.066 2.026±0.169 F＝16.45 P＜0.01 2.149±0.092 |
The ANOV statistical analysis method
2. mice forced swimming test
Choose 60 of the male mices of body weight 20～24g, grouping and administration are with test 1.Dosage sees Table 2.30 minutes begin to test after the 5th administration.Mice is put into the graduated cylinder (high 20cm, diameter 14cm) of depth of water 10cm, 30 ℃ of water temperatures.The dead time of back 4min in the record animal 6min.Test once before the administration, administration was tested once after 5 days.Calculate the difference of twice dead time of animal self and after 1g (X+45) conversion, carry out statistical analysis, the results are shown in Table 2.
The result confirms, the dead time when 4 kinds of Folium Ginkgo extract that tried and imipramine all can prolong the mice forced swimming, with the normal saline group relatively, can prolong 18.09～34.14%.Through variance analysis, 6 experimental mice dead time differences are significantly different, and highly significant statistical significance (P＜0.01) is arranged.By through the Newman-Keuls statistical analysis, relatively there is remarkable statistical significance (P all＜0.01) dead time that imipramine and 4 kinds of Folium Ginkgo extract reduce in the mice forced swimming with normal saline respectively.Imipramine, total lactone composition group drug effect are organized strong (P is all＜0.01) than GA: GB again,
See Table 2.
Four kinds of Folium Ginkgo extract of table 2 to the influence of mice forced swimming test (n=10,
| Group | Medicine (mgkg -1) | Dead time (s) | Difference 1g (X+45) | |
| Before the medication | After the medication | |||
| NS BB total lactone composition GA: GB high activity imipramine | 5.0 7.2 5.0 60.0 50.0 | 107.4±16.4 99.6±23.9 98.8±23.5 102.7±16.7 106.7±16.6 99.8±13.1 | 105.1±21.7 87.4±21.1 26.1±16.6 38.3±13.2 29.4±13.7 25.9±17.7 | 1.550±0.376 1.830±0.172 ※※ 2.074±0.084 ※※ 2.036±0.049 ※※ 2.021±0.197 ※※ 2.079±0.105 ※※ F＝13.24 P＜0.01 |
※ ※ANOV and Newman-Keuls statistical analysis method are compared with the NS group in P＜0.01
3. the depressed test of rat anti
Observe the antidepressant effect of medicine with acquired helpless electric shock model.Choose 70 of male rats, body weight 180～200g is divided into 7 groups at random by body weight, promptly normal control group, normal saline matched group (model group, NS), BB group, total lactone composition group, GA: GB group, high activity group and imipramine group, 10 every group.By body weight gastric infusion respectively, dosage sees Table 3, and the normal saline group such as gavages at the capacity normal saline, once a day, and totally 35 days.Begin experiment after 30 minutes in the 30th administration.Test and carried out " helpless bringing out " in first day, with one 20 * 10 * 10cm
3The bottom be the cage of copper grid, impose unavoidable foots electric shock (every 1min ± 15s gives once for 0.8mA, 15s) at random 60 times to animal, rats in normal control group is put into the identical time of cage but is not given electric shock.Begin to carry out avoidance training behind the 48h.With 60 * 20 * 30cm
3Shuttle box, the base copper grid are spaced apart 1.0cm.Animal is individually put into shuttle box one end, allow it adapt to the avoidance training that carries out 20 times behind the 5min, each 30s at interval.Give a light signal during training earlier, allow animal to reach the other end during this period to escape electric shock, if reactionless generation, then optical signal continues to occur 3s again, a 0.8mA also appears simultaneously, the foot electric shock of 3s, if still reactionless generation, electric shock and optical signal stop immediately and remember and do once to escape failure.Training was carried out 5 days altogether.Write down every rat frequency of training every day and escape number of success, the 5th training result is carried out statistical analysis.
According to test result analysis, the NS group compares with normal group, and rat successfully escapes number of times and obviously reduces (t=3.99, P＜0.01), illustrates that the rat depression model is successful.Test all has the improvement effect with 4 kinds of Folium Ginkgo extract and imipramine to the depressive state rat that unavoidable electric shock causes, especially remarkable with the total lactone composition group, through variance analysis, 7 experimental group rats escape significantly difference of number of success, and highly significant statistical significance (P＜0.01) is arranged.Further analyze through the Newman-Keuls statistic law again, 4 kinds of Folium Ginkgo extract and imipramine relatively have remarkable statistical significance (P all＜0.01) to effect and the normal saline of depressed rat, and more all there were significant differences for the pharmacological action of total lactone composition and other 3 kinds of extracts, P all＜0.01 does not more then have marked difference (P＞0.05) with imipramine.A little less than in addition drug effect with BB was between 3 kinds of extracts, drug effect was not then seen marked difference between GA: GB and high activity extract.These 3 kinds of extract drug effects are weak (P all＜0.01) than imipramine all.See Table 3.
Four kinds of Folium Ginkgo extract of table 3 to the influence of rat depressive state (n=10,
| Group | Medicine (mgkG -1) | Number of times (5d) is escaped in success |
| Normal NS BB total lactone composition GA: GB high activity imipramine | 2.5 3.6 2.5 30.0 25.0 | 18.7±1.3 12.9±4.4 9.2±4.8 ※※△△ 17.4±2.3 ※※ 14.8±2.5 ※※△△ 15.2±4.3 ※※△△ 17.5±1.8 ※※ F＝9.157 P＜0.01 |
※ ※Compare with the NS group P＜0.01,
△ △Compare with the total lactone composition group p＜0.01.ANOV and Newman-Keuls statistical analysis method
Embodiment 9: gingko total terpene lactone compounded medicinal composition angst resistance effect research of the present invention
Material
With embodiment 6.
Method and result
Observe the influence of medicine with the prologue water drinking test to the rat anxiety state.Choose 50 of male rats, body weight 180-200g is divided into 5 groups at random by body weight, and promptly normal saline matched group (NS), BB group, total lactone composition group, GA: GB organize and the high activity group 10 every group.By body weight gastric infusion respectively, dosage sees Table 4, and the normal saline group such as gavages at the capacity normal saline, once a day, and totally 21 days.Begin experiment after 30 minutes in the 21st administration.With one 36 * 36 * 36cm
3The transparent organic glass case, the bottom is a black, open-top, case central authorities reversal of the natural order of things one water bottle, liftoff 10cmm, liftoff 50cm place, case top establishes a 25W incandescent lighting usefulness, except that one side, other three face of beginning all uses the black dividing plate to block to get rid of extra visible stimulation.Tested preceding 3 days, rat 1hr every day (3:00pm-4:00pm), and stroked at least 1 minute.During experiment rat was placed experimental box central authorities 10 minutes, observe and record rat drinking-water incubation period and drinking-water time.For ease of statistics, the rat that does not drink water drinks water and calculates by 600s incubation period, and the result changes through 1g.The time of drinking water also changes through 1g (X+1).
The result shows that rat all presents anxiety state in various degree in this experiment.4 kinds of Folium Ginkgo extract are different to the anxiety state influence of rat.The F check analysis shows, has 4 treated animals of the behavior of drinking water to drink water and marked difference arranged (P＜0.05) incubation period.In 4 kinds of Folium Ginkgo extract, BB, total lactone composition and high activity treated animal time of drinking water is long than normal saline treated animal time of drinking water, with the T method of inspection relatively with BB group and NS, significance, P＜0.05, promptly BB can significantly improve the rat anxiety state.GA: GB has then increased the weight of the anxiety of rat, does not have the behavior of only drinking water in 10 animals.See Table 4.
Four kinds of Folium Ginkgo extract of table 4 to the influence of rat anxiety state (n=10,
| Group | Medicine (mg.kg -1) | (S) 1gX drinks water incubation period | (s) 1g (x+1) drinks water the time |
| NS BB total lactone composition GA: GB high activity | 2.5 3.6 2.5 30.0 | 2.650±0.292 2.708±0.067 2.270±0.686 / 2.662±0.195 | 0.475±0.743 1.202±1.038 t＝2.232※0.889±1.028 0±0 0.809±1.057 |
| F＝2.682 0.05＞P＞0.01 | F＝1.346 P＞0.05 |
※P＜0.05 T-test and ANOV statistical analysis method
Embodiment 10: gingko total terpene lactone compounded medicinal composition nootropic effect research of the present invention
Material
With embodiment 6.
Method and result
Observe the nootropic effect of medicine with Morris water labyrinth.Choose 50 of male rats, body weight 170～190g is divided into 5 groups at random by body weight, normal saline matched group (NS), BB group, total lactone composition group, GA: GB group and high activity group, 10 every group.By body weight gastric infusion respectively, dosage sees 5, and the normal saline group such as gavages at the capacity normal saline, once a day, and totally 30 days.Begin experiment after 30 minutes in the 25th administration.Morris water labyrinth diameter 150cm, high 60cm, depth of water 50cmm, platform are 10 * 10cm size, 30 ℃ of water temperatures.The water surface is placed the plastic foam fritter of modest size during experiment.Tested first day, and platform is placed the I quadrant and surfaced, amplify the Mus entry, allow it seek platform and climb up platform totally 2 times, stop more than the 5s at every turn in the III quadrant.Tested second day, platform is hidden in the water, still amplify the Mus entry in the III quadrant, allow it seek platform, record is sought the platform time once, fails behind the 180s to find then to be designated as 180s.Tested the 3rd day, and amplified the Mus entry, allow it seek platform and also write down the searching platform time once in the IV quadrant.Tested the 4th day, and removed platform, amplify the Mus entry in the III quadrant, allow it seek platform, the record animal via is crossed the number of times of platform position.The result carries out variance analysis after the 1g conversion.
4 kinds of Folium Ginkgo extract can increase the number of times of rat through the platform position.Do variance analysis according to result of the test, test has significant difference, (P＜0.05 and P＜0.01) with first day, the second day searching platform time of 5 treated animals.Test in the 4th day also has significant difference, P＜0.01 through the platform number of times.Further analyze with the T method of inspection, total lactone composition group, GA: GB group and high activity group and normal saline more once test result remarkable statistical significance (P＜0.01) is arranged, and first day test result of BB is better, with normal saline group relatively there were significant differences (t=2.89, P＜0.01), then two days gradually poor, and test result was worse than the normal saline group in the 4th day, but statistics does not relatively have significant difference (P＞0.05), sees Table 5.
Four kinds of Folium Ginkgo extract of table 5 to rat the influence of Morris water labyrinth behavior (n=10,
| Group | Medicine (mg.kg) | Seek the platform time (1gs) | Through platform position number of times (1gs) | ||
| (1d) | (2d) | (3d) | (4d) | ||
| NS BB total lactone composition GA: GB high activity | 2.5 3.6 2.5 30.0 | 2.102±0.248 1.737±0.303 t＝2.89 1.744±0.237 1.831±0.391 1.740±0.386 t＝2.48※※ | 1.938±0.449 1.879±0.428 1.388± 0.216 t＝3.5※ 1.718±0.309 1.540±0.403 | 1.608±0.499 1.887±0.321 1.489±0.453 1.684±0.360 1.580±0.461 | 0.584±0.272 0.368±0.290 0.781±0.152 0.793±0.109 t＝2.24※※0.706±0.198 |
| F＝2.588 P＜0.05 | F＝3.37 P＜0.01 | F＝1.25 P＞0.05 | F＝6.739 P＜0.01 | ||
※ ※ANOV and T-test statistical analysis method are compared with the NS group in P＜0.01
Embodiment 11: gingko total terpene lactone compounded medicinal composition sedation research of the present invention
Material
With embodiment 6.
Method and result
The photocell method is measured the maincenter sedation of medicine.Choose 50 of male mices, body weight 19-21g is divided into 5 groups at random by body weight, and promptly normal saline matched group (NS), BB group, total lactone composition group, GA: GB organize and the high activity group 10 every group.By body weight gastric infusion respectively, dosage sees 6, and the normal saline group such as gavages at the capacity normal saline, once a day, and totally 4 days.After the administration second time 30 minutes,, once a day, survey altogether 3 times with spontaneous activity in mice monitor (diameter 17cm, high 10cm) record mice spontaneous activity number of times in 5 minutes.
Result of the test confirms that in 3 tests, 4 kinds of Folium Ginkgo extract all have sedation to mice, GA: the GB group measurement result first time and normal saline group compare, and suppression ratio reaches 54.30%.Test result is through variance analysis for the first time, and 5 experimental mice activity number of times are significantly different, and remarkable statistical significance (P＜0.01) is arranged.Again through the Newman-Keuls statistical analysis, 4 kinds of Folium Ginkgo extract relatively have remarkable statistical significance (P＜0.01) to sedation and the normal saline of mice, but this sedation difference between 4 kinds of extracts does not have statistical significance (P＜0.05), sees Table 6.
Four kinds of Folium Ginkgo extract of table 6 to the sedation of mice (n=10,
| Group | Medicine (mg.kg -1) | Movable number of times/5min | Suppression ratio (%) |
| NS BB total lactone composition GA: GB high activity | 5.0 7.2 5.0 60.0 F＝16.68 | 126.5±17.4 71.1±15.4 ※※ 73.1±16.1 ※※ 57.8±21.1 ※※ 62.4±23.8 ※※ P＜0.01 | 43.79 42.20 54.30 50.67 |
※ ※ANOV and Newman-Keuls statistical analysis method are compared with the NS group in P＜0.01
Embodiment 12: tablet
Tablet formulation
Gingko total terpene lactone compounded compositions (by embodiment 6 preparations) 0.3kg
Corn starch 0.6kg
Hydroxypropyl starch 0.06kg
Microcrystalline Cellulose 0.02kg
Aluminium silicate 0.02kg
Low-substituted hydroxypropyl cellulose 0.03kg
Magnesium stearate 0.0003kg
Method for making is with ginkgo biloba leaf total terpene lactone extract (crossing 80 mesh sieves); adding starch (80 ℃ of bakings), hydroxypropyl starch, microcrystalline Cellulose, aluminium silicate, low-substituted hydroxypropyl cellulose puts in the fluidised bed granulator spraying 2%HPMC ethanol and granulates; cross 14 mesh sieve granulate; add magnesium stearate; mixing; press 10000, promptly.
Embodiment 13: capsule
The capsule prescription
Gingko total terpene lactone compounded compositions (by embodiment 6 preparations) 0.3kg
Starch 0.45kg
Microcrystalline Cellulose 0.025kg
Magnesium stearate 0.004kg
Method for making adds starch (80 ℃ of bakings), microcrystalline Cellulose, magnesium stearate with ginkgo biloba leaf total terpene lactone extract (crossing 80 mesh sieves), and mixing is sub-packed in 10000 capsules, promptly.
Claims (7)
1. gingko total terpene lactone compounded medicinal composition, it is characterized in that: wherein the weight content of bilobalide J is 3%-15%, the weight content of ginkalide C is 8%-30%, the weight content of bilobalide is 20%-65%, the weight content of ginkalide A is 15%-50%, and the weight content of ginkalide B is 3%-40%.
2. according to the gingko total terpene lactone compounded medicinal composition of claim 1, wherein the weight content of bilobalide J is 3%-10%, the weight content of ginkalide C is 10%-20%, the weight content of bilobalide is 38%-55%, the weight content of ginkalide A is 18%-30%, and the weight content of ginkalide B is 4%-15%.
3. according to the gingko total terpene lactone compounded medicinal composition of claim 2, wherein the weight content of bilobalide J is 3%-5%, the weight content of ginkalide C is 12%-20%, the weight content of bilobalide is 40%-52%, the weight content of ginkalide A is 20%-30%, and the weight content of ginkalide B is 5%-15%.
4. according to the preparation method of the gingko total terpene lactone compounded medicinal composition of one of claim 1-3, this method comprises: get terpene lactones bilobalide J, ginkalide C, bilobalide, ginkalide A and ginkalide B monomeric compound in proportion compatibility be mixed with and form.
5. be used to prepare the purposes of the medicine for the treatment of depression according to the gingko total terpene lactone compounded medicinal composition of one of claim 1-3.
6. pharmaceutical composition for the treatment of depression, it contains gingko total terpene lactone compounded medicinal composition and the pharmaceutically acceptable auxiliaries of one of with good grounds claim 1-3.
7. according to the pharmaceutical composition of claim 6, it is tablet, capsule, granule, drop pill, injection, oral cavity rapid release preparation or sustained-release preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559085B (en) * | 2008-04-16 | 2011-09-07 | 上海信谊百路达药业有限公司 | Extracting method for improving content of bilobalide in folium ginkgo extract |
| WO2022122040A1 (en) * | 2020-12-11 | 2022-06-16 | 成都百裕制药股份有限公司 | Use of bilobalide or ginkgolide composition in preparation of sedative drug |
| US11524041B2 (en) | 2017-12-29 | 2022-12-13 | Jiangsu Kanion Pharmaceutical Co., Ltd | Ginkgo diterpene lactone composition |
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2005
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559085B (en) * | 2008-04-16 | 2011-09-07 | 上海信谊百路达药业有限公司 | Extracting method for improving content of bilobalide in folium ginkgo extract |
| US11524041B2 (en) | 2017-12-29 | 2022-12-13 | Jiangsu Kanion Pharmaceutical Co., Ltd | Ginkgo diterpene lactone composition |
| WO2022122040A1 (en) * | 2020-12-11 | 2022-06-16 | 成都百裕制药股份有限公司 | Use of bilobalide or ginkgolide composition in preparation of sedative drug |
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