CN104497060A - Method for preparing sterile fructose diphosphate arginine salt - Google Patents
Method for preparing sterile fructose diphosphate arginine salt Download PDFInfo
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- CN104497060A CN104497060A CN201410823301.4A CN201410823301A CN104497060A CN 104497060 A CN104497060 A CN 104497060A CN 201410823301 A CN201410823301 A CN 201410823301A CN 104497060 A CN104497060 A CN 104497060A
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- fructose diphosphate
- aseptic
- fructose
- acid salt
- arginine
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Abstract
The invention discloses a method for preparing a sterile fructose diphosphate arginine salt, and relates to the technical field of preparation of composite salts or phosphate ester compounds. The method comprises the steps that fructose dipllosphate sodium salt is prepared into an aqueous liquid, and sodium ions are removed by adsorption of cation exchange resin to obtain a fructose diphosphate liquid; after the concentration of a nanofiltration membrane, arginine is added to dissolve completely; the active carbon decoloration is performed, and the resulting feed liquid is subjected to four-stage membrane filtration; and the solvent-out crystallization is performed in a sterile room, and finally the sterile fructose diphosphate arginine salt is obtained. The preparation method provided by the invention has the advantages of simple production process and high product purity, stable sterile powder can be produced to be used by other dosage forms, the problems of various adverse reactions and hypernatronemia risks caused by the original fructose diphosphate arginine salt in treatment of cardiovascular and cerebrovascular diseases are solved, and the synergistic therapeutic effect is realized.
Description
Technical field
The present invention relates to the preparing technical field of composite salt or phosphate compounds.
Background technology
Fructose Diphosphate is a kind of clinical commonly used drug; be mainly used in the assisting therapy of cardiovascular and cerebrovascular diseases; its effect is by activating phosphatase fructokinase and pyruvate kinase; the concentration of ATP and phosphocreatine in cell is increased; promote stream in potassium ion; increase the stability of cytolemma, prevent cell from producing oxyradical, thus provide protection is produced to the cell of damage.Point out in sodium fructose diphosphate injection specification sheets, in injection uses, there will be lip numbness, injection site pain phenomenon, the side effects such as accidental dizziness, uncomfortable in chest and anaphylaxis, other patients that may suffer from hypernatremia are unsuitable for the product of taking this medicine.
For avoiding this phenomenon, application number be 200710026495.5 patent of invention disclose a kind of 1, the arginic acid salt of 6-diphospho-D-fructose ester and pharmaceutical use thereof, this 1, the arginic acid salt of 6-diphospho-D-fructose ester can play the effect of synergy in treatment myocardial ischemia, a large amount of sodium ion is avoided to take in, pungency is little, toxicity is low, be expected to be developed as newtype drug, 1 is disclosed in the embodiment of this (application number is 200710026495.5) patent of invention, the simple preparation process of the arginic acid salt of 6-diphospho-D-fructose ester, aseptically process is not related in this process, and what last crystallisation process adopted is lyophilization, its gained medicine degradation product is more, for metamict crystals, poor stability.A kind of new preparation method is still needed to produce the composite salt that can increase medicine stability, to solve the problem at present.
Summary of the invention
The technical problem to be solved in the present invention is for above-mentioned the deficiencies in the prior art, there is provided a kind of method preparing aseptic fructose diphosphate arginic acid salt, the method production technique is simple, and product purity is high, the aseptic powder of stable performance can be produced, for the use of other formulations of medicine.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
(1) fructose diphosphate sodium salt is made the aqueous solution, gained feed liquid is carried out secondary cation exchange resin Adsorption sodium ion, obtain fructose diphosphate solution;
Or, directly adopt and transform obtain fructose diphosphate solution through enzyme process, fermentation method;
(2) by above-mentioned fructose diphosphate solution after nanofiltration membrane is concentrated, add arginine and be dissolved to completely;
(3) below 60 DEG C, carry out activated carbon decolorizing to gained solution in step (2), activated carbon dosage is the 0.15%-3% of solution material gross weight, and gained feed liquid carries out level Four membrane filtration;
(4) in sterilisable chamber, carry out solvent crystal after, finally obtain aseptic fructose diphosphate arginine composite salt.
As preferably, in the present invention, fructose diphosphate sodium salt makes the mass concentration of the aqueous solution is 5%-55%.
As preferably, the arginine adopted in the present invention is L-arginine.
As preferably, in the present invention, fructose diphosphate and arginic mol ratio are (1-1.2): 1.
As preferably, the solvent adopted in the present invention is one or more mixing in ethyl acetate, ethanol, Virahol, acetone.
As preferably, in the present invention, the aseptic fructose diphosphate arginic acid salt of gained contains crystal water.
Beneficial effect of the present invention is: the method production technique of preparation provided by the invention aseptic fructose diphosphate arginic acid salt is simple, products obtained therefrom purity is high, stable aseptic composite powder can be produced, for the use of other formulations of medicine, the various discomfort reaction that the former Fructose Diphosphate of effective solution causes and the problem of hypernatremia risk, play the effect of synergy in the clinical assisting therapy of cardiovascular and cerebrovascular diseases.
Embodiment
Further illustrate the present invention below by specific embodiment, but can not be used for being interpreted as uniquely limiting the present invention.
Embodiment 1: producing of high density fructose diphosphate arginine solution
Get Trisodium fructose 1,6-diphosphate eight hydrate 120kg, be dissolved completely in 300L water, Trisodium fructose 1,6-diphosphate salts solution is carried out cationic exchange resin adsorption, collect flow liquid 470L and carry out mixed bed second adsorption, remove sodium ion, cross flow liquid to collect after 610L and carry out nanofiltration membrane concentrate crossing flow liquid, after concentrated concentrated phase 295L, detecting fructose diphosphate content is 36.7%.In solution, add arginine, adding mol ratio is 1.03:1, dissolves and obtains high density fructose diphosphate arginine solution completely.
Embodiment 2: aseptic fructose diphosphate arginine composite salt crystallization
Fructose diphosphate arginine solution is imported D level clean area, and in feed liquid, add gac, activated carbon dosage is 2% of fructose diphosphate arginine wt, and the feed liquid after adsorption bleaching is crossed decarburizing filter, removing gac.Sterile workshop crystallizer is entered after level Four 0.22 micron membrane filter is degerming, slowly stir in crystallizer, control temperature is at 25 degrees Celsius, add the dehydrated alcohol of 1 times amount, within 10 minutes afterwards, often spend slow cooling to 0 degree Celsius, stirred crystallization 3 hours, a large amount of sterile solids is had to separate out, obtain fructose diphosphate arginine crystal water solid through three-in-one suction filtration, drying can obtain 104kg, and yield is 84.0%.
Embodiment 3: the preparation of aseptic fructose diphosphate arginine composite salt
Get the fructose diphosphate solution 2000L that fermentation method obtains, after purifying, concentrating, obtain 297L solution, detecting fructose diphosphate content is 36.9%.1.2:1 adds arginine in solution in molar ratio, and dissolve and obtain fructose diphosphate arginine solution completely, volume is 320L.This fructose diphosphate arginine solution is imported D level clean area, in feed liquid, adds Medicinal Charcoal, Medicinal Charcoal consumption is 1% of fructose diphosphate acid and arginine gross weight, and the feed liquid after adsorption bleaching crosses decarburizing filter, removing gac.Sterile workshop 1000L crystallizer is entered after secondary 0.22 micron membrane filter is degerming, slowly stir in crystallizer, control temperature 25 DEG C, add the dehydrated alcohol of 1 times amount, within 10 minutes afterwards, often spend slow cooling to 0 DEG C, stirred crystallization 3 hours, a large amount of sterile solids is had to separate out, obtain fructose diphosphate arginine crystal water solid through three-in-one suction filtration, drying can obtain 97.8kg, and yield is 79.2%.
Embodiment 4: the preparation of aseptic fructose diphosphate arginic acid salt
Get fructose diphosphate sodium salt 80kg, be dissolved completely in water, strength of solution is 5%, fructose diphosphate sodium salt solution is carried out secondary cation exchange resin Adsorption sodium ion, collects the laggard row nanofiltration membrane of flow liquid and concentrates, and detected fructose diphosphate content 35.6%.In solution, add arginine, adding mol ratio is 1:1, dissolves and obtains high density fructose diphosphate arginine solution completely.Fructose diphosphate arginine solution is imported D level clean area, in feed liquid, adds the gac accounting for material gross weight 0.15%, the feed liquid after adsorption bleaching is crossed decarburizing filter, removing gac.Sterile workshop crystallizer is entered after level Four 0.22 micron membrane filter is degerming, slowly stir in crystallizer, control temperature is at 25 DEG C, add the ethyl acetate of 3 times amount, within 10 minutes afterwards, often spend slow cooling to 0 DEG C, stirred crystallization 3 hours, a large amount of sterile solids is had to separate out, obtain fructose diphosphate arginine crystal water solid through three-in-one suction filtration, drying can obtain 67kg, and yield is 82.9%.
Embodiment 5: the preparation of aseptic fructose diphosphate arginic acid salt
Get fructose diphosphate sodium salt 150kg, be dissolved completely in water, strength of solution is 55%, fructose diphosphate sodium salt solution is carried out secondary cation exchange resin Adsorption sodium ion, collect the laggard row nanofiltration membrane of flow liquid to concentrate, detect fructose diphosphate content 37.2%.In solution, add arginine with mol ratio 1.05:1, dissolve and obtain high density fructose diphosphate arginine solution completely.Fructose diphosphate arginine solution is imported D level clean area, the gac accounting for material gross weight 3% is added in feed liquid, feed liquid after adsorption bleaching is crossed decarburizing filter, removing gac, sterile workshop crystallizer is entered after level Four 0.22 micron membrane filter is degerming, slowly stir in crystallizer, control temperature is at 25 DEG C, add the Virahol of 3 times amount, within 10 minutes afterwards, often spend slow cooling to 0 DEG C, stirred crystallization 3 hours, a large amount of sterile solids is had to separate out, fructose diphosphate arginine crystal water solid is obtained through three-in-one suction filtration, drying can obtain 126kg, yield is 83.7%.
The method production technique of preparation provided by the invention aseptic fructose diphosphate arginic acid salt is simple, product purity is high, stable aseptic composite powder can be produced, for the use of other formulations of medicine, the various discomfort reaction that the former Fructose Diphosphate of effective solution causes and the problem of hypernatremia risk, play the effect of synergy in the clinical assisting therapy of cardiovascular and cerebrovascular diseases.
Claims (6)
1. prepare a method for aseptic fructose diphosphate arginic acid salt, it is characterized in that comprising the steps:
(1) fructose diphosphate sodium salt is made the aqueous solution, gained feed liquid is carried out secondary cation exchange resin Adsorption sodium ion, obtain fructose diphosphate solution;
Or, directly adopt and transform obtain fructose diphosphate solution through enzyme process, fermentation method;
(2) by above-mentioned fructose diphosphate solution after nanofiltration membrane is concentrated, add arginine and be dissolved to completely;
(3) below 60 DEG C, carry out activated carbon decolorizing to gained solution in step (2), activated carbon dosage is the 0.15%-3% of solution material gross weight, and gained feed liquid carries out level Four membrane filtration;
(4) in sterilisable chamber, carry out solvent crystal after, finally obtain aseptic fructose diphosphate arginic acid salt.
2. the method for the aseptic fructose diphosphate arginic acid salt of preparation according to claim 1, is characterized in that the mass concentration that described fructose diphosphate sodium salt makes the aqueous solution is 5%-55%.
3. the method for the aseptic fructose diphosphate arginic acid salt of preparation according to claim 1, is characterized in that described arginine is L-arginine.
4. the method for the aseptic fructose diphosphate arginic acid salt of the preparation according to claim 1,2 or 3, is characterized in that in described step (2), fructose diphosphate and arginic mol ratio are (1-1.2): 1.
5. the method for the aseptic fructose diphosphate arginic acid salt of preparation according to claim 1, is characterized in that described solvent is one or more mixing in ethyl acetate, ethanol, Virahol, acetone.
6. the method for the aseptic fructose diphosphate arginic acid salt of preparation according to claim 1, is characterized in that described aseptic fructose diphosphate arginic acid salt contains crystal water.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3497497A (en) * | 1967-01-02 | 1970-02-24 | Prodotti Antibiotici Spa | Amino acid salts of hexose-phosphates |
| CN1089654A (en) * | 1993-01-11 | 1994-07-20 | 欧阳平凯 | 1, the production method of 6-hexose diphosphate |
| CN1211577A (en) * | 1998-08-28 | 1999-03-24 | 重庆医科大学 | Sodium magnesium D-fructose-1,6-diphosphate and its preparation method and application |
| CN1302808A (en) * | 2000-12-16 | 2001-07-11 | 暨南大学 | Zinc fructose-diphosphate and its preparing process and application |
| WO2001053306A2 (en) * | 2000-01-21 | 2001-07-26 | Danisco Sweeteners Oy | Manufacture of five-carbon sugars and sugar alcohols |
| CN1309132A (en) * | 2001-02-27 | 2001-08-22 | 暨南大学 | Magnesium zinc fructose diphosphate and its preparing process and application in preparing medicines |
| CN101007829A (en) * | 2007-01-24 | 2007-08-01 | 广东中科药物研究有限公司 | 1,6-diphospho-D-fructose ester arginine salt and its pharmaceutical uses |
-
2014
- 2014-12-26 CN CN201410823301.4A patent/CN104497060A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3497497A (en) * | 1967-01-02 | 1970-02-24 | Prodotti Antibiotici Spa | Amino acid salts of hexose-phosphates |
| CN1089654A (en) * | 1993-01-11 | 1994-07-20 | 欧阳平凯 | 1, the production method of 6-hexose diphosphate |
| CN1211577A (en) * | 1998-08-28 | 1999-03-24 | 重庆医科大学 | Sodium magnesium D-fructose-1,6-diphosphate and its preparation method and application |
| WO2001053306A2 (en) * | 2000-01-21 | 2001-07-26 | Danisco Sweeteners Oy | Manufacture of five-carbon sugars and sugar alcohols |
| CN1302808A (en) * | 2000-12-16 | 2001-07-11 | 暨南大学 | Zinc fructose-diphosphate and its preparing process and application |
| CN1309132A (en) * | 2001-02-27 | 2001-08-22 | 暨南大学 | Magnesium zinc fructose diphosphate and its preparing process and application in preparing medicines |
| CN101007829A (en) * | 2007-01-24 | 2007-08-01 | 广东中科药物研究有限公司 | 1,6-diphospho-D-fructose ester arginine salt and its pharmaceutical uses |
Non-Patent Citations (1)
| Title |
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| 李维平: "《生物工艺学》", 28 February 2010 * |
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