CN110218267A - A kind of Preparation method and use of iron-dextrin - Google Patents
A kind of Preparation method and use of iron-dextrin Download PDFInfo
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- CN110218267A CN110218267A CN201910597974.5A CN201910597974A CN110218267A CN 110218267 A CN110218267 A CN 110218267A CN 201910597974 A CN201910597974 A CN 201910597974A CN 110218267 A CN110218267 A CN 110218267A
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- dextran
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- dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
Abstract
The present invention provides a kind of Preparation method and use of iron-dextrin, belongs to glucose polymer technical field, and preparation method includes are as follows: prepares special scintilla dextran with dextranase enzymatic hydrolysis medium molecular dextran；Using TEMPO/CuBr2/ NaClO oxidation reaction system oxidation special scintilla the dextran prepares oxidized dextran solution；Liquor ferri trichloridi and aqueous slkali will be added dropwise simultaneously in the oxidized dextran solution, carries out complex reaction and prepare iron-dextrin complex liquid, purify to get iron-dextrin.The purposes that the present invention also provides iron-dextrins in iron-supplementing preparation.The readily available quality of preparation method of the present invention stablizes point, the special scintilla dextran that cloth breadth index is small, range of molecular weight distributions is narrow, the selectivity of oxidation reaction is high in the preparation method, side reaction is few, oxidation effectiveness is good, and the carboxyl-content of gained oxidized dextran is high, water-soluble good, strong to the complexing power of heavy metal ion.
Description
Technical field
The invention belongs to glucose polymer technical fields, and in particular to a kind of preparation method and use of iron-dextrin
On the way.
Background technique
Dextran (dextran), is a kind of high molecular polymer as made of several glucose polymerisations, and also referred to as Portugal is poly-
Sugar since the glucose molecule number of polymerization is different, and generates the product of different molecular weight, comprising: high molecular dextran (weight
Average molecular weight 100-200kDa), medium molecular dextran (weight average molecular weight 60-80kDa), D-40 (divide equally again
Son amount 20-40kDa), Dextran 10 (weight average molecular weight 10-20kDa), scintilla dextran (weight average molecular weight 7-
10kDa) and special scintilla dextran (weight average molecular weight 3-6kDa)；Iron-dextrin can be obtained in dextran and iron complexing.
Iron dextran injection is to generally acknowledge that preferable piglet mends iron injection both at home and abroad at present, by after piglet is born one in 1~4d
Secondary property intramuscular injection 1mL iron content is the iron dextran injection of 150mgmL-1, can meet piglet entire nursing period to iron
Needs, prevent piglet iron-deficiency anemia, promote piglet growth, reduce the piglet death rate.But the dextrose of current domestic production
The weight average molecular weight of acid anhydride rail injection liquid is larger, mostly 7000~24000Da, this to body after intramuscular injection to the absorption of drug extremely
It is unfavorable, it causes injection site to have the necrosis region of black more and influences the carcase quality of pig.And weight average molecular weight be 3000~
The iron dextran injection of 6000Da is the preferable iron dextran injection of quality generally acknowledged both at home and abroad at present.And dextrorotation
The weight average molecular weight of sugared acid anhydride iron depends primarily on the molecular weight and iron core size of dextran, therefore, the preparation of iron-dextrin
A most important link is the degradation of dextran in the process, the followed by preparation of oxidized dextran, i.e., with molysite network
Before conjunction, dextran molecule itself have to be degraded to required weight average molecular weight in advance, then be activated again, i.e., must incite somebody to action
Terminal hydroxyl is oxidized to carboxyl.The palliating degradation degree of dextran decides size and the distribution system of its obtained weight average molecular weight
Several sizes, and the quality of oxidized dextran preparation directly affects its complexing degree with molysite, to influence the yield of iron.
Authorization Notice No. is that the patent of invention of 104031170 B of CN discloses a kind of people's iron-dextrin original used for intravenous injection
Material and preparation method thereof, people's injectable iron dextran pass through hydrolysis, ultrafiltration or gel column by dextran, oxidation, complexing, surpass
Filter is exquisite, obtained after alcohol precipitation or spray drying weight average molecular weight between 139000~157000, molecular weight distribution less than 2.0,
People's dextran iron material used for intravenous injection can be met.Authorization Notice No. is that the patent of invention of 104829745 B of CN discloses one
The preparation method of kind iron-dextrin, adjusts its pH after complex liquid is made, keeps iron-dextrin solubility property big
To improve, iron content is up to 40% or more in iron-dextrin obtained；Solubility in cold water up to 4g/100g cold water with
On；And the content of Na+, Cl- plasma substantially reduces, the purity of product is higher.Authorization Notice No. is 104829745 B's of CN
Patent of invention discloses a kind of new method for generating iron-dextrin, mainly point four steps: 1) being carried out in the event of high temperatures with hydrochloric acid
Dextran is become the D-40 needed by hydrolysis；2) it is aoxidized using the method for hydrogen peroxide step-by-step oxidation,
Certain temperature is kept, the dextran of appropriate configuration when complexing is obtained；3) method being at the uniform velocity added dropwise simultaneously using soda acid, temperature control
Rate controlling prepares iron-dextrin, keeps product more stable by high temperature ageing；4) final products pass through filtering and ceramic membrane ultrafitration
Desalination concentration.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation method of iron-dextrin, the readily available quality of the preparation method is steady
Divide calmly, the special scintilla dextran that cloth breadth index is small, range of molecular weight distributions is narrow, the choosing of oxidation reaction in the preparation method
Selecting property is high, and side reaction is few, and oxidation effectiveness is good, and the carboxyl-content of gained oxidized dextran is high, water solubility is good, to heavy metal ion
Complexing power it is strong.
The technical solution that the present invention is taken to achieve the above object are as follows:
A kind of preparation method of iron-dextrin, comprising the following steps:
S1: special scintilla dextran is prepared with dextranase enzymatic hydrolysis medium molecular dextran；
S2: TEMPO/CuBr is used2/ NaClO oxidation reaction system oxidation special scintilla the dextran prepares oxygen
Change dextran solution；
S3: liquor ferri trichloridi and aqueous slkali will be added dropwise simultaneously in the oxidized dextran solution, be complexed anti-
Iron-dextrin complex liquid should be prepared, is purified to get iron-dextrin.
A most important ring is the preparation of oxidized dextran in the preparation process of iron-dextrin, i.e., is complexed with molysite
Before, dextran molecule itself have to activate in advance, i.e., terminal hydroxyl must be oxidized to carboxyl.Oxidized dextran preparation
Quality directly affect its complexing degree with molysite, to influence the yield of iron, it is right especially to prepare oxidized form spy scintilla
Sugared acid anhydride is revolved, preparation method is higher compared with the requirement of oxidized form scintilla and Dextran 10.Present invention oxidation reaction body
In system, TEMPO passes through CuBr2Corresponding nitrone cation and TEMPOH, nitrone cation are converted to after oxidation becomes tool
Have the oxidant of strong oxidizing property, can rapidly by the C6 primary hydroxy group of polysaccharide at aldehyde radical and other hydroxyls are unaffected,
CuBr2Be reduced to monovalence copper, and TEMPOH and monovalence copper can reoxidize for and cupric, then carry out catalysis oxidation circulation；Together
When, NaClO and CuBr2Aldehyde radical further can be oxidized to carboxyl by the NaBrO that reaction generates.The present invention has with oxidation reaction system
The features such as selective high, reaction condition is mild, degradation rate is low, be simple and efficient, energy conservation and environmental protection, specific manifestation are as follows: can selectivity
Primary hydroxyl on special scintilla dextran molecule chain C6 is catalytically oxidized to carboxyl by ground, substantially not to the secondary hydroxyl on C2, C3
It influences, the side reaction in oxidation process can be effectively reduced；Present invention oxidation reaction system can improve carboxylic in oxidized dextran
Base content substantially increases oxidized dextran to the complexing power of heavy metal ion, and greatly reduces special scintilla dextrorotation
The quantity of hydroxyl in sugared acid anhydride, and remaining hydroxyl is not enough to be formed intermolecular and intramolecular high-sequential crystal structure, oxidation
Generation can reduce crystal region ratio so that polycrystalline structure, to amorphous transformation, crystal structure is corrupted such that the infiltration of hydrone
It becomes easy thoroughly, improves the water solubility of oxidized dextran, and carboxyl also can be improved oxidation dextrorotation as hydrophilic radical
The water solubility of sugared acid anhydride.
Preferably, in S1, the concentration of enzymatic hydrolysis system medium molecular dextran is 20-50g/L, and the concentration of dextranase is
60-80U/g substrate.
Preferably, in S1, hydrolysis temperature is 40-60 DEG C, time 10-20min.
It is furthermore preferred that being carried out before medium molecular dextran enzymatic hydrolysis through triethanolamine/paratoluenesulfonic acid sodium salt/aqueous systems in S1
Pretreatment.The pretreatment can not only destroy the crystal structure of medium molecular dextran, and it is most strong to reduce intermolecular binding force, increase
Distance between macromolecular improves enzyme digestion reaction system so that dextranase is easier to the inside into low medium molecular dextran
To the accessibility of medium molecular dextran；And medium molecular dextran can be made to expose more hydroxyls, molecule in enhancing
Dextran enzyme digestion reaction system solubility property, with improve enzyme digestion reaction system to the accessibility of medium molecular dextran,
Enzyme digestion reaction activity and the homogeneity of reaction, it is easier to which the progress of enzyme digestion reaction, stable point of readily available quality, cloth width refer to
The special scintilla dextran that number is small, range of molecular weight distributions is narrow.The special scintilla dextran that the pretreatment can also make
Crystallinity it is low so that subsequent oxidation is easier to carry out, improve the oxidation effectiveness of special scintilla dextran.
Preferably, in S2, every 1g spy's scintilla dextran, the dosage of TEMPO is 2-5mmol, CuBr2Dosage be
The dosage of 0.2-0.5mmol, NaClO are 1-3mmol.TEMPO,CuBr2With the reasonable volume of NaClO, taken so that aoxidizing
Between it is less, carboxyl production quantity is larger, oxidized dextran degradation is less, carboxyl contains on obtained oxidized dextran strand
Amount is high, and rate of weight loss is lower.
Preferably, in S2, the temperature of oxidation reaction is 40-60 DEG C, and the time of oxidation reaction is 1-3h.
Preferably, in S3, aqueous slkali is sodium hydroxide solution, dextran: ferric trichloride: the weight ratio of sodium hydroxide is
1:2.2-2.6:1.2-1.8。
Of the invention is also disclosed iron-dextrin made from a kind of above-mentioned preparation method.
Preferably, the weight average molecular weight of iron-dextrin is 3000-6000Da, polydispersity 1.0-1.5, and iron content is
38-42wt%.The requirement of the dextran iron material of injection can be met.Polydispersity is more preferably 1.2-1.4, this is relatively narrow
The polydispersity of range not only ensures the uniformity of molecular weight, and the present inventors have additionally discovered that it helps to ensure that and ensures
Uniformity in the release of iron and the presence for eliminating unstable iron.
Of the invention is also disclosed purposes of the above-mentioned iron-dextrin in iron-supplementing preparation.Above-mentioned iron-supplementing preparation for prevent or
The hypoferric anemia in animal or people experimenter is treated, provides good product for prevention hypoferric anemia.
Compared with prior art, the invention has the benefit that preparation method oxidation reaction system of the present invention can select
Property the primary hydroxyl on special scintilla dextran molecule chain C6 is catalytically oxidized to carboxyl, the pair reduced in oxidation process is anti-
It answers, improves carboxyl-content in oxidized dextran, improve the water solubility of oxidized dextran, to the complexing power of heavy metal ion
By force；Preparation method pretreatment of the present invention can improve accessibility, enzyme digestion reaction of the enzyme digestion reaction system to medium molecular dextran
Activity and the homogeneity of reaction, stable point of readily available quality, the special differential that cloth breadth index is small, range of molecular weight distributions is narrow
Sub- dextran, and the crystallinity for the special scintilla dextran that can also make is low, so that subsequent oxidation is easier to carry out, mentions
The oxidation effectiveness of high spy's scintilla dextran；The weight average molecular weight for the iron-dextrin that preparation method of the present invention obtains is
3000-6000Da, polydispersity 1.0-1.5, iron content 30-40wt% can meet the dextran iron material of injection
Requirement.
Present invention employs above-mentioned technical proposals to provide a kind of Preparation method and use of iron-dextrin, compensates for existing
The deficiency of technology, reasonable design, easy operation.
Detailed description of the invention
Fig. 1 is the Fourier transform infrared spectroscopy of oxidized dextran in test example 1 of the present invention；
Fig. 2 is carboxyl group content in oxidized dextran in test example 1 of the present invention；
Fig. 3 is the water-soluble measurement result of oxidized dextran in test example 1 of the present invention.
Specific embodiment
The exemplary embodiments for embodying inventive features and advantage will describe in detail in the following description.It should be understood that this hair
It is bright to have various variations in different embodiments, it neither departs from the scope of the present invention, and description therein is at this
It is to be illustrated as being used in matter, rather than to limit the present invention.
An embodiment of the present invention provides a kind of preparation method of iron-dextrin, comprising the following steps:
S1: special scintilla dextran is prepared with dextranase enzymatic hydrolysis medium molecular dextran；
S2: TEMPO/CuBr is used2/ NaClO oxidation reaction system oxidation special scintilla the dextran prepares oxygen
Change dextran solution；
S3: liquor ferri trichloridi and aqueous slkali will be added dropwise simultaneously in the oxidized dextran solution, be complexed anti-
Iron-dextrin complex liquid should be prepared, is purified to get iron-dextrin.
A most important ring is the preparation of oxidized dextran in the preparation process of iron-dextrin, i.e., is complexed with molysite
Before, dextran molecule itself have to activate in advance, i.e., terminal hydroxyl must be oxidized to carboxyl.Oxidized dextran preparation
Quality directly affect its complexing degree with molysite, to influence the yield of iron, it is right especially to prepare oxidized form spy scintilla
Sugared acid anhydride is revolved, preparation method is higher compared with the requirement of oxidized form scintilla and Dextran 10.Present invention oxidation reaction body
In system, TEMPO passes through CuBr2Corresponding nitrone cation and TEMPOH, nitrone cation are converted to after oxidation becomes tool
Have the oxidant of strong oxidizing property, can rapidly by the C6 primary hydroxy group of polysaccharide at aldehyde radical and other hydroxyls are unaffected,
CuBr2Be reduced to monovalence copper, and TEMPOH and monovalence copper can reoxidize for and cupric, then carry out catalysis oxidation circulation；Together
When, NaClO and CuBr2Aldehyde radical further can be oxidized to carboxyl by the NaBrO that reaction generates.The present invention has with oxidation reaction system
The features such as selective high, reaction condition is mild, degradation rate is low, be simple and efficient, energy conservation and environmental protection, specific manifestation are as follows: can selectivity
Primary hydroxyl on special scintilla dextran molecule chain C6 is catalytically oxidized to carboxyl by ground, substantially not to the secondary hydroxyl on C2, C3
It influences, the side reaction in oxidation process can be effectively reduced；Present invention oxidation reaction system can improve carboxylic in oxidized dextran
Base content substantially increases oxidized dextran to the complexing power of heavy metal ion, and greatly reduces special scintilla dextrorotation
The quantity of hydroxyl in sugared acid anhydride, and remaining hydroxyl is not enough to be formed intermolecular and intramolecular high-sequential crystal structure, oxidation
Generation can reduce crystal region ratio so that polycrystalline structure, to amorphous transformation, crystal structure is corrupted such that the infiltration of hydrone
It becomes easy thoroughly, improves the water solubility of oxidized dextran, and carboxyl also can be improved oxidation dextrorotation as hydrophilic radical
The water solubility of sugared acid anhydride.
In an embodiment of the present invention, preparation method the following steps are included:
S1: medium molecular dextran is added to the water, and stirring, which is warming up to after dextran is completely dissolved, to cool down, and dextrorotation is added
Sugared acid anhydride enzyme is warming up to 80-90 DEG C by dextran enzyme-deactivating, then using ultrafiltration apparatus retention or gel column point after isothermal reaction
From the dextran by molecular weight greater than 6000Da, less than 3000Da removes respectively, and obtaining absolute molecular weight is 3000-
The dextran solution of 6000Da, i.e., special scintilla dextran solution；
S2: in mass concentration 20-30% spy's scintilla dextran solution, TEMPO, CuBr is then added2With
NaClO, oxidation finish, and are adjusted holding system to the pH value of system in oxidation process and maintain pH value in 9.0-10.0；
S3: liquor ferri trichloridi and quality that mass concentration 40-50% is added dropwise in oxidized dextran solution simultaneously is dense
The aqueous slkali of 30-40% is spent, the complexation temperature of control system is in 40-60 DEG C, pH 3.0-5.0, complex reaction during dropwise addition
3-4h, the final ph that product is adjusted with sodium hydroxide is 8.0-10.0, starts to warm up and is maintained at 95-105 DEG C, sustained response 1-
1.5h is then allowed to stand the reaction solution for 24 hours, obtained through 3000-6000rpm centrifugation except solid impurity, molecular cut off range 3000-
The ultrafiltration membrane ultrafiltration of 6000Da removes metal and foreign ion, after detecting iron content and indices qualification, can directly dilute or dense
Contracting is allocated as the iron dextran injection of different proportion, can also be freeze-dried or be spray-dried to obtain iron-dextrin.
In an embodiment of the present invention, in S1, the concentration of enzymatic hydrolysis system medium molecular dextran is 20-50g/L, such as
22g/L, 25g/L, 30g/L, 35.4g/L, 40g/L, 44g/L, 47g/L etc., the concentration of dextranase are 60-80U/g substrate,
Such as 62U/g, 66U/g, 70.2U/g, 75.4U/g, 76U/g, 79U/g etc..
In an embodiment of the present invention, in S1, hydrolysis temperature be 40-60 DEG C, such as 42 DEG C, 43 DEG C, 45 DEG C, 48 DEG C,
52 DEG C, 54 DEG C, 56 DEG C, 57 DEG C etc., time 10-20min, for example, 11min, 12min, 13min, 14min, 15.5min,
16min, 17min, 18min, 19min etc..
In an embodiment of the present invention, in S1, through triethanolamine/p-methyl benzenesulfonic acid before medium molecular dextran enzymatic hydrolysis
Sodium/aqueous systems are pre-processed.The pretreatment can not only destroy the crystal structure of medium molecular dextran, reduce intermolecular
Binding force is most strong, increases intermolecular distance, so that dextranase is easier to the inside into low medium molecular dextran, improves
Accessibility of the enzyme digestion reaction system to medium molecular dextran；And medium molecular dextran can be made to expose more hydroxyls
Base enhances medium molecular dextran in the solubility property of enzyme digestion reaction system, to improve enzyme digestion reaction system centering molecule dextrorotation
Accessibility, enzyme digestion reaction activity and the homogeneity of reaction of sugared acid anhydride, it is easier to which the progress of enzyme digestion reaction, readily available quality are steady
Fixed point, the special scintilla dextran that cloth breadth index is small, range of molecular weight distributions is narrow.The spy that the pretreatment can also make is micro-
The crystallinity of molecule dextran is low, so that subsequent oxidation is easier to carry out, improves the oxidation effectiveness of special scintilla dextran.
The weight ratio of triethanolamine, paratoluenesulfonic acid sodium salt and water is 5-10:3-8 in triethanolamine/paratoluenesulfonic acid sodium salt/aqueous systems:
100.Pretreated process are as follows: medium molecular dextran is added to triethanolamine/p-methyl benzenesulfonic acid for 1:10-20 by solid-to-liquid ratio
In sodium/aqueous systems, 6-12h is stood after mixing evenly, is then rinsed with water to being in neutrality, is dried.
In an embodiment of the present invention, in S2, every 1g spy's scintilla dextran, the dosage of TEMPO is 2-5mmol,
Such as 2.4mmol, 2.6mmol, 3.0mmol, 3.5mmol, 4.1mmol, 4.4mmol, 4.7mmol etc., CuBr2Dosage be
0.2-0.5mmol, for example, 0.24mmol, 0.26mmol, 0.31mmol, 0.33mmol, 0.37mmol, 0.39mmol,
0.43mmol, 0.48mmol etc., the dosage of NaClO are 1-3mmol, for example, 1.2mmol, 1.5mmol, 1.9mmol, 2.1mmol,
2.5mmol, 2.6mmol, 2.8mmol, 2.9mmol etc..TEMPO,CuBr2With the reasonable volume of NaClO, taken so that aoxidizing
Between it is less, carboxyl production quantity is larger, oxidized dextran degradation is less, carboxyl contains on obtained oxidized dextran strand
Amount is high, and rate of weight loss is lower.
In an embodiment of the present invention, in S2, the temperature of oxidation reaction is 40-60 DEG C, for example, 42 DEG C, 43 DEG C, 45 DEG C,
48 DEG C, 52 DEG C, 54 DEG C, 56 DEG C, 57 DEG C etc., the time of oxidation reaction is 1-3h, such as 1.5h, 2.0h, 2.5h etc..
In an embodiment of the present invention, in S3, aqueous slkali is sodium hydroxide solution, dextran: ferric trichloride: hydrogen-oxygen
Change sodium weight ratio be 1:2.2-2.6:1.2-1.8, such as 1:2.2:1.3,1:2.2:1.4,1:2.2:1.5,1:2.2:1.6,
1:2.2:1.7、1:2.3:1.3、1:2.3:1.4、1:2.3:1.5、1:2.3:1.6、1:2.3:1.7、1:2.4:1.3、1:2.4:
1.4、1:2.4:1.5、1:2.4:1.6、1:2.4:1.7、1:2.5:1.3、1:2.5:1.4、1:2.5:1.5、1:2.5:1.6、1:
2.5:1.7,1:2.5:1.8,1:2.6:1.3,1:2.6:1.4,1:2.6:1.5,1:2.6:1.6,1:2.6:1.7 etc..
An embodiment of the present invention provides iron-dextrin made from a kind of above-mentioned preparation method.The weight of iron-dextrin
Average molecular weight is 3000-6000Da, polydispersity 1.0-1.5, iron content 38-42wt%.The dextrorotation of injection can be met
The requirement of sugared acid anhydride iron material.Polydispersity is more preferably 1.2-1.4, and the polydispersity of this narrower range not only ensures point
The uniformity of son amount, and the present inventors have additionally discovered that it helps to ensure that and ensures the uniformity in the release of iron and row
In addition to the presence of unstable iron.
An embodiment of the present invention provides purposes of the above-mentioned iron-dextrin in iron-supplementing preparation.Above-mentioned iron-supplementing preparation is used
In preventing or treating the hypoferric anemia in animal or people experimenter, good product is provided for prevention hypoferric anemia.
It is done in the following, obtaining preparation method and its usage to the iron-dextrin of an embodiment of the present invention in conjunction with specific embodiments
It further illustrates.
Embodiment 1:
A kind of preparation method of iron-dextrin, comprising the following steps:
S1: medium molecular dextran is added to the water, and makes the concentration 20g/L of molecule dextran, and stirring is warming up to the right side
It revolves after sugared acid anhydride is completely dissolved and cools down, dextranase is added, the concentration of dextranase is 60U/g substrate, the constant temperature at 80 DEG C
80 DEG C are warming up to after reaction 10min by dextran enzyme-deactivating, then using ultrafiltration apparatus retention or gel post separation, respectively will
Molecular weight is greater than 6000Da, the dextran less than 3000Da removes, and obtains the dextrose that absolute molecular weight is 3000-6000Da
Anhydride solution, i.e., special scintilla dextran solution；
S2: in the special scintilla dextran solution of mass concentration 20%, TEMPO, CuBr is then added2And NaClO, often
1g spy's scintilla dextran, the dosage of TEMPO are 2mmol, CuBr2Dosage be 0.2mmol, the dosage of NaClO is
1mmol, oxidation reaction 1h finishes obtained oxidized dextran solution at being 40 DEG C in temperature, to the pH value of system in oxidation process
Being adjusted holding system maintains pH value in 9.0-10.0；
S3: the liquor ferri trichloridi and mass concentration of mass concentration 40% will be added dropwise simultaneously in oxidized dextran solution
30% sodium hydroxide solution, dextran: ferric trichloride: the weight ratio of sodium hydroxide is 1:2.2:1.2, is controlled during being added dropwise
The complexation temperature of system processed is 8.0 with the final ph that sodium hydroxide adjusts product in 40 DEG C, pH 3.0, complex reaction 3h,
It starts to warm up and is maintained at 95 DEG C, sustained response 1h, be then allowed to stand the reaction solution for 24 hours, obtained through 3000rpm centrifugation except solid is miscellaneous
The ultrafiltration membrane ultrafiltration of matter, molecular cut off range 3000-6000Da removes metal and foreign ion, detects iron content and indices
After qualification, the iron dextran injection for being allocated as different proportion can be directly diluted or be concentrated, can also be freeze-dried or do by spraying
It is dry to obtain iron-dextrin.The weight average molecular weight of iron-dextrin is 5428Da, and polydispersity 1.42, iron content is
38.9wt%.
Embodiment 2:
A kind of preparation method of iron-dextrin, comprising the following steps:
S1: medium molecular dextran is added to the water, and makes the concentration 50g/L of molecule dextran, and stirring is warming up to the right side
It revolves after sugared acid anhydride is completely dissolved and cools down, dextranase is added, the concentration of dextranase is 80U/g substrate, the constant temperature at 90 DEG C
90 DEG C are warming up to after reaction 20min by dextran enzyme-deactivating, then using ultrafiltration apparatus retention or gel post separation, respectively will
Molecular weight is greater than 6000Da, the dextran less than 3000Da removes, and obtains the dextrose that absolute molecular weight is 3000-6000Da
Anhydride solution, i.e., special scintilla dextran solution；
S2: in the special scintilla dextran solution of mass concentration 30%, TEMPO, CuBr is then added2And NaClO, often
1g spy's scintilla dextran, the dosage of TEMPO are 5mmol, CuBr2Dosage be 0.5mmol, the dosage of NaClO is
3mmol, oxidation reaction 3h finishes obtained oxidized dextran solution at being 60 DEG C in temperature, to the pH value of system in oxidation process
Being adjusted holding system maintains pH value in 9.0-10.0；
S3: the liquor ferri trichloridi and mass concentration of mass concentration 50% will be added dropwise simultaneously in oxidized dextran solution
40% sodium hydroxide solution, dextran: ferric trichloride: the weight ratio of sodium hydroxide is 1:2.6:1.8, is controlled during being added dropwise
The complexation temperature of system processed is 10.0 with the final ph that sodium hydroxide adjusts product in 60 DEG C, pH 5.0, complex reaction 4h,
It starts to warm up and is maintained at 105 DEG C, sustained response 1.5h, be then allowed to stand the reaction solution for 24 hours, obtained through 6000rpm centrifugation except solid
The ultrafiltration membrane ultrafiltration of impurity, molecular cut off range 3000-6000Da removes metal and foreign ion, detects iron content and items refer to
After mark is qualified, the iron dextran injection for being allocated as different proportion can be directly diluted or be concentrated, can also be freeze-dried or spraying
It is dried to obtain iron-dextrin.The weight average molecular weight of iron-dextrin is 5526Da, and polydispersity 1.37, iron content is
39.7wt%.
Embodiment 3:
A kind of preparation method of iron-dextrin, comprising the following steps:
S1: medium molecular dextran is added to the water, and makes the concentration 35g/L of molecule dextran, and stirring is warming up to the right side
It revolves after sugared acid anhydride is completely dissolved and cools down, dextranase is added, the concentration of dextranase is 70U/g substrate, the constant temperature at 85 DEG C
85 DEG C are warming up to after reaction 16min by dextran enzyme-deactivating, then using ultrafiltration apparatus retention or gel post separation, respectively will
Molecular weight is greater than 6000Da, the dextran less than 3000Da removes, and obtains the dextrose that absolute molecular weight is 3000-6000Da
Anhydride solution, i.e., special scintilla dextran solution；
S2: in the special scintilla dextran solution of mass concentration 26%, TEMPO, CuBr is then added2And NaClO, often
1g spy's scintilla dextran, the dosage of TEMPO are 4mmol, CuBr2Dosage be 0.3mmol, the dosage of NaClO is
2mmol, oxidation reaction 2h finishes obtained oxidized dextran solution at being 50 DEG C in temperature, to the pH value of system in oxidation process
Being adjusted holding system maintains pH value in 9.0-10.0；
S3: the liquor ferri trichloridi and mass concentration of mass concentration 45% will be added dropwise simultaneously in oxidized dextran solution
32% sodium hydroxide solution, dextran: ferric trichloride: the weight ratio of sodium hydroxide is 1:2.5:1.5, is controlled during being added dropwise
The complexation temperature of system processed is 90.0 with the final ph that sodium hydroxide adjusts product in 50 DEG C, pH 4.0, complex reaction 3h,
It starts to warm up and is maintained at 100 DEG C, sustained response 1h, be then allowed to stand the reaction solution for 24 hours, obtained through 5000rpm centrifugation except solid is miscellaneous
The ultrafiltration membrane ultrafiltration of matter, molecular cut off range 3000-6000Da removes metal and foreign ion, detects iron content and indices
After qualification, the iron dextran injection for being allocated as different proportion can be directly diluted or be concentrated, can also be freeze-dried or do by spraying
It is dry to obtain iron-dextrin.The weight average molecular weight of iron-dextrin is 4852Da, and polydispersity 1.24, iron content is
41.2wt%.
Embodiment 4:
With embodiment 3 the difference is that: following pretreatment before medium molecular dextran enzymatic hydrolysis: being 1 by solid-to-liquid ratio:
The weight ratio that medium molecular dextran is added to triethanolamine, paratoluenesulfonic acid sodium salt and water is 5-10:3-8:100's by 10-20
In triethanolamine/paratoluenesulfonic acid sodium salt/aqueous systems, 6-12h is stood after mixing evenly, is then rinsed with water to being in neutrality, is dried.
The weight average molecular weight of iron-dextrin is 4822Da, polydispersity 1.14, iron content 42.0wt%.
Compared to embodiment 3,4 gained iron-dextrin polydispersity of embodiment is smaller, and iron content is higher, this illustrates to implement
The pretreatment of example 4 can improve enzyme digestion reaction system to the accessibility of medium molecular dextran, enzyme digestion reaction activity and reaction
Homogeneity is easy to the progress of enzyme digestion reaction, and it is micro- to obtain the spy that quality stabilization is divided, cloth breadth index is small, range of molecular weight distributions is narrow
Molecule dextran.And the crystallinity of special scintilla dextran that the pretreatment can also make is low, so that subsequent oxidation is more
It is easy to carry out, improves the oxidation effectiveness of special scintilla dextran.
Comparative example 1:
With embodiment 3 the difference is that: in S2, oxidation reaction system be CuBr2/NaClO。
Comparative example 2:
With embodiment 3 the difference is that: in S2, oxidation reaction system be TEMPO/NaClO.
Comparative example 3:
With embodiment 3 the difference is that: in S2, oxidation reaction system be TEMPO/CuBr2。
Test example 1:
1. the analysis of carboxylic group in oxidized dextran
1.1 ftir analysis
Fourier transform infrared spectroscopy determines carboxylic group in oxidized dextran, using KBr as solid diluent, is pressed into thin
Piece is detected, method particularly includes: it is accurate respectively first to weigh the drying dextran of 1mg and the sample of oxidized dextran
It in mortar, is uniformly ground under infrared lamp, then the accurate dry KBr of 100mg that weighs is added thereto (the ratio of KBr and sample
For 100:1), about 30min is ground together, until the two is thoroughly mixed；Then suitable sample to be tested tabletting 30s in mold is taken,
It laminates to be detected.Background is swept with blank KBr sample in advance, then sample is scanned with Fourier Transform Infrared Spectrometer.Knot
Fruit is as shown in Figure 1, in the infrared spectrum of special scintilla dextran, 3450cm-1The relatively broad peak at place is between dextran molecule
Hydrogen bond O-H stretching vibration peak, 2915cm-1Place is the saturation C-H stretching vibration peak in saccharide ring, 1164cm-1Place is C- in saccharide ring
O absorption peak, 1025cm-1The spike at place can prove the presence of α -1,6- glycosidic bond in dextran long-chain.All peaks are all in figure
It is with 3397cm-1The relatively broad peak at place is that standard is calibrated.Product Fourier transform infrared spectroscopy figure and original right after oxidation
The sugared acid anhydride of rotation is quite similar, and still, oxidized dextran is in 1615cm-1There is the suction not having in original graph at one at neighbouring wavelength
Peak is received, this absorption peak is the absorption peak of carbonyl in carboxyl, this peak confirms the generation of carboxyl, and 1164cm-1The saccharide ring C-O at place
Absorption peak and 1025cm-1The spike at place still has, and this also illustrates product still retains a large amount of α-D- pyrans Portugal after oxidation
Grape sugar unit and be still to have certain degree of polymerization.And 1615cm in 3 spectrogram of embodiment-1The peak intensity of neighbouring absorption peak is bright
Aobvious to be better than comparative example 1-3, i.e. the degree of oxidation of embodiment 3 is better than comparative example 1-3, this illustrates present invention oxidation reaction system energy
The primary hydroxyl on special scintilla dextran molecule chain C6 is selectively catalytically oxidized to carboxyl, to the secondary hydroxyl on C2, C3
It has substantially no effect on, the side reaction in oxidation process can be effectively reduced；Present invention oxidation reaction system can improve oxidized dextran
Carboxyl-content in acid anhydride substantially increases oxidized dextran to the complexing power of heavy metal ion, and greatly reduces special differential
The quantity of hydroxyl in sub- dextran.1615cm in 4 spectrogram of embodiment-1The peak intensity of neighbouring absorption peak is significantly stronger than embodiment 3,
That is the degree of oxidation of embodiment 4 is better than embodiment 3, this illustrates that the pretreatment of embodiment 4 can also make medium molecular dextran sudden and violent
The crystallinity for the special scintilla dextran for exposing more hydroxyls, and making is low, so that subsequent oxidation is easier to carry out, mentions
The oxidation effectiveness of high spy's scintilla dextran.
Carboxyl group content in 1.2 oxidized dextrans
Titration determines carboxyl-content after the oxidation of low molecule quality dextran, and precision weighs 5g oxidized dextran,
30mL contains in the hydrochloric acid solution of 0.1mol/L under stirring condition, dissolution 30min or so, is dialysed 16h with bag filter, and use pure water
Repeatedly washing is until chloride ion completely removes.By 40 DEG C of drying 48h of sample after dialysis treatment.Sample after drying is added to
In the beaker of 600mL, and dissolved with the pure water of 250mL, and boil 15min until being completely dissolved.The hydrogen of sample 0.1mol/L
Sodium hydroxide solution titration, and use phenolphthalein as indicator.Blank control is dissolved in the pure water of 30mL, is ibid handled.Carboxyl matter
It is as follows to measure score calculating:
In formula:
C-NaOH concentration of standard solution/(mol/L)；
Volume/mL that V-NaOH titer is consumed in titration end-point；
Quality/g of M- sample.
As a result as shown in Fig. 2, embodiment 3, which obtains carboxyl group content in oxidized dextran, is higher than comparative example 1-3, illustrate reality
The degree of oxidation for applying example 3 is better than comparative example 1-3；And embodiment 4 obtains carboxyl group content in oxidized dextran and is higher than embodiment
4, illustrate that the degree of oxidation of embodiment 4 is better than embodiment 3.
The water-soluble measurement of 1.3 oxidized dextrans
It weighs oxidized dextran 20mg and is dissolved in 0.4mL, oscillation is dissolved it sufficiently, is then centrifuged at 13400rpm
2min.Supernatant liquor is poured out later, and is dried, by sample precision weighing its quality after drying, with its quality divided by sample
Quality obtains water solubility.As a result as shown in figure 3, embodiment 3 obtains the good water solubility of oxidized dextran in comparative example 1-3, explanation
3 oxidation process of embodiment greatly reduces the quantity of hydroxyl in special scintilla dextran, and remaining hydroxyl is not enough to be formed
The crystal structure of intermolecular and intramolecular high-sequential, the generation of oxidation can reduce crystal region ratio, so that polycrystalline structure is to nothing
Setting changes, and crystal structure is corrupted such that the infiltration of hydrone becomes easy, improves the water solubility of oxidized dextran,
And carboxyl also can be improved the water solubility of oxidized dextran as hydrophilic radical；And embodiment 4 obtains oxidized dextran
Good water solubility illustrates that the crystallinity for the special scintilla dextran that the pretreatment of embodiment 4 can make is low in embodiment 4, and
Oxidized dextran is set to obtain more carboxyls.
The prior art of routine techniques dawn known to those skilled in the art in above-described embodiment, therefore herein no longer in detail
It repeats.
The above embodiments are only used to illustrate the present invention, and not limitation of the present invention, the ordinary skill people of this field
Member can also make a variety of changes and modification without departing from the spirit and scope of the present invention.Therefore, all equivalent
Technical solution also belong to scope of the invention, scope of patent protection of the invention should be defined by the claims.
Claims (10)
1. a kind of preparation method of iron-dextrin, it is characterised in that: the following steps are included:
S1: special scintilla dextran is prepared with dextranase enzymatic hydrolysis medium molecular dextran；
S2: TEMPO/CuBr is used2/ NaClO oxidation reaction system oxidation special scintilla dextran preparation oxidation the dextrorotation
Sugared anhydride solution；
S3: liquor ferri trichloridi and aqueous slkali will be added dropwise simultaneously in the oxidized dextran solution, carries out complex reaction system
Standby iron-dextrin complex liquid, purifies to get iron-dextrin.
2. a kind of preparation method of iron-dextrin according to claim 1, it is characterised in that: in the S1, digest body
The concentration for being medium molecular dextran is 20-50g/L, and the concentration of dextranase is 60-80U/g substrate.
3. a kind of preparation method of iron-dextrin according to claim 1, it is characterised in that: in the S1, enzymatic hydrolysis temperature
Degree is 40-60 DEG C, time 10-20min.
4. a kind of preparation method of iron-dextrin according to claim 1 or 2 or 3, it is characterised in that: in the S1,
It is pre-processed before medium molecular dextran enzymatic hydrolysis through triethanolamine/paratoluenesulfonic acid sodium salt/aqueous systems.
5. a kind of preparation method of iron-dextrin according to claim 1, it is characterised in that: in the S2, every 1g is special
Scintilla dextran, the dosage of TEMPO are 2-5mmol, CuBr2Dosage be 0.2-0.5mmol, the dosage of NaClO is 1-
3mmol。
6. a kind of preparation method of iron-dextrin according to claim 1 or 5, it is characterised in that: in the S2, oxidation
The temperature of reaction is 40-60 DEG C, and the time of oxidation reaction is 1-3h.
7. a kind of preparation method of iron-dextrin according to claim 1, it is characterised in that: in the S3, aqueous slkali
For sodium hydroxide solution, dextran: ferric trichloride: the weight ratio of sodium hydroxide is 1:2.2-2.6:1.2-1.8.
8. iron-dextrin made from preparation method described in a kind of claim 1-7.
9. a kind of iron-dextrin according to claim 8, it is characterised in that: the weight average molecular weight of iron-dextrin is
3000-6000Da, polydispersity 1.0-1.5, iron content 38-42wt%.
10. purposes of the iron-dextrin described in claim 8 or 9 in iron-supplementing preparation.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100480275C (en) * | 2002-10-23 | 2009-04-22 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing the complexes |
| CN102429865A (en) * | 2011-12-01 | 2012-05-02 | 广西壮族自治区化工研究院 | Preparation method of super-micro molecular iron dextran |
| CN102942638A (en) * | 2012-10-16 | 2013-02-27 | 广西壮族自治区化工研究院 | Preparation method for dextran with weight average molecular weight of 3000-6000Da |
| CN103015264A (en) * | 2013-01-08 | 2013-04-03 | 北京林业大学 | Paper straightening agent prepared from glucomannan and production and use method of paper straightening agent |
| CN104640883A (en) * | 2012-07-05 | 2015-05-20 | 亨茨曼国际有限公司 | Process for preparing derivatized polysaccharides |
| CN104945448A (en) * | 2015-05-22 | 2015-09-30 | 苏州大学 | Oxidized beta-1,4-oligoglucuronic acid, and preparation method and application thereof |
| ES2562429T3 (en) * | 2006-04-26 | 2016-03-04 | B. Braun Melsungen Ag | Production and use of modified polysaccharide-chitosan compounds and method to improve the preparation of HES-drug compounds |
| CN107201387A (en) * | 2017-07-26 | 2017-09-26 | 合肥工业大学 | A kind of preparation method of iron-dextrin |
| CN107404924A (en) * | 2015-04-03 | 2017-11-28 | 纳幕尔杜邦公司 | The dextran of oxidation |
-
2019
- 2019-07-04 CN CN201910597974.5A patent/CN110218267B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100480275C (en) * | 2002-10-23 | 2009-04-22 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing the complexes |
| ES2562429T3 (en) * | 2006-04-26 | 2016-03-04 | B. Braun Melsungen Ag | Production and use of modified polysaccharide-chitosan compounds and method to improve the preparation of HES-drug compounds |
| CN102429865A (en) * | 2011-12-01 | 2012-05-02 | 广西壮族自治区化工研究院 | Preparation method of super-micro molecular iron dextran |
| CN104640883A (en) * | 2012-07-05 | 2015-05-20 | 亨茨曼国际有限公司 | Process for preparing derivatized polysaccharides |
| CN102942638A (en) * | 2012-10-16 | 2013-02-27 | 广西壮族自治区化工研究院 | Preparation method for dextran with weight average molecular weight of 3000-6000Da |
| CN103015264A (en) * | 2013-01-08 | 2013-04-03 | 北京林业大学 | Paper straightening agent prepared from glucomannan and production and use method of paper straightening agent |
| CN107404924A (en) * | 2015-04-03 | 2017-11-28 | 纳幕尔杜邦公司 | The dextran of oxidation |
| CN104945448A (en) * | 2015-05-22 | 2015-09-30 | 苏州大学 | Oxidized beta-1,4-oligoglucuronic acid, and preparation method and application thereof |
| CN107201387A (en) * | 2017-07-26 | 2017-09-26 | 合肥工业大学 | A kind of preparation method of iron-dextrin |
Non-Patent Citations (3)
| Title |
|---|
| EKASITH SOMSOOK ET AL.: "Interactions between iron(III) and sucrose, dextran, or starch in complexes", 《CARBOHYDRATE POLYMERS》 * |
| 李锦成等: "《肿瘤外科麻醉》", 31 January 2006, 天津科学技术出版社 * |
| 陈爽等: "低分子质量右旋糖酐的氧化改性及其理化特性", 《食品科学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110804107A (en) * | 2019-09-29 | 2020-02-18 | 山东金洋药业有限公司 | Method for preparing dextran iron aqueous solution by using dextran |
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Denomination of invention: Preparation method and application of iron dextran Effective date of registration: 20220421 Granted publication date: 20200807 Pledgee: Bank of China Limited by Share Ltd. Heyuan branch Pledgor: Herbon International Polysaccharide Biotechnology (Heyuan) Co.,Ltd. Registration number: Y2022980004547 |