CN1277831C - Composition of ginkgo internal ester B and its preparation and use thereof - Google Patents
Composition of ginkgo internal ester B and its preparation and use thereof Download PDFInfo
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- CN1277831C CN1277831C CN 03132146 CN03132146A CN1277831C CN 1277831 C CN1277831 C CN 1277831C CN 03132146 CN03132146 CN 03132146 CN 03132146 A CN03132146 A CN 03132146A CN 1277831 C CN1277831 C CN 1277831C
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Abstract
The present invention discloses a bilobalide B compound whose general formula is (I), and a composition which is prepared by mixing the bilobalide B compound and medicine carriers which are acceptable to pharmacy. G in the general formula refers to a nitrogenous organic substance of C1-C8. The present invention also discloses a preparation method and a therapeutic application of the compound. The bilobalide B compound of the present invention changes the physical characteristics of bilobalide B. The bilobalide B compound also has the advantages of good water solubility and higher stability. When the bilobalide B compound is used for medicines for treating ischemic apoplexy as an effective component, the medicines are suitable for the administration of various ways, such as oral administration, intravenous injection, etc. The compound of the present invention can maintain the natural structure of the bilobalide B. When the bilobalide B compound enters human bodies as an effective component, the activity of the bilobalide B can be sufficiently exerted, and the purpose of disease treatment is achieved. The present invention has great social and economic significance.
Description
Technical field
The present invention relates to a kind of mixture of Ginkgolide B; Its preparation method; Also relate to this mixture as the application of effective ingredient in treatment ishemic stroke disease.
Background technology
Bilobalide is to extract the active substance that obtains in the middle of the herbal medicine Ginkgo Leaf, this material can also further be subdivided into Ginkgolide A on structure, B, C, bilobalide etc., extracting method for bilobalide has had detailed bibliographical information, for example, people such as Li Xingang have introduced the laboratory extracting method of bilobalide (referring to Li Xingang etc., the laboratory Study on Extraction Method of bilobalide in the Ginkgo Leaf, 1998 the 1st phases of Chinese Journal of Pharmaceuticals), Chinese patent literature CN1195665A has introduced the extracting method of bilobalide and has contained the preparation of bilobalide, this method is that Ginkgo Leaf is extracted with water boil, with sorbent material extraction filtrate is adsorbed, use the ethanol desorption again, reclaim ethanol, with the crystallization dissolving of separating out, recrystallization, drying makes bilobalide.Chinese patent literature CN1313287A discloses a kind of production technique of bilobalide.The method of separating ginkgolide monomer in the middle of the general extractive of bilobalide, a lot of relevant bibliographical informations are also arranged, for example, people such as You Song have introduced the separation of bilobalide in the Ginkgo Leaf and structure determination method (referring to You Song etc., the separation of bilobalide and structure determination in the Ginkgo Leaf, Chinese pharmaceutical chemistry magazine the 4th phase of nineteen ninety-five).Chinese patent literature CN1287121A discloses the method that is prepared medicine Ginkgolide A, B by Ginkgo Leaf or Ginkgo Leaf medicinal extract.About the pharmacological action of bilobalide, comparatively detailed bibliographical information (referring to Chen Weijun etc., the chemical structure of bilobalide and Advance on Pharmacological Activities, 1998 the 9th phases of Chinese Pharmaceutical Journal) has been arranged.Although the research for bilobalide and preparation thereof in the middle of the prior art has had a lot of reports,, never stop for the research of bilobalide, particularly, bibliographical information is arranged constantly for the separation of ginkgolide monomer and the research of derivative thereof.For the research of effective monomer in the middle of the bilobalide, structures such as Ginkgolide A, B, C have been reported at present.Ginkgolide B might be developed to the clinical treatment medicine that plays an important role as the higher thrombocyte antagonism factor of a kind of activity in the pathologic processes such as shock that thrombosis, organ-graft refection, senile dementia, acute inflammation, heart allergy, intracellular toxin cause.But, because Ginkgolide B is difficult to separation and purification, being insoluble in water, reason such as oral absorption is slow, and bioavailability is low has restricted the Application and Development of Ginkgolide B preparation, does not still have the listing of Ginkgolide B preparation both at home and abroad at present.
Summary of the invention
Technical problem to be solved by this invention is at the deficiencies in the prior art, proposes a kind of mixture with good water-solubility, stable Ginkgolide B.
Another technical problem to be solved by this invention provides the preparation method of the mixture of Ginkgolide B.
Another technical problem to be solved by this invention provides the purposes of Ginkgolide B mixture in treatment ishemic stroke disease.
Technical problem to be solved by this invention is to realize by following technical scheme.The present invention is the Ginkgolide B mixture of a kind of general formula for (I),
Wherein G is selected from a kind of in the following substances: 1) arginine, Methionin, Histidine, glycine etc. and derivative thereof; 2) methylamine, ethamine, propylamine, butylamine, quadrol, meglumine, urea, Guanidinium hydrochloride, 1, thanomin etc. and derivative thereof; 3) amidess such as methane amide, dimethyl formamide, pantothenol, niacinamide; 4) alkyl imidazole, alkyl pyridine, alkyl trimethyl amine salt, thiamine hydrochloride etc.The mixture of best Ginkgolide B of the present invention is that wherein G is the mixture of the general formula of arginine or Methionin or meglumine for (I).
The present invention also provides with Ginkgolide B mixture and the composition that mix to form of acceptable pharmaceutical carrier pharmaceutically, for example, mixes the composition of formation with pharmaceutical carrier tamanori, suspending agent, solubility promoter, solid dispersion, inclusion agents etc.
Technical problem to be solved by this invention can also further realize by following technical scheme.A kind of preparation method of mixture of Ginkgolide B is characterized in: Ginkgolide B and G are 1: 0.6～2.5 ratio with mol ratio, form mixture in water and/or alcoholic solvent.Like this, can make it all form mixture.
Mixture of the present invention can form mixture in water and/or alcoholic solvent in the preparation process; After also can being the mixture that in water and/or alcoholic solvent, forms earlier, form solid composite after drying, be used further to preparation.
Technical problem to be solved by this invention can also further realize by following technical scheme.The preparation method of the mixture of above-described Ginkgolide B is characterized in, its step is as follows: get G, add the dissolving of water 100～1000 parts by volume, be heated to 70-90 ℃, add the Ginkgolide B that porphyrize is crossed 80 mesh sieves, the purity of described Ginkgolide B is greater than 90%, be heated to dissolving, add needle-use activated carbon 1.0-3.0 weight part, carbon removal is filtered in stirring at room absorption 20-40 minute, filtrate spraying drying or lyophilize promptly get the mixture of Ginkgolide B.
Technical problem to be solved by this invention can also further realize by following technical scheme.The preparation method of the mixture of above-described Ginkgolide B, be characterized in, its step is as follows, gets G, adds 10～95% ethanol or the dissolving of dehydrated alcohol 20～100 parts by volume, be heated to 40-60 ℃, add porphyrize and cross the Ginkgolide B of 80 mesh sieves, the purity of described Ginkgolide B is filtered greater than 90%, the filtrate decompression concentrate drying promptly gets the mixture of Ginkgolide B.
Technical problem to be solved by this invention can also further realize by following technical scheme.The mixture of above-described Ginkgolide B has purposes in the medicine of treatment ishemic stroke disease as effective ingredient in preparation, described medicine is any formulation on the pharmaceutics, comprise tablet, capsule, sprays, granule, dripping pill, oral liquid, injection liquid, lyophilized injectable powder, infusion solution, lipidosome injection, target administration injection, suppository, sustained release preparation, controlled release preparation.
The complex formulation of Ginkgolide B of the present invention can be by patient oral, that snuffing is gone into, the mode of rectum or administered parenterally is applied to ishemic stroke disease, can be made into solid preparation, also can be made into liquid preparation or injection formulations, wherein, preferred form is tablet, capsule, granule, dripping pill, oral liquid, injection.The Ginkgolide B mixture is as the medicine of treatment ishemic stroke disease among the present invention, and its oral dose is to be equivalent to 50～150 milligrams of Ginkgolide Bs every day, and the consumption of injection is to be equivalent to 20～100 milligrams of Ginkgolide Bs every day.Its discriminating and detection method are as follows:
1. tlc identification method
The preparation of need testing solution
Getting Ginkgolide B mixture solid preparation or injection is dissolved in water and becomes to be equivalent to bilobalide-containing B 5mg/ml, get its solution 1ml or get injection liquid or oral liquid 1ml, with 6mol/L hydrochloric acid soln 0.2ml acidifying, to be crystallized separating out, placed 30 minutes, centrifugal (3000 rev/mins) 10 minutes, abandoning supernatant, precipitation adds the 1ml acetone solution promptly after being washed till neutrality with less water.
It is an amount of that the Ginkgolide B reference substance is got in the preparation of reference substance solution, adds acetone solution, makes every 1mL and contain 1mg respectively, promptly.
Assay method is according to tlc (appendix VIB of Chinese Pharmacopoeia version in 2000), with the micro-sampling device get respectively above-mentioned trial-product and reference substance solution respectively 10 μ L point samples contain 4% sodium-acetate in same, the silica gel G F that makes with 0.5%CMC-Na solution
254On the thin layer plate, be developping agent with sherwood oil (30～60 ℃)-acetone-methyl alcohol (10: 2.5: 0.3), ascending development, take out, dry up, in 160 ℃ of heating 30 minutes, put under the ultraviolet lamp 365nm and inspect, trial-product and reference substance should show the spot of same color on correspondence position.
[assay] measured according to high performance liquid chromatography (2000 editions one appendix VI D of Chinese Pharmacopoeia).
Chromatographic condition and system flexibility experiment: with octadecylsilane chemically bonded silica is weighting agent; With Virahol-methanol-water (8: 24: 80) is moving phase; Detect wavelength 220nm.Theoretical plate number should be not less than 7000 by Ginkgolide B, and each peak-to-peak resolution should meet the pharmacopeia requirement.
The preparation of reference substance solution: it is an amount of that precision takes by weighing 105 ℃ of Ginkgolide B reference substances that are dried to constant weight, respectively with 50% acetone solution, makes the solution that every 1mL contains 0.5mg, promptly.
The preparation of need testing solution:
1) getting Ginkgolide B mixture solid preparation or injection precision is dissolved in water and becomes to be equivalent to bilobalide-containing B 5mg/ml, get its solution 5ml or get injection liquid or oral liquid 5ml, put in the 10ml measuring bottle, the hydrochloric acid soln 1ml that adds 6mol/L, room temperature was placed 3.5 hours, with acetone solution and be diluted to scale, shake up, placed 30 minutes, and filtered through millipore filtration (aperture 0.45 μ m), promptly.This test solution should be measured in 2 hours.
2) or get Ginkgolide B preparation precision and add acetone and be dissolved into the solution that is equivalent to bilobalide-containing B 2.5mg/ml in right amount, filter, get subsequent filtrate promptly.
Assay method: precision measures need testing solution and each 20 μ L of contrast solution inject liquid chromatograph respectively, measures, and calculates promptly.
Ginkgolide B mixture of the present invention has good pharmacologically active, and the result is as follows for its pharmacological experiment study:
1, the general pharmacology of Ginkgolide B is learned research
(1), Ginkgolide B mixture 10,20,40mg/kg tail vein injection all do not have obvious influence to mouse behavior and coordinated movement, vetanarcol to sub-threshold dose also do not have synergy, show that three dosage of this medicine are to mouse spirit neural system non-evident effect.
(2), Ginkgolide B mixture 5,10, the quiet notes administration of 20mg/kg all do not have obvious influence to blood pressure, heart rate, electrocardio, respiratory rate and the amplitude of anesthetized dog, shows that three dosage of this medicine are to the anesthetized dog cardiovascular system respiratory system non-evident effect of unifying.
2, the pharmacodynamic study of Ginkgolide B
(1), Ginkgolide B mixture 2.5,5.0,10.0mg/kg iV can make the cerebral apoplexy scoring of MCAO rat reduce, the MCAO infarction size dwindles, brain water content reduces (P＜0.01), its action intensity and Ginaton injection comparison no significant difference.
(2), Ginkgolide B mixture 2.5,5.0,10.0mg/kg iV can make the MDA in the cerebral tissue of focal cerebral ischemia rat reperfusion injury, the LA equal size reduces (P＜0.01), shows that cerebral tissue hypoxic-ischemic and peroxidation degree are subjected to obvious inhibition; SOD and GSH content increase (P＜0.01) simultaneously, have reflected that medicine has raising to antioxidant ability of organism and the ability of removing free radical.
(3), Ginkgolide B mixture 72.5,5.0,10.0mg/kg iV can obviously protect the cerebral tissue structure of focal cerebral ischemia rat reperfusion injury; pyknosis, the karyolysis degree of pallium pyramidal cell and brain essence neurocyte obviously alleviate than ischemic control group, and softening kitchen range reduces.
(4), Ginkgolide B mixture 72.5,5.0,10.0mg/kg iV compare with model group that the EEG that can make diffusivity global brain ischemia rat recovers normal time and (P＜0.01) is obviously shortened in righting reflex time of recovery, make the Evans Blue permeability significantly reduce (P＜0.01), its effect does not relatively have statistical significant difference with the Ginaton injection.
(5), the Ginkgolide B mixture can obviously increase the survival number of acute imperfection cerebral ischemia mouse.Press the ED that the Bliss method is calculated Ginkgolide B mixture iV
50Be 22.4 (17.6-25.6) mg/kg; The ED of bilobalide ig
50Be 30.7 (16.5-51.7) mg/kg; The ED of Ginaton iV
50Count 12.2 (6.3-23.3) mg/kg, ED with Semen Ginkgo extrac
50Value compares indifference through between t check group.
(6), Ginkgolide B composite I v8min promptly begins onset, about peak time 20min, the time length can reach more than the 100min; And this medicine ig onset time 20-30min, about peak time 45min, the time length can reach more than the 120min.The effect of same dosage group iV is better than ig.
(7) but, Ginkgolide B mixture 6,12, the survival time (P＜0.01) of 24mg/kg iV significant prolongation mouse under anoxic condition.
(8), Ginkgolide B mixture 1.5,3.0,6.0.0mg/kg iV all do not have obvious influence (P＞0.05) to anesthetized dog CBF, CVR, SBP, DBP, MBP and HR, shows that three dosage of this medicine do not influence cerebral blood flow (CBF), cerebral vascular resistance, blood pressure and the heart rate of anesthetized dog.
(9), Ginkgolide B mixture 0.5,1.0,2.0 μ g/ml induce the rabbit extracorporeal platelet aggregation that obvious restraining effect (P＜0.01) is all arranged to PAF, and obvious unzipping (P＜0.01) are arranged.To ADP induced platelet congregation weak (P＜0.05 or P＜0.01), there is not obvious unzipping (P＞0.05).This medicine iV0.75,1.50,3.0mg/kg all have obvious restraining effect (P＜0.01) to platelet aggregation in the PAF inductive rabbit body, and middle and high dosage group also has obvious unzipping (P＜0.01).The rabbit platelet number there is not obvious effect (P＞0.05).
(10), Ginkgolide B composite I v1.0,2.0mg/kg can obviously reduce rabbit erythrocyte hematocrit (P＜0.01) and whole blood viscosity (ratio) especially to whole blood viscosity (ratio) effect more obvious (P＜0.01) of high shear rate.
(11), it is moving that Ginkgolide B mixture iv 0.75,1.50,3.0mg/kg can obviously suppress rabbit---the thrombosis (P＜0.01) of vein bypass.
(12), Ginkgolide B mixture iv1.5,3.0,6.0mg/kg are moving to rat---and vein bypass thrombus has obvious thrombolytic effect (P＜0.01).
(13), Ginkgolide B mixture iv2.5,5.0,10.0mg/kg can obviously prolong clotting time of mice (P＜0.01).
(14), obvious prolong rats clotting time during 10min-20min behind the Ginkgolide B mixture iv6mg/kg, during the peak about 12min, can make rat cruor time extending about 32%, 45min is effective behind the ig50mg/kg, continue 120mm, during the peak about 69min, rat cruor time extending about 48%.
(15), just can obviously suppress PAF behind the Ginkgolide B mixture iv 1.5mg/kg medicine immediately induces and exempts from the body platelet aggregation and obvious unzipping (P＜0.01) is arranged, effect continues 30min, be 5min during its peak, the anticoagulant rate can reach about 78%, and depolymerization in 1 minute is about 80%.30min can obviously suppress PAF and induces in the rabbit body platelet aggregation and obvious unzipping (P＜0.01) is arranged behind the bilobalide ig25mg/kg medicine, continue 60min, be about 42min during its peak, the maximum gathering of thrombocyte inhibiting rate is about 40%, and the depolymerization rate was about 36% in 1 minute.
(16), Ginkgolide B mixture iV prolongs the IC of clotting time of mice
50Be 5.23mg/kg, bilobalide ig prolongs the IC of clotting time of mice
50Be 22.73mg/kg.Ginkgolide B mixture iv is to the IC of platelet aggregation in tame rabbit platelet and the PAF inductor
50Be 1.89mg/kg, bilobalide ig is to the IC of platelet aggregation in tame rabbit platelet and the PAF inductor
50Be 56.08mg/kg.
Experiment showed, that Ginkgolide B mixture of the present invention can be used for the prevention and the clinical treatment of ishemic stroke, safe and effective, and it has no side effect.
Ginkgolide B mixture of the present invention has good water-solubility, and its stability is higher, when it is used for the treatment of the medicine of ishemic stroke disease as effective ingredient, is fit to the number of ways administration, as oral, intravenous injection etc.Mixture of the present invention can keep the natural structure of Ginkgolide B, after it enters human body as effective ingredient, can bring into play the activity of Ginkgolide B fully, to reach the purpose of curing the disease.Have great social significance and economic implications.
Embodiment
Embodiment one.
A kind of Ginkgolide B arginine mixture.Preparation by the following method: get arginase 12 .5 gram, add water 1000ml dissolving, be heated to 80 ℃, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, the filtrate spraying drying promptly gets Ginkgolide B arginine mixture.
Embodiment two.
A kind of Ginkgolide B arginine mixture.Preparation by the following method: get arginase 12 .5 gram, add ethanol 20ml dissolving, be heated to 60 ℃, add the Ginkgolide B that 5 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, filter, the filtrate decompression concentrate drying promptly gets Ginkgolide B arginine mixture.
Embodiment three.
A kind of Ginkgolide B meglumine mixture.Preparation by the following method: get meglumine 4 grams, add dehydrated alcohol 30ml dissolving, be heated to 50 ℃, add the Ginkgolide B that 10 gram porphyrizes are crossed 80 mesh sieves, filter, the filtrate decompression concentrate drying promptly gets Ginkgolide B meglumine mixture.
Embodiment four.
A kind of Ginkgolide B Histidine mixture.Preparation by the following method: get Histidine 2.0 grams, add 10% ethanolic soln 100ml dissolving, be heated to 85 ℃, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 1.0 grams, stirring at room absorption 30 minutes, filter carbon removal, lyophilize promptly gets Ginkgolide B Histidine mixture.
Embodiment five.
A kind of injection that is used for the treatment of ishemic stroke disease with the Ginkgolide B meglumine as effective ingredient.Preparation by the following method: get hydroxypropyl-beta-cyclodextrin 350 grams and add injection water 5000ml, reflux 30 minutes gets solution I, and 80 ℃ of insulations are standby; Other gets 65g Ginkgolide B meglumine mixture and dissolves, and is incubated 60 minutes, puts and is chilled to room temperature, filter filtering with microporous membrane (0.22 μ m), packing (5ml/ bottle), lyophilize promptly gets Ginkgolide B meglumine injection, is used for the treatment to ishemic stroke disease.
Embodiment six.
A kind of injection that is used for the treatment of ishemic stroke disease with the Ginkgolide B arginine as effective ingredient.Preparation by the following method: get arginine 5 grams and add fresh water for injection 1000ml dissolving, in 120 ℃ of autoclavings 30 minutes, take out the back and be heated to 80 ℃ in proportioning room, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add 8 gram NaCl, needle-use activated carbon 2.0 grams, carbon removal is filtered in stirring at room absorption 30 minutes, add fresh water for injection to total amount 1000ml, serve as a contrast 0.22 μ m filtering with microporous membrane in sterile workshop down with aseptic filter plate, injection liquid is made in 100 of packing.Be used for treatment to ishemic stroke disease.
Embodiment seven.
A kind of Ginkgolide B Histidine injection for the treatment of ishemic stroke disease.Preparation by the following method: get fresh water for injection 1000ml and be heated to 80 ℃, add 8 gram porphyrizes and cross the Ginkgolide B Histidine mixture of 80 mesh sieves, be heated to dissolving, be cooled to after the room temperature aqueous citric acid solution accent pH to 8.0 with 10%, add 8 gram NaCl, needle-use activated carbon 2.0 grams, carbon removal is filtered in stirring at room absorption 30 minutes, add fresh water for injection to total amount 1000ml, serve as a contrast 0.22 μ m filtering with microporous membrane in sterile workshop down with aseptic filter plate, injection liquid is made in 100 of packing.
Embodiment eight.
A kind of Ginkgolide B Methionin injection for the treatment of ishemic stroke disease, preparation by the following method: get Methionin 2.0 grams and add fresh water for injection 1000ml dissolving, in 115 ℃ of autoclavings 35 minutes, take out the back and be heated to 90 ℃ in proportioning room, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add 8 gram NaCl, needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, add fresh water for injection, serve as a contrast 0.22 μ m filtering with microporous membrane down with aseptic filter plate in sterile workshop to total amount 1000ml, 100 of packing are made lyophilized injectable powder through the freeze-drying operation.
Embodiment nine.
A kind of Ginkgolide B glycine mixture.Preparation by the following method: get glycine 4 grams, add water 500ml dissolving, be heated to 80 ℃, add 8 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 1.0 grams, stirring at room absorption 30 minutes, filter carbon removal, the filtrate spraying drying promptly gets Ginkgolide B glycine mixture.
Embodiment ten.
A kind of Ginkgolide B Guanidinium hydrochloride mixture.Preparation by the following method: get Guanidinium hydrochloride 4 grams, add water 800ml dissolving, be heated to 90 ℃, add 8 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 1.0 grams, stirring at room absorption 20 minutes, filter carbon removal, the filtrate spraying drying promptly gets Ginkgolide B Guanidinium hydrochloride mixture.Get fresh water for injection 1000ml and be heated to 80 ℃, add 9 gram porphyrizes and cross the Ginkgolide B Guanidinium hydrochloride mixture of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add 8 gram NaCl, needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, add fresh water for injection to total amount 1000ml, serve as a contrast 0.22 μ m filtering with microporous membrane, 110 of packing down with aseptic filter plate in sterile workshop, make injection liquid, be used for treatment ishemic stroke disease.
Embodiment 11.
A kind of Ginkgolide B thanomin mixture.Preparation by the following method: get thanomin 6 grams, add 60% ethanol 30ml dissolving, be heated to 50 ℃, add 12 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, filter the filtrate decompression concentrate drying, promptly get Ginkgolide B thanomin mixture, and add conventional medical accessory, and make granule with ordinary method, be used for the treatment of ishemic stroke disease.
Embodiment 12.
A kind of Ginkgolide B urea mixture.Its preparation method is as follows: get urea 3 grams, add 50% ethanol 30ml dissolving, be heated to 45 ℃, add 6 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, filter the filtrate decompression concentrate drying, promptly get Ginkgolide B urea mixture, add medical accessory according to a conventional method, make tablet, be used for the treatment of ishemic stroke disease.
Embodiment 13.
A kind of Ginkgolide B Guanidinium hydrochloride mixture.As follows by its preparation method: as to get Guanidinium hydrochloride 4 grams, add 80% ethanol 25ml dissolving, be heated to 55 ℃, add 8 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, filter the filtrate decompression concentrate drying, promptly get Ginkgolide B Guanidinium hydrochloride mixture, add medical accessory according to a conventional method, make capsule, be used for the treatment of ishemic stroke disease.
Embodiment 14.
A kind of Ginkgolide B 1 mixture, its preparation method is as follows: get 1,2-quadrol 2 grams add 20% ethanol 90ml dissolving, are heated to 60 ℃, add 4 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, filter, the filtrate decompression concentrate drying promptly gets Ginkgolide B 1,2-quadrol mixture, add medical accessory according to a conventional method, make sprays, be used for the treatment of ishemic stroke disease.
Embodiment 15.
A kind of Ginkgolide B methane amide mixture.Its preparation method is as follows: get methane amide 6 grams, add water 900ml dissolving, be heated to 75 ℃, add 15 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 1.0 weight parts, stirring at room absorption 30 minutes, filter carbon removal, filtrate spraying drying or lyophilize promptly get the mixture of Ginkgolide B methane amide, add medical accessory according to a conventional method, make dripping pill, be used for the treatment of ishemic stroke disease.
Embodiment 16.
A kind of Ginkgolide B dimethyl formamide mixture, its preparation method is as follows: get dimethyl formamide 2 grams, add water 800ml dissolving, be heated to 85 ℃, add the Ginkgolide B that 4 gram porphyrizes are crossed 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 1.0 weight parts, stirring at room absorption 25 minutes is filtered carbon removal, filtrate spraying drying or lyophilize, promptly get the mixture of Ginkgolide B dimethyl formamide, add medical accessory according to a conventional method, make oral liquid, be used for the treatment of ishemic stroke disease.
Embodiment 17.
A kind of Ginkgolide B pantothenol mixture, its preparation method is as follows: get pantothenol 5 grams, add water 1000ml dissolving, be heated to 90 ℃, add the Ginkgolide B that 10 gram porphyrizes are crossed 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 2.5 weight parts, stirring at room absorption 40 minutes is filtered carbon removal, filtrate spraying drying or lyophilize, promptly get the mixture of Ginkgolide B pantothenol, add medical accessory according to a conventional method, make suppository, be used for the treatment of ishemic stroke disease.
Embodiment 18.
A kind of Ginkgolide B niacinamide mixture.Its preparation method is as follows: get niacinamide 5 grams, add water 900ml dissolving, be heated to 90 ℃, add 10 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 3.0 weight parts, stirring at room absorption 35 minutes, filter carbon removal, filtrate spraying drying or lyophilize promptly get the mixture of Ginkgolide B niacinamide.Ginkgolide B niacinamide injection with this mixture preparation treatment ishemic stroke disease, preparation by the following method: get fresh water for injection 1000ml and be heated to 80 ℃, add 8 gram porphyrizes and cross the Ginkgolide B niacinamide mixture of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add 8 gram NaCl, needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, add fresh water for injection, serve as a contrast 0.22 μ m filtering with microporous membrane down with aseptic filter plate in sterile workshop to total amount 1000ml, injection liquid is made in 100 of packing.
Embodiment 19.
A kind of Ginkgolide B alkyl imidazole mixture.Its preparation method is as follows: get alkyl imidazole 2 grams, add 40% ethanol 60ml dissolving, be heated to 50 ℃, add 4 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, filter the filtrate decompression concentrate drying, promptly get Ginkgolide B alkyl imidazole mixture, add medical accessory according to a conventional method, make capsule, be used for the treatment of ishemic stroke disease.
Embodiment 20.
A kind of Ginkgolide B alkyl pyridine mixture.Preparation by the following method: get alkyl pyridine 2 grams, add 30% ethanolic soln 90ml dissolving, be heated to 85 ℃, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 3.0 grams, stirring at room absorption 30 minutes, filter carbon removal, lyophilize promptly gets Ginkgolide B alkyl pyridine mixture, adds medical accessory according to a conventional method, make tablet, be used for the treatment of ishemic stroke disease.
Embodiment 21.
A kind of Ginkgolide B alkyl trimethyl amine salt mixture.Preparation by the following method: get alkyl trimethyl amine salt 2.5 grams, add 50% ethanolic soln 50ml dissolving, be heated to 80 ℃, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 2.0 grams, stirring at room absorption 40 minutes, filter carbon removal, lyophilize promptly gets Ginkgolide B alkyl trimethyl amine salt mixture, adds medical accessory according to a conventional method, make capsule, be used for the treatment of ishemic stroke disease.
Embodiment 22.
A kind of Ginkgolide B thiamine hydrochloride mixture.The preparation method is as follows: get thiamine hydrochloride 2.5 grams, add 60% ethanolic soln 40ml dissolving, be heated to 80 ℃, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 2.0 grams, stirring at room absorption 40 minutes, filter carbon removal, lyophilize promptly gets Ginkgolide B thiamine hydrochloride mixture.Injection with Ginkgolide B thiamine hydrochloride mixture preparation treatment ishemic stroke disease, preparation by the following method: get fresh water for injection 1000ml and be heated to 80 ℃, add 8 gram porphyrizes and cross the Ginkgolide B thiamine hydrochloride mixture of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add 8 gram NaCl, needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, add fresh water for injection, serve as a contrast 0.22 μ m filtering with microporous membrane down with aseptic filter plate in sterile workshop to total amount 1000ml, injection liquid is made in 100 of packing.
Embodiment 23.
A kind of Ginkgolide B methylamine mixture.Preparation by the following method: get methylamine 2 grams, add 95% ethanolic soln 25ml dissolving, be heated to 85 ℃, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 3.0 grams, stirring at room absorption 28 minutes, filter carbon removal, lyophilize promptly gets Ginkgolide B methylamine mixture, adds medical accessory according to a conventional method, make granule, be used for the treatment of ishemic stroke disease.
Embodiment 24.
A kind of Ginkgolide B ethamine mixture.Its preparation method is as follows: get ethamine 6 grams, add water 1000ml dissolving, be heated to 85 ℃, add 12 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 3.0 weight parts, stirring at room absorption 30 minutes, filter carbon removal, filtrate spraying drying or lyophilize promptly get the mixture of Ginkgolide B ethamine.Ginkgolide B ethamine injection with this mixture preparation treatment ishemic stroke disease, preparation by the following method: get fresh water for injection 1000ml and be heated to 80 ℃, add 8 gram porphyrizes and cross the Ginkgolide B ethamine mixture of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add 8 gram NaCl, needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, add fresh water for injection, serve as a contrast 0.22 μ m filtering with microporous membrane down with aseptic filter plate in sterile workshop to total amount 1000ml, injection liquid is made in 100 of packing.
Embodiment 25.
A kind of Ginkgolide B propylamine injection for the treatment of ishemic stroke disease, preparation by the following method: get propylamine 2.0 grams and add fresh water for injection 1000ml dissolving, in 115 ℃ of autoclavings 35 minutes, take out the back and be heated to 90 ℃ in proportioning room, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, transfer pH to 8.0 with 10% aqueous citric acid solution after being cooled to room temperature, add 8 gram NaCl, needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, add fresh water for injection, serve as a contrast 0.22 μ m filtering with microporous membrane down with aseptic filter plate in sterile workshop to total amount 1000ml, 100 of packing are made lyophilized injectable powder through the freeze-drying operation.
Embodiment 26.
A kind of Ginkgolide B butylamine mixture.Preparation by the following method: get butylamine 4 grams, add 10% ethanolic soln 100ml dissolving, be heated to 85 ℃, add 8 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 2.5 grams, stirring at room absorption 38 minutes, filter carbon removal, lyophilize promptly gets Ginkgolide B butylamine mixture.
Embodiment 27.
A kind of Ginkgolide B quadrol mixture.Preparation by the following method: get quadrol 2.5 grams, add water 1000ml dissolving, be heated to 80 ℃, add 5 gram porphyrizes and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 2.0 grams, stirring at room absorption 30 minutes, filter carbon removal, the filtrate spraying drying promptly gets Ginkgolide B quadrol mixture.Add medical accessory, be made into capsule, be used for treatment ishemic stroke disease with ordinary method.
Above embodiment can make those skilled in the art more fully understand the present invention, but must not limit the present invention by any way.
Claims (6)
1, a kind of general formula is the mixture of the Ginkgolide B of (I),
Wherein G is selected from: arginine, Methionin, Histidine, glycine, methylamine, ethamine, propylamine, butylamine, quadrol, meglumine, urea, Guanidinium hydrochloride, 1, thanomin, methane amide, dimethyl formamide, pantothenol, niacinamide, alkyl imidazole, alkyl pyridine, alkyl trimethyl amine salt or thiamine hydrochloride.
2, a kind of general formula is the mixture and the composition that mix to form of acceptable pharmaceutical carrier pharmaceutically of the Ginkgolide B of (I), wherein G is selected from: arginine, Methionin, Histidine, glycine, methylamine, ethamine, propylamine, butylamine, quadrol, meglumine, urea, Guanidinium hydrochloride, 1, thanomin, methane amide, dimethyl formamide, pantothenol, niacinamide, alkyl imidazole, alkyl pyridine, alkyl trimethyl amine salt or thiamine hydrochloride.
3, a kind of preparation method of mixture of Ginkgolide B as claimed in claim 1 is characterized in that: Ginkgolide B and G are 1: 0.6～2.5 ratio with mol ratio, form mixture in water and/or alcoholic solvent.
4, the preparation method of the mixture of Ginkgolide B according to claim 3, it is characterized in that its step is as follows: get G, add the dissolving of water 100～1000 parts by volume, be heated to 70-90 ℃, add porphyrize and cross the Ginkgolide B of 80 mesh sieves, be heated to dissolving, add needle-use activated carbon 1.0-3.0 weight part, stirring at room absorption 20-40 minute, filter carbon removal, filtrate spraying drying or lyophilize promptly get the mixture of Ginkgolide B.
5, the preparation method of the mixture of Ginkgolide B according to claim 3, it is characterized in that, its step is as follows, get G, add 10～95% ethanol or the dissolving of dehydrated alcohol 20～100 parts by volume, be heated to 40-60 ℃, add porphyrize and cross the Ginkgolide B of 80 mesh sieves, filter, the filtrate decompression concentrate drying promptly gets the mixture of Ginkgolide B.
6, the mixture of the described Ginkgolide B of claim 1 has purposes in the medicine of treatment ishemic stroke disease as effective ingredient in preparation, and described medicine is any formulation on the pharmaceutics.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103127059A (en) * | 2011-11-29 | 2013-06-05 | 秦引林 | Oral administration preparation composed of bilobalide B derivative and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006116905A1 (en) * | 2005-04-29 | 2006-11-09 | Yinlin Qin | Medicinal compounds as antagonists of the platelet- activating factor receptor |
| CN101647830B (en) * | 2008-08-12 | 2012-05-23 | 江苏康缘药业股份有限公司 | Quality control method of ginkgolide medicinal preparation |
| CN101912364B (en) * | 2010-08-09 | 2015-07-15 | 刘会梅 | Ginkgolide B liposome medicinal composition |
| CN103156022B (en) * | 2011-12-09 | 2014-12-17 | 四川科伦药物研究有限公司 | Ginkgo leaf health-care tea and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103127059A (en) * | 2011-11-29 | 2013-06-05 | 秦引林 | Oral administration preparation composed of bilobalide B derivative and preparation method thereof |
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