CN102002052A - Ginkgolides K and compound thereof as well as preparation method and use thereof - Google Patents
Ginkgolides K and compound thereof as well as preparation method and use thereof Download PDFInfo
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Abstract
The invention discloses a compound of ginkgolides K of which a general formula is shown in (I), and a composition is prepared by mixing the ginkgolides K compound and pharmaceutically-acceptable medicine carrier, wherein G is alkaline substances. The invention also discloses a preparation method of the compound and treatment use thereof. In the invention, the ginkgolides K compound changes the physical property of the ginkgolides K, thereby the invention has the advantages of good stability, and the ginkgolides K compound has good water-solubility and higher stability. In the compound, a natural structure of the ginkgolides K can be kept, and when the compound is used as an effective component to enter the human body, the activity of the ginkgolides K can be fully developed to achieve the aim of treating an illness.
Description
The application is dividing an application of CN200510094106.3, and the applying date of original application is on August 25th, 2005, and application number is CN200510094106.3, and invention and created name is: bilobalide K and mixture thereof and preparation method thereof and purposes.
Technical field
The present invention relates to a kind of bilobalide-like substances and mixture thereof; Particularly a kind of bilobalide K and mixture thereof the invention still further relates to the preparation method and the purposes of this bilobalide K and mixture thereof.
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.
A kind of new material that (I) of the present invention finds for calendar year 2001 report (referring to Wang Ying etc., the LC/DAD/ESI/MS of trace ingredients analyzes and the structure evaluation in the bilobalide extract, Acta Pharmaceutica Sinica Acta Pharmaceutica Sinica 2001,36 (8): 606-608), the called after bilobalide K.Because bilobalide K content in ginkgo is extremely low, has only about 5/1000000ths, has restricted the Application and Development of bilobalide K preparation, do not see bilobalide K Pharmacological action study report as yet, lack the basis that is developed to the medicine industrialization.Still there is not the listing of bilobalide K preparation at present both at home and abroad.
Summary of the invention
Technical problem to be solved by this invention is at the deficiencies in the prior art, proposes a kind of bilobalide K and mixes the bilobalide K composition that forms with acceptable pharmaceutical carrier pharmaceutically.
Another technical problem to be solved by this invention is to propose a kind of bilobalide K mixture with good water-solubility, stability.
Another technical problem to be solved by this invention provides a kind of preparation method of bilobalide K.
Another technical problem to be solved by this invention provides a kind of preparation method of mixture of bilobalide K.
Another technical problem to be solved by this invention provides the medicinal use of bilobalide K and mixture thereof.
Technical problem to be solved by this invention is to realize by following technical scheme.The present invention is bilobalide K and mixture (I) G thereof of a kind of general formula for (I),
And, with bilobalide K or its mixture (I) G and pharmaceutically the acceptable pharmaceutical carrier mix and form composition, for example, mixes the composition of formation with pharmaceutical carrier tamanori, suspending agent, solubility promoter, solid dispersion, inclusion agents etc.; Wherein G is an alkaline matter, for example: 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.5) metal alkaline material such as sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta etc.
Technical problem to be solved by this invention can also further realize by following technical scheme.The mixture of above-described bilobalide K (I) G is characterized in, G is selected from and contains an itrogenous organic substance to eight carbon atoms in metal alkaline material or the molecule.
Technical problem to be solved by this invention can also further realize by following technical scheme.The mixture of above-described bilobalide K (I) G is characterized in, described G is arginine or Methionin or meglumine or sodium hydroxide.
Technical problem to be solved by this invention can also further realize by following technical scheme.The present invention also provides a kind of preparation method of bilobalide K, be characterized in, its step is as follows: (1) is at alkaline aqueous solution or alkaline water, mixed alkoxide solution or in water, mixed alkoxide solution, add Ginkgolide B or contain the bilobalide extract of Ginkgolide B, the heating in water bath dissolving, insulation;
(2) after Ginkgolide B transforms fully substantially after testing, regulate pH value to solution with acidic aqueous solution then and be acid, leave standstill, filter or the centrifugal throw out that gets, taking precipitate adds water washing, uses organic solvent dissolution again, concentrate, recrystallization to purity reaches more than 90%, promptly;
Perhaps,
(2) after Ginkgolide B transforms fully substantially after testing, concentrate crystallization, get crystallization and use organic solvent dissolution again, concentrate, recrystallization to purity reaches more than 90%, promptly.
Technical problem to be solved by this invention can also further realize by following technical scheme.The preparation method of above-described a kind of bilobalide K is characterized in, described alkaline aqueous solution is sodium hydroxide or potassium hydroxide or arginine or meglumine or lysine solution; Described alcohol is methyl alcohol, ethanol or propyl carbinol; Described acidic solution is the hydrochloric acid soln or the citric acid solution of any concentration, is preferably hydrochloric acid soln or the citric acid solution of 0.2～1.0mol/L; Described organic solution is methyl alcohol, ethanol, acetone or propyl carbinol.
Technical problem to be solved by this invention can also further realize by following technical scheme.The present invention also provides the preparation method of a kind of mixture (I) G of bilobalide K, is characterized in, bilobalide K and alkaline matter are 1: 0.2～5 ratio with mol ratio, form mixture in water and/or alcoholic solvent.Like this, can make it all form mixture.
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 a kind of bilobalide K (I) G is characterized in that its step is as follows: get alkaline matter, be dissolved in water, be heated to 70-90 ℃, add bilobalide K, stirring and dissolving concentrates, dry enriched material, promptly.
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 a kind of bilobalide K (I) G, be characterized in that its step is as follows: get alkaline matter, add water and dissolve than mixing solutions arbitrarily with organic solvent, be heated to 40-70 ℃, add alcohol (methyl alcohol, ethanol, propylene glycol, the propyl carbinol etc.) solution of bilobalide K or bilobalide K, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim organic solvent, dry enriched material, promptly.
The mixture of best bilobalide K of the present invention is that wherein G is the mixture of the general formula of arginine or Methionin or meglumine for (I).
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.Above-described bilobalide K or its mixture (I) G have the treatment ischemia apoplexy as effective ingredient in preparation, the purposes in the medicine of the shock that control thrombosis, senile dementia, organ-graft refection, acute inflammation, heart allergy, intracellular toxin cause.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.
Bilobalide K of the present invention and complex formulation thereof can by oral, snuffing is gone into, the mode of rectum or administered parenterally is applied to the patient, 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.Its discriminating and detection method are as follows:
1. tlc identification method
The preparation of need testing solution
Getting the bilobalide K complex formulation is dissolved in water and/or is diluted to and be equivalent to bilobalide-containing K5mg/ml, get its solution 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.Perhaps get the bilobalide K extract formulation and after pre-treatment, obtain the bilobalide K extract, add the need testing solution that acetone solution becomes 5mg/ml.
It is an amount of that the bilobalide K 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 (an appendix VI of Chinese Pharmacopoeia version in 2000 B), get each 10 μ L point sample of above-mentioned trial-product and reference substance solution respectively with the micro-sampling device and contain 4% sodium-acetate in same, on the silica GF254 thin layer plate made from 0.5%CMC-Na solution, with sherwood oil (30～60 ℃)-acetone-methyl alcohol (10: 2.5: 0.3) is developping agent, 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 bilobalide K, 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 bilobalide K 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) gets the bilobalide K complex formulation, be dissolved in water and/or be diluted to and be equivalent to bilobalide-containing K 5mg/ml, get its solution 5ml or get injection liquid or oral liquid 5ml, put in the 10ml measuring bottle, add the hydrochloric acid soln 1ml of 6mol/L, room temperature was placed 3.5 hours, with acetone solution and be diluted to scale, shake up, placed 30 minutes, filter through millipore filtration (aperture 0.45 μ m), promptly.This test solution should be measured in 2 hours.
2) or get bilobalide K preparation precision and add acetone and be dissolved into the solution that is equivalent to bilobalide-containing K2.5mg/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.
Bilobalide K 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 bilobalide K is learned research
(1), bilobalide K 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), bilobalide K 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 bilobalide K
(1), bilobalide K mixture 1.0,3.0,9.0mg/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 significantly is better than the Ginaton injection.
(2), bilobalide K mixture 1.0,3.0,9.0mg/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), bilobalide K mixture 1.0,3.0,9.0mg/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), bilobalide K mixture 1.0,3.0,9.0mg/kg iV compare with model group that the EEG that can make diffusivity global brain ischemia rat recovers normal time and time of recovery is obviously shortened (P＜0.01) in righting reflex, makes the Evans Blue permeability significantly reduce (P＜0.01).
(5), bilobalide K 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.
(6) but, bilobalide K mixture 2,4, the survival time (P＜0.01) of 8mg/kg iV significant prolongation mouse under anoxic condition.
(7), bilobalide K mixture 0.25,0.5,1.0mg/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 iV0.25,0.50,1.0mg/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).
(8), it is moving that bilobalide K mixture iv 0.25,0.50,1.0mg/kg can obviously suppress rabbit---the thrombosis (P＜0.01) of vein bypass.
(9), bilobalide K mixture iv0.5,1.0,2.0mg/kg are moving to rat---and vein bypass thrombus has obvious thrombolytic effect (P＜0.01).
(10), just can obviously suppress PAF behind the bilobalide K mixture iv 0.5mg/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 79%, and depolymerization in 1 minute is about 82%.30min can obviously suppress PAF and induces in the rabbit body platelet aggregation and obvious unzipping (P＜0.01) is arranged behind the bilobalide K ig1.5mg/kg medicine, continue 60min, be about 42min during its peak, the maximum gathering of thrombocyte inhibiting rate is about 45%, and the depolymerization rate was about 40% in 1 minute.
(11) influence of senile dementia rat model
11.1 influence to ability of learning and memory and space exploration ability
The result shows, along with the increase of training fate, all shorten each latent period of organizing rat, respectively organizes rat there was no significant difference in latent period on the the 1st, 2 two day, begins to occur significant difference on the 3rd day.Model group relatively obviously prolongs with blank group latent period, and the number of times of crossing over platform reduces (P＜0.01); Significantly be shorter than model group, significant difference (P＜0.01) latent period that gastric infusion is respectively organized rat.Experimental result sees Table 1.
Table 1 pair water maze laboratory latent period and the influence of crossing over the platform number of times
Annotate: compare with the blank group,
△ △P＜0.01.Compare with the AD model group,
*P＜0.05,
*P＜0.01.
11.2 to SOD activity in the senile dementia rat model cerebral tissue, the influence of MDA content
The result shows, the relatively active obviously reduction of SOD of AD model group and blank group, and MDA content raises, (P＜0.01); Gastric infusion is respectively organized rat SOD activity and is compared the rising that all has in various degree with the AD model group, and MDA content all has in various degree reduction and AD model group to compare significant difference.The results are shown in Table 2.
SOD activity in the table 2 pair senile dementia rat model cerebral tissue, the influence of MDA content
Annotate: compare with the blank group,
△ △P＜0.01.Compare with the AD model group,
*P＜0.05,
*P＜0.01.
(12) to influence to senile dementia rat hippocampus neurotransmitter
Model group hippocampus Ach content significantly is lower than false damage group, significant difference (P＜0.01); After the medicine filling stomach treatment through 20d, each medicine group hippocampus Ach content of gastric infusion all is higher than model group, has significant difference (P＜0.01).The results are shown in Table 3.
The influence of table 3 couple rat hippocampus Ach, 5-HT and NE content
Annotate: compare with the blank group,
△ △P＜0.01.Compare with the AD model group,
*P＜0.05,
*P＜0.01.
(13) to the influence of mouse senile dementia model
13.1 the influence to senile dementia mouse active learning and memory: compare with the normal control group, model control group mouse test phase is initiatively avoided latent period (T1) and is initiatively avoided number of times (N1) and obviously reduce, and passive avoidance latent period (Ts) and passive avoidance number of times (Ns) obviously increase, have significant statistical significance (P＜0.01), show senile dementia model modeling success; With model control group relatively, ig administration group can significantly raise (T1) and (N1), reduction (Ts) and (Ns), significant difference (P＜0.01).The results are shown in Table 4.
The initiatively influence of learning and memory of table 4 pair senile dementia mouse
Annotate: compare with the blank group,
△P＜0.05,
△ △P＜0.01.Compare with the AD model group,
*P＜0.05,
*P＜0.01.
13.2 influence to senile dementia mouse blood SOD, MDA and MAO content
Compare with normal group, obviously increase, do not see remarkable meaning though the MAO content of model group mouse significantly improves MDA content; SOD does not have obvious change.After the ig administration, the administration group can significantly reduce MAO content, in, heavy dose of group also has remarkable reduction to MDA content, but the SOD level do not had obvious influence.The results are shown in Table 5.
The influence of table 5 couple senile dementia mouse blood SOD, MDA and MAO content
| Group | Dosage | The example number | SOD(μg/gHB) | MDA(μmol/L) | MAO(10-3U/L) |
| The normal control group | - | 10 | 275.2±29.3 | 3.6±0.3 | 39.0±3.2 |
| Model control group | - | 10 | 259.1±27.6 | 3.7±0.2 | 43.5±3.1 △△ |
| The Ginkgo Biloba Leaf Preparation group | 0.012 | 10 | 275.2±23.1 | 3.5±0.3 | 38.6±4.1 ** |
| Low dose group | 10 | 261.3±35.2 | 3.5±0.4 | 40.6±4.3 ** | |
| Middle dosage group | 10 | 265.1±37.4 | 3.3±0.2 ** | 38.2±3.2 ** | |
| High dose group | 10 | 270.1±24.6 | 3.3±0.2 ** | 37.6±2.8 ** |
Annotate: compare with the blank group,
△P＜0.05,
△ △P＜0.01.Compare with the AD model group,
*P＜0.05,
*P＜0.01.
Experimental results show that, bilobalide K of the present invention and mixture thereof can be used for preparation treatment ischemia apoplexy, the medicine of the shock that control thrombosis, senile dementia, organ-graft refection, acute inflammation, heart allergy, intracellular toxin cause, and it has no side effect.
The present invention utilizes Ginkgolide B to carry out derivatize, produce bilobalide K, solved the Technology of the refining bilobalide K of extensive extraction, and make medicinal preparations and carried out pharmacological toxicology research, found that bilobalide K is the very high thrombocyte antagonism factor of a kind of activity, can be developed to the clinical treatment medicine that plays an important role in the pathologic processes such as shock that thrombosis, organ-graft refection, senile dementia, acute inflammation, heart allergy, intracellular toxin cause.
Bilobalide K mixture of the present invention has good water-solubility, and its stability is higher, when it is used for medicine 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 bilobalide K, after it enters human body as effective ingredient, can bring into play the activity of bilobalide K fully, to reach the purpose of curing the disease.Have great social significance and economic implications.
Embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but must not limit the present invention by any way.
Embodiment 1.A kind of preparation method of bilobalide K, its step is as follows: in alkaline aqueous solution, add Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to solution with acidic aqueous solution then and be acid, leave standstill, filter throw out, taking precipitate adds water washing, uses organic solvent dissolution again, concentrates, recrystallization to purity reaches more than 90%, promptly.
Embodiment 2.A kind of preparation method of bilobalide K, its step is as follows: in alkaline water, mixed alkoxide solution, add the bilobalide extract that contains Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to solution with acidic aqueous solution then and be acid, leave standstill, the centrifugal throw out that gets, taking precipitate adds water washing, uses organic solvent dissolution again, concentrates, and recrystallization to purity reaches more than 90%, promptly.
Embodiment 3.A kind of preparation method of bilobalide K, its step is as follows: in water, mixed alkoxide solution, add Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, concentrate crystallization, get crystallization and use organic solvent dissolution again, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 4.A kind of preparation method of bilobalide K, its step is as follows: in aqueous sodium hydroxide solution, add Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to solution with hydrochloric acid soln then and be acid, leave standstill, filter throw out, taking precipitate adds water washing, uses dissolve with methanol again, concentrates, recrystallization to purity reaches more than 90%, promptly.
Embodiment 5.A kind of preparation method of bilobalide K, its step is as follows: in the potassium hydroxide and the methanol mixed aqueous solution, add the bilobalide extract that contains Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to solution with aqueous citric acid solution then and be acid, leave standstill, the centrifugal throw out that gets, taking precipitate adds water washing, uses dissolve with ethanol again, concentrates, and recrystallization to purity reaches more than 90%, promptly.
Embodiment 6.A kind of preparation method of bilobalide K, its step is as follows: in aqueous ethanolic solution, add Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, concentrate crystallization, get crystallization again with the propyl alcohol dissolving, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 7.A kind of preparation method of bilobalide K, its step is as follows: in the arginine aqueous solution, add Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to solution with the hydrochloric acid soln of 0.2mol/L then and be acid, leave standstill, filter throw out, taking precipitate adds water washing, with the propyl alcohol dissolving, concentrated, recrystallization to purity reaches more than 90%, promptly again.
Embodiment 8.A kind of preparation method of bilobalide K, its step is as follows: in meglumine and ethanol mixed aqueous solution, add the bilobalide extract that contains Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to solution with the hydrochloric acid soln of 1mol/L then and be acid, leave standstill, the centrifugal throw out that gets, taking precipitate adds water washing, with the propyl carbinol dissolving, concentrates again, and recrystallization to purity reaches more than 90%, promptly.
Embodiment 9.A kind of preparation method of bilobalide K, its step is as follows: in aqueous propanol solution, add Ginkgolide B, heating in water bath dissolving, insulation; After Ginkgolide B transforms fully substantially after testing, concentrate crystallization, get the dissolving of crystallization propyl alcohol, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 10.A kind of preparation method of bilobalide K, its step is as follows: in lysine solution, add Ginkgolide B, the dissolving in 24 hours of 70 ℃ of heating in water bath, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to 1 with the citric acid solution of 0.2mol/L then, left standstill 3 hours, filter throw out, taking precipitate adds water washing 3 times, uses dissolve with methanol again, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 11.A kind of preparation method of bilobalide K, its step is as follows: in Methionin and propyl alcohol mixed aqueous solution, add the bilobalide extract that contains Ginkgolide B, the dissolving in 12 hours of 85 ℃ of heating in water bath, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to 2 with the citric acid solution of 1.0mol/L then, left standstill 2 hours, the centrifugal throw out that gets, taking precipitate adds water washing 1 time, dissolves with propyl carbinol again, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 12.A kind of preparation method of bilobalide K, its step is as follows: in n-butanol aqueous solution, add the extract that contains Ginkgolide B, the dissolving in 48 hours of 50 ℃ of heating in water bath, insulation; After Ginkgolide B transforms fully substantially after testing, concentrate crystallization, get the dissolving of crystallization propyl alcohol, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 13.A kind of preparation method of bilobalide K, its step is as follows: in methanol aqueous solution, add the extract that contains Ginkgolide B, the dissolving in 72 hours of 90 ℃ of heating in water bath, insulation; After Ginkgolide B transforms fully substantially after testing, concentrate crystallization, get the crystallization dissolve with ethanol, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 14.A kind of preparation method of bilobalide K, its step is as follows: in potassium hydroxide and propyl carbinol mixed aqueous solution, add the bilobalide extract that contains Ginkgolide B, the dissolving in 48 hours of 60 ℃ of heating in water bath, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to 3 with the citric acid solution of 0.5mol/L then, left standstill 5 hours, the centrifugal throw out that gets, taking precipitate adds water washing 2 times, uses dissolve with ethanol again, concentrate, recrystallization to purity reaches more than 90%, promptly.
Embodiment 15.A kind of preparation method of bilobalide K, its step is as follows: in sodium hydroxide and propyl alcohol mixed aqueous solution, add Ginkgolide B, the dissolving in 60 hours of 40 ℃ of heating in water bath, insulation; After Ginkgolide B transforms fully substantially after testing, regulate pH value to 6 with the hydrochloric acid soln of 0.5mol/L then, left standstill 10 hours, the centrifugal throw out that gets, taking precipitate adds water washing 1 time, uses dissolve with ethanol again, concentrates, and recrystallization to purity reaches more than 90%, promptly.
Embodiment 16.The preparation method of a kind of mixture of bilobalide K (I) G, bilobalide K and alkaline matter are 1: 0.2 ratio with mol ratio, form mixture in water.
Embodiment 17.The preparation method of a kind of mixture of bilobalide K (I) G, bilobalide K and alkaline matter are 1: 5 ratio with mol ratio, form mixture in water and alcoholic solvent.
Embodiment 18.The preparation method of a kind of mixture of bilobalide K (I) G, bilobalide K and alkaline matter are 1: 2.5 ratio with mol ratio, form mixture in alcoholic solvent.
Embodiment 19.The preparation method of a kind of mixture of bilobalide K (I) G, its step is as follows: get alkaline matter, be dissolved in water, be heated to 80 ℃, add bilobalide K, stirring and dissolving concentrates, dry enriched material, promptly.The bilobalide K of present embodiment and the mol ratio of alkaline matter are 1: 1.
Embodiment 20.The preparation method of a kind of mixture of bilobalide K (I) G, its step is as follows: get alkaline matter, add water and dissolve than mixing solutions arbitrarily, be heated to 55 ℃, add the alcoholic solution of bilobalide K or bilobalide K with organic solvent, be stirred to dissolving, filter, filtrate decompression concentrates, and reclaims organic solvent, dry enriched material, promptly.The bilobalide K of present embodiment and the mol ratio of alkaline matter are 1: 2.
Embodiment 21.A kind of bilobalide K arginine mixture, preparation by the following method: get arginine, add water 1000ml dissolving, be heated to 70 ℃, add the bilobalide K that porphyrize is crossed 80 mesh sieves, stirring and dissolving concentrates, dry enriched material, promptly; The aseptic subpackaged bilobalide K arginine powder injection that promptly gets; The bilobalide K of present embodiment and the mol ratio of alkaline matter are 1: 4.
Embodiment 22.A kind of bilobalide K Methionin mixture, preparation by the following method: get Methionin 2.5 grams, add ethanol 20ml dissolving, be heated to 40 ℃, add the bilobalide K that 5 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, filter, filtrate decompression concentrates, and reclaims ethanol, dry enriched material promptly gets bilobalide K Methionin mixture.
Embodiment 23.A kind of bilobalide K meglumine mixture, preparation by the following method: get meglumine 4 grams, add dehydrated alcohol 100ml dissolving, be heated to 70 ℃, add 10 gram bilobalide Ks, be stirred to dissolving, filter, filtrate decompression concentrates, and reclaims ethanol, dry enriched material promptly gets bilobalide K meglumine mixture.
Embodiment 24.A kind of bilobalide K Histidine mixture, preparation by the following method: get Histidine 2.0 grams, add water 100ml dissolving, be heated to 90 ℃, add bilobalide K, stirring and dissolving concentrates, and dry enriched material promptly gets bilobalide K Histidine mixture.
Embodiment 25.A kind of bilobalide K butylamine mixture.Preparation by the following method: get butylamine 4 grams, add water 500ml dissolving, be heated to 75 ℃, add the bilobalide K that 8 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, concentrate, the spraying drying enriched material promptly gets bilobalide K butylamine mixture.
Embodiment 26.A kind of bilobalide K Guanidinium hydrochloride mixture.Preparation by the following method: get Guanidinium hydrochloride 4 grams, add water 800ml dissolving, be heated to 85 ℃, add 8 gram bilobalide Ks, stirring and dissolving concentrates, and dry enriched material promptly gets bilobalide K Guanidinium hydrochloride mixture.
Embodiment 27.A kind of bilobalide K thanomin mixture.Preparation by the following method: get thanomin 6 grams, add 60% methyl alcohol 50ml dissolving, be heated to 50 ℃, add 12 gram bilobalide Ks, be stirred to dissolving, filter, filtrate decompression concentrates, and reclaims methyl alcohol, and the spraying drying enriched material promptly gets bilobalide K thanomin mixture.
Embodiment 28.A kind of bilobalide K urea mixture.Its preparation method is as follows: get urea 3 grams, add 50% propyl carbinol 100ml dissolving, be heated to 60 ℃, add the bilobalide K that 6 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim propyl carbinol, the spraying drying enriched material promptly gets bilobalide K urea mixture.
Embodiment 29.A kind of bilobalide K quadrol mixture.As follows by its preparation method: get quadrol 4 grams, add 80% propyl alcohol 20ml dissolving, be heated to 45 ℃, add 8 gram bilobalide Ks, be stirred to dissolving, filter, filtrate decompression concentrates, and reclaims propyl alcohol, and dry enriched material promptly gets bilobalide K quadrol mixture.
Embodiment 30.A kind of bilobalide K 1 mixture, its preparation method is as follows: get 1,2-quadrol 2 grams add 20% ethanol 90ml dissolving, are heated to 65 ℃, add 4 gram bilobalide Ks, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim ethanol, dry enriched material promptly gets bilobalide K 1 mixture.
Embodiment 31.A kind of bilobalide K methane amide mixture.Its preparation method is as follows: get methane amide 6 gram, add water 900ml dissolving, be heated to 75 ℃, add the bilobalide K that 15 gram porphyrizes are crossed 80 mesh sieves, stirring and dissolving concentrates, and the lyophilize enriched material promptly gets the mixture of bilobalide K methane amide.
Embodiment 32.A kind of bilobalide K dimethyl formamide mixture, its preparation method is as follows: get dimethyl formamide 2 grams, add water 200ml dissolving, be heated to 85 ℃, add 4 gram bilobalide K powder, stirring and dissolving, concentrate, the spraying drying enriched material promptly gets the mixture of bilobalide K dimethyl formamide.
Embodiment 33.A kind of bilobalide K pantothenol mixture, its preparation method is as follows: get pantothenol 5 grams, add water 1000ml dissolving, be heated to 90 ℃, add the bilobalide K powder that 10 gram porphyrizes are crossed 80 mesh sieves, stirring and dissolving, concentrate, the spraying drying enriched material promptly gets the mixture of bilobalide K pantothenol.
Embodiment 34.A kind of bilobalide K niacinamide mixture.Its preparation method is as follows: get niacinamide 5 gram, add water 400ml dissolving, be heated to 86 ℃, add the bilobalide K powder that 10 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, concentrate, the spraying drying enriched material promptly gets the mixture of bilobalide K niacinamide.
Embodiment 35.A kind of bilobalide K alkyl imidazole mixture.Its preparation method is as follows: get alkyl imidazole 2 grams, add 40% propyl alcohol 60ml dissolving, be heated to 50 ℃, add 4 gram bilobalide K powder, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim propyl alcohol, the spraying drying enriched material promptly gets bilobalide K alkyl imidazole mixture.
Embodiment 36.A kind of bilobalide K alkyl pyridine mixture.Preparation by the following method: get alkyl pyridine 2 grams, add 30% ethanolic soln 90ml dissolving, be heated to 45 ℃, add 5 gram bilobalide Ks, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim ethanol, the spraying drying enriched material promptly gets bilobalide K alkyl pyridine mixture.
Embodiment 37.A kind of bilobalide K alkyl trimethyl amine salt mixture.Preparation by the following method: get alkyl trimethyl amine salt 2.5 grams, add 50% ethanolic soln 200ml dissolving, be heated to 55 ℃, add 5 gram porphyrizes and cross the bilobalide K of 80 mesh sieves, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim ethanol, the spraying drying enriched material promptly gets bilobalide K alkyl trimethyl amine salt mixture.
Embodiment 38.A kind of bilobalide K thiamine hydrochloride mixture.The preparation method is as follows: get thiamine hydrochloride 2.5 grams, add 60% ethanolic soln 40ml dissolving, be heated to 50 ℃, add the bilobalide K that 5 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim ethanol, the spraying drying enriched material promptly gets bilobalide K thiamine hydrochloride mixture.
Embodiment 39.A kind of bilobalide K methylamine mixture.Preparation by the following method: get methylamine 2 grams, add 95% ethanolic soln 25ml dissolving, be heated to 48 ℃, add the bilobalide K that 5 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim ethanol, the spraying drying enriched material promptly gets bilobalide K methylamine mixture.
Embodiment 40.A kind of bilobalide K ethamine mixture.Its preparation method is as follows: get ethamine 6 gram, add water 800ml dissolving, be heated to 80 ℃, add the bilobalide K that 12 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, concentrate, the spraying drying enriched material promptly gets the mixture of bilobalide K ethamine.
Embodiment 41.A kind of bilobalide K hydrated barta mixture.Preparation by the following method: get hydrated barta 4 grams, add 10% ethanolic soln 100ml dissolving, be heated to 70 ℃, add 8 gram bilobalide K powder, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim ethanol, the spraying drying enriched material promptly gets bilobalide K hydrated barta mixture.
Embodiment 42.A kind of bilobalide K calcium hydroxide mixture.Preparation by the following method: get calcium hydroxide 2.5 grams, add water 1000ml dissolving, be heated to 80 ℃, add the bilobalide K powder that 5 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, concentrate, the spraying drying enriched material promptly gets bilobalide K calcium hydroxide mixture.
Embodiment 43.A kind of bilobalide K sodium hydroxide mixture.Preparation by the following method: get sodium hydroxide 0.45 gram, add water 500ml dissolving, be heated to 80 ℃, add the bilobalide K that 5 gram porphyrizes are crossed 80 mesh sieves, be stirred to dissolving, concentrate, the spraying drying enriched material promptly gets bilobalide K sodium hydroxide mixture.
Embodiment 44.A kind of bilobalide K potassium hydroxide mixture.Preparation by the following method: get potassium hydroxide 0.45 gram, add ethanol 1000ml water-bath dissolving, make the ethanol hydrogen production potassium oxide solution; Other gets 5 gram bilobalide K powder, adds ethanol 500ml, and 60 ℃ of stirring and dissolving are filtered, filtrate and the merging of ethanol hydrogen production potassium oxide solution, and stirring and evenly mixing, 65 ℃ of water-baths 2～4 hours, concentrating under reduced pressure, drying promptly gets bilobalide K potassium hydroxide mixture.
Embodiment 45.A kind of bilobalide K sodium hydroxide mixture.Preparation by the following method: get sodium hydroxide 0.45 gram, add ethanol 500ml water-bath dissolving, make the ethanol hydrogen production sodium hydroxide solution; Other gets 5 gram bilobalide K powder, adds ethanol 200ml, and 65 ℃ of stirring and dissolving are filtered, filtrate and the merging of ethanol hydrogen production sodium hydroxide solution, and stirring and evenly mixing, 70 ℃ of water-baths 2～4 hours, concentrating under reduced pressure, drying promptly gets bilobalide K sodium hydroxide mixture.
Embodiment 46.A kind of pharmaceutical preparation of bilobalide K, it is the medicament of being made by following materials of weight proportions:
Bilobalide K 50 grams
Microcrystalline Cellulose 30 grams
Lactose 30 grams
Sodium starch glycolate 5 grams
2%HPMCE5 solution 10 grams that contain 5% tween 80
Magnesium Stearate 2 grams
Its preparation method is to get bilobalide K and be dissolved in small amount of ethanol; Microcrystalline Cellulose, lactose, sodium starch glycolate are crossed 100 mesh sieves respectively and are mixed, and add bilobalide K ethanolic soln and fully stirring, and ethanol is all volatilized; With the 2%HPMC solution that contains 5% tween 80 is tackiness agent system softwood, crosses 20 mesh sieve system particles, and wet granular is in 40 ℃ of baking oven forced air dryings; Dried particle is crossed the whole grain of 20 mesh sieves, with the Magnesium Stearate mixing, in can 1000 capsules.
Embodiment 47.A kind of pharmaceutical preparation of bilobalide K, it is the medicament of being made by following materials of weight proportions:
Bilobalide K 100 grams
Microcrystalline Cellulose 60 grams
Sucrose 100 grams
Hydroxypropylated starch 7 grams
2%HPMCE5 solution (containing 5% tween 80) 20 grams
Stearic acid 3 grams
Its preparation method is as follows:
Get bilobalide K and be dissolved in small amount of ethanol; Microcrystalline Cellulose, sucrose, hydroxypropylated starch are crossed 100 mesh sieves respectively and are mixed, and add bilobalide K ethanolic soln and fully stirring, and ethanol is all volatilized; HPMC solution with tween 80 is tackiness agent system softwood, crosses 20 mesh sieve system particles, and wet granular is in 50 ℃ of baking oven forced air dryings; Dried particle is crossed the whole grain of 20 mesh sieves, with the Magnesium Stearate mixing, is pressed into 1000.
Embodiment 48.A kind of pharmaceutical preparation of bilobalide K, it is the tablet of being made by following materials of weight proportions:
Bilobalide K 150mg
Microcrystalline Cellulose 300mg
Hypromellose K4M 80mg
3% HPMC (E5) aqueous solution 30mg
Talcum powder 4mg
Bilobalide K, Microcrystalline Cellulose, hypromellose K4M are crossed 60 mesh sieves and be mixed, add 3% HPMC (E5) aqueous solution and make softwood in right amount, cross 20 mesh sieves and granulate.The whole grain of 20 mesh sieves is crossed in 40 ℃ of baking oven forced air dryings, dried particle, adds the talcum powder of recipe quantity, mixes, and presses No. 1 capsule of recipe quantity can, every bilobalide-containing K 150mg.
Embodiment 49.A kind of pharmaceutical preparation of bilobalide K, it is the tablet of being made by following materials of weight proportions:
Bilobalide K 120mg
N.F,USP MANNITOL 200mg
Hypromellose K4M 80mg
3% HPMC (E5) aqueous solution 15mg
Talcum powder 3mg
Bilobalide K, N.F,USP MANNITOL, hypromellose K4M are crossed 60 mesh sieves and be mixed, add 3% HPMC (E5) aqueous solution and make softwood in right amount, cross 20 mesh sieves and granulate.The whole grain of 20 mesh sieves is crossed in 50 ℃ of baking oven forced air dryings, dried particle, adds the talcum powder of recipe quantity, mixes compressing tablet, every bilobalide-containing K 120mg.
Embodiment 50.A kind of pharmaceutical preparation of bilobalide K is used for the treatment to ishemic stroke disease, and it is the capsule of being made by following materials of weight proportions:
Bilobalide K 150 grams
Dextrin 150 grams
Starch 150 grams
Calcium carboxymethylcellulose 10 grams
Polyvidone 10 grams
Calcium stearate 5 grams
The preparation method is as follows: bilobalide K is dissolved in small amount of ethanol; Dextrin, starch, calcium carboxymethylcellulose are crossed 100 mesh sieves respectively and are mixed, and add bilobalide K ethanolic soln and fully stirring, and ethanol is all volatilized; With the povidone solution is tackiness agent system softwood, crosses 20 mesh sieve system particles, and wet granular is in 60 ℃ of baking oven forced air dryings; Dried particle is crossed the whole grain of 20 mesh sieves, with the calcium stearate mixing, in can 1000 capsules.
Embodiment 51.A kind of pharmaceutical preparation of bilobalide K, it is the capsule of being made by following materials of weight proportions:
Bilobalide K 130 grams
Calcium phosphate 200 grams
Hydroxypropylated starch 8 grams
Pregelatinized Starch 6 grams
Micropowder silica gel 3 grams
The preparation method is as follows: bilobalide K is dissolved in small amount of ethanol; Calcium phosphate, hydroxypropylated starch are crossed 100 mesh sieves respectively and are mixed, and add bilobalide K ethanolic soln and fully stirring, and ethanol is all volatilized; With pregelatinized Starch solution is tackiness agent system softwood, crosses 20 mesh sieve system particles, and wet granular is in 55 ℃ of baking oven forced air dryings; Dried particle is crossed the whole grain of 20 mesh sieves, with the micropowder silica gel mixing, in can 1000 capsules.
Embodiment 52.A kind of pharmaceutical preparation of bilobalide K, it is the tablet of being made by following materials of weight proportions:
Bilobalide K 80 grams
Secondary calcium phosphate 100 grams
Hydroxypropylcellulose 3 grams
Hypromellose 5 grams
Macrogol 4000 1 gram
Get bilobalide K and be dissolved in small amount of ethanol; Secondary calcium phosphate, hydroxypropylcellulose are crossed 100 mesh sieves respectively and are mixed, and add bilobalide K ethanolic soln and fully stirring, and ethanol is all volatilized; With hypromellose solution is tackiness agent system softwood, crosses 20 mesh sieve system particles, and wet granular is in 50 ℃ of baking oven forced air dryings; Dried particle is crossed the whole grain of 20 mesh sieves, with the Macrogol 4000 mixing, is pressed into 1000, can be used for the treatment to ishemic stroke disease.
Embodiment 53.A kind of pharmaceutical preparation of bilobalide K meglumine, it is to be made by following materials of weight proportions,
Bilobalide K meglumine 10-100 gram
Microcrystalline Cellulose 30-50 gram
Lactose 30-50 gram
Sodium starch glycolate 5-10 gram
2%HPMCE5 solution (containing 5% tween 80) is an amount of
Magnesium Stearate 1-5 gram
Its preparation method is to get the bilobalide K meglumine and be dissolved in small amount of ethanol; Microcrystalline Cellulose, lactose, sodium starch glycolate are crossed 100 mesh sieves respectively and are mixed, and add bilobalide K meglumine ethanolic soln and fully stirring, and ethanol is all volatilized; HPMC solution with tween 80 is tackiness agent system softwood, crosses 20 mesh sieve system particles, and wet granular is in 50--60 ℃ of baking oven forced air drying; Dried particle is crossed the whole grain of 20 mesh sieves, with the Magnesium Stearate mixing, in can 1000 capsules.
Embodiment 54.A kind of pharmaceutical preparation of bilobalide K Methionin, it is to be made by following materials of weight proportions,
Bilobalide K Methionin 10-100 gram
Microcrystalline Cellulose 30-50 gram
Lactose 30-50 gram
Sodium starch glycolate 5-10 gram
2%HPMCE5 solution (containing 5% tween 80) is an amount of
Magnesium Stearate 1-5 gram
Its preparation method is to get bilobalide K Methionin and be dissolved in small amount of ethanol; Microcrystalline Cellulose, lactose, sodium starch glycolate are crossed 100 mesh sieves respectively and are mixed, and add bilobalide K Methionin ethanolic soln and fully stirring, and ethanol is all volatilized; HPMC solution with tween 80 is tackiness agent system softwood, crosses 20 mesh sieve system particles, and wet granular is in 50--60 ℃ of baking oven forced air drying; Dried particle is crossed the whole grain of 20 mesh sieves, with the Magnesium Stearate mixing, is pressed into 1000.
Embodiment 55.The preparation of the arginic slow releasing capsule of a kind of bilobalide K,
Bilobalide K arginine 100mg
Microcrystalline Cellulose 20mg
Hypromellose K4M 80mg
3% HPMC (E5) aqueous solution is an amount of
Talcum powder 4mg
Bilobalide K arginine, Microcrystalline Cellulose, hypromellose K4M are crossed 60 mesh sieves and be mixed, add 3% HPMC (E5) aqueous solution and make softwood in right amount, cross 20 mesh sieves and granulate.40-50 ℃ of baking oven forced air drying.Dried particle is crossed the whole grain of 20 mesh sieves, adds the talcum powder of recipe quantity, mixes.Press No. 1 capsule of recipe quantity can, every bilobalide-containing K arginine 100mg.
Embodiment 56.The preparation of the arginic slow releasing tablet of a kind of bilobalide K,
Bilobalide K arginase 12 0mg
Lactose 20mg
Hypromellose K4M 80mg
3% HPMC (E5) aqueous solution is an amount of
Talcum powder 4mg
Bilobalide K arginine, lactose, hypromellose K4M are crossed 60 mesh sieves and be mixed, add 3% HPMC (E5) aqueous solution and make softwood in right amount, cross 20 mesh sieves and granulate.40-50 ℃ of baking oven forced air drying.Dried particle is crossed the whole grain of 20 mesh sieves, adds the talcum powder of recipe quantity, mixes compressing tablet, every bilobalide-containing K20mg.
Embodiment 57.A kind of preparation of bilobalide K soft capsule,
Content glue shell
Bilobalide K 50g gelatin 46.00%
Soybean oil 0.51 glycerine 17.82%
Water 36.18%
Get bilobalide K and be added in the soybean oil, mill is even, is made into soft capsule.Every bilobalide-containing K 50mg.
Embodiment 58.A kind of preparation of bilobalide K injection,
Bilobalide K 20mg
Soxylat A 25-7 Viscotrol C 1.0mg
Dehydrated alcohol 5.0mg
Water for injection adds to 5.0mL
Bilobalide K is dissolved in dehydrated alcohol, add 20% Soxylat A 25-7 Viscotrol C (CremophorELP), mixing, reduction vaporization is removed ethanol, add an amount of water for injection and be mixed into clear solution, through 0.22 μ m filtering with microporous membrane, coating-dividing sealing, in 100 ℃ of flowing steam sterilizations 30 minutes promptly, every bilobalide-containing K 20mg.
Embodiment 59.A kind of preparation of bilobalide K arginine injection,
Bilobalide K 20.0g
Arginase 12 2.2g
N.F,USP MANNITOL 32.0g
Water for injection is to 2000ml
Get bilobalide K and arginine and put in the appropriate vessel, add injection water 1800ml, stir, ultrasonic to dissolving, add the N.F,USP MANNITOL stirring and make dissolving; Add needle-use activated carbon by 0.1%, stirred 30 minutes, and took off the charcoal suction filtration in the container of cleaning, add water for injection to 2000ml through the titanium core, solution stirring was made evenly in 5 minutes, again through 0.22 μ m filtering with microporous membrane, the filtrate can in the 7ml cillin bottle, every bottle of 2ml, butyl rubber bung beyond the Great Wall partly then, deliver on the flaggy in the freeze drying box, insert temp probe, close chamber door.Press the freeze-drying curve lyophilize, the final drying temperature is more than 35 ℃ and kept 2 hours.Close plug, venting, outlet rolls lid.
Embodiment 60.A kind of preparation of bilobalide K suspension type injection,
Bilobalide K 20mg
Xylo-Mucine 10mg
Polysorbate 80 0.1mg
Ethyl p-hydroxybenzoate 0.5mg
Propylben 0.5mg
Potassium primary phosphate 16.7mg
Dipotassium hydrogen phosphate 1.7mg
Water for injection adds to 2ml
Bilobalide K is carried out comminution by gas stream, get the following micro mist of particle diameter 10 μ m.Potassium primary phosphate and dipotassium hydrogen phosphate are dissolved in the water for injection, add ethyl p-hydroxybenzoate and propyl ester, add Xylo-Mucine again, make whole dissolvings under 60 ℃ of conditions.Morellic acid after the micronization is placed container, add Polysorbate 80 and be ground into thin pasty state, above-mentioned solution is added gradually, after stirring, grind 5 to 10 times through colloidal mill.Routinely measuring method measure content qualified after, be divided in the ampoule, in 100 ℃ of flowing steam sterilizations 30 minutes promptly, every bilobalide-containing K 20mg.
The injection of present embodiment also can be selected following auxiliary material for use: solubilizing agent is as Tweens, pluronic F-68, Soxylat A 25-7 castor-oil plant wet goods; Solubility promoter is as amides such as urea, ethanamide, thiocarbamide, benzamide etc.; Suspending agent is as Xylo-Mucine, polyvidone, HPMC etc.; Sanitas is as: Metagin, second, third and butyl ester; The pH regulator agent is as Citric Acid and citrate, phosphoric acid salt etc.; Solvent is as water for injection, injection ethanol, propylene glycol etc.
Embodiment 61.The preparation of the compound sustained-released tablet of a kind of bilobalide K arginine,
Bilobalide K arginase 12 0mg
Selagine 50 μ g
Lactose 20mg
Hypromellose K4M 80mg
3% HPMC (E5) aqueous solution is an amount of
Talcum powder 4mg
Bilobalide K arginine, lactose, hypromellose K4M are crossed 60 mesh sieves and be mixed, add 3% HPMC (E5) aqueous solution and make softwood in right amount, cross 20 mesh sieves and granulate.40-50 ℃ of baking oven forced air drying.Dried particle is crossed the whole grain of 20 mesh sieves, adds the talcum powder of recipe quantity, mixes compressing tablet, every bilobalide-containing K arginase 12 0mg, selagine 50 μ g.
Embodiment 62.A kind of preparation of bilobalide K arginine injection, get bilobalide K arginine 10 grams and add fresh water for injection 1000ml dissolving, the aqueous citric acid solution with 10% is transferred pH to 8.0, adds 8 gram NaCl, needle-use activated carbon 2.0 grams, carbon removal is filtered in stirring at room absorption 30 minutes, adds 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, packing, injection is made in freeze-drying.
Embodiment 63.A kind of bilobalide K propylamine injection, 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 bilobalide K 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 64.A kind of with the injection of bilobalide K glycine as effective ingredient.Preparation by the following method: get hydroxypropyl-beta-cyclodextrin 350 grams and add injection water 5000ml, reflux 30 minutes gets the solution I, and 80 ℃ of insulations are standby; Other gets 65g bilobalide K glycine mixture and dissolves, and is incubated 60 minutes, puts and is chilled to room temperature, filter, and filtering with microporous membrane (0.22 μ m), packing (5ml/ bottle), lyophilize promptly gets bilobalide K glycine injection.
Embodiment 65.A kind of bilobalide K methylamine injection.Preparation by the following method: get methylamine 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 bilobalide K 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.
Embodiment 66.A kind of bilobalide K ethamine injection.Preparation by the following method: get fresh water for injection 1000ml and be heated to 80 ℃, add 8 gram porphyrizes and cross the bilobalide K ethamine 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.
Claims (7)
1. a bilobalide K and mixture (I) G thereof that general formula is (I),
And, with bilobalide K or its mixture (I) G and pharmaceutically the acceptable pharmaceutical carrier mix and form composition; Wherein G is an alkaline matter.
2. the mixture of bilobalide K according to claim 1 (I) G is characterized in that, G is selected from and contains an itrogenous organic substance to eight carbon atoms in metal alkaline material or the molecule.
3. the mixture of bilobalide K according to claim 1 (I) G is characterized in that, described G is arginine or Methionin or meglumine or sodium hydroxide.
4. the preparation method of the mixture of a bilobalide K (I) G is characterized in that, bilobalide K and alkaline matter are 1: 0.2～5 ratio with mol ratio, form mixture in water and/or alcoholic solvent.
5. the preparation method of the mixture of a kind of bilobalide K according to claim 4 (I) G is characterized in that its step is as follows: get alkaline matter, be dissolved in water, be heated to 70-90 ℃, add bilobalide K, stirring and dissolving, concentrate, dry enriched material, promptly.
6. the preparation method of the mixture of a kind of bilobalide K according to claim 4 (I) G, it is characterized in that its step is as follows: get alkaline matter, add water and dissolve than mixing solutions arbitrarily with organic solvent, be heated to 40-70 ℃, add the alcoholic solution of bilobalide K or bilobalide K, be stirred to dissolving, filter, filtrate decompression concentrates, reclaim organic solvent, dry enriched material, promptly.
7. claim 1 or 2 or 3 described bilobalide Ks or its mixture (I) G purposes in the medicine of the shock that preparation treatment ischemia apoplexy, control thrombosis, senile dementia, organ-graft refection, acute inflammation, heart allergy, intracellular toxin cause.
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| CN102400872A (en) * | 2011-11-03 | 2012-04-04 | 张建城 | Heat generation device with complementary energy storage of solar energy and wind energy |
| CN104892628A (en) * | 2015-06-29 | 2015-09-09 | 成都百裕科技制药有限公司 | Bilobalide K derivative and preparation method and application thereof |
| CN107773763A (en) * | 2016-08-25 | 2018-03-09 | 江苏康缘药业股份有限公司 | Bilobalide K beta cyclodextrin clathrate and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1257907C (en) * | 2002-08-23 | 2006-05-31 | 江苏康缘药业股份有限公司 | Ginkgo lactone compound and its preparation and medicinal composition containing it |
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2005
- 2005-08-25 CN CN 201010528887 patent/CN102002052B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102400872A (en) * | 2011-11-03 | 2012-04-04 | 张建城 | Heat generation device with complementary energy storage of solar energy and wind energy |
| CN102400872B (en) * | 2011-11-03 | 2013-08-14 | 张建城 | Heat generation device with complementary energy storage of solar energy and wind energy |
| CN104892628A (en) * | 2015-06-29 | 2015-09-09 | 成都百裕科技制药有限公司 | Bilobalide K derivative and preparation method and application thereof |
| CN107773763A (en) * | 2016-08-25 | 2018-03-09 | 江苏康缘药业股份有限公司 | Bilobalide K beta cyclodextrin clathrate and preparation method thereof |
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| CN102002052B (en) | 2013-07-17 |
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