CN102311432B

CN102311432B - Stable vinpocetine compound and pharmaceutical composition thereof

Info

Publication number: CN102311432B
Application number: CN201110248975A
Authority: CN
Inventors: 贺金凤
Original assignee: Individual
Current assignee: Hebei Sanhe Shichuang Biotechnology Co ltd
Priority date: 2011-08-26
Filing date: 2011-08-26
Publication date: 2012-10-17
Anticipated expiration: 2031-08-26
Also published as: CN102311432A

Abstract

The invention relates to a stable vinpocetine compound and a pharmaceutical composition thereof. A preparation method of the stable vinpocetine compound comprises carrying out recrystallization of a vinpocetine crude product 1 to 3 times by a solvent prepared form ethyl acetate and methanol according to a ratio of 2: 1, and simultaneously, carrying out decoloration by active carbon to obtain almost white crystals.

Description

A kind of more stable vinpocetin compound and pharmaceutical composition thereof

Technical field:

The present invention relates to a kind of preparation of medical compounds, the spy is the preparation of suppressing panting calming medicine vinpocetin compound fully.

Background technology:

Vinpocetin is a kind of cerebral vasodilator, chemical name: vincamine amino acid ester, and structural formula is:

Vinpocetin can suppress phosphodiesterase activity, increases the effect of the courier c-GMP of vascular smooth muscle relaxation, optionally the cerebral blood flow increasing amount; Can also suppress platelet aggregation in addition, reduce human blood viscosity, strengthen RBC deformation power; Improve blood fluidity and microcirculation; Promote the cerebral tissue ingestion of glucose, increase the brain oxygen-consumption, improve the brain metabolism.Distribute in the vinpocetin body extensively, eliminate comparatively fast from blood plasma, can get into cerebral tissue through hemato encephalic barrier, concentration is 1/30 of blood concentration in the cerebrospinal fluid, can get into placenta.With the human plasma protein fraction combination rate be 66%, the liver main metabolites is a A Piao Changchun amino acid, by RE, its pharmacological action is similar with the original shape medicine, but drug effect is lower.These article do not have the tendency of accumulating in vivo.Indication is: improve the various symptoms that cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis etc. are brought out.

At present, the vinpocetin injection has injection liquid and freeze-dried powder, if when existing vinpocetin injection storage period is long, color can be turned to be yellow slightly, through measuring, relates to due to isomer and degraded product increase.Because the vinpocetin injection is intravenous administration, so higher to the purity requirement of its bulk drug vinpocetin, total impurities content should be less than 1% according to pharmacopeia, and wherein the content of each related impurities all should be less than 0.1%.But it is recrystallization solvent that prior art adopts acetone-water=1: 1, though the content of vinpocetin is greater than 99% behind the recrystallization, wherein the content of the related impurities of 2 unknown structure is all greater than 0.2%.

For improving production quality, overcome the problem of major ingredient degraded and foreign matter content, we have carried out the design and the research of a large amount of technical schemes, finally successfully optimize the new technical scheme of a cover, have solved above-mentioned technological deficiency.

Summary of the invention:

The present invention provides a kind of vinpocetin preparation method, and this method is more stable than prior art after being processed into the vinpocetin injection through the refining vinpocetin that obtains, and prolong storage period.The content of the vinpocetin that obtains is more than 99.0%, and wherein the content of each related impurities is less than 0.1%.

Vinpocetin preparation method of the present invention is characterized in that step is following:

The bullion vinpocetin, use ETHYLE ACETATE: methyl alcohol=2: 1 is solvent recrystallization 1-3 time, gets the off-white color crystallization with activated carbon decolorizing simultaneously; Proportioning raw materials wherein: vinpocetin bullion: gac: ETHYLE ACETATE and methanol mixed solvent=1: 0.05: 8.

Preferred finished product is refining to be recrystallization 2 times.

Wherein said vinpocetin bullion can obtain with prior art for preparing; Also can buy and obtain from market; Through detecting, the content that does not meet vinpocetin is more than 99.0%, and wherein the content of each related impurities is less than any vinpocetin bulk drug of 0.1% standard.

The purification step that focuses on the vinpocetin compound of the present invention; The vinpocetin raw material of the purifying that obtains; Foreign matter content is few, the injection good stability of processing, and this depends primarily on the use of solvent in the treating process; The present invention adopts ETHYLE ACETATE: methyl alcohol=2: 1 (v/v) obtains through screening as recrystallization solvent, and screening process is following:

After the thick product of synthetic vinpocetin adopted following different solvent treatment respectively, the content of impurity was seen table 1 in each sample.

The thick product of the pure article of table 1 vinpocetin is handled the content of impurity in each sample of back with different solvents

Solvent	Impurity (%)
		Methyl alcohol	0.74
Ethanol	0.88
		Methylene dichloride	0.86
ETHYLE ACETATE	0.85
		Acetone	0.70
ETHYLE ACETATE: methyl alcohol (1: 1)	0.54
		ETHYLE ACETATE: methyl alcohol (1: 5)	0.63
ETHYLE ACETATE: methyl alcohol (1: 4)	0.62
		ETHYLE ACETATE: methyl alcohol (2: 1)	0.48

ETHYLE ACETATE: methyl alcohol (4: 1)	0.53
		ETHYLE ACETATE: methyl alcohol (5: 1)	0.63

Below, further specify the present invention through experimental data:

The product that table 2 couple the present invention and prior art obtain carries out HPLC to be analyzed, and purity and foreign matter content % are following:

	With acetone-water as recrystallization solvent	The embodiment of the invention 1
			Vinpocetin	99.21	99.52
Unknown impuritie 1	0.32	0.09
			Unknown impuritie 2	0.12	0.09
Unknown impuritie 3	0.24	-

The vinpocetin injection of buying on table 3 pair vinpocetin injection of the present invention and the market detects, and detects heavy metal and foreign matter content, result such as following table:

The injection liquid of preparing with the vinpocetin of ethyl alcohol recrystallization in table 4 pair vinpocetin injection of the present invention and the prior art carries out permanent stability relatively, and the result is following:

See that from testing data injection heavy metal and the foreign matter content of embodiment 2 are less than the medicine that has gone on the market.

Injection of the present invention is more stable simultaneously, and degradation speed is slow.

Therefore, the present invention also comprises, the vinpocetin of the purifying that obtains with preparation method of the present invention becomes injection as the feedstock production of injection, and per 1000 injections are composed of the following components:

Its preparation method is following:

Get vinpocetin 10-20g, with the PEG-400 mixed grinding, to use the pH value prepare be Sodium phosphate, dibasic-phosphate sodium dihydrogen buffer solution 8000ml of 6.5 dissolves the abrasive material of vinpocetin and PEG-400, adds 0.5% gac; Be heated to 80 ℃ and kept 15 minutes, filter carbon removal, add sodium sulfite anhy 96 then, Zonon D; Stirring makes dissolving, adds phosphoric acid disodium hydrogen-phosphate sodium dihydrogen buffer solution to 10000ml, adds 0.5% activated carbon, boils; Filter with the millipore filtration of 0.45 μ m is smart, and carry out Sterile Filtration with the millipore filtration of 0.20 μ m, canned; Sterilization, labeling promptly gets.

Injection of the present invention can be prepared into the liquid preparation of injection, and also further processing and preparing becomes cryodesiccated injection freeze-dried powder.

The preparation of vinpocetin of the present invention belongs to process modification, mainly contains following some advantage:

Make with extra care and use solvent ethyl acetate: methyl alcohol=2: 1 (v/v) makes product purity reach 99.25%, and crystal form is good, and stability is stronger, and productive rate is high, and purification efficiency is high, simple, with low cost, the suitable scale operation of technology.Particularly being mixed with injection, to make this injection have a foreign matter content low, the characteristics that stability is strong.

Embodiment:

Below further specify the present invention through embodiment, but not as limitation of the present invention.

Embodiment 1:

With of ETHYLE ACETATE and methyl alcohol=2: 1 (v/v) mixed solvent dissolving of vinpocetin bullion with 8 times of amounts of its weight, add the gac of liquor capacity amount about 5% (w/v) weight, be heated to reflux temperature; Continue 1 hour, room temperature was placed 24 hours, separated out crystallization; Obtain crystallization behind the suction filtration, repeat above step, obtain recrystallized product for the second time; Use washing with alcohol, promptly get the pure article of vinpocetin after the drying, detect through HPLC; The pure article of gained vinpocetin, purity 99.52%, unknown impuritie content is all less than 0.1%.

Embodiment 2

Its preparation method is following:

Get vinpocetin 10g, with the PEG-400 mixed grinding, to use the pH value prepare be Sodium phosphate, dibasic-phosphate sodium dihydrogen buffer solution 8000ml of 6.5 dissolves the abrasive material of vinpocetin and PEG-400, adds 0.5% gac; Be heated to 80 ℃ and kept 15 minutes, filter carbon removal, add sodium sulfite anhy 96 then, Zonon D; Stirring makes dissolving, adds phosphoric acid disodium hydrogen-phosphate sodium dihydrogen buffer solution to 10000ml, adds 0.5% activated carbon, boils; Filter with the millipore filtration of 0.45 μ m is smart, and carry out Sterile Filtration with the millipore filtration of 0.20 μ m, canned; Sterilization, labeling promptly gets.

Embodiment 3

Its preparation method is following:

Get vinpocetin 20g, with the PEG-400 mixed grinding, to use the pH value prepare be Sodium phosphate, dibasic-phosphate sodium dihydrogen buffer solution 8000ml of 6.5 dissolves the abrasive material of vinpocetin and PEG-400, adds 0.5% gac, is heated to 80 ℃ and kept 15 minutes; Filter carbon removal, add sodium sulfite anhy 96 then, Zonon D stirs and makes dissolving; Add phosphoric acid disodium hydrogen-phosphate sodium dihydrogen buffer solution to 10000ml, add 0.5% activated carbon, boil, with the smart filter of the millipore filtration of 0.45 μ m; And carry out Sterile Filtration with the millipore filtration of 0.20 μ m, and canned, partly seal, put into freeze drying box; Freeze-drying is sealed, labeling, and packing promptly gets.

Embodiment 4

The preparation of Sodium phosphate, dibasic-phosphate sodium dihydrogen buffer solution:

The Sodium phosphate, dibasic aqueous solution of preparation 0.2mol/L, the biphosphate sodium water solution of preparation 0.2mol/L mixed both that can to obtain the pH value be Sodium phosphate, dibasic-phosphate sodium dihydrogen buffer solution of 6.5 according to 31.5: 68.5 volume ratio.

Claims

1. the preparation method of the vinpocetin compound that a structure is following is characterized in that step is following:

With of ETHYLE ACETATE and methyl alcohol=2:1 (v/v) the mixed solvent dissolving of vinpocetin bullion with 8 times of amounts of its weight, add the gac of liquor capacity amount 5% (w/v) weight, be heated to reflux temperature; Continue 1 hour, room temperature was placed 24 hours, separated out crystallization; Obtain crystallization behind the suction filtration, repeat above step, obtain recrystallized product for the second time; Use washing with alcohol, promptly get the pure article of vinpocetin after the drying.