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
- Publication number
- CN102002052A CN102002052A CN 201010528887 CN201010528887A CN102002052A CN 102002052 A CN102002052 A CN 102002052A CN 201010528887 CN201010528887 CN 201010528887 CN 201010528887 A CN201010528887 A CN 201010528887A CN 102002052 A CN102002052 A CN 102002052A
- Authority
- CN
- China
- Prior art keywords
- ginkgolide
- bilobalide
- compound
- dissolving
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 238000002360 preparation method Methods 0.000 title claims abstract description 75
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- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 claims description 201
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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 a divisional application of CN200510094106.3, the original application date is 25/8/2005, the application number is CN200510094106.3, and the invention creation name is: bilobalide K and its compound, and its preparation method and application are provided.
Technical Field
The invention relates to a bilobalide substance and a compound thereof; in particular to ginkgolide K and a compound thereof, and also relates to a preparation method and application of the ginkgolide K and the compound thereof.
Background
Bilobalide is an effective substance extracted from Chinese herbal medicine ginkgo leaves, and the substance can be further subdivided into bilobalide A, B, C, bilobalide and the like in structure, and detailed literature reports are reported on the extraction method of bilobalide, for example, Li Xingang et al describes a laboratory extraction method of bilobalide (see Li Xingang et al, research on the laboratory extraction method of bilobalide in ginkgo leaves, No. 1 of 1998 of Chinese medical industry journal), and Chinese patent document CN1195665A describes an extraction method of bilobalide and a preparation containing bilobalide, wherein ginkgo leaves are extracted by boiling with water, an extraction filtrate is adsorbed by an adsorbent, then desorbed by ethanol, ethanol is recovered, precipitated crystals are dissolved, recrystallized and dried to obtain the bilobalide. Chinese patent document CN1313287A discloses a process for producing ginkgolides. There are many reports on the method of separating ginkgolide monomers from the total extract of ginkgolides, for example, pinus sylvestris et al have described the method of separating and structurally determining ginkgolides from ginkgo leaves (see pinus sylvestris et al, separation and structural determination of ginkgolides from ginkgo leaves, 4 th of 1995, china journal of pharmaceutical chemistry). Chinese patent document CN1287121A discloses a method for preparing pharmaceutical ginkgolide A, B from folium ginkgo or folium ginkgo extract. There are more detailed reports on the pharmacological actions of ginkgolides (see Chengwet et al, the progress of the study of the chemical structure and pharmacological actions of ginkgolides, the 9 th stage of 1998 in the Chinese journal of pharmacy). Although many studies on ginkgolides and preparations thereof have been reported in the prior art, the studies on ginkgolides have not been stopped, and particularly, studies on the isolation of ginkgolide monomers and derivatives thereof have been reported in the literature. The current researches on effective monomers in ginkgolides have reported structures of ginkgolide A, B, C and the like.
The invention relates to a novel substance (I) which is reported and found in 2001 (see Wang Ying et al, LC/DAD/ESI/MS analysis and structure identification of trace components in ginkgolide extract, Acta pharmaceutical Sinica 2001, 36 (8): 606-608), and is named as ginkgolide K. Because the content of the ginkgolide K in the ginkgo is very low, only about five parts per million is needed, the development and the application of the ginkgolide K preparation are restricted, the research report of the pharmacological action of the ginkgolide K is not seen, and the basis of developing the industrialization of the medicament is lacked. At present, no ginkgolide K preparation is available on the market at home and abroad.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a ginkgolide K composition formed by mixing ginkgolide K and a pharmaceutically acceptable drug carrier.
The invention aims to solve another technical problem of providing a ginkgolide K compound with good water solubility and stability.
The invention aims to solve the technical problem of providing a preparation method of ginkgolide K.
The invention aims to solve the technical problem of providing a preparation method of a ginkgolide K compound.
The invention aims to solve the technical problem of providing medical application of the ginkgolide K and the compound thereof.
The technical problem to be solved by the present invention is achieved by the following technical means. The invention relates to a ginkgolide K with a general formula (I) and a compound (I). G thereof,
and, the composition is formed by mixing the bilobalide K or the compound (I). G thereof and a pharmaceutically acceptable drug carrier, for example, a composition formed by mixing a drug carrier adhesive, a suspending agent, a cosolvent, a solid dispersing agent, an inclusion agent and the like; wherein G is a basic substance, for example: 1) arginine, lysine, histidine, glycine and the like and derivatives thereof; 2) methylamine, ethylamine, propylamine, butylamine, ethylenediamine, meglumine, urea, guanidine hydrochloride, 1, 2-ethylenediamine, ethanolamine and the like and derivatives thereof; 3) amides such as formamide, dimethylformamide, pantothenic acid, and nicotinamide; 4) alkyl imidazole, alkyl pyridine, alkyl trimethyl amine salt, thiamine hydrochloride, etc. 5) Metal alkaline substances such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The ginkgolide K compound (I). G is characterized in that G is selected from metal basic substances or nitrogen-containing organic substances containing one to eight carbon atoms in the molecule.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The ginkgolide K compound (I). G is characterized in that G is arginine, lysine, meglumine or sodium hydroxide.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The invention also provides a preparation method of the ginkgolide K, which is characterized by comprising the following steps: (1) adding bilobalide B or bilobalide extract containing bilobalide B into alkaline water solution or alkaline water-alcohol mixed solution or water-alcohol mixed solution, heating in water bath for dissolving, and keeping the temperature;
(2) detecting that the ginkgolide B is basically completely converted, then adjusting the pH value of the solution to be acidic by using an acidic aqueous solution, standing, filtering or centrifuging to obtain a precipitate, taking the precipitate, adding water for washing, dissolving by using an organic solvent, concentrating, and recrystallizing until the purity reaches over 90 percent to obtain the ginkgolide B;
or,
(2) detecting that the ginkgolide B is basically completely converted, concentrating and crystallizing, dissolving the crystal with an organic solvent, concentrating, and recrystallizing until the purity reaches over 90 percent.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The preparation method of the ginkgolide K is characterized in that the alkaline aqueous solution is an aqueous solution of sodium hydroxide, potassium hydroxide, arginine, meglumine or lysine; the alcohol is methanol, ethanol or n-butanol; the acid solution is hydrochloric acid solution or citric acid solution with any concentration, and preferably 0.2-1.0 mol/L hydrochloric acid solution or citric acid solution; the organic solution is methanol, ethanol, acetone or n-butanol.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The invention also provides a preparation method of the ginkgolide K compound (I). G, which is characterized in that the ginkgolide K and alkaline substances form a compound in water and/or alcohol solvent according to the molar ratio of 1: 0.2-5. In this way, it is possible to form a complex in its entirety.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The preparation method of the ginkgolide K compound (I). G is characterized by comprising the following steps: dissolving alkaline substance in water, heating to 70-90 deg.C, adding bilobalide K, stirring for dissolving, concentrating, and drying the concentrate.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The preparation method of the ginkgolide K compound (I). G is characterized by comprising the following steps: dissolving alkaline substance in mixed solution of water and organic solvent at any ratio, heating to 40-70 deg.C, adding bilobalide K or alcohol (methanol, ethanol, propylene glycol, n-butanol, etc.) solution of bilobalide K, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering organic solvent, and drying the concentrate.
The most preferred compound of ginkgolide K of the present invention is a compound of formula (I) wherein G is arginine or lysine or meglumine.
The complex of the invention can form a complex in water and/or alcohol solvent in the process of preparation; or the compound is firstly formed in water and/or alcohol solvent, and then dried to form a solid compound which is then used in the preparation.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The ginkgolide K or the compound (I). G thereof is used as an effective component for preparing the medicine for treating ischemic cerebral apoplexy, preventing and treating thrombosis, senile dementia, organ transplant rejection, acute inflammation, cardiac allergy and shock caused by endotoxin. The medicine is any one of dosage forms in pharmaceutics, including tablets, capsules, sprays, granules, dropping pills, oral liquid, injection, freeze-dried powder injection, infusion solution, liposome injection, targeted administration injection, suppositories, sustained release preparations and controlled release preparations.
The ginkgolide K and the compound preparation thereof can be applied to patients by oral administration, nasal inhalation, rectal administration or parenteral administration, can be prepared into solid preparations, and can also be prepared into liquid preparations or injection preparations, wherein the preferable forms are tablets, capsules, granules, dropping pills, oral liquid and injections. The identification and detection method comprises the following steps:
1. thin layer chromatography identification method
Preparation of test solution
Dissolving and/or diluting bilobalide K compound preparation with water to obtain solution equivalent to bilobalide K5mg/ml, acidifying 1ml of the solution with 6mol/L hydrochloric acid solution 0.2ml, standing for 30min, centrifuging (3000 r/min) for 10 min, discarding supernatant, washing precipitate with small amount of water to neutrality, and dissolving with 1ml of acetone. Or pretreating bilobalide K extract preparation to obtain bilobalide K extract, and dissolving with acetone to obtain 5mg/ml sample solution.
Preparation of reference solution A proper amount of bilobalide K reference is taken, and dissolved in acetone to obtain solutions containing 1mg per 1 mL.
The determination method comprises adopting thin layer chromatography (appendix VI B of first part of Chinese pharmacopoeia 2000 edition), respectively applying 10 μ L of the above sample solution and control solution to the same silica gel GF254 thin layer plate containing 4% sodium acetate and 0.5% CMC-Na solution, spreading with petroleum ether (30-60 deg.C) -acetone-methanol (10: 2.5: 0.3) as developing agent, taking out, drying, heating at 160 deg.C for 30min, and inspecting under ultraviolet lamp 365nm to obtain spots with the same color at corresponding positions of the sample and control.
[ measurement of content ] measurement was carried out according to high performance liquid chromatography (appendix VI D of the first part of the Chinese pharmacopoeia 2000 edition).
Chromatographic conditions and system adaptability experiment: octadecylsilane chemically bonded silica is used as a filling agent; using isopropanol-methanol-water (8: 24: 80) as a mobile phase; the detection wavelength is 220 nm. The theoretical plate number is not less than 7000 according to ginkgolide K, and the separation degree between peaks is in accordance with pharmacopoeia requirements.
Preparation of control solutions: precisely weighing appropriate amount of ginkgolide K reference substance dried at 105 deg.C to constant weight, dissolving with 50% acetone respectively, and making into solution containing 0.5mg per 1 mL.
Preparation of a test solution:
1) dissolving and/or diluting bilobalide K compound preparation with water to 5mg/ml equivalent to bilobalide K, taking 5ml of the solution or taking 5ml of injection or oral liquid, placing into a 10ml measuring flask, adding 1ml of 6mol/L hydrochloric acid solution, standing at room temperature for 3.5 hours, dissolving with acetone and diluting to scale, shaking, standing for 30 minutes, and filtering with microporous membrane (aperture 0.45 μm). The test solution should be measured within 2 hours.
2) Or dissolving bilobalide K preparation in acetone to obtain solution containing bilobalide K2.5mg/ml, and filtering to obtain filtrate.
The determination method comprises the following steps: precisely measuring 20 μ L of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph, measuring, and calculating.
The ginkgolide K compound has good pharmacological activity, and the pharmacological experiment research result is as follows:
1. general pharmacological study of ginkgolide K
(1) The tail vein injection of 10 mg/kg, 20mg/kg and 40mg/kg of ginkgolide K compound has no obvious influence on the behavior and coordinated movement of mice, and has no synergistic effect on the sodium pentobarbital with subthreshold dose, which indicates that the three doses of the composition have no obvious side effect on the mental nervous system of the mice.
(2) The intravenous injection administration of 5, 10 and 20mg/kg of ginkgolide K compound has no obvious influence on the blood pressure, heart rate, electrocardio, respiratory frequency and amplitude of the anesthetized dog, and the fact that the three doses of the ginkgolide K compound have no obvious side effect on the cardiovascular system and the respiratory system of the anesthetized dog is shown.
2. Pharmacodynamic study of ginkgolide K
(1) The ginkgolide K compound of 1.0, 3.0 and 9.0mg/kg iV can reduce the stroke score of MCAO rats, reduce the MCAO infarction range and reduce the water content of brain tissues (P is less than 0.01), and the action intensity of the ginkgolide K compound is obviously superior to that of the disodium aurantiate injection.
(2) The contents of MDA, LA and the like in brain tissues of rats with focal cerebral ischemia reperfusion injury can be reduced by 1.0, 3.0 and 9.0mg/kg iV of the ginkgolide K compound (P is less than 0.01), which shows that the ischemia and anoxia and peroxidation degree of the brain tissues are obviously inhibited; meanwhile, the contents of SOD and GSH are increased (P is less than 0.01), which reflects that the oxidation resistance and the free radical removing capability of the medicine to the organism are improved.
(3) The ginkgolide K compound 1.0, 3.0 and 9.0mg/kg iV can obviously protect the cerebral tissue structure of the reperfusion injury of the rats with focal cerebral ischemia, and the nuclear shrinkage and nuclear lysis degree of cerebral cortical pyramidal cells and brain parenchymal nerve cells is obviously reduced compared with that of an ischemia control group, and softened foci are reduced.
(4) Compared with a model group, 1.0, 3.0 and 9.0mg/kg iV of the ginkgolide K compound can obviously shorten the recovery time of the EEG and the righting reflex of the diffuse cerebral ischemia rat (P is less than 0.01) and obviously reduce the permeability of Evans blue (P is less than 0.01).
(5) The ginkgolide K compound Iv starts to take effect after 8min, the peak reaching time is about 20min, and the duration time can reach more than 100 min; the onset time of the medicine ig is 20-30min, the peak reaching time is about 45min, and the duration time can reach more than 120 min. The same dose group iV had a stronger effect than ig.
(6) And the ginkgolide K compound 2, 4 and 8mg/kg iV can obviously prolong the survival time of the mouse in an anoxic state (P is less than 0.01).
(7) And the ginkgolide K compound has the obvious inhibiting effect (P is less than 0.01) on PAF (platelet aggregation) induced in vitro of rabbits at 0.25, 0.5 and 1.0mg/ml, and has the obvious depolymerization effect (P is less than 0.01). The ADP-induced platelet aggregation effect is weak (P is less than 0.05 or P is less than 0.01), and no obvious depolymerization effect is generated (P is more than 0.05). The iV0.25, 0.50 and 1.0mg/kg of the medicine have obvious inhibition effect (P is less than 0.01) on platelet aggregation in rabbits induced by PAF, and the medium and high dose groups also have obvious depolymerization effect (P is less than 0.01). Has no obvious effect on the number of rabbit platelets (P is more than 0.05).
(8) The ginkgolide K compound iv0.25, 0.50 and 1.0mg/kg can obviously inhibit the thrombosis of rabbit artery-vein bypass (P is less than 0.01).
(9) And the ginkgolide K compound iv is 0.5, 1.0 and 2.0mg/kg, and has obvious thrombolysis effect on rat artery-vein bypass thrombus (P is less than 0.01).
(10) After 0.5mg/kg of the ginkgolide K compound iv is taken, PAF can be obviously inhibited from inducing in-vivo platelet aggregation and has obvious depolymerization effect (P is less than 0.01), the effect lasts for 30min, the peak time is 5min, the platelet aggregation inhibition rate can reach about 79 percent, and the depolymerization rate in 1 min is about 82 percent. After 30min, the ginkgolide K ig1.5mg/kg can obviously inhibit PAF (platelet aggregation) induced in-vivo platelet aggregation of rabbits and has obvious depolymerization effect (P is less than 0.01), the duration is 60min, the peak time is about 42min, the maximum inhibition rate of platelet aggregation is about 45%, and the depolymerization rate in 1 min is about 40%.
(11) Effect of Alzheimer's disease model rats
11.1 Effect on learning and memory and spatial exploration
The results show that the latency of each group of rats is shortened along with the increase of the training days, the latency of each group of rats on the 1 st day and the 2 nd day has no significant difference, and the significant difference starts to appear on the 3 rd day. Compared with a blank group, the model group has obviously prolonged latency and reduced platform crossing times (P is less than 0.01); the incubation period of the rats in each group after gastric lavage is obviously shorter than that in the model group, and the difference is obvious (P is less than 0.01). The results are shown in Table 1.
TABLE 1 Effect on Water maze Experimental latency and number of platform crossings
Note: compared with the blank control group, the composition of the composition,△△p＜0.01. in comparison to the AD model group,*p＜0.05，**p＜0.01。
11.2 Effect on SOD activity and MDA content in brain tissue of rat model of senile dementia
The result shows that compared with the blank control group, the AD model group has obviously reduced SOD activity and increased MDA content (P is less than 0.01); compared with the AD model group, the SOD activity of rats administrated by gastric lavage is increased to different degrees, the MDA content is reduced to different degrees, and the difference is obvious compared with the AD model group. The results are shown in Table 2.
TABLE 2 Effect on SOD activity and MDA content in brain tissue of rat model of Alzheimer's disease
Note: compared with the blank control group, the composition of the composition,△△p is less than 0.01. In comparison to the AD model group,*p＜0.05，**p＜0.01。
(12) effect on Alzheimer's disease rat hippocampal neurotransmitter
The content of hippocampal Ach in the model group is obviously lower than that in the false injury group, and the difference is obvious (P is less than 0.01); after 20 days of drug gavage treatment, the content of hippocampus Ach in each drug group subjected to gavage administration is higher than that in the model group, and the statistical difference is realized (P is less than 0.01). The results are shown in Table 3.
TABLE 3 Effect on rat hippocampal Ach, 5-HT and NE content
Note: compared with the blank control group, the composition of the composition,△△p is less than 0.01. In comparison to the AD model group,*p＜0.05，**p＜0.01。
(13) effects on mouse model of Alzheimer
13.1 Effect on active learning and memory of Alzheimer's disease mice: compared with a normal control group, the test period of the model control group mouse obviously reduces the active avoidance latency (T1) and the active avoidance times (N1), while the passive avoidance latency (Ts) and the passive avoidance times (Ns) obviously increase, so the model control group mouse has obvious statistical significance (P is less than 0.01), and the model making success of the senile dementia model is shown; compared with the model control group, the ig administration group can obviously increase (T1) and (N1), reduce (Ts) and (Ns), and have obvious difference (P < 0.01). The results are shown in Table 4.
TABLE 4 influence on active learning and memory of Alzheimer's disease mice
Note: compared with the blank control group, the composition of the composition,△p＜0.05，△△p is less than 0.01. In comparison to the AD model group,*p＜0.05，**p＜0.01。
13.2 Effect on blood SOD, MDA and MAO content in Alzheimer's mice
Compared with the normal group, the MAO content of the model group mouse is obviously improved, but the MDA content is obviously improved, but the obvious significance is not shown; the SOD had no obvious change. After ig administration, the MAO content of the administration group can be obviously reduced, and the MDA content of the medium and large dose groups is also obviously reduced, but the SOD level is not obviously influenced. The results are shown in Table 5.
TABLE 5 Effect on blood SOD, MDA and MAO levels in Alzheimer's mice
| Group of | Dosage form | Number of examples | SOD(μg/gHB) | MDA(μmol/L) | MAO(10-3U/L) |
| 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△△ |
| Yinchuo 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 dose 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** |
Note: compared with the blank control group, the composition of the composition,△p＜0.05，△△p is less than 0.01. In comparison to the AD model group,*p＜0.05，**p＜0.01。
experiments prove that the ginkgolide K and the compound thereof can be used for preparing the medicine for treating ischemic cerebral apoplexy, preventing and treating thrombosis, senile dementia, organ transplant rejection, acute inflammation, heart allergy and shock caused by endotoxin, and have no toxic or side effect.
The invention utilizes the ginkgolide B to carry out derivatization to produce the ginkgolide K, solves the technical problem of extracting and refining the ginkgolide K in a large scale, and prepares medicinal preparations for pharmacological and toxicological research, and the result shows that the ginkgolide K is a platelet antagonistic factor with high activity and can be developed into clinical treatment medicaments which play an important role in pathological processes such as thrombosis, organ transplant rejection, senile dementia, acute inflammation, heart allergy, shock caused by endotoxin and the like.
The ginkgolide K compound has good water solubility and high stability, and is suitable for administration in various ways such as oral administration, intravenous injection and the like when being used as an effective component in a medicament. The compound of the invention can keep the natural structure of the ginkgolide K, and can fully exert the activity of the ginkgolide K after the ginkgolide K as an effective component enters a human body so as to achieve the purpose of treating diseases. Has important social significance and economic significance.
Detailed Description
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.
Example 1. A preparation method of ginkgolide K comprises the following steps: adding bilobalide B into alkaline water solution, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value of the solution to be acidic by using an acidic aqueous solution, standing, filtering to obtain a precipitate, taking the precipitate, washing the precipitate with water, dissolving the precipitate by using an organic solvent, concentrating, and recrystallizing until the purity reaches over 90 percent.
Example 2. A preparation method of ginkgolide K comprises the following steps: adding bilobalide extract containing bilobalide B into mixed solution of alkaline water and alcohol, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value of the solution to be acidic by using an acidic aqueous solution, standing, centrifuging to obtain a precipitate, taking the precipitate, washing the precipitate with water, dissolving the precipitate by using an organic solvent, concentrating, and recrystallizing until the purity reaches over 90 percent.
Example 3. A preparation method of ginkgolide K comprises the following steps: adding bilobalide B into mixed solution of water and alcohol, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, concentrating and crystallizing, dissolving the crystal with an organic solvent, concentrating, and recrystallizing until the purity reaches over 90 percent.
Example 4. A preparation method of ginkgolide K comprises the following steps: adding bilobalide B into sodium hydroxide water solution, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then regulating the pH value of the solution to be acidic by using a hydrochloric acid solution, standing, filtering to obtain a precipitate, taking the precipitate, washing the precipitate with water, dissolving the precipitate with methanol, concentrating, and recrystallizing until the purity reaches over 90 percent.
Example 5. A preparation method of ginkgolide K comprises the following steps: adding bilobalide extract containing bilobalide B into mixed aqueous solution of potassium hydroxide and methanol, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value of the solution to be acidic by using a citric acid aqueous solution, standing, centrifuging to obtain a precipitate, taking the precipitate, adding water for washing, dissolving by using ethanol, concentrating, and recrystallizing until the purity reaches over 90 percent.
Example 6. A preparation method of ginkgolide K comprises the following steps: adding bilobalide B into ethanol water solution, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, concentrating and crystallizing, dissolving the crystal with propanol, concentrating, and recrystallizing until the purity reaches over 90%.
Example 7. A preparation method of ginkgolide K comprises the following steps: adding bilobalide B into arginine water solution, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value of the solution to be acidic by using 0.2mol/L hydrochloric acid solution, standing, filtering to obtain a precipitate, taking the precipitate, washing the precipitate with water, dissolving the precipitate with propanol, concentrating, and recrystallizing until the purity reaches more than 90 percent.
Example 8. A preparation method of ginkgolide K comprises the following steps: adding bilobalide extract containing bilobalide B into mixed aqueous solution of meglumine and ethanol, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value of the solution to be acidic by using 1mol/L hydrochloric acid solution, standing, centrifuging to obtain a precipitate, taking the precipitate, adding water for washing, dissolving by using n-butanol, concentrating, and recrystallizing until the purity reaches more than 90%.
Example 9. A preparation method of ginkgolide K comprises the following steps: adding bilobalide B into propanol water solution, heating in water bath for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, concentrating and crystallizing, dissolving crystalline propanol, concentrating, and recrystallizing until the purity reaches over 90%.
Example 10. A preparation method of ginkgolide K comprises the following steps: adding bilobalide B into lysine water solution, heating in 70 deg.C water bath for 24 hr for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value to 1 by using 0.2mol/L citric acid solution, standing for 3 hours, filtering to obtain a precipitate, taking the precipitate, adding water to wash for 3 times, dissolving by using methanol, concentrating, and recrystallizing until the purity reaches more than 90 percent.
Example 11. A preparation method of ginkgolide K comprises the following steps: adding bilobalide extract containing bilobalide B into mixed water solution of lysine and propanol, heating in water bath at 85 deg.C for 12 hr for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then regulating the pH value to 2 by using 1.0mol/L citric acid solution, standing for 2 hours, centrifuging to obtain a precipitate, taking the precipitate, adding water to wash for 1 time, dissolving by using n-butanol, concentrating, and recrystallizing until the purity reaches more than 90%.
Example 12. A preparation method of ginkgolide K comprises the following steps: adding extract containing bilobalide B into n-butanol water solution, heating in water bath at 50 deg.C for 48 hr for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, concentrating and crystallizing, dissolving crystalline propanol, concentrating, and recrystallizing until the purity reaches over 90%.
Example 13. A preparation method of ginkgolide K comprises the following steps: adding extract containing bilobalide B into methanol water solution, heating in water bath at 90 deg.C for 72 hr for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, concentrating and crystallizing, dissolving the crystal in ethanol, concentrating, and recrystallizing until the purity reaches over 90%.
Example 14. A preparation method of ginkgolide K comprises the following steps: adding bilobalide extract containing bilobalide B into mixed water solution of potassium hydroxide and n-butanol, heating in water bath at 60 deg.C for 48 hr for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value to 3 by using 0.5mol/L citric acid solution, standing for 5 hours, centrifuging to obtain a precipitate, taking the precipitate, adding water to wash for 2 times, dissolving by using ethanol, concentrating, and recrystallizing until the purity reaches more than 90 percent.
Example 15. A preparation method of ginkgolide K comprises the following steps: adding ginkgolide B into mixed aqueous solution of sodium hydroxide and propanol, heating in water bath at 40 deg.C for 60 hr for dissolving, and keeping the temperature; detecting that the ginkgolide B is basically completely converted, then adjusting the pH value to 6 by using 0.5mol/L hydrochloric acid solution, standing for 10 hours, centrifuging to obtain a precipitate, taking the precipitate, adding water to wash for 1 time, dissolving by using ethanol, concentrating, and recrystallizing until the purity reaches more than 90 percent.
Example 16. A method for preparing ginkgolide K complex (I). G comprises mixing ginkgolide K and alkaline substance at a molar ratio of 1: 0.2 in water to form complex.
Example 17. A method for preparing ginkgolide K complex (I). G comprises mixing ginkgolide K and alkaline substance at a molar ratio of 1: 5 in water and alcohol solvent to form complex.
Example 18. A method for preparing ginkgolide K complex (I). G comprises mixing ginkgolide K and alkaline substance at a molar ratio of 1: 2.5 in alcohol solvent to form complex.
Example 19. A method for preparing a ginkgolide K complex (I). G comprises the following steps: dissolving alkaline substance in water, heating to 80 deg.C, adding bilobalide K, stirring for dissolving, concentrating, and drying the concentrate. The molar ratio of ginkgolide K to basic substance in this example was 1: 1.
Example 20. A method for preparing a ginkgolide K complex (I). G comprises the following steps: dissolving alkaline substance in water and organic solvent at any ratio, heating to 55 deg.C, adding bilobalide K or bilobalide K alcoholic solution, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering organic solvent, and drying the concentrate. The molar ratio of ginkgolide K to basic substance in this example was 1: 2.
Example 21. A ginkgolide K-arginine complex is prepared by the following steps: dissolving arginine in 1000ml of water, heating to 70 ℃, adding the ground 80-mesh-screened ginkgolide K, stirring to dissolve, concentrating, and drying the concentrate to obtain the product; sterile packaging to obtain ginkgolide K-arginine powder for injection; the molar ratio of ginkgolide K to basic substance in this example was 1: 4.
Example 22. A ginkgolide K-lysine complex is prepared by the following steps: dissolving 2.5 g of lysine in 20ml of ethanol, heating to 40 ℃, adding 5g of ginkgolide K which is ground and sieved by a 80-mesh sieve, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering the ethanol, and drying the concentrate to obtain the ginkgolide K-lysine compound.
Example 23. A ginkgolide K-meglumine compound is prepared by the following steps: dissolving meglumine 4 g in anhydrous ethanol 100ml, heating to 70 deg.C, adding bilobalide K10 g, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering ethanol, and drying the concentrate to obtain bilobalide K-meglumine compound.
Example 24. A ginkgolide K-histidine complex is prepared by the following steps: dissolving histidine 2.0g in 100ml of water, heating to 90 ℃, adding bilobalide K, stirring for dissolving, concentrating, and drying the concentrate to obtain the bilobalide K-histidine compound.
Example 25. A ginkgolide K-butylamine complex. The preparation method comprises the following steps: dissolving butylamine 4 g in water 500ml, heating to 75 deg.C, adding ginkgolide K ground into powder and sieved with 80 mesh sieve 8 g, stirring to dissolve, concentrating, and spray drying the concentrate to obtain ginkgolide K-butylamine complex.
Example 26. A ginkgolide K-guanidine hydrochloride compound is provided. The preparation method comprises the following steps: dissolving 4 g of guanidine hydrochloride in 800ml of water, heating to 85 ℃, adding 8 g of ginkgolide K, stirring for dissolving, concentrating, and drying the concentrate to obtain the ginkgolide K-guanidine hydrochloride compound.
Example 27. A bilobalide K-ethanolamine compound. The preparation method comprises the following steps: taking 6 g of ethanolamine, adding 50ml of 60% methanol for dissolving, heating to 50 ℃, adding 12 g of ginkgolide K, stirring until the mixture is dissolved, filtering, concentrating the filtrate under reduced pressure, recovering the methanol, and spray-drying the concentrate to obtain the ginkgolide K-ethanolamine compound.
Example 28. A ginkgolide K-urea compound. The preparation method comprises the following steps: dissolving urea 3 g in 50% n-butanol 100ml, heating to 60 deg.C, adding 6 g of fine 80 mesh sieved bilobalide K, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering n-butanol, and spray drying the concentrate to obtain bilobalide K-urea compound.
Example 29. A ginkgolide K-ethylenediamine complex is provided. The preparation method comprises the following steps: dissolving 4 g of ethylenediamine in 20ml of 80% propanol, heating to 45 ℃, adding 8 g of ginkgolide K, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering the propanol, and drying the concentrate to obtain the ginkgolide K-ethylenediamine compound.
Example 30. A ginkgolide K.1, 2-ethylenediamine compound is prepared by the following steps: dissolving 1, 2-ethylenediamine 2g in 20% ethanol 90ml, heating to 65 deg.C, adding 4 g of ginkgolide K, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering ethanol, and drying the concentrate to obtain ginkgolide K.1, 2-ethylenediamine compound.
Example 31. A bilobalide K-formamide complex is provided. The preparation method comprises the following steps: dissolving formamide 6 g in 900ml of water, heating to 75 ℃, adding 15 g of ginkgolide K which is ground and sieved by a 80-mesh sieve, stirring for dissolving, concentrating, and freeze-drying the concentrate to obtain the ginkgolide K-formamide compound.
Example 32. A bilobalide K-dimethylformamide compound is prepared by the following steps: dissolving 2g of dimethylformamide in 200ml of water, heating to 85 ℃, adding 4 g of ginkgolide K powder, stirring for dissolving, concentrating, and spray-drying the concentrate to obtain the ginkgolide K-dimethylformamide compound.
Example 33. A ginkgolide K-pantothenic acid complex is prepared by the following steps: dissolving 5g of pantothenic acid in 1000ml of water, heating to 90 ℃, adding 10 g of ginkgolide K powder which is ground and sieved by a 80-mesh sieve, stirring for dissolving, concentrating, and spray-drying the concentrate to obtain the ginkgolide K-pantothenic acid compound.
Example 34. A ginkgolide K-nicotinamide complex is provided. The preparation method comprises the following steps: dissolving nicotinamide 5g in water 400ml, heating to 86 deg.C, adding bilobalide K powder 10 g, stirring to dissolve, concentrating, and spray drying the concentrate to obtain bilobalide K-nicotinamide compound.
Example 35. A bilobalide K-alkyl imidazole complex. The preparation method comprises the following steps: taking 2g of alkyl imidazole, adding 60ml of 40% propanol for dissolving, heating to 50 ℃, adding 4 g of ginkgolide K powder, stirring until the ginkgolide K powder is dissolved, filtering, concentrating the filtrate under reduced pressure, recovering the propanol, and spray-drying the concentrate to obtain the ginkgolide K-alkyl imidazole compound.
Example 36. A bilobalide K-alkylpyridine complex is provided. The preparation method comprises the following steps: taking 2g of alkyl pyridine, adding 90ml of 30% ethanol solution for dissolving, heating to 45 ℃, adding 5g of ginkgolide K, stirring until the mixture is dissolved, filtering, concentrating the filtrate under reduced pressure, recovering ethanol, and spray-drying the concentrate to obtain the ginkgolide K-alkyl pyridine compound.
Example 37. A bilobalide K-alkyltrimethylammonium salt compound is provided. The preparation method comprises the following steps: taking 2.5 g of alkyl trimethyl amine salt, adding 200ml of 50% ethanol solution for dissolving, heating to 55 ℃, adding 5g of ginkgolide K which is ground and sieved by a 80-mesh sieve, stirring until the mixture is dissolved, filtering, concentrating the filtrate under reduced pressure, recovering ethanol, and spray-drying the concentrate to obtain the ginkgolide K-alkyl trimethyl amine salt compound.
Example 38. A ginkgolide K-thiamine hydrochloride compound. The preparation method comprises the following steps: taking 2.5 g of thiamine hydrochloride, adding 40ml of 60% ethanol solution for dissolving, heating to 50 ℃, adding 5g of ginkgolide K which is ground and sieved by a 80-mesh sieve, stirring until the mixture is dissolved, filtering, concentrating the filtrate under reduced pressure, recovering ethanol, and spray-drying the concentrate to obtain the ginkgolide K-thiamine hydrochloride compound.
Example 39. A bilobalide K-methylamine complex. The preparation method comprises the following steps: dissolving methylamine 2g in 95% ethanol solution 25ml, heating to 48 deg.C, adding 5g of fine 80 mesh sieved bilobalide K, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering ethanol, and spray drying the concentrate to obtain bilobalide K-methylamine complex.
Example 40. A ginkgolide K-ethylamine complex is provided. The preparation method comprises the following steps: dissolving 6 g of ethylamine in 800ml of water, heating to 80 ℃, adding 12 g of ginkgolide K which is ground and sieved by a 80-mesh sieve, stirring to dissolve, concentrating, and spray-drying the concentrate to obtain the ginkgolide K-ethylamine compound.
Example 41. A bilobalide K-barium hydroxide compound. The preparation method comprises the following steps: dissolving barium hydroxide 4 g in 10% ethanol solution 100ml, heating to 70 deg.C, adding bilobalide K powder 8 g, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering ethanol, and spray drying the concentrate to obtain bilobalide K-barium hydroxide compound.
Example 42. A ginkgolide K-calcium hydroxide compound is provided. The preparation method comprises the following steps: dissolving calcium hydroxide 2.5 g in water 1000ml, heating to 80 deg.C, adding 5g of fine 80 mesh powder of bilobalide K, stirring to dissolve, concentrating, and spray drying the concentrate to obtain bilobalide K-calcium hydroxide compound.
Example 43. A bilobalide K-sodium hydroxide compound. The preparation method comprises the following steps: dissolving sodium hydroxide 0.45 g in water 500ml, heating to 80 deg.C, adding 5g of 80 mesh sieved bilobalide K, stirring to dissolve, concentrating, and spray drying the concentrate to obtain bilobalide K-sodium hydroxide compound.
Example 44. A bilobalide K-potassium hydroxide compound. The preparation method comprises the following steps: taking 0.45 g of potassium hydroxide, adding 1000ml of ethanol for water bath dissolution to prepare ethanol hydrogen-producing potassium oxide solution; and adding 500ml of ethanol into 5g of ginkgolide K powder, stirring and dissolving at 60 ℃, filtering, mixing the filtrate with the ethanol hydrogen-producing potassium oxide solution, stirring and uniformly mixing, carrying out water bath at 65 ℃ for 2-4 hours, concentrating under reduced pressure, and drying to obtain the ginkgolide K-potassium hydroxide compound.
Example 45. A bilobalide K-sodium hydroxide compound. The preparation method comprises the following steps: taking 0.45 g of sodium hydroxide, adding 500ml of ethanol for water bath dissolution to prepare ethanol hydrogen-producing sodium oxide solution; and adding 200ml of ethanol into 5g of ginkgolide K powder, stirring and dissolving at 65 ℃, filtering, mixing the filtrate with the ethanol hydrogen-producing sodium oxide solution, stirring and uniformly mixing, carrying out water bath at 70 ℃ for 2-4 hours, concentrating under reduced pressure, and drying to obtain the ginkgolide K-sodium hydroxide compound.
Example 46. A pharmaceutical preparation of ginkgolide K is prepared from the following raw materials in parts by weight:
bilobalide K50 g
Microcrystalline cellulose 30 g
Lactose 30 g
Sodium carboxymethyl starch 5g
10 g of 2% HPMCE5 solution containing 5% Tween 80
Magnesium stearate 2g
The preparation method comprises dissolving bilobalide K in small amount of ethanol; respectively sieving microcrystalline cellulose, lactose and sodium carboxymethyl starch with 100 mesh sieve, mixing, adding bilobalide K ethanol solution, and stirring to volatilize ethanol; preparing soft material with 2% HPMC solution containing 5% Tween 80 as binder, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in oven at 40 deg.C; sieving the dried granules with a 20-mesh sieve, granulating, mixing with magnesium stearate, and encapsulating into 1000 capsules.
Example 47. A pharmaceutical preparation of ginkgolide K is prepared from the following raw materials in parts by weight:
bilobalide K100 g
Microcrystalline cellulose 60 g
Sucrose 100 g
Hydroxypropyl starch 7 g
20 g of 2% HPMCE5 solution (containing 5% Tween 80)
Stearic acid 3 g
The preparation method comprises the following steps:
dissolving bilobalide K in small amount of ethanol; respectively sieving microcrystalline cellulose, sucrose and hydroxypropyl starch with 100 mesh sieve, mixing, adding bilobalide K ethanol solution, and stirring to volatilize ethanol; preparing soft material with HPMC solution containing Tween 80 as adhesive, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in oven at 50 deg.C; sieving the dried granules with a 20-mesh sieve, granulating, mixing with magnesium stearate, and tabletting to obtain 1000 tablets.
Example 48. A pharmaceutical preparation of ginkgolide K is a tablet prepared from the following raw materials in parts by weight:
bilobalide K150 mg
Microcrystalline cellulose 300mg
Hydroxypropyl methylcellulose K4M 80mg
3% hydroxypropylmethylcellulose (E5) aqueous solution 30mg
Talcum powder 4mg
Sieving ginkgolide K, microcrystalline cellulose and hydroxypropyl methylcellulose K4M with 60 mesh sieve, mixing, adding 3% hydroxypropyl methylcellulose (E5) water solution, making into soft mass, sieving with 20 mesh sieve, and granulating. Drying by blowing in an oven at 40 ℃, sieving dry granules with a 20-mesh sieve, grading, adding the prescribed amount of talcum powder, mixing uniformly, and filling No. 1 capsules according to the prescribed amount, wherein each capsule contains 150mg of ginkgolide K.
Example 49. A pharmaceutical preparation of ginkgolide K is a tablet prepared from the following raw materials in parts by weight:
ginkgolide K120 mg
Mannitol 200mg
Hydroxypropyl methylcellulose K4M 80mg
15mg of 3% hydroxypropylmethylcellulose (E5) aqueous solution
Talcum powder 3mg
Sieving ginkgolide K, mannitol, and hydroxypropyl methylcellulose K4M with 60 mesh sieve, mixing, adding 3% hydroxypropyl methylcellulose (E5) water solution, making soft mass, sieving with 20 mesh sieve, and granulating. Drying in oven at 50 deg.C by blowing, sieving with 20 mesh sieve, grading, adding pulvis Talci, mixing, and tabletting to obtain tablet containing ginkgolide K120 mg.
Example 50. A pharmaceutical preparation of ginkgolide K is used for treating ischemic stroke, and is a capsule prepared from the following raw materials in parts by weight:
ginkgolide K150 g
Dextrin 150 g
Starch 150 g
Carboxymethyl cellulose calcium 10 g
Povidone 10 g
Calcium stearate 5g
The preparation method comprises the following steps: dissolving bilobalide K in small amount of ethanol; respectively sieving dextrin, starch and carboxymethylcellulose calcium with 100 mesh sieve, mixing, adding bilobalide K ethanol solution, and stirring to completely volatilize ethanol; preparing soft material with polyvidone solution as binder, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in 60 deg.C oven; sieving the dry granules with a 20-mesh sieve, grading, mixing with calcium stearate, and filling into 1000 capsules.
Example 51. A pharmaceutical preparation of ginkgolide K is a capsule prepared from the following raw materials in parts by weight:
ginkgolide K130 g
Calcium phosphate 200 g
Hydroxypropyl starch 8 g
Pregelatinized starch 6 g
Silica gel micropowder 3 g
The preparation method comprises the following steps: dissolving bilobalide K in small amount of ethanol; sieving calcium phosphate and hydroxypropyl starch with 100 mesh sieve respectively, mixing, adding bilobalide K ethanol solution, and stirring to volatilize ethanol completely; preparing soft material with pregelatinized starch solution as binder, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in 55 deg.C oven; sieving the dry granules with a 20-mesh sieve, grading, mixing with the silica gel micropowder, and filling into 1000 capsules.
Example 52. A pharmaceutical preparation of ginkgolide K is a tablet prepared from the following raw materials in parts by weight:
bilobalide K80 g
Calcium hydrogen phosphate 100 g
Hydroxypropyl cellulose 3 g
Hydroxypropyl methylcellulose 5g
Polyethylene glycol 40001 g
Dissolving bilobalide K in small amount of ethanol; sieving calcium hydrogen phosphate and hydroxypropyl cellulose with 100 mesh sieve respectively, mixing, adding bilobalide K ethanol solution, and stirring to volatilize ethanol completely; preparing a soft material by taking a hydroxypropyl methylcellulose solution as an adhesive, sieving with a 20-mesh sieve to prepare particles, and drying the wet particles in a 50 ℃ oven by air blast; sieving the dry granules with 20 mesh sieve, grading, mixing with polyethylene glycol 4000, and tabletting to obtain 1000 tablets for treating ischemic stroke.
Example 53. A pharmaceutical preparation of bilobalide K-meglumine is prepared from the following raw materials (by weight ratio),
10-100 g of ginkgolide K-meglumine
30-50 g of microcrystalline cellulose
Lactose 30-50 g
5-10 g of sodium carboxymethyl starch
Appropriate amount of 2% HPMCE5 solution (containing 5% Tween 80)
Magnesium stearate 1-5 g
The preparation method comprises dissolving bilobalide K-meglumine in small amount of ethanol; respectively sieving microcrystalline cellulose, lactose and sodium carboxymethyl starch with 100 mesh sieve, mixing, adding bilobalide K-meglumine ethanol solution, and stirring to volatilize ethanol; preparing soft material with HPMC solution containing Tween 80 as adhesive, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in oven at 50-60 deg.C; sieving the dried granules with a 20-mesh sieve, granulating, mixing with magnesium stearate, and encapsulating into 1000 capsules.
Example 54. A pharmaceutical preparation of ginkgolide K-lysine is prepared from the following raw materials (by weight ratio),
10-100 g of ginkgolide K-lysine
30-50 g of microcrystalline cellulose
Lactose 30-50 g
5-10 g of sodium carboxymethyl starch
Appropriate amount of 2% HPMCE5 solution (containing 5% Tween 80)
Magnesium stearate 1-5 g
The preparation method comprises dissolving bilobalide K-lysine in small amount of ethanol; respectively sieving microcrystalline cellulose, lactose and sodium carboxymethyl starch with 100 mesh sieve, mixing, adding bilobalide K-lysine ethanol solution, and stirring to volatilize ethanol; preparing soft material with HPMC solution containing Tween 80 as adhesive, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in oven at 50-60 deg.C; sieving the dried granules with a 20-mesh sieve, granulating, mixing with magnesium stearate, and tabletting to obtain 1000 tablets.
Example 55. A sustained release capsule of bilobalide K-arginine is prepared,
bilobalide K arginine 100mg
Microcrystalline cellulose 20mg
Hydroxypropyl methylcellulose K4M 80mg
Proper amount of 3% hydroxypropyl methylcellulose (E5) aqueous solution
Talcum powder 4mg
Sieving ginkgolide K.arginine, microcrystalline cellulose and hydroxypropyl methylcellulose K4M with 60 mesh sieve, mixing, adding 3% hydroxypropyl methylcellulose (E5) water solution, making soft mass, sieving with 20 mesh sieve, and granulating. Drying in an oven at 40-50 deg.C by blowing. Sieving the dry granules with a 20-mesh sieve, grading, adding the prescribed amount of talcum powder, and uniformly mixing. Filling No. 1 capsules according to the prescription amount, wherein each capsule contains 100mg of ginkgolide K & arginine.
Example 56. A sustained release tablet of bilobalide K-arginine is prepared,
bilobalide K arginine 20mg
Lactose 20mg
Hydroxypropyl methylcellulose K4M 80mg
Proper amount of 3% hydroxypropyl methylcellulose (E5) aqueous solution
Talcum powder 4mg
Sieving ginkgolide K.arginine, lactose, and hydroxypropyl methylcellulose K4M with 60 mesh sieve, mixing, adding appropriate amount of hydroxypropyl methylcellulose (E5) water solution of 3% to make soft mass, sieving with 20 mesh sieve, and granulating. Drying in an oven at 40-50 deg.C by blowing. Sieving the dry granules with a 20-mesh sieve, grading, adding the prescribed amount of talcum powder, uniformly mixing, and tabletting, wherein each granule contains ginkgolide K20 mg.
Example 57. A method for preparing ginkgolide K soft capsule,
content rubber shell
Ginkgolide K50 g gelatin 46.00%
Soybean oil 0.51% glycerin 17.82%
36.18 percent of water
Adding bilobalide K into soybean oil, grinding, and making into soft capsule. Each capsule contains 50mg of bilobalide K.
Example 58. A method for preparing ginkgolide K injection,
bilobalide K20mg
Polyoxyethylene Ether Castor oil 1.0mg
Anhydrous ethanol 5.0mg
The water for injection is added to 5.0mL
Dissolving bilobalide K in anhydrous ethanol, adding 20% polyoxyethylene ether castor oil (cremophor ELP), mixing, evaporating under reduced pressure to remove ethanol, adding appropriate amount of water for injection, mixing to obtain clear transparent solution, filtering with 0.22 μm microporous membrane, packaging, sealing, and sterilizing with flowing steam at 100 deg.C for 30min to obtain the final product, each containing bilobalide K20 mg.
Example 59. A preparation method of ginkgolide K-arginine injection,
bilobalide K20.0 g
Arginine 22.2g
Mannitol 32.0g
Water for injection up to 2000ml
Putting bilobalide K and arginine into a proper container, adding 1800ml of water for injection, stirring uniformly, performing ultrasonic treatment to dissolve, adding mannitol, and stirring to dissolve; adding 0.1% of active carbon for a needle, stirring for 30 minutes, decarburizing by using a titanium sand core, performing suction filtration on the decarburizing solution to a clean container, adding 2000ml of water for injection, stirring the solution for 5 minutes to be uniform, filtering the solution by using a 0.22-micron microporous membrane, filling the filtrate into 7ml of penicillin bottles with 2ml of each penicillin bottle, partially plugging butyl rubber plugs, conveying the penicillin bottles onto a plate layer in a freeze-drying box, inserting a temperature probe, and closing a box door. Freeze drying according to freeze drying curve, and keeping the final drying temperature above 35 deg.C for 2 hr. Sealing, deflating, taking out of the box and capping.
Example 60. A preparation method of bilobalide K suspension injection,
bilobalide K20mg
Sodium carboxymethylcellulose 10mg
Polysorbate 800.1 mg
Nipagin ethyl ester 0.5mg
Propyl p-hydroxybenzoate 0.5mg
Potassium dihydrogen phosphate 16.7mg
Dipotassium hydrogen phosphate 1.7mg
Adding water for injection to 2ml
Jet milling bilobalide K to obtain micropowder with particle diameter of less than 10 μm. Dissolving potassium dihydrogen phosphate and dipotassium hydrogen phosphate in water for injection, adding ethylparaben and propyl ester, adding sodium carboxymethylcellulose, and dissolving at 60 deg.C. Placing micronized gambogic acid in a container, adding polysorbate 80, grinding into fine paste, gradually adding the above solution, stirring, and grinding with a colloid mill for 5-10 times. And (3) after the content is qualified according to the conventional determination method, subpackaging in ampoules, and sterilizing for 30 minutes at 100 ℃ by circulating steam to obtain the ginkgo lactone K containing 20 mg.
The injection of the embodiment can also be selected from the following auxiliary materials: solubilizers such as: tween, pluronic F-68, polyoxyethylene ether castor oil, etc.; and the cosolvent comprises: amide compounds such as urea, acetamide, thiourea, benzamide and the like; suspending agents such as: sodium carboxymethylcellulose, povidone, hydroxypropylmethylcellulose, and the like; preservatives such as: methyl, ethyl, propyl and butyl parabens; pH adjusting agents such as: citric acid and citrate, phosphate, etc.; solvents such as: water for injection, ethanol for injection, propylene glycol, and the like.
Example 61. A preparation method of a ginkgolide K-arginine compound sustained-release tablet,
bilobalide K arginine 20mg
Huperzine A50 μ g
Lactose 20mg
Hydroxypropyl methylcellulose K4M 80mg
Proper amount of 3% hydroxypropyl methylcellulose (E5) aqueous solution
Talcum powder 4mg
Sieving ginkgolide K.arginine, lactose, and hydroxypropyl methylcellulose K4M with 60 mesh sieve, mixing, adding appropriate amount of hydroxypropyl methylcellulose (E5) water solution of 3% to make soft mass, sieving with 20 mesh sieve, and granulating. Drying in an oven at 40-50 deg.C by blowing. Sieving the dry granules with a 20-mesh sieve, grading, adding the prescribed amount of talcum powder, uniformly mixing, and tabletting, wherein each granule contains 20mg of ginkgolide K & arginine and 50 mu g of huperzine A.
Example 62. A ginkgolide K-arginine injection is prepared by dissolving ginkgolide K-arginine 10 g in fresh water for injection 1000ml, adjusting pH to 8.0 with 10% citric acid aqueous solution, adding NaCl 8 g and activated carbon 2.0g for injection, stirring at room temperature for adsorption for 30min, filtering to remove carbon, adding fresh water for injection to total amount of 1000ml, filtering with 0.22 μm microporous membrane under sterile filter plate in sterile workshop, packaging, and lyophilizing to obtain injection.
Example 63. An injection of ginkgolide K propylamine is prepared by the following steps: dissolving propylamine 2.0g in fresh water for injection 1000ml, autoclaving at 115 deg.C for 35 min, taking out, heating to 90 deg.C in proportioning room, adding bilobalide K which is ground into fine powder and passed through 80 mesh sieve, heating to dissolve, cooling to room temperature, regulating pH to 8.0 with 10% citric acid aqueous solution, adding NaCl 8 g and active carbon 2.0g for injection, stirring at room temperature for adsorption for 30min, filtering to remove carbon, adding fresh water for injection to total amount of 1000ml, filtering with 0.22 μm microporous membrane under aseptic filter plate in aseptic workshop, packaging into 100 pieces, and lyophilizing to obtain lyophilized powder for injection.
Example 64. An injection containing bilobalide K.glycine as effective component is provided. The preparation method comprises the following steps: taking 350 g of hydroxypropyl-beta-cyclodextrin, adding 5000ml of water for injection, heating and refluxing for 30 minutes to obtain a solution I, and keeping the temperature at 80 ℃ for later use; dissolving 65g of ginkgolide K-glycine compound, keeping the temperature for 60 minutes, cooling to room temperature, filtering with microporous membrane (0.22 μm), packaging (5 ml/bottle), and freeze drying to obtain ginkgolide K-glycine injection.
Example 65. A ginkgolide K-methylamine injection. The preparation method comprises the following steps: dissolving 5g of methylamine in 1000ml of fresh water for injection, sterilizing at 120 ℃ for 30 minutes under high pressure, taking out, heating to 80 ℃ in a batching room, adding 5g of ginkgolide K which is ground and sieved by a sieve of 80 meshes, heating to dissolve, cooling to room temperature, adjusting the pH to 8.0 by using 10% citric acid aqueous solution, adding 8 g of NaCl, using 2.0g of activated carbon for injection, stirring and adsorbing at room temperature for 30 minutes, filtering to remove carbon, adding fresh water for injection to the total amount of 1000ml, filtering by using a microporous filter membrane with the diameter of 0.22 mu m under an aseptic filter plate in an aseptic workshop, and subpackaging 100 samples to prepare the injection.
Example 66. A ginkgolide K ethylamine injection. The preparation method comprises the following steps: heating 1000ml of fresh water for injection to 80 ℃, adding 8 g of ginkgolide K-ethylamine compound which is ground and sieved by a 80-mesh sieve, heating to dissolve, cooling to room temperature, adjusting the pH to 8.0 by using 10% citric acid aqueous solution, adding 8 g of NaCl, using 2.0g of activated carbon for injection, stirring and adsorbing for 30 minutes at room temperature, filtering to remove carbon, adding fresh water for injection to 1000ml of the total amount, filtering by using a 0.22 mu m microporous filter membrane under an aseptic filter plate in an aseptic workshop, and subpackaging by 100 to prepare the injection.
Claims (7)
1. A ginkgolide K with general formula (I) and its complex (I). G,
and, mixing bilobalide K or its complex (I). G with pharmaceutically acceptable medicinal carrier to form composition; wherein G is an alkaline substance.
2. The ginkgolide K complex (I). G according to claim 1, wherein G is selected from a metal basic substance or a nitrogen-containing organic substance having one to eight carbon atoms in the molecule.
3. The ginkgolide K complex (I). G of claim 1, wherein G is arginine or lysine or meglumine or sodium hydroxide.
4. A preparation method of a ginkgolide K compound (I). G is characterized in that the ginkgolide K and an alkaline substance form a compound in water and/or an alcohol solvent according to the molar ratio of 1: 0.2-5.
5. The method for preparing the ginkgolide K complex (I). G according to claim 4, comprising the steps of: dissolving alkaline substance in water, heating to 70-90 deg.C, adding bilobalide K, stirring for dissolving, concentrating, and drying the concentrate.
6. The method for preparing the ginkgolide K complex (I). G according to claim 4, comprising the steps of: dissolving alkaline substance in mixed solution of water and organic solvent at any ratio, heating to 40-70 deg.C, adding bilobalide K or bilobalide K alcoholic solution, stirring to dissolve, filtering, concentrating the filtrate under reduced pressure, recovering organic solvent, and drying the concentrate.
7. Use of the ginkgolide K or its complex (I). G of claim 1, 2 or 3 for the preparation of a medicament for treating ischemic cerebral stroke, preventing and treating thrombosis, senile dementia, organ transplant rejection, acute inflammation, cardiac allergy, endotoxin-induced shock.
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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| 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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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| 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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