CN105434483B - Bilobanoate composition and its dripping pill and application - Google Patents
Bilobanoate composition and its dripping pill and application Download PDFInfo
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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)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
Abstract
The present invention provides a kind of Bilobanoate composition and its dripping pill and application, and effective effective component of the composition is Bilobanoate and dencichine.Specifically, effective effective component of the composition is that Bilobanoate and dencichine are mixed in the ratio of 1:0.1-1:0.2.More specifically, the dencichine can be dencichine phosphatide complexes.Bilobanoate composition and its dripping pill provided by the invention can be effectively improved bleeding problems caused by Bilobanoate is used for a long time.
Description
Technical field
The present invention relates to a kind of Bilobanoate composition and its dripping pill and applications.
Background technique
Ginkgo leaf, it is sweet in flavor, bitter, puckery, it is mild-natured；Activating microcirculation and removing stasis medicinal is removed obstruction in channels to relieve pain, and astringing lung-QI is relievingd asthma, and changes turbid lipid-loweringing；It is hindered for hemostasis
Network, chest impediment and cardialgia, hemiplegia, deficiency syndrome of the lung cough and asthma, hyperlipidemia；The medicinal history in China has about 3000.60 years 20th century
In generation, Germany scientist discovery ginkgo leaf contains the effective component for reducing cholesterol, to cause grinding for ginkgo leaf pharmacological action
Study carefully and develops.And Bilobanoate is in ginkgo class extract uniquely by two kind new medicines (effective portion of national Bureau of Drugs Supervision's approval
Position), authentication code: national drug standard Z20000049, composition is clear, and safety validity is high.
It is activating microcirculation and removing stasis medicinal dredging collateral by the function of bilobanone ester dropping pills made of raw material of Bilobanoate, is mainly used for treating the stasis of blood
It is stuttering that blood hinders chest impediment and cardialgia caused by network, apoplexy, hemiplegia, the strong language of tongue；Treating Stable Angina Pectoris of Coronary Artery Disease, cerebral infarction are shown in above-mentioned card
Hou Zhe.In clinical application, the application of bilobanone ester dropping pills is not limited only to the cardiovascular and cerebrovasculars disease such as coronary heart diseases and angina pectoris and hypertension
Disease, it may also be used for the human-subject test for improving patients with Alzheimer disease, the development for inhibiting asthma reaction, adjuvant treatment diabetes
Deng.The either cardiovascular and cerebrovascular diseases such as coronary heart diseases and angina pectoris and hypertension or Alzheimer's disease, asthma and diabetes, mesh
Preceding medical level is all difficult to eradicate, can only prolonged administration of drugs to control the development of the state of an illness improve the quality of life of patient.
Although gingko leaf preparation is curative for effect, also its very important adverse reaction.Gingko leaf preparation at present, including ginkgo
The adverse reaction of ketone ester dropping pill include nausea and vomiting, the reaction that causes bleeding, cause granulocyte reduction, erythrocyte hemolysis, allergic reaction,
Blood vessel redness, stimulating central nervous system etc..Matthews Jr MK.(Association of Ginkgo biloba with
Intracerebral hemorrhage, Neurology, 1998,50:1933.) Vale S. (Subarachnoid
Haemorrhage associated with Ginkgo biloba, Lancet, 1998,352:36.) Rosenblatt M,
Mindel J.(Spontaneous hyphema associated with ingestion of Ginkgo biloba
Extract, New EnglandJournal Medicine, 1977,336:1108.) Rowin J, Lewis SL.
(Spontaneous bilateral subdural hematomas associated with chronic Ginkgo
Biloba ingestion.Neurology, 1996,46:1775.) the researchs report report gingko leaf preparation long-time service such as has out
The adverse reaction of blood tendency, such as seriously intracranials hemorrhage, serious subarachnoid hemorrhage, spontaneous eye hyphema, severe bilateral
Subdural hematoma etc..The adverse reaction risk of hemorrhagic tendency is larger, need to cause enough attention.
Dencichine also known as dencichine are the main actives stopped blooding in Radix Notoginseng.Entitled β-N- the grass of dencichine chemistry
Acyl-L- α, β-diaminopropionic acid (β-ODAP), molecular formula C5H8N2O5, relative molecular mass 176.13,1981, day undergraduate course
Scholar's first discovery dencichine is the ingredient in Radix Notoginseng with styptic activity.Because poor bioavailability, mesh is administered orally in dencichine
Preceding administration mode is mainly injecting drug use.(influence and hemostatic mechanism of the dencichine to coagulation function, Chinese new drug are miscellaneous by Wang Zhen etc.
Will, 2014,23 (3): 356--359) research report, when rat dencichine injecting drug use, consumption per day has obviously in 5-40mg/kg
Haemostatic effect, and with the increase of dencichine dosage, haemostatic effect is more and more stronger.Aik-Jiang Lau etc.
(Antiplatelet and anticoagulant effects of Panax notoginseng:Comparison of
raw and steamed Panax notoginseng with Panax ginseng and Panax quinquefolium,
Journal ofEthnopharmacology, 2009,125:380-386.) research report 25mg/kg dencichine oral administration
When, have not been changed the mouse bleeding time.The above result of study shows that dencichine oral administration haemostatic effect stops blooding not as good as drug administration by injection
Effect is obvious, and low dosage dencichine oral administration haemostatic effect is poor.Due to the distinctive phospholipid bilayer structure of cell membrane,
Therefore drug molecule will penetrate into cell, it is necessary to have suitable fat-soluble with water-soluble, i.e., suitable Determination of oil-water partition coefficient.
Under normal circumstances, drug of the logP less than 0 is relatively suitble to drug administration by injection, and drug of the logP between 0--3 is relatively suitble to oral administration.
Li Lin etc. (dencichine Ligustrazine hydrochloride characteristic research, Chinese herbal medicine, 2015,46:2563-2567.) research report dencichine
Apparent solubility is 981.04 ± 17.61mg/ml, and Determination of oil-water partition coefficient logP=-1.66 ± 0.04 is not suitable for oral administration.
Summary of the invention
In order to solve bleeding problems caused by Bilobanoate is used for a long time in the prior art, the embodiment of the present invention provides one kind
Bilobanoate composition and its dripping pill and application.
As the one aspect of the embodiment of the present invention, it is related to a kind of Bilobanoate composition, effective medicine of the composition
Imitating ingredient is Bilobanoate and dencichine.Specifically, effective effective component of the composition is Bilobanoate and dencichine
It is mixed in the ratio of 1:0.1-1:0.2.More specifically, the dencichine can be dencichine phosphatide complexes.
As the other side of the embodiment of the present invention, it is related to a kind of bilobanone ester dropping pills, the dripping pill contains above-mentioned
Bilobanoate composition.
As the another aspect of the embodiment of the present invention, be related to above-mentioned Bilobanoate composition preparation treatment coronary heart disease,
Application in the drug of the diseases such as angina pectoris, hypertension, Alzheimer disease, asthma, diabetes and apoplexy.
As another aspect of the embodiment of the present invention, it is related to above-mentioned bilobanone ester dropping pills in preparation and treats coronary heart disease, the heart
Application in the drug of the diseases such as colic pain, hypertension, Alzheimer disease, asthma, diabetes and apoplexy.
The embodiment of the present invention at least realizes following technical effect:
Bilobanoate composition and its dripping pill provided by the invention can be effectively improved caused by Bilobanoate long-time service
Bleeding problems.
Specific embodiment
The present invention is further explained in the light of specific embodiments, so that those skilled in the art can be better
Understand the present invention and can be practiced, but illustrated embodiment is not as a limitation of the invention.
The present invention is low for dencichine oral administration biaavailability, and dencichine is prepared into dencichine phosphatide complexes, to
The fat-soluble of dencichine is improved, is conducive to the absorption of dencichine, and then improve the Orally taken hemostatic effect of dencichine.
The present invention is used for a long time for Bilobanoate the adverse reaction of hemorrhagic tendency, by a small amount of natural component dencichine with
Composition is made in Bilobanoate, selects optimum proportioning by animal model, which is not influencing the normal drug effect of Bilobanoate
While performance, hemorrhagic tendency caused by prolonged application Bilobanoate can be reduced, dripping pill is made with the proportion, it is long to prepare a kind of energy
Phase safe medication, Bilobanoate composition and dripping pill containing a small amount of dencichine.
1, the preparation of dencichine
Xie Guoxiang (in Radix Notoginseng dencichine isolate and purify and structure elucidation, research and development of natural products, 2007,19:
1059-1061), Tan Chaoyang (the isolating and purifying research, traditional Chinese medicine Leader, 2010,16 (1): 63-65 of compound components of panax notoginseng),
Yu Ping (the extraction separation of dencichine and assay, Shanxi Chinese medicine, 2009,25 (10): 55-56 in Radix Notoginseng) et al. is studied respectively
And the extraction separation method of dencichine is reported, using its method reported in the literature, extract separation dencichine.By notoginseng drying powder
After last 12 times of amount slow diacolations of 70% ethyl alcohol, residue adds appropriate distilled water immersion 24 hours, 10 times of amount distilled water ultrasonic extractions 3
Secondary, each 1h obtains Aqueous extracts.Aqueous extracts are concentrated into right amount at 80 DEG C, obtain dencichine concentrate.Using ion exchange resin
Dencichine concentrate is isolated and purified, dencichine crude product is obtained；The higher dencichine of purity is obtained after recrystallization, and (dencichine purity is big
In 96%), commercially available dencichine can also be used.
2, the preparation of dencichine phosphatide complexes
It weighs 2g soybean lecithin (can be Fabaceous Lecithin, lecithin, cephalin, lipositol, phosphatidic acid) and is dissolved in 5ml second
In acetoacetic ester (reaction dissolvent can also be tetrahydrofuran, methylene chloride, dioxane and methanol (7:3), dehydrated alcohol, methanol),
60 DEG C are heated to, after making its reflux dissolution, dencichine 1g is added, after being stirred at reflux 1h, rotary evaporation removes solvent, and vacuum is dry
It is dry, it crushes to get dencichine phosphatide complexes.The ratio of dencichine and phosphatide is between 1:1~1:10.
3, Bilobanoate
It is limited from the scientific and technological medicine company share of Shanghai apricot spirit using commercially available Bilobanoate (national drug standard Z20000049)
Company is the active component of ginkgo biloba p.e.
4, the preparation of the composition of Bilobanoate dencichine
Bilobanoate is uniformly mixed by a certain percentage with dencichine phosphatide complexes, is most preferably made by animal model selection
Hemorrhagic tendency caused by Bilobanoate long-term administration, system are reduced in the case where not influencing the performance of Bilobanoate drug effect with ratio
Long-term, the Bilobanoate of safe medication and dencichine the composition for a kind of energy.The Bilobanoate Radix Notoginseng that this patent is hereafter said
Promotor composition refers both to the composition of Bilobanoate Yu dencichine phosphatide complexes.Wherein dosage refers both to the administration of effective component
Amount, the i.e. dosage of Bilobanoate and dencichine.
The current country of bilobanone ester dropping pills shares the authentication code that three enterprises obtain State Bureau, every ball composition containing ginkgo in prescription
Ketone ester 10mg once takes 4 balls, and 3 times a day, the adult amount for taking Bilobanoate on the 1st is 120mg, is converted into rat dosage
About 11.30mg/kg.
We have surprisingly found that when Bilobanoate: can achieve anticipation when the proportion of dencichine is between 1:0.2~1:0.1
It is required that and it was found that the dosage of dencichine is far below normal usage reported in the literature in the ratio.
The influence of experimental example 1, dencichine phosphatide complexes to the clotting time
Healthy kunming mice 80 (weight 20g ± 2g), half male and half female are fed after a week by normal requirement, are divided into 8 groups,
Be respectively dencichine low dose group, dencichine middle dose group, dencichine high dose group, dencichine phosphatide complexes low dose group,
Dencichine phosphatide complexes middle dose group, dencichine phosphatide complexes high dose group, blank control group, etamsylate group.Every group
Give relative medicine, daily stomach-filling 1 time respectively, blank control group gives isometric distilled water, and successive administration 3 days, last
After secondary administration 1h, blood is taken with the capillary eye socket of diameter 0.5mm, manual time-keeping breaks a disconnected capillary every 10s, until going out
The now thin trace of blood, record clotting time (to there is the trace of blood since blood sampling, the time experienced is the clotting time).It the results are shown in Table 1.
Influence of the 1 dencichine phosphatide complexes of table to the clotting time
Note: P < 0.05 * (compared with blank control group)
It does not make significant difference the results show that 2.5-40mg/kg are administered orally in dencichine to the clotting time, and dencichine phosphatide
After 2.5-40mg/kg of compound oral administration, the clotting time of mouse significantly shortens, and has statistical significance, therefore, by three
After seven elements is prepared into dencichine phosphatide complexes, dencichine oral absorption situation is improved, the bioavilability of dencichine is improved,
The dosage of oral dencichine can be reduced.
The pharmacological action of experimental example 2, Bilobanoate Radix Notoginseng promotor composition to hyperlipidemia
Healthy SD rat 270 (weight 200g ± 20g), half male and half female are fed after a week by normal requirement, survey serum
TC, TG normal value.Wherein 240 SD rats give high lipid food (79% basal feed, 1% cholesterol, 10% yolk powder,
10% lard) it feeds, continuous 10 days, there is hyperlipemia in induction.Another 30 rats continue to feed by normal requirement, as normal
Group.The SD rat of 240 hyperlipemias is randomly divided into 8 groups, every group 30, respectively high blood lipid model group, Bilobanoate three
Seven promotor composition groups (1:0.8), Bilobanoate Radix Notoginseng promotor composition group (1:0.4), Bilobanoate Radix Notoginseng promotor composition group (1:
0.2), Bilobanoate Radix Notoginseng promotor composition group (1:0.1), Bilobanoate Radix Notoginseng promotor composition group (1:0.05), dencichine phosphatide
Compound group, Bilobanoate group (positive controls).Except normal group is fed by normal requirement, other each groups continue to feed high in fat
Feed, and relative medicine is given respectively, daily stomach-filling 1 time, successive administration 14 days, normal group was with high blood lipid model group with isometric
Distilled water stomach-filling.After 14 days, every group takes 10 SD rats measurement serum TCs, TG, the results are shown in Table 2.
Effect of the 2 Bilobanoate Radix Notoginseng promotor composition of table to hyperlipemia rat
Note: #p < 0.05 P < 0.05 (compared with Normal group) * (compared with model control group)
The results show that Bilobanoate group has significant difference compared with model group；And dencichine phosphatide complexes group and mould
Type group is compared, without significant difference；Composition group has significant difference compared with model group.Prove Bilobanoate dencichine
Composition can significantly reduce serum cholesterol, and the addition of dencichine does not have an impact the drug effect of Bilobanoate.
After having surveyed serum TC value and TG value, every group of remaining 20 SD rat, doubling dosage continues to be administered, right after 28 days
A situation arises for observation cavum subarachnoidale region bleeding after all rat intracranial dissections, the results are shown in Table 3, Bilobanoate group occurs 4
2 subarachnoid hemorrhage occur for subarachnoid hemorrhage, Bilobanoate and Radix Notoginseng promotor composition group (1:0.05).
3 cavum subarachnoidale region bleeding table of table
The result shows that Bilobanoate Radix Notoginseng promotor composition compared with Bilobanoate group, can significantly reduce cavum subarachnoidale area
Number of cases occurs for domain bleeding, and when dencichine ratio is lower, i.e., when the ratio of Bilobanoate dencichine is 1:0.05, effect is
It reduces.
Experimental example 3, Bilobanoate Radix Notoginseng promotor composition merge the pharmacological action of hyperlipidemia to coronary heart disease
Healthy SD rat 270 (weight 200g ± 20g), half male and half female are fed after a week by normal requirement.Wherein 240
SD rat gives high lipid food (79% basal feed, 1% cholesterol, 10% yolk powder, 10% lard) nursing, and continuous 10
It, the 8th day starts, be injected intraperitoneally pituitrin 30u/kg while giving high lipid food, continuous 3 times, every minor tick for 24 hours,
It is induced the model of coronary heart disease occur.The physiological saline of the capacity such as another 30 normal rats injection, continues to feed by normal requirement
It supports, as normal group.The SD rat of 240 coronary heart disease is randomly divided into 8 groups, every group 30, respectively coronary heart disease model group, silver
Apricot ketone ester Radix Notoginseng promotor composition group (1:0.8), Bilobanoate Radix Notoginseng promotor composition group (1:0.4), the combination of Bilobanoate dencichine
Object group (1:0.2), Bilobanoate Radix Notoginseng promotor composition group (1:0.1), Bilobanoate Radix Notoginseng promotor composition group (1:0.05), Radix Notoginseng
Plain phosphatide complexes group, Bilobanoate group (positive controls).Except normal group is fed by normal requirement, other each groups continue to feed
High lipid food is supported, and gives relative medicine respectively, daily stomach-filling 1 time, successive administration 28 days.After 28 days, every group takes 10 SD
Rat detects the variation of TC, TG, HCY level and ECG ST section, the results are shown in Table 4.
4 Bilobanoate Radix Notoginseng promotor composition of table merges the effect of hyperlipemia rat to coronary heart disease
Note: #p < 0.05 P < 0.05 (compared with Normal group) * (compared with model control group)
Compare TC, TG, HCY value of each group SD rat and the variation of ECG ST section, Bilobanoate group compared with model group,
There is significant difference；When the ratio of Bilobanoate dencichine is 1:0.8,1:0.4, compared with model group, TC value has aobvious with TG value
Sex differernce is write, there was no significant difference with ECG ST section (P >=0.05) for HCY value；When Bilobanoate dencichine ratio be 1:0.2,
When 1:0.1,1:0.05, compared with model group, there is significant difference.Illustrate that the additional proportion of dencichine can not be excessively high, otherwise can
Influence the performance of Bilobanoate drug effect.When Bilobanoate dencichine ratio is between 1:0.2~1:0.05, Bilobanoate Radix Notoginseng
Element combination, which merges hyperlipemia to coronary heart disease, therapeutic effect, and the addition of dencichine does not influence the treatment effect of Bilobanoate
Fruit.
After the completion of detection, every group of remaining 20 SD rat, doubling dosage continues to be administered, after 28 days, to all rat craniums
The bleeding of cavum subarachnoidale region is observed after interior dissection, and a situation arises, the results are shown in Table 5,5 cavum subarachnoidales occur for Bilobanoate group
3 subarachnoid hemorrhage occur for bleeding, Bilobanoate Radix Notoginseng promotor composition group (1:0.05).
5 cavum subarachnoidale region bleeding table of table
The result shows that Bilobanoate Radix Notoginseng promotor composition compared with Bilobanoate group, can significantly reduce cavum subarachnoidale area
Number of cases occurs for domain bleeding, and when dencichine ratio is lower, i.e., when the ratio of Bilobanoate and dencichine is 1:0.05, effect has
It is reduced.
The protective effect of experimental example 4, Bilobanoate Radix Notoginseng promotor composition to cerebral ischemia re-pouring
Healthy SD rat 90 (weight 200g ± 20g), half male and half female are fed by normal requirement after a week, by 90 SD
Rat is randomly divided into 9 groups, every group 10, respectively sham-operation group, cerebral ischemia re-pouring model group, the combination of Bilobanoate dencichine
Object group (1:0.8), Bilobanoate Radix Notoginseng promotor composition group (1:0.4), Bilobanoate Radix Notoginseng promotor composition group (1:0.2), ginkgo
Ketone ester Radix Notoginseng promotor composition group (1:0.1), Bilobanoate Radix Notoginseng promotor composition group (1:0.05), dencichine phosphatide complexes group,
Bilobanoate group (positive controls).Every group is given relative medicine, daily stomach-filling 1 time, sham-operation group and model group difference respectively
Give isometric distilled water, continuous 14 days.After 14 days, wherein 80 SD rats by intraperitoneal injection chloraldurate solution 350mg/kg
Anesthesia, fixation of lying on the back, separation right carotid, internal carotid and external carotid artery ligature right carotid and external carotid artery,
After closing internal carotid distal end with artery clamp folder, always moved in the neck away from external carotid artery and internal carotid crotch about 0.5cm rapidly
A kerf is done at arteries and veins, insertion one end is coated with the nylon wire (diameter 0.285mm) of paraffin, and insertion depth 18.5mm realizes brain
Middle cerebral artery occlusion leads to cerebral ischemia.Inlet is ligatured, 1cm, skin suture are stayed outside nylon wire.Gently stayed the end of a thread is lifted extremely after 3h
Slightly resistance is to realize arteria cerebri media Reperfu- sion.Rat anus temperature is maintained to exist with electric blanket in ischemic 3h and Reperfu- sion 0.5h
36.5—37.5℃.Another 10 SD rats equally separate outside arteria carotis communis, internal carotid and neck as sham-operation group with other groups
Artery, but only ligature right carotid.
Nervous symptoms scoring is carried out after modeling for 24 hours.Impassivity injury symptoms are 0 point；It is unable to full extension and is good for side fore paw be 1
Point；Turn-take to strong side is 2 points；Falling to strong inclination is 3 points；It spontaneous cannot walk, the loss of consciousness is 4 points.In 24 hours neurosises
After shape scores, break end to SD rat, be immediately placed on ice pan and take brain, remove olfactory bulb, cerebellum and low brain stem, after by brain
It is uniformly cut into 6 to be put into the bottle for filling TTC, and puts it into 37 DEG C of incubators and be incubated for 30min, 10% good fortune is transferred to after incubation
You fix Malin's solution.Non- ischemic section dyes rose, and ischemic section is white.Carefully by ischemic portion after brain tissue is fixed
Divide and non-ischemic section separated and weighed, determines Brain stem injury by following formula:
Brain stem injury=infarcted region weight/full brain weight * 100%
Measurement result is shown in Table 6.
Protective effect of the 6 Bilobanoate Radix Notoginseng promotor composition of table to cerebral ischemia re-pouring
Note: #p < 0.05 P < 0.05 (compared with Normal group) * (compared with model control group)
The results show that Bilobanoate group, compared with model group, nervous symptoms scoring has significant difference with Brain stem injury；
When the ratio of Bilobanoate dencichine is 1:0.8,1:0.4, compared with model group, there was no significant difference for nervous symptoms scoring (P >=
0.05), Brain stem injury has significant difference, but cerebral infarction percentage is apparently higher than the Bilobanoate dencichine group of other ratios
Close object；When Bilobanoate dencichine ratio is 1:0.2,1:0.1,1:0.05, compared with model group, nervous symptoms scoring and brain
Infarction size has significant difference.Illustrate that the additional proportion of dencichine can not be excessively high, otherwise will affect Bilobanoate drug effect
It plays.When Bilobanoate dencichine ratio is between 1:0.2~1:0.05, Bilobanoate Radix Notoginseng promotor composition to cerebral ischemia again
It is perfused with protective effect, the addition of dencichine does not influence the therapeutic effect of Bilobanoate.
The improvement of experimental example 5, Bilobanoate Radix Notoginseng promotor composition to subarachnoid hemorrhage adverse reaction
Healthy SD rat 180 (weight 200g ± 20g), half male and half female are fed after a week by normal requirement.By 180
SD rat is randomly divided into 9 groups, every group 20, respectively sham-operation group, model of subarachnoid hemorrhage group, Bilobanoate dencichine
Composition group (1:0.8), Bilobanoate Radix Notoginseng promotor composition group (1:0.4), Bilobanoate Radix Notoginseng promotor composition group (1:0.2),
Bilobanoate Radix Notoginseng promotor composition group (1:0.1), Bilobanoate Radix Notoginseng promotor composition group (1:0.05), dencichine phosphatide complexes
Group, Bilobanoate group.Every group is given relative medicine, daily stomach-filling 1 time respectively, and sham-operation group and model group are given in equal volume respectively
Distilled water, continuous 28 days.After 28 days, rat is anaesthetized.By anesthetized rat neck midsection skin, successively separation is right
The total artery of side strength (CCA), external carotid artery (ECA) and internal carotid (ICA), and ligature the nearly internal carotid bifurcated punishment of external carotid artery
Branch, including superior thyroid artery and ascending pharyngeal artery etc., ligature and cut in ECA distal end, ECA, which is straightened, makes it with ICA at always
Line.3-0 filament nylon line (being about 5cm, inclined-plane is cut into knife blade in front end) is imported into ICA through ECA, will be entered with surgical forceps
The nylon wire of internal carotid continues into, and when proceeding to arteria pterygopalatina and surpassing beginning portion, light external carotid artery of lifting makes bending herein disappear,
It is passed through with sharp nylon wire.To nylon wire is distally continued into internal carotid intracranial segment, the left side 2mm is inserted into after having resistance sense
The right side punctures willis ring, causes subarachnoid hemorrhage, rapidly extracts nylon wire, and whole process is no more than 30s.Sham-operation group
In addition to not puncturing blood vessel, remaining operation is identical.
After neurological deficit score for 24 hours, by rat anesthesia bloodletting, after the dissection of model of subarachnoid hemorrhage rat intracranial
The observation of cavum subarachnoidale region bleeding range is carried out, is scored by the standard in table 7.
According to standards of grading, to bleeding range in cavum subarachnoidale region is carried out after experimental subarachnoid hemorrhage modeling for 24 hours
Scoring, the results are shown in Table 8.
7 subarachnoid hemorrhage standards of grading of table
8 cavum subarachnoidale region bleeding scale scores table of table
Note: #p < 0.05 P < 0.05 (compared with Normal group) * (compared with model control group)
As can be seen from the table, when the ratio of Bilobanoate dencichine is between 1:0.1~1:0.8, Bilobanoate three
Seven promotor composition groups are postoperative, and there were significant differences compared with model group for 24 hours；When Bilobanoate dencichine ratio is 1:0.05, with mould
Type group is compared, and there was no significant difference (P >=0.05)；There was no significant difference compared with model group for Bilobanoate group (P >=0.05)；Three
Seven plain phosphatide complexes groups have significant difference compared with model group, show that dencichine can improve subarachnoid hemorrhage, work as silver
After apricot ketone ester dencichine is mixed in a certain proportion (Bilobanoate: the ratio of dencichine is 1:0.1~1:0.8), it can also improve
Subarachnoid hemorrhage.
To sum up, the optimum proportioning range of final choice Bilobanoate and dencichine is 1:0.1~1:0.2, within this range,
The presence of a small amount of dencichine has no effect on the performance of Bilobanoate drug effect, but can reduce the number of cases of experimental subarachnoid hemorrhage
And range.
Experimental example 6, Bilobanoate Radix Notoginseng promotor composition dripping pill preparation
Using in the prior art, the preparation process of dripping pill prepares the dripping pill of Bilobanoate Radix Notoginseng promotor composition.For example, ginkgo
Using commercially available, dencichine can refer to document and isolates and purifies from Radix Notoginseng ketone ester, and commercially available dencichine can also be used.By Bilobanoate with
Dencichine phosphatide complexes are mixed by preset ratio, for example are uniformly mixed (Bilobanoate and dencichine ratio in 1:0.45 ratio
For 1:0.15), dripping pill is prepared.First by 35.5g Macrogol 4000 (or Macrogol 6000, PEG 8000, Bo Luosha
Nurse, glycerin gelatine, polyvinylpyrrolidone) heating melting, 10g Bilobanoate and 4.5g dencichine phosphatide complexes are added, stir
It mixes and is uniformly dissolved, heat preservation instills in atoleine (or dimethicone, vegetable oil), and 1000 balls are made, and removes surface oil stain, i.e.,
Obtain dripping pill.
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention
It encloses without being limited thereto.Those skilled in the art's made equivalent substitute or transformation on the basis of the present invention, in the present invention
Protection scope within.
Claims (4)
1. a kind of Bilobanoate composition, which is characterized in that effective effective component of the composition is Bilobanoate and Radix Notoginseng
Element, the Bilobanoate are 1: 0.1-1: 0.2 than the ratio of dencichine, and dencichine phosphatide complexes are made in the dencichine.
2. a kind of bilobanone ester dropping pills, which is characterized in that the dripping pill contains Bilobanoate composition described in claim 1.
3. Bilobanoate composition described in claim 1 preparation treatment coronary heart diseases and angina pectoris, hypertension, Alzheimer disease,
Application in the drug of asthma, diabetes and apoplexy.
4. bilobanone ester dropping pills described in claim 2 treat coronary heart diseases and angina pectoris, hypertension, Alzheimer disease, heavy breathing in preparation
Application in the drug of asthma, diabetes and apoplexy.
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Non-Patent Citations (3)
| Title |
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| "三七素体外经皮渗透特性研究";李琳等;《中草药》;20150930;第46卷(第17期);第2563-2567页，尤其是第2566页右栏第1段 |
| "听广播谈体会‘血管清道夫’三七、银杏科学配伍之功效";释真利;《http://www.360doc.com/content/14/1126/13/8407612_428202407.shtml》;20141126;第1页小链接部分及其上方第2段 |
| "银杏酮酯滴丸的临床应用";刘崇应等;《内蒙古中医药》;20120331(第6期);第49页，尤其是摘要下左栏第1段以及临床应用部分 |
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Address after: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee after: Li Hong Patentee after: Zhejiang Shangyao Jiuxu Pharmaceutical Co.,Ltd. Address before: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee before: Li Hong Patentee before: ZHEJIANG JIUXU PHARMACEUTICAL Co.,Ltd. |