CN104083329A - Vinpocetine special ultrafine powder lyophilized preparation and preparation method thereof - Google Patents
Vinpocetine special ultrafine powder lyophilized preparation and preparation method thereof Download PDFInfo
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- CN104083329A CN104083329A CN201410059789.8A CN201410059789A CN104083329A CN 104083329 A CN104083329 A CN 104083329A CN 201410059789 A CN201410059789 A CN 201410059789A CN 104083329 A CN104083329 A CN 104083329A
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Abstract
The invention discloses a vinpocetine special ultrafine powder lyophilized preparation and a preparation method thereof. The preparation method includes: taking (3alpha, 14beta, 16alpha)-14, 15-dihydro-14-hydroxyl eburnamenine-14-carboxylic acid methyl ester as a raw material, carrying out elution, concentration and cooling to obtain purified vinpocetine, conducting jet milling on the purified vinpocetine to obtain ultrafine powder, then dissolving the vinpocetine special ultrafine powder in water for injection, performing low temperature pre-freezing, then carrying out low temperature pressure reduction vacuum drying, and finally conducting high temperature drying, thus obtaining the vinpocetine special ultrafine powder lyophilized preparation.
Description
Technical field
The present invention relates to extraordinary superfine powder lyophilized formulations of a kind of vinpocetine and preparation method thereof, belong to medical technical field.
Background technology
Vinpocetine, its chemical name is: ethyl (13as, 13bs)-13a-ethyl-2,3,5,6-13a, 13b six hydrogen-1H-indole [3,2,1-de] pyridine [3,2,1-ij] [1,5]-benzodiazine-12-carboxylic acid, English Vinpocetine by name, molecular formula: C22H26N2O2, molecular weight: 350.46, structural formula is as follows:
Vinpocetine is a kind of alkaloid extracting from apocynaceae plant, is the derivant of vincamine.Vinpocetine optionally suppresses cerebrovascular smooth muscle calcium ion according to lazyness phosphodiesterase, makes cerebral vasodilators, then increases cerebral blood volume, improves cerebral circulation, little on heart and blood pressure impact.At present clinical in giddy, headache, dysmnesia, action obstacle, aphasia, hypertensive encephalopathy etc., the spirituality or the nerve symptom that also cause for cerebrum blood circulatory disturbance.Vinpocetine is rapid-action, better tolerance, and untoward reaction is little, becomes one of clinical common medicine.
In December, 1999, " extraordinary superfine powder technology of preparing " obtains first-class National Scientific and Technological Progress Award, prize-winning unit: Institutes Of Technology Of Nanjing (Li Fengsheng), certificate number: 30-1-003-01.On January 2nd, 2014, Institutes Of Technology Of Nanjing exclusively assigns in Chang Dian pharmaceuticals about " application of extraordinary superfine powder technology of preparing in pharmaceutical preparation ", and corresponding product is carried out to formulation development and industrialization.
Disclose both at home and abroad the method for multiple synthetic vinpocetine, but existing vinpocetine exists that purity is low, granule is large, powder sizing is poor, product stability is poor, and the production cycle is long, high in cost of production shortcoming.
Summary of the invention
The object of the present invention is to provide extraordinary superfine powder lyophilized formulations of a kind of vinpocetine and preparation method thereof, make vinpocetine there is the advantages such as purity is high, granule is little, powder sizing is good, dissolubility is good, biological activity is good.
For solving the problems of the technologies described above, extraordinary superfine powder lyophilized formulations (3 α of vinpocetine of the present invention, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester is raw material, become the vinpocetine of purification through a series of eluting, after concentrated, cooling, then after super-dry, air flow super, lyophilizing, obtain the extraordinary superfine powder lyophilized formulations of vinpocetine.
For solving the problems of the technologies described above, the preparation method of the extraordinary superfine powder lyophilized formulations of vinpocetine of the present invention, the method comprises the steps:
Step 1, by (3 α, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester adds in dehydrated alcohol, then adds pure cerium hydroxide potassium, reflux, to thin layer detection nothing (3 α, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester, then the ph value of reactant liquor is adjusted to 6 with concentrated hydrochloric acid, concentration response is to dry, add water washing to neutral, sucking filtration is dry, and the product obtaining is Changchun amino acid;
Step 2, is placed in dehydrated alcohol by step 1 gained Changchun amino acid and dissolves, then add styrene cation exchange resin, the temperature that simultaneously raises, in the time that temperature rises to 75-80 DEG C, drips concentrated acid, back flow reaction to thin layer detects without Changchun amino acid, then will react cooling, reactant liquor ph is adjusted to 9 after cooling;
Step 3, the reactant liquor that is 9 by the ph value of step 2 gained, with dichloromethane extraction, is washed to neutrality by dichloromethane, concentrated placement crystallization, sucking filtration, a small amount of ethanol rinsing for solid, dry, obtain the vinpocetine of purifying;
Step 4, the vinpocetine of purification is become to superfine powder with comminution by gas stream, then extraordinary vinpocetine superfine powder is dissolved in to water for injection, carry out low temperature pre-freeze, carry out again low-temperature reduced-pressure vacuum drying, finally carry out high temperature drying and make the extraordinary superfine powder lyophilized formulations of vinpocetine.
As improvement of the present invention, the dehydrated alcohol in this step 1 is (3 α, 14 β, 16 α)-14, the dehydrated alcohol of 10 times of amount volumes of 15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester; Pure cerium hydroxide potassium in described step 1 is (3 α, 14 β, 16 α)-14, the pure cerium hydroxide potassium of 2 times of quality of 15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester.
As improvement of the present invention, the dehydrated alcohol in this step 2 is the dehydrated alcohol that the 35-40 of Changchun amino acid doubly measures volume, and wherein optimal case is the dehydrated alcohol of 38 times of amount volumes of Changchun amino acid; Styrene cation exchange resin in described step 2 is the styrene cation exchange resin of 4-5 times of quality of Changchun amino acid, and wherein optimal case is the styrene cation exchange resin of 4 times of quality of Changchun amino acid.
As improvement of the present invention, the concentrated acid dripping in this step 2 is concentrated hydrochloric acid or the concentrated sulphuric acid of 5 times of quality of Changchun amino acid, and wherein optimal case is the concentrated sulphuric acid of 5 times of quality of Changchun amino acid.
As improvement of the present invention, in this step 3, be the ethanol of concentration 85% for the ethanol of rinsing.
As improvement of the present invention, the drying means in this step 3 is boulton process, comprises the following steps: normal pressure filters, and filter cake is put into the vacuum tank that 50 DEG C is 0.08MPa with vacuum and is dried 12 hours after repeatedly washing with deionized water.
As improvement of the present invention, the comminution by gas stream in this step 4 adopts multi-stage crushing.
As improvement of the present invention, the air velocity of the comminution by gas stream in step 4 is 350～450m/s, and the particle diameter of superfine powder is 0.6～3 μ m.
As improvement of the present invention, the vinpocetine in step 4 is 35～45g, and water for injection adds to 2000ml, makes 1000 bottles after lyophilizing; Pre-freeze temperature is-35 DEG C, and the pre-freeze time is 2～4 hours; The dry temperature of reduced vacuum is-35～8 DEG C, and be 24～28 hours drying time; High temperature drying temperature is 35 DEG C, and be 6～8 hours drying time.
Compared with prior art, the extraordinary superfine powder preparation of vinpocetine of the present invention has the advantages that purity is high, impurity is few.The extraordinary superfine powder preparation of vinpocetine of the present invention has the advantages that granule is little, powder sizing is good, dissolubility is good, makes it have good dispersibility and absorption property.In the time of dosing, can dissolve fully, dissolve rapidly, can improve the utilization rate of effective ingredient, reduce drug consumption.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further described in detail, the embodiment providing is only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
Embodiment 1
By (3 α, 14 β, 16 α)-14 of 2kg, 15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester is placed in the dehydrated alcohol of 10 times of amount volumes, then adds the pure cerium hydroxide potassium of 2 times of quality, reflux, to thin layer detection nothing (3 α, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester, with concentrated hydrochloric acid, the ph value of reactant liquor is adjusted to 6 again, concentration response, to dry, adds water washing to neutral, sucking filtration is dry, obtains product Changchun amino acid.
Again the product Changchun amino acid obtaining is placed in to the anhydrous alcohol solution of 38 times of amount volumes, add again the styrene cation exchange resin of 4 times of quality, the temperature that simultaneously raises is during to 75-80 DEG C, drip the concentrated sulphuric acid of 5 times of quality, back flow reaction to thin layer detects without Changchun amino acid, to react again cooling, reactant liquor ph will be adjusted to 9 after cooling; The reactant liquor that is 9 by ph value again, with dichloromethane extraction, is washed to neutrality by dichloromethane, concentrated placement crystallization, sucking filtration, 85% ethanol rinsing for solid, then put into the dry vinpocetine of purifying of obtaining for 12 hours of vacuum tank that 50 DEG C and vacuum are 0.08MPa.
The vinpocetine of purification is ground into superfine powder with Multi-stage airflow, and air velocity control is 400m/s, and being ground into particle diameter is the extraordinary superfine powder of 0.6～2 μ m.
Analyze through HPLC, the purity of vinpocetine is 99.9%.
Get gained vinpocetine 40g, water for injection adds to 2000ml, makes 1000 bottles after lyophilizing; Pre-freeze temperature is-35 DEG C, pre-freeze 4 hours; The dry temperature of reduced vacuum is-40 DEG C, and be 26 hours drying time; High temperature drying temperature is 35 DEG C, the dry extraordinary superfine powder lyophilized formulations that makes vinpocetine for 6 hours.
Embodiment 2
By (3 α, 14 β, 16 α)-14 of 2kg, 15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester is placed in the dehydrated alcohol of 10 times of amount volumes, then adds the pure cerium hydroxide potassium of 2 times of quality, reflux, to thin layer detection nothing (3 α, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester, with concentrated hydrochloric acid, the ph value of reactant liquor is adjusted to 6 again, concentration response, to dry, adds water washing to neutral, sucking filtration is dry, obtains product Changchun amino acid.
Again the product Changchun amino acid obtaining is placed in to the anhydrous alcohol solution of 40 times of amount volumes, add again the styrene cation exchange resin of 4 times of quality, the temperature that simultaneously raises is during to 75-80 DEG C, drip the concentrated sulphuric acid of 5 times of quality, back flow reaction to thin layer detects without Changchun amino acid, to react again cooling, reactant liquor ph will be adjusted to 9 after cooling; The reactant liquor that is 9 by ph value again, with dichloromethane extraction, is washed to neutrality by dichloromethane, concentrated placement crystallization, sucking filtration, 85% ethanol rinsing for solid, then put into the dry vinpocetine of purifying of obtaining for 12 hours of vacuum tank that 50 DEG C and vacuum are 0.08MPa.
The vinpocetine of purification is ground into superfine powder with Multi-stage airflow, and air velocity control is 380m/s, and being ground into particle diameter is the extraordinary superfine powder of 0.8～3 μ m.
Analyze through HPLC, the purity of vinpocetine is 99.82%.
Get gained vinpocetine 40g, water for injection adds to 2000ml, makes 1000 bottles after lyophilizing; Pre-freeze temperature is-35 DEG C, pre-freeze 4 hours; The dry temperature of reduced vacuum is-40 DEG C, and be 26 hours drying time; High temperature drying temperature is 35 DEG C, the dry extraordinary superfine powder lyophilized formulations that makes vinpocetine for 6 hours.
Embodiment 3(contrast)
Adopt the method step identical with embodiment 1 to make the vinpocetine of purification.
The vinpocetine of purification is become to superfine powder with comminution by gas stream, and air velocity control is 500m/s, and being ground into particle diameter is the extraordinary superfine powder of 0.6～2.5 μ m.
Adopt high pressure draught to spray grinding mode and prepare superfine powder, production process is simple and easy to control, can make product fineness reach 0.5～5 μ m, and Granularity Distribution is narrower, and particle surface is smooth, grain shape rule.Adopting air flow multi-stage to pulverize can reasonable energy utilization, less energy consumption, and can control as required sub-micron-powder diameter.
When air velocity reaches 350～450m/s, when particle diameter can reach 0.6～3 μ m, can make vinpocetine there is good dissolubility.In the time that air velocity exceedes 450m/s, fineness of the particles is not further dwindled with the increase of speed; On the other hand, in the time that particle diameter is less than 0.5 μ m, dissolubility no longer increases along with diminishing of particle diameter.Therefore, the particle diameter of the superfine powder of vinpocetine employing 0.6～3 μ m is very cost-effective.
The extraordinary superfine powder lyophilized formulations of taking the vinpocetine that aforesaid way makes, compared with prior art, the extraordinary superfine powder preparation of vinpocetine of the present invention has the advantages that purity is high, impurity is few.The extraordinary superfine powder preparation of vinpocetine of the present invention has the advantages that granule is little, powder sizing is good, dissolubility is good, makes it have good dispersibility and absorption property.In the time of dosing, can dissolve fully, dissolve rapidly, can improve the utilization rate of effective ingredient.
Claims (10)
1. the extraordinary superfine powder lyophilized formulations of a vinpocetine, it is characterized in that: the extraordinary superfine powder of described vinpocetine is with (3 α, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester is raw material, become the vinpocetine of purification through a series of eluting, after concentrated, cooling, then after super-dry, air flow super, lyophilizing, obtain the extraordinary superfine powder lyophilized formulations of vinpocetine.
2. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 1, is characterized in that: the method comprises the steps:
Step 1, by (3 α, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester adds in dehydrated alcohol, then adds pure cerium hydroxide potassium, reflux, to thin layer detection nothing (3 α, 14 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester, then the ph value of reactant liquor is adjusted to 6 with concentrated hydrochloric acid, concentration response is to dry, add water washing to neutral, sucking filtration is dry, and the product obtaining is Changchun amino acid;
Step 2, is placed in dehydrated alcohol by step 1 gained Changchun amino acid and dissolves, then add styrene cation exchange resin, the temperature that simultaneously raises, in the time that temperature rises to 75-80 DEG C, drips concentrated acid, back flow reaction to thin layer detects without Changchun amino acid, then will react cooling, reactant liquor ph is adjusted to 9 after cooling;
Step 3, the reactant liquor that is 9 by the ph value of step 2 gained, with dichloromethane extraction, is washed to neutrality by dichloromethane, concentrated placement crystallization, sucking filtration, a small amount of ethanol rinsing for solid, dry, obtain the vinpocetine of purifying;
Step 4, the vinpocetine of purification is become to superfine powder with comminution by gas stream, then extraordinary vinpocetine superfine powder is dissolved in to water for injection, carry out low temperature pre-freeze, carry out again low-temperature reduced-pressure vacuum drying, finally carry out high temperature drying and make the extraordinary superfine powder lyophilized formulations of vinpocetine.
3. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, it is characterized in that: the dehydrated alcohol in described step 1 is (3 α, 14 β, 16 α)-14, the dehydrated alcohol of 10 times of amount volumes of 15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester; Pure cerium hydroxide potassium in described step 1 is (3 α, 14 β, 16 α)-14, the pure cerium hydroxide potassium of 2 times of quality of 15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester.
4. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, is characterized in that: the dehydrated alcohol in described step 2 is the dehydrated alcohol that the 35-40 of Changchun amino acid doubly measures volume; Styrene cation exchange resin in described step 2 is the styrene cation exchange resin of 4-5 times of quality of Changchun amino acid.
5. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, is characterized in that: the concentrated acid dripping in described step 2 is concentrated hydrochloric acid or the concentrated sulphuric acid of 5 times of quality of Changchun amino acid.
6. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, is characterized in that: in described step 3, be the ethanol of concentration 85% for the ethanol of rinsing.
7. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, it is characterized in that: the drying means in described step 3 is boulton process, comprise the following steps: normal pressure filters, filter cake is put into the vacuum tank that 50 DEG C is 0.08MPa with vacuum and is dried 12 hours after repeatedly washing with deionized water.
8. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, is characterized in that: the comminution by gas stream in described step 4 adopts multi-stage crushing.
9. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, is characterized in that: the air velocity of the comminution by gas stream in described step 4 is 350～450m/s, and the particle diameter of superfine powder is 0.6～3 μ m.
10. the preparation method of the extraordinary superfine powder lyophilized formulations of a kind of vinpocetine according to claim 2, is characterized in that: the vinpocetine 35～45g in described step 4, and water for injection adds to 2000ml, makes 1000 bottles after lyophilizing; Pre-freeze temperature is-35 DEG C, and the pre-freeze time is 2～4 hours; The dry temperature of reduced vacuum is-35～8 DEG C, and be 24～28 hours drying time; High temperature drying temperature is 35 DEG C, and be 6～8 hours drying time.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101264064A (en) * | 2008-04-17 | 2008-09-17 | 孙向阳 | Vinpocetine freeze-dried powder for injection and preparation thereof |
| CN102040606A (en) * | 2011-01-26 | 2011-05-04 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of vinpocetine |
| CN103121998A (en) * | 2013-02-06 | 2013-05-29 | 罗军 | Vinpocetine compound and drug composition thereof |
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2014
- 2014-02-21 CN CN201410059789.8A patent/CN104083329A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101264064A (en) * | 2008-04-17 | 2008-09-17 | 孙向阳 | Vinpocetine freeze-dried powder for injection and preparation thereof |
| CN102040606A (en) * | 2011-01-26 | 2011-05-04 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of vinpocetine |
| CN103121998A (en) * | 2013-02-06 | 2013-05-29 | 罗军 | Vinpocetine compound and drug composition thereof |
Non-Patent Citations (3)
| Title |
|---|
| 刘宏英等: "超细粉体的应用及制备", 《江苏化工》 * |
| 姜华等: "长春西汀的半合成工艺", 《暨南大学学报(自然科学版)》 * |
| 葛晓陵: "药物超细粉碎技术的研究", 《中国粉体技术》 * |
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