CN103121998B - Vinpocetine compound and drug composition thereof - Google Patents
Vinpocetine compound and drug composition thereof Download PDFInfo
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- CN103121998B CN103121998B CN201310048709.4A CN201310048709A CN103121998B CN 103121998 B CN103121998 B CN 103121998B CN 201310048709 A CN201310048709 A CN 201310048709A CN 103121998 B CN103121998 B CN 103121998B
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Abstract
The invention belongs to the technical field of medicine, and particularly relates to vinpocetine compound. The vinpocetine compound is shown in an X-ray powder diffraction spectra I measured by a Cu-K alpha ray. A preparation method of the vinpocetine compound, and a drug composition containing the vinpocetine compound are also provided by the invention. The vinpocetine compound disclosed by the invention is long in storage time, less in impurity content, and good in storage stability; and the drug composition containing the vinpocetine compound is good in storage stability and high in safety performance.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of Vinpocetine compound, the preparation method of this Vinpocetine compound and pharmaceutical composition thereof.
Background technology
Vinpocetine: English name Vinpocetinum; Molecular formula C22H26N2O2; Molecular weight 350.45; For a kind of alkaloid extracted from Zhu Tao section plant, it is the derivative of vincamine (vlncamlne).Vinpocetin can suppress phosphodiesterase activity, increase the effect of the courier c-GMP of vascular smooth muscle relaxation, optionally increase cerebral blood flow (CBF), can also platelet aggregation be suppressed in addition, reduce human blood viscosity, strengthen erythrocyte deformabiliy, improve blood fluidity and microcirculation, promote cerebral tissue ingestion of glucose, increase brain oxygen-consumption, improve brain metabolism, but affect little on cardiovascular and blood pressure; Better tolerance, untoward reaction is little; Also can be used for giddy, headache, dysmnesia, action obstacle, aphasia, hypertensive encephalopathy etc., the spirituality also caused for cerebral blood circulation obstacle or Neurological signs.
CN201110028452.7 disclose a kind of can ensure product purity and productive rate prerequisite under realize the semisynthesis of suitability for industrialized production vinpocetin, this invention adopts African growing plants Ma Lingguo to extract synthesis desired raw material tabersonine (tobersonina), through four step synthesis vinpocetins.It is specifically 1 years old) to prepare Changchun climing not bright; 2) vincamine is prepared; 3) Changchun amino acid is prepared; 4) synthesize vinpocetin, obtain the vinpocetin that content is 99%.This invention creates a complete process from tabersonine to vinpocetin, and technique is simple, and yield is high, and cost is lower; Suitability for industrialized production vinpocetin can be realized under guarantee product purity and productive rate prerequisite.
CN201210151559.5 discloses the synthetic method of vinpocetin, adds in there-necked flask, add toluene subsequently by raw material vincamine, agitation and dropping triethylamine and Methanesulfonyl chloride in ice-water bath, stirs and is slowly warming up to room temperature after 2 hours, then continue stirring 5 hours; Termination reaction, solvent evaporated, adds second alcohol and water, regulates PH=12 with unsaturated carbonate potassium solution, and solid is separated out, and filter, vacuum-drying, obtains vinpocetin intermediate; Dehydrated alcohol is added in there-necked flask, stir in ice-water bath after 1 hour and slowly add sodium ethylate, stir and add vinpocetin intermediate after 0.5 hour, subsequently reaction flask is positioned in oil bath, set temperature is 80 DEG C, react and steam most of solvent after 12 hours, then solution is poured in hydrochloric acid, be extracted with ethyl acetate, aqueous phase regulates pH value=12, solid is separated out, and filtration drying, obtains vinpocetin.The reactions steps of this invention synthetic method is short, product purity and yield high, energy consumption is low, and environmental pollution is little.
The stability in storage of vinpocetin of the prior art is poor, and in illumination and moist environment, its related substance can significantly increase, in order to obtain a kind of Vinpocetine compound of more excellent performance, and special proposition the present invention.
Summary of the invention
The present invention first object is to provide a kind of Vinpocetine compound, and the Vinpocetine compound provided has better stability in storage.
The present invention second object is the preparation method providing a kind of above-mentioned vinpocetin.
The third object of the present invention is to provide a kind of pharmaceutical composition containing above-mentioned Vinpocetine compound.
In order to realize foregoing invention object, the present invention takes following technical scheme:
A kind of Vinpocetine compound, the structural formula of described Vinpocetine compound is:
The X-ray powder diffractogram that described Vinpocetine compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
Vinpocetine compound provided by the invention is crystal, the change of its internal crystal structure result in its physicals and also correspondingly there occurs change, by stability experiment, contriver finds that the special crystallized form of Vinpocetine compound provided by the present invention is compared with the solid form of the vinpocetin of prior art, has stronger stability in storage.
A kind of preparation method of foregoing Vinpocetine compound, described preparation method comprises: by N, N-METHYLFORMAMIDE and ethanol are mixed with mixed solvent with the volume ratio of 2 ~ 4:1, get Vinpocetione crude drug, add N, the mixed solvent of dinethylformamide and ethanol, the volume of described mixed solvent is 4 ~ 6ml:1g with the ratio of the quality of vinpocetin, be warming up to 60 ~ 70 DEG C, be stirred to whole dissolving, insulation, the pH of solution is adjusted to 5.5 ~ 6.0, add decolorizing with activated carbon, filter, obtain settled solution, settled solution is moved in reactor, 12 ~ 48h is placed in 100 ~ 120 DEG C of baking ovens, naturally cooling is left standstill, when temperature is down to below 70 DEG C, drive still, frozen water is added in settled solution, filter, obtain filter cake, washing leaching cake, drying under reduced pressure 2 ~ 4h again, obtain white micro-crystals powder.
In the present invention, contriver is by experiment repeatedly, continuous change crystallization method and crystallization condition, finally prepare a kind of Vinpocetine compound crystal with brand-new crystal formation, this Vinpocetine compound crystal has very high lattice energy, vinpocetin molecule is larger by lattice constraint, has good preservation stability.
The volume of described frozen water and the volume ratio of mixed solvent are 5-15:1.
It is described that to add activated carbon degerming be this area common technology means, can see any desolventing technology, those skilled in the art are without the need to paying any creative work, and the prior art can grasped according to himself carries out appropriate selection, and realizes the object of the invention.
In order to improve formulation products quality further, the present invention also can be filtered into use ultrafiltration membrance filter preferably after decolouring.
Present invention also offers a kind of pharmaceutical composition containing foregoing Vinpocetine compound.
The present invention is by changing the solid structure of Vinpocetine compound, the vinpocetin obtained has higher stability in storage, and then improve the stability in storage of the pharmaceutical composition containing vinpocetin, compared with the Vinpocetine medicine composition of prior art, pharmaceutical composition containing vinpocetin provided by the invention has better stability in storage, drastically increases the drug safety of patient.
Described pharmaceutical composition is solid preparation or liquid preparation.
Preferably, described liquid preparation is aqueous injection; Described solid preparation is sterile powder injection, lyophilized injectable powder or tablet.
By weight, described sterile powder injection comprises vinpocetin 10 parts, solubility promoter 5-15 part.
Preferably, the solubility promoter in described sterile powder injection comprise in xitix, tartrate and citric acid one or more.
By weight, described Vinpocetine freeze-dried powder for injection comprises the vinpocetin of 10 parts, the frozen-dried supporting agent of 30-70 part, the solubility promoter of 5-15 part.
Preferably, described frozen-dried supporting agent is selected from one or more in N.F,USP MANNITOL, glucose, sorbyl alcohol, sucrose, lactose.
Preferably, the solubility promoter in described frozen-dried supporting agent comprise in xitix, tartrate and citric acid one or more.
By weight, described tablet is Vinpocetine dispersible tablet, and described Vinpocetine dispersible tablet comprises: vinpocetin 10 parts, weighting agent 20-38 part, disintegrating agent 20-48 part, tackiness agent 1.5-4.5 part, lubricant 0.5-2 part.
Preferably, described weighting agent comprise in lactose, pregelatinized Starch, dextrin, Microcrystalline Cellulose, medical cane sugar, medicinal fructose one or more, described disintegrating agent comprise in cross-linked polyvinylpyrrolidone, croscarmellose sodium, hydroxypropylcellulose one or more, described tackiness agent be selected from polyvinylpyrrolidone, Vltra tears, Xylo-Mucine, methylcellulose gum, starch slurry one or more, described lubricant be selected from Magnesium Stearate, talcum powder, micropowder silica gel, polyoxyethylene glycol one or more.
By weight, described aqueous injection comprises vinpocetin 10 parts, solubility promoter 15-25 part, antioxidant 0.5-2 part, physically stable agent 20-100 part, vascular stimulation conditioning agent 10-25 part.
Preferably, in described aqueous injection, described antioxidant comprises Sodium Pyrosulfite, described solubility promoter solubility promoter comprise in xitix, tartrate and citric acid one or more, described physically stable agent comprises sorbyl alcohol, and described vascular stimulation conditioning agent comprises phenylcarbinol.
In the present invention, described sterile powder injection, lyophilized injectable powder, aqueous injection, dispersible tablet all can adopt the preparation method of prior art, those skilled in the art are without the need to paying any creative work, the prior art can grasped according to himself carries out appropriate selection, and realizes the object of the invention.
Compared with prior art, Vinpocetine compound provided by the invention and pharmaceutical composition tool thereof have the following advantages:
(1) Vinpocetine compound long-time storage foreign matter content of the present invention is few, and stability in storage is good;
(2) the pharmaceutical composition stability in storage containing vinpocetin of the present invention is good, and safety performance is higher.
Accompanying drawing explanation
The X-ray powder diffraction pattern of the Vinpocetine compound that Fig. 1 provides for the embodiment of the present invention 1.
Embodiment
Below by specific embodiment, summary of the invention of the present invention is described further, but does not therefore limit content of the present invention.
Embodiment 1
The preparation of Vinpocetine compound
By N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 2:1, get Vinpocetione crude drug, add N, the mixed solvent of N-METHYLFORMAMIDE and ethanol, the volume of described mixed solvent is 4ml:1g with the ratio of the quality of vinpocetin, be warming up to 60 DEG C, be stirred to whole dissolving, insulation, the pH of solution is adjusted to 5.5, add decolorizing with activated carbon, the consumption of gac is the 0.3%(g/ml of the solvent mixture volume), stir 30min, filter, obtain settled solution, settled solution is moved in reactor, 48h is placed in 100 DEG C of baking ovens, naturally cooling is left standstill, when temperature is down to below 70 DEG C, drive still, frozen water is added in settled solution, the volume of described frozen water and the volume ratio of mixed solvent are 15:1, filter, obtain filter cake, with the washing with alcohol filter cake 3 times of 0 DEG C, drying under reduced pressure 4h again, obtain white micro-crystals powder.Yield 74.4%, HPLC content 99.78%.
The X-ray powder diffractogram that the measurement of use Cu-K alpha-ray obtains is shown by Fig. 1.
Embodiment 2
The preparation of Vinpocetine compound
By N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 4:1, get Vinpocetione crude drug, add N, the mixed solvent of N-METHYLFORMAMIDE and ethanol, the volume of described mixed solvent is 6ml:1g with the ratio of the quality of vinpocetin, be warming up to 70 DEG C, be stirred to whole dissolving, insulation, the pH of solution is adjusted to 6.0, add decolorizing with activated carbon, the consumption of gac is the 0.3%(g/ml of the solvent mixture volume), stir 30min, filter, obtain settled solution, settled solution is moved in reactor, 12h is placed in 120 DEG C of baking ovens, naturally cooling is left standstill, when temperature is down to below 70 DEG C, drive still, frozen water is added in settled solution, the volume of described frozen water and the volume ratio of mixed solvent are 5:1, filter, obtain filter cake, with the washing with alcohol filter cake 3 times of 5 DEG C, drying under reduced pressure 2h again, obtain white micro-crystals powder.Yield 72.5%, HPLC content 99.83%.
The X-ray powder diffraction figure using the measurement of Cu-K alpha-ray to obtain is consistent with the result of embodiment 1.
Embodiment 3
The preparation of vinpocetin sterile powder injection
Aseptically take vinpocetin 10 parts, 5 parts, xitix prepared by embodiment 1, be placed in solid powder mixer Homogeneous phase mixing, gained raw material proceeds to sterile preparation workshop, delicate metering packing, containing vinpocetin 0.5g, jump a queue, roll lid for every bottle, the also censorship of finished product packing warehouse-in.
Embodiment 4
The preparation of vinpocetin sterile powder injection
Aseptically take vinpocetin 10 parts, 15 parts, tartrate prepared by embodiment 1, be placed in solid powder mixer Homogeneous phase mixing, gained raw material proceeds to sterile preparation workshop, delicate metering packing, containing vinpocetin 1.0g, jump a queue, roll lid for every bottle, the also censorship of finished product packing warehouse-in.
Embodiment 5
Vinpocetine freeze-dried powder for injection
Take embodiment 2 prepare vinpocetin 10g, N.F,USP MANNITOL 30g and xitix 5g in liquid-compounding cup, add water for injection 2000ml, then with 1mol/L hydrochloric acid soln adjustment pH to 3.5, vinpocetin is dissolved completely.Add 0.3% (g/ml) gac accounting for liquid total amount, stirred at ambient temperature adsorbs 30 minutes, filtering decarbonization, and subsequent filtrate, again after filtering with microporous membrane, supplies filling for subsequent use.
By filling for subsequent filtrate in injection bottle, freeze-drying is carried out: with 1.5 hours, shelf temperature is down to about-45 DEG C by following freeze-dry process, after products temperature reaches-35 DEG C, start timing insulation about 4 hours, after being incubated, condenser temperature is down to less than-50 DEG C fast, opens case trap valve, be evacuated to about 10pa, shelf temperature be set and be-3 DEG C.With being no less than 2 hours, shelf temperature slowly being risen to-3 DEG C, being incubated and disappearing to ice crystal, then continuing insulation 4 hours.With 40 minutes, shelf temperature was risen to 18 DEG C of maintenances after 1 hour, shelf continues to be warming up to 40 DEG C, when products temperature reaches 35 DEG C, starts timing insulation about 3 hours, checks vacuum tightness changing conditions, terminate whole freeze-drying process, total head plug, outlet.Every bottle containing vinpocetin 1.0g.
Embodiment 6
Vinpocetine freeze-dried powder for injection
Take embodiment 2 prepare vinpocetin 10g, sorbyl alcohol 70g and tartrate 15g in liquid-compounding cup, add water for injection 2000ml, then with 1mol/L hydrochloric acid soln adjustment pH to 3.5, vinpocetin is dissolved completely.Add 0.3% (g/ml) gac accounting for liquid total amount, stirred at ambient temperature adsorbs 30 minutes, filtering decarbonization, and subsequent filtrate, again after filtering with microporous membrane, supplies filling for subsequent use.
By filling for subsequent filtrate in injection bottle, freeze-drying is carried out: with 1.5 hours, shelf temperature is down to about-45 DEG C by following freeze-dry process, after products temperature reaches-35 DEG C, start timing insulation about 4 hours, after being incubated, condenser temperature is down to less than-50 DEG C fast, opens case trap valve, be evacuated to about 10pa, shelf temperature be set and be-3 DEG C.With being no less than 2 hours, shelf temperature slowly being risen to-3 DEG C, being incubated and disappearing to ice crystal, then continuing insulation 4 hours.With 40 minutes, shelf temperature was risen to 18 DEG C of maintenances after 1 hour, shelf continues to be warming up to 40 DEG C, when products temperature reaches 35 DEG C, starts timing insulation about 3 hours, checks vacuum tightness changing conditions, terminate whole freeze-drying process, total head plug, outlet.Every bottle containing vinpocetin 1.0g.
Embodiment 7
Vinpocetine dispersible tablet
Vinpocetin 10g, Microcrystalline Cellulose 20g, hydroxypropylcellulose 48g, Xylo-Mucine 1.5g prepared by Example 2, silicon-dioxide 2g, mixing is that wetting agent is granulated with 95% ethanol, 60 DEG C of dryings, whole grain; After passed examination, be pressed into 1000, packing.
Embodiment 8
Vinpocetine dispersible tablet
Vinpocetin 10g, Microcrystalline Cellulose 38g, hydroxypropylcellulose 20g, silicon-dioxide 0.2g, Xylo-Mucine 4.5g prepared by Example 2, mixing is that wetting agent is granulated with 95% ethanol, 60 DEG C of dryings, whole grain; After passed examination, be pressed into 1000, packing.
Embodiment 9
Vinpocetin aqueous injection
Get 100 parts of vinpocetins, 150 parts of Trisodium Citrates, 5 parts of Sodium Pyrosulfites, 200 parts of sorbyl alcohols, 100 parts of phenylcarbinols, it is vinpocetin weight 1000 times that water for injection adds to liquor capacity, add the salt acid for adjusting pH value to 3.5 of 1mol/L, carry out packing according to specification 0.1g/ bottle or 0.2g/ bottle, prepare aqueous injection.
Embodiment 10
Vinpocetin aqueous injection
Get 100 parts of vinpocetins, 250 parts of Trisodium Citrates, 20 parts of Sodium Pyrosulfites, 1000 parts of sorbyl alcohols, 250 parts of phenylcarbinols, it is vinpocetin weight 1000 times that water for injection adds to liquor capacity, add the salt acid for adjusting pH value to 3.5 of 1mol/L, carry out packing according to specification 0.1g/ bottle or 0.2g/ bottle, prepare aqueous injection.
Experimental example 1
This test example detects related substance in the vinpocetin prepared by embodiment 1 ~ 2, and this test is carried out according to Chinese Pharmacopoeia 2010 editions second annex VIII P residual solvent assay method, annex XIX F medicine impurity analysis governing principle, and it the results are shown in Table 1:
The assay of table 1 related substance
| Preparation | DMF | Ethanol | Other related substance |
| Embodiment 1 product | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Embodiment 2 product | Conform with the regulations | Conform with the regulations | Conform with the regulations |
Experimental example 2
This experimental example has investigated the stability of vinpocetin provided by the invention
This test is carried out according to Chinese Pharmacopoeia 2005 editions second annex XIX C medicine stability test governing principle, and result is as follows:
Table 2, accelerated test assay result
| 0 month | 1 month | 3 months | 6 months | 9 months | |
| 1 | 99.98% | 99.97% | 99.95% | 99.90% | 99.70% |
| 2 | 99.75% | 99.74% | 99.71% | 99.67% | 99.49% |
| 3 | 99.79% | 99.77% | 99.60% | 99.02% | 98.30% |
| 4 | 99.85% | 99.79% | 99.44% | 99.15% | 98.50% |
Table 3, test of long duration assay result
| 0 month | 3 months | 6 months | 9 months | 15 months | 24 months | |
| 1 | 99.98% | 99.93% | 99.90% | 99.85% | 99.70% | 99.58% |
| 2 | 99.75% | 99.69% | 99.65% | 99.60% | 99.41% | 99.21% |
| 3 | 99.79% | 99.72% | 99.67% | 99.32% | 98.65% | 97.81% |
| 4 | 99.85% | 99.78% | 99.44% | 99.15% | 98.53% | 97.75% |
Sample 1 is the product of the embodiment of the present invention 1;
Sample 2 is the product of the embodiment of the present invention 2;
Sample 3 is the vinpocetin prepared with reference to CN201110028452.7 embodiment 1, and HPLC is 99.874%;
Sample 4 is the vinpocetin prepared with reference to CN201210151559.5 embodiment 1, and HPLC is 99.86%;
By the accelerated test of this experimental example and test of long duration known, compared with prior art, the stability of vinpocetin provided by the invention is better.
Claims (10)
1. a vinpocetin crystal, is characterized in that, the structural formula of described vinpocetin crystal is:
The X-ray powder diffractogram that described vinpocetin crystal uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. the preparation method of a vinpocetin crystal according to claim 1, it is characterized in that, described preparation method comprises: by N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 2 ~ 4:1, get Vinpocetione crude drug, add N, the mixed solvent of dinethylformamide and ethanol, the volume of described mixed solvent is 4 ~ 6ml:1g with the ratio of the quality of vinpocetin, be warming up to 60 ~ 70 DEG C, be stirred to whole dissolving, insulation, the pH of solution is adjusted to 5.5 ~ 6.0, add decolorizing with activated carbon, filter, obtain settled solution, settled solution is moved in reactor, 12 ~ 48h is placed in 100 ~ 120 DEG C of baking ovens, naturally cooling is left standstill, when temperature is down to below 70 DEG C, drive still, frozen water is added in settled solution, filter, obtain filter cake, washing leaching cake, drying under reduced pressure 2 ~ 4h again, obtain white micro-crystals powder.
3. preparation method according to claim 2, is characterized in that, the volume of described frozen water and the volume ratio of mixed solvent are 5-15:1.
4. the pharmaceutical composition containing vinpocetin crystal according to claim 1.
5. pharmaceutical composition according to claim 4, is characterized in that, described pharmaceutical composition is solid preparation or liquid preparation.
6. pharmaceutical composition according to claim 5, is characterized in that, described liquid preparation is aqueous injection; Described solid preparation is sterile powder injection, lyophilized injectable powder or tablet.
7. pharmaceutical composition according to claim 6, is characterized in that, by weight, described sterile powder injection comprises 10 parts, vinpocetin crystal, solubility promoter 5-15 part.
8. pharmaceutical composition according to claim 6, is characterized in that, by weight, described lyophilized injectable powder comprises the vinpocetin crystal of 10 parts, the frozen-dried supporting agent of 30-70 part, the solubility promoter of 5-15 part.
9. pharmaceutical composition according to claim 6, is characterized in that, by weight, described tablet is Vinpocetine dispersible tablet, and described Vinpocetine dispersible tablet comprises: 10 parts, vinpocetin crystal, weighting agent 20-38 part, disintegrating agent 20-48 part, tackiness agent 1.5-4.5 part, lubricant 0.5-2 part.
10. pharmaceutical composition according to claim 6, it is characterized in that, by weight, described aqueous injection comprises 10 parts, vinpocetin crystal, solubility promoter 15-25 part, antioxidant 0.5-2 part, physically stable agent 20-100 part, vascular stimulation conditioning agent 10-25 part.
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| CN104083329A (en) * | 2014-02-21 | 2014-10-08 | 杭州长典医药科技有限公司 | Vinpocetine special ultrafine powder lyophilized preparation and preparation method thereof |
| CN105837567A (en) * | 2015-01-13 | 2016-08-10 | 匈牙利吉瑞大药厂 | Method for preparing vinpocetine through new technology and application of vinpocetine to prepare pharmaceutical composition |
| CN111171016B (en) * | 2020-01-07 | 2021-03-23 | 北京大学 | Pharmaceutical use of indole alkaloids and derivatives thereof |
| CN112326843A (en) * | 2020-11-27 | 2021-02-05 | 北京康立生医药技术开发有限公司 | Quantitative method of related substances of vinpocetine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058966A (en) * | 1991-08-30 | 1992-02-26 | 东北制药总厂 | The novel method of vincamine amino acid ester preparation |
| CN102311432A (en) * | 2011-08-26 | 2012-01-11 | 贺金凤 | Stable vinpocetine compound and pharmaceutical composition thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058966A (en) * | 1991-08-30 | 1992-02-26 | 东北制药总厂 | The novel method of vincamine amino acid ester preparation |
| CN102311432A (en) * | 2011-08-26 | 2012-01-11 | 贺金凤 | Stable vinpocetine compound and pharmaceutical composition thereof |
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