CN105837567A - Method for preparing vinpocetine through new technology and application of vinpocetine to prepare pharmaceutical composition - Google Patents
Method for preparing vinpocetine through new technology and application of vinpocetine to prepare pharmaceutical composition Download PDFInfo
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Abstract
The invention belongs to the technical field of a medicine, and discloses a method for preparing vinpocetine through new recrystallization purification technology, a method for preparing a vinpocetine pharmaceutical composition through vinpocetine obtained through new purification technology, and an application of the method. Compared to a bulk drug of vinpocetine prepared in the prior art, a bulk drug of vinpocetine prepared according to the technical scheme is less in impurities, is more stable, and has less difference of impurities in different batches, and is white crystalline powder. The conventional technical defects can be effectively overcome. The vinpocetine pharmaceutical composition, including orally-administrated tablets and injection liquids, prepared from the bulk drug of vinpocetine, is relatively low in impurities and better in stability, and has bright application prospects in clinic.
Description
Technical field
The invention belongs to pharmaceutical technology field, relate to a kind of method utilizing novel production process to prepare vinpocetine.It is more particularly related to a kind of drug manufacture equipment using routine, utilizing new recrystallization purifying technique to prepare Vinpocetione crude drug, the crude drug character of gained and impurity are superior to Vinpocetione crude drug prepared by existing purifying process；Pharmaceutical composition prepared by the Vinpocetione crude drug utilizing new technology to obtain, including Vinpocetine oral tablet and injection, its impurity is lower, and stability is more preferable, has more preferable application prospect clinically.
Background technology
Vinpocetine (Vinpocetine), have another name called Apovincaminic Acid Ethyl Ester, it is by I company (Gedeon Richter Plc., Huangary girui Gyogyszergyar) research worker 1971 application patent HU163434 in the openest, within 1977, list with trade name Kai Wentong (CAVINTON), including oral formulations and injection.Vinpocetine is the derivant of alkaloid vincamine (Vincamine), is to be studied the most extensive compound in this Alkaloid family.Vinpocetine can improve the pathological metabolism situation of ischemia cerebral tissue, and can optionally increase cerebral blood circulation and improve microcirculation.Clinical application proves that, can be used for treating various forms disturbance of cerebral circulation, treat including after apoplexy, vascular dementia, cerebral arteriosclerosis, after wound and hypertensive encephalopathy, VBI etc..Psychology or the Neurological signs that disturbance of cerebral circulation causes can be alleviated simultaneously.This product is also widely used for ophthalmology simultaneously and treats field, clinical effectiveness also demonstrate that this medicine can be used for treating choroid and amphiblestroid chronic vascular disease, such as hardening retinal vasculopathy, hypertension retinal vasculopathy, retinal angiospasm and maincenter retinal artery occlusion, diabetic retina vascular lesion and optic nerve injury etc..In the exploratory study treating otology, good clinical effectiveness illustrates that this medicine can be also used for treatment and has consciousness type presbyacusis, Meniere and tinnitus.Vinpocetine is current clinical treatment and the first-line drug of prevention ischemic cerebrovascular, having multinomial prospective result of study to point out in the recent period, vinpocetine has potential using value to some brain neuroblastoma disease such as Alzheimer and vascular dementia etc..
Vinpocetine chemistry entitled (3S, 16S)-eburnamenine-14-carboxylic acid, ethyl ester, molecular formula: C22H26N2O2, relative molecular weight: 350.5, it is 42971-09-5 that U.S. chemical abstract services society (CAS) registration number, and chemical structural formula is as follows:
Highly purified vinpocetine is white crystalline powder, odorless, tasteless；In chloroform or glacial acetic acid readily soluble, the most molten in acetone, ethyl acetate or dimethylformamide, slightly soluble in methanol, ethanol or ether, insoluble in water；Fusing point about 150 DEG C.
At present the preparation method of vinpocetine have two kinds: one be chemically carry out complete synthesis；Two is to extract vincamine from the plant containing vincamine to be that raw material is carried out semi-synthetic.
Chemistry total synthesis method is more about the route of report, mostly rests on laboratory stage.The most only Gedeon Richter company is applied to industrialized production for initiation material through the method for the complete synthesis vinpocetine of multistep reaction with color ammonia.Document uses ethanol to be that solvent carries out recrystallization substantially, and synthetic route is as follows:
Patent US4035370 reports the semisynthesis of a kind of vinpocetine, with vincamine (Vincamine) as raw material, it is apo-vincamine (Apovincamine) through dehydration, hydrolyze to obtain its acid (Apovincaminic acid) again, obtain vinpocetine through esterification.Employing ethanol is recrystallization solvent, and synthetic route is as follows:
Vinpocetine is the medicine of a purification more difficulty, and the vinpocetine of two kinds of method synthesis all there is a problem that impurity is more, higher；These impurity cause again medicine its colour changed into yellow；Impurity between each production batch differs greatly.Patent US4035370 and DE10311850 all use ethanol to carry out recrystallization purifying, and existing technique is in ethanol solution by vinpocetine dissolving crude product, add thermosol and add activated carbon decolorizing the most afterwards, and cooling separates out crystallization, filters, is drying to obtain vinpocetine.Repeating test and prove to be difficult to effectively remove impurity and the color of vinpocetine crude product, such as EP (European Pharmacopoeia), USP (American Pharmacopeia) are wider to the requirement of the crude drug limit of impurities, and character also requires nothing more than white to light yellow crystalline powder.It is shown in Table 1.
Table 1:EP (European Pharmacopoeia), USP (American Pharmacopeia) vinpocetine table of limits
We learn through overtesting, defining the high polymer that some are yellow during the chemosynthesis of vinpocetine crude product, these high polymers are difficult to by using the adsorptivity scarvenger of conventional method (such as activated carbon, kieselguhr etc.) effectively to remove in recrystallization purifying technique.During crystallization, high polymer parcel impurity causes product to be difficult to purification, and these are that the high polymer of yellow makes product become faint yellow.These high polymers play the catalytic action accelerating vinpocetine degraded simultaneously, cause preparation impurity to be continuously increased, and the holding time shortens.
The reason causing disadvantage mentioned above is that existing vinpocetine recrystallizing technology can not effectively remove these high polymers, although current various novel compound purification technique has been obtained for being widely applied, such as: column chromatography technology, separated technology etc., but major part new technique comprises high production cost, advanced equipment, complicated technique, the restriction of intellectual property and loaded down with trivial details mentality of designing, and has certain limitation for medicine new technique of different nature.Recrystallization technology with its cheap cost, need not the advantages such as special installation and be always the first-selection of compound purification technique.
For overcoming drawbacks described above to prepare the industrial purification production method of vinpocetine, we are on the basis of document report uses ethyl alcohol recrystallization method, having carried out design and the research of a large amount of technical scheme, final optimization pass goes out a set of new vinpocetine technique for purifying crude technique for preparing vinpocetine.Existing recrystallization purifying method is that ethanol dissolves vinpocetine crude product, activated carbon decolorizing, and cooling separates out crystallization；The method of present invention design is divided into two steps, and the first step is the concentrated solution of preparation effectively decolouring, is used for removing high polymer, and second step, for preparing vinpocetine crystal, is used for removing organic impurities.Method be briefly described into, the organic solvent high first by dissolubility dissolves vinpocetine crude product, add our the mixed type adsorptivity scarvenger of design and carry out purification targetedly, filter, decompression is distilled off organic solvent and obtains concentrated solution, then adds alcohol organic solvent precipitation vinpocetine crystallization in concentrated solution；Solve above-mentioned technological deficiency.
Vinpocetine preparation is oral formulations and injection.Vinpocetine poor stability, high temperature and light note cause it to degrade, and impurity increases sharply.Particularly injection, the control to impurity is the strictest.The vinpocetine that we utilize new purification technique to prepare is developed for the pharmaceutical composition of oral formulations and injection, and the preparation impurity obtained is less, and stability is more preferable, has more preferable application prospect clinically.
Summary of the invention
It is desirable to provide a kind of effective, easy method utilizing recrystallization purifying technology to prepare vinpocetine, the vinpocetine that the method prepares has lower impurity compared with prior art, more stable, color is white powder, and different batches mutual impurity difference is less.And vinpocetine prepared by new purification technique is used for the pharmaceutical composition exploitation of oral formulations and injection.
The recrystallization purifying method preparing vinpocetine that the present invention provides, preparation technology is characterized in that: the vinpocetine crude product prepared with semi-synthesis method or complete synthesizing process is as raw material, by vinpocetine dissolving crude product in organic solvent, adding adsorptivity scarvenger purification in the solution, filtration, evaporate filtrate, concentrated solution crystallizes in alcohol organic solvent, filtering crystals, and wash with above-mentioned solvent, it being dried, dry product is ground into powder and i.e. obtains Vinpocetione crude drug.
More detailed preparation technology is characterised by that described method comprises the following steps:
(1) concentrated solution of preparation effectively decolouring
A vinpocetine crude product is mixed by () with organic solvent, heating for dissolving, refluxes half an hour.
B () uses the adsorptivity scarvenger that surface area is bigger to make solution become clarification at 30-45 DEG C.
C () is by settled solution filtered while hot, and use the organic solvent of step (a) to wash.
D () filtrate makes volume reduce by decompression distillation, obtain concentrated solution.
(2) vinpocetine crystal is prepared
E () adds alcohol organic solvent in concentrated solution, and at 0-5 DEG C of shake suspension less than 1 hour, stand and separate out crystal after shake.
F () filtering for crystallizing thing, with the alcohol organic solvent wash crystallization thing of step (e).
G () crystal is dried under the conditions of 40-100 DEG C, and be ground into powder.
In above-mentioned preparation method, described vinpocetine crude product can be prepared by semi-synthesis method or complete synthesizing process, and wherein prepared by preferably total synthesis method；
Vinpocetine crude product measures with the content analysis method of EP, it is desirable to the content of vinpocetine is more than 97%；
The organic solvent of step (a) is selected from dichloromethane, chloroform, one or more mixed solvent of ethyl acetate, wherein preferred dichloromethane；
The adsorptivity scarvenger that surface area that step (b) uses is bigger, selected from aluminium oxide, activated carbon, one or more mixing scarvenger diatomaceous, the wherein mixing scarvenger of preferential oxidation aluminum and activated carbon；
In mixing scarvenger, the ratio of aluminium oxide and activated carbon is 5:1 to 1:5, wherein preferably 1:1；
The adsorptivity scarvenger fed intake is 1:10 to 1:100 with the part by weight of vinpocetine crude product, wherein preferably 1:15 to 1:30；
The concentrated solution weight ratio that the vinpocetine crude product fed intake and step (d) obtain is 1:0.9 to 1:5, wherein preferably 1:1 to 1:2；
Alcohol organic solvent is selected from methanol, ethanol and one or more mixed solvent of ethylene glycol, wherein preferred alcohol；
The vinpocetine crude product fed intake is 1:5 to 1:50 with the weight ratio of alcohol organic solvent, wherein preferably 1:10 to 1:30；
The temperature standing precipitation crystal after shake described in step (e) is 0-10 DEG C, and the time is 2-24 hour, wherein preferably 6-12 hour；
Filtering for crystallizing thing described in step (g) is dried under the conditions of 40-100 DEG C, wherein preferably 60-70 DEG C；
The Vinpocetione crude drug prepared according to technical scheme, impurity is less, and color is white powder, and stability is greatly improved；The mutual difference of different batches is less, hence it is evident that be better than the Vinpocetione crude drug of former technique.Quality analysis is shown in Table 2.
The vinpocetine that this technology obtains, may be used for the oral pharmaceutical composition with drug administration by injection approach of preparation, the pharmaceutical composition preferred tablet of oral administration route, the preferred injection with small volume of pharmaceutical composition of drug administration by injection approach.We utilize the pharmaceutical composition impurity of oral tablet that this vinpocetine develops and injection less, and stability is more preferable.
Detailed description of the invention
It is an advantage of the current invention that vinpocetine recrystallization purifying new technology cannot remove the problem of impurity and color and luster when solving original ethyl alcohol recrystallization purification, so that the vinpocetine impurity prepared is lower, more stable, color is white powder.Oral formulations and injection medicine compositions impurity prepared by the vinpocetine utilizing this technology to obtain are less, and stability is more preferable.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention rather than limit the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to normal condition or according to the condition proposed by manufacturer, but is not limited to these embodiments specifically recorded.
For clearer explanation advantages of the present invention, the vinpocetine also prepared the vinpocetine prepared by the present invention and original recrystallizing technology compares research.
Embodiment 1
Each material amounts:
Preparation method:
(1) concentrated solution of preparation effectively decolouring
Vinpocetine crude product in upper table is mixed according to above-mentioned quantity with organic solvent, is heated to refluxing half an hour after solid dissolves；When solution is cooled to 30-35 DEG C, adding adsorptivity scarvenger, backflow makes solution become clarification；By settled solution filtered while hot, and the organic solvent in upper table is used to wash；Filtrate makes volume reduce by decompression distillation, obtains concentrated solution.
(2) vinpocetine crystal is prepared
In concentrated solution, add the alcohol organic solvent in upper table, and at 0-5 DEG C of shake suspension less than 1 hour, stand after shake and separate out crystal；Filtering for crystallizing thing, with the alcohol organic solvent wash crystallization thing in table, crystal is dried under the conditions of 60-70 DEG C, and is ground into powder.
Yield: 92.5%
Embodiment 2
Each material amounts:
Preparation method: see embodiment 1 preparation method.
Yield: 91.3%
Embodiment 3
Each material amounts:
Preparation method: see embodiment 1 preparation method.
Yield: 92.8%
Embodiment 4
Each material amounts:
Preparation method: see embodiment 1 preparation method.
Yield: 94.2%
Embodiment 5
Each material amounts:
Preparation method: see embodiment 1 preparation method.
Yield: 93.1%
Embodiment 6
Each material amounts:
Preparation method: see embodiment 1 preparation method.
Yield: 93.6%
Embodiment 7
Each material amounts:
Preparation method: see embodiment 1 preparation method.
Yield: 89.2%
Embodiment 8
Each material amounts:
Preparation method: see embodiment 1 preparation method.
Yield: 81.5%
Vinpocetine prepared by the vinpocetine that embodiment 1-8 is prepared by we according to EP (European Pharmacopoeia) regulation and original recrystallizing technology compares research.The results are shown in Table 2:
Table 2: the character of vinpocetine prepared by each embodiment and former technique, have the analytical data of related substance and content
In terms of above testing result, the vinpocetine limit of impurities prepared by each embodiment is significantly better than that product prepared by original weight crystallization purifying technique；In embodiments, embodiment 3,7,8 can be good at obtaining white crystalline powder, and the vinpocetine that impurity content is prepared significantly lower than other embodiments, for preferred embodiment；Can effectively decolour from our new technology of above analytic explanation and control impurity, wherein with dichloromethane as organic solvent, the aluminium oxide of 1:1, activated carbon be adsorptivity scarvenger and ethanol be alcohol organic solvent make the outward appearance of product more preferably, impurity is lower, yield is higher, therefore the optimum recrystallization purifying method that embodiment 3 is vinpocetine, it is suitable for large-scale industrial production.
Embodiment 3 preparation vinpocetine have related substance high-efficient liquid phase chromatogram to see (each chromatographic peak shown in figure is respectively 1. Changchun propylhomoserin ethyl esters to accompanying drawing 1,2. the climing ketoxime in Changchun, the 3. climing ketone in Changchun, 4. dihydro vinpocetine, 5. apo-vincamine, 6. vinpocetine).Vinpocetine prepared by original weight crystallization purifying technique have related substance high-efficient liquid phase chromatogram to see (each chromatographic peak shown in figure is respectively 1. Changchun propylhomoserin ethyl esters to accompanying drawing 2,2. the climing ketoxime in Changchun, 3. the climing ketone in Changchun, 4. dihydro vinpocetine, 5. apo-vincamine, 6. methoxyl group vinpocetine, 7. vinpocetine)
Embodiment 9
Prepare the formulation and technology of tablet
Making 1000 altogether, every weight about 200mg, specification is 10mg, repeats 3 batches
Pelletize and the production technology of tabletting: preheat after starting material vinpocetine, lactose monohydrate and corn starch weighing, mixing, spray into adhesive (corn starch and purified water mix) and pelletize；Granule adds fluidizer (Pulvis Talci and anhydrous silica gel) after drying and mixes, granulate；Granule after granulate is mixed in a mixer with magnesium stearate, tabletting；Discrete piece is packaged in PVC blister and In Aluminium Foil Packing.
Embodiment 10
Prepare the formulation and technology of injection
Making 1000 altogether, every specification is 10mg/2ml, repeats 3 batches
Production technology: water for injection 1600ml is added in Agitation Tank and is heated to 50 DEG C, the unclassified stores being sequentially added in table, stirring makes material be completely dissolved, with pH value regulator regulation pH value to 3.0-3.6, add 0.05% activated carbon to stir 20 minutes in 50 DEG C, filter, filtrate is mended water for injection to 2000ml, fine straining, uses the ampoule bottle fill of 2ml；Inflated with nitrogen, sealing by fusing, sterilizing, the qualified rear packaging of lamp inspection and get final product.
The oral tablet prepared by the vinpocetine using above-described embodiment 3 to obtain and injection, oral tablet and injection impurity are less after testing, and stability is more preferable.
The features described above that the present invention mentions, or the feature that embodiment is mentioned can be in any combination.All features disclosed in this case description can be with any composition forms use, each feature disclosed in description, and the alternative characteristics of identical, impartial or similar purpose any can be provided to replace.Therefore except there being special instruction, disclosed feature is only the impartial or general example of similar features.
Embodiment described above only presently preferred embodiments of the present invention or be used as reduced parameter to show optimum embodiment, it is not limited to the substantial technological context of the present invention, the substantial technological content of the present invention is broadly to be defined in the right of application, any technology entities that other people complete or method, if with application right defined in identical, also or the change of a kind of equivalence, all it is covered by being considered among this right.
Claims (13)
1. effective, the easy method utilizing recrystallization technology purification vinpocetine, it is characterised in that institute
The method stated comprises the following steps:
(1) concentrated solution of preparation effectively decolouring
A vinpocetine crude product is mixed by () with organic solvent, heating for dissolving, refluxes half an hour.
B () uses the adsorptivity scarvenger that surface area is bigger to make solution become clarification at 30-45 DEG C.
C () is by settled solution filtered while hot, and use the organic solvent of step (a) to wash.
D () filtrate makes volume reduce by decompression distillation, obtain concentrated solution.
(2) vinpocetine crystal is prepared
E () adds alcohol organic solvent in concentrated solution, and little less than 1 at 0-5 DEG C of shake suspension
Time, stand after shake and separate out crystal.
F () filtering for crystallizing thing, with the alcohol organic solvent wash crystallization thing of step (e).
G () crystal is dried under the conditions of 40-100 DEG C, and be ground into powder.
Preparation method the most according to claim 1, described vinpocetine crude product can by semi-synthesis method or
Prepared by person's complete synthesizing process, wherein prepared by preferably total synthesis method；
Preparation method the most according to claim 1, described vinpocetine crude product provides with European Pharmacopoeia
Content analysis method measure, it is desirable to the content of vinpocetine be more than 97%；
Preparation method the most according to claim 1, the organic solvent of described step (a) is selected from two
Chloromethanes, chloroform, one or more mixed solvent of ethyl acetate, wherein preferred dichloromethane；
Preparation method the most according to claim 1, the surface area that described step (b) uses is bigger
Adsorptivity scarvenger, selected from aluminium oxide, activated carbon, one or more mixing purification diatomaceous
Agent, wherein the mixing scarvenger of preferential oxidation aluminum and activated carbon；
In mixing scarvenger the most according to claim 5, the ratio of aluminium oxide and activated carbon is that 5:1 arrives
1:5, wherein preferably 1:1；
Preparation method the most according to claim 1, the adsorptivity scarvenger fed intake and vinpocetine crude product
Part by weight be 1:10 to 1:100, wherein preferably 1:15 to 1:30；
Preparation method the most according to claim 1, the vinpocetine crude product fed intake obtains with step (d)
To concentrated solution weight ratio be 1:0.9 to 1:5, wherein preferably 1:1 to 1:2；
Preparation method the most according to claim 1, described alcohol organic solvent is selected from methanol, ethanol
With one or more mixed solvent of ethylene glycol, wherein preferred alcohol；
Preparation method the most according to claim 1, the described vinpocetine crude product fed intake and alcohols
The weight ratio of organic solvent is 1:5 to 1:50, wherein preferably 1:10 to 1:30；
11. preparation methoies according to claim 1, stand after the shake described in step (e) and separate out knot
The temperature of brilliant thing is 0-10 DEG C, and the time is 2-24 hour, wherein preferably 0-5 DEG C, stand 6-12 hour；
12. preparation methoies according to claim 1, the filtering for crystallizing thing described in step (g) exists
It is dried under the conditions of 40-100 DEG C, wherein preferably 60-70 DEG C；
The vinpocetine that 13. preparation methoies according to claim 1 obtain, may be used for preparation oral
With the Vinpocetine medicine composition of drug administration by injection approach, the preferred sheet of pharmaceutical composition of oral administration route
Agent, the preferred injection with small volume of pharmaceutical composition of drug administration by injection approach.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311432A (en) * | 2011-08-26 | 2012-01-11 | 贺金凤 | Stable vinpocetine compound and pharmaceutical composition thereof |
| CN102532136A (en) * | 2010-12-17 | 2012-07-04 | 江苏斯威森生物医药工程研究中心有限公司 | Industrial production process for indole alkaloid tabersonine |
| CN103121998A (en) * | 2013-02-06 | 2013-05-29 | 罗军 | Vinpocetine compound and drug composition thereof |
| CN103664934A (en) * | 2013-12-06 | 2014-03-26 | 湖南科源生物制品有限公司 | Preparation method for vinpocetine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532136A (en) * | 2010-12-17 | 2012-07-04 | 江苏斯威森生物医药工程研究中心有限公司 | Industrial production process for indole alkaloid tabersonine |
| CN102311432A (en) * | 2011-08-26 | 2012-01-11 | 贺金凤 | Stable vinpocetine compound and pharmaceutical composition thereof |
| CN103121998A (en) * | 2013-02-06 | 2013-05-29 | 罗军 | Vinpocetine compound and drug composition thereof |
| CN103664934A (en) * | 2013-12-06 | 2014-03-26 | 湖南科源生物制品有限公司 | Preparation method for vinpocetine |
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Application publication date: 20160810 |