• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A porous mineral support such as a porous mineral oxide coated with an aminated polysaccharide polymer has cationic characteristics and is capable of reversibly fixing thereto biological macromolecules. This material is employed in the separation and purification of said biologic maromolecules.
    公开号:SU1268105A3
    申请号:SU792712252
    申请日:1979-01-15
    公开日:1986-10-30
    发明作者:Тэйо Жан-Луи；Тарди Мишель
    申请人:Энститю Мерье (Фирма)；
    IPC主号:
    专利说明:


    SP
    The invention relates to chemical technology, namely to composite material for anion exchange and its preparation, and can be used in the separation and purification of proteins.
    The aim of the invention is to give the material a high activity to b.ellas.
    Prim; E.I.KIOr porous silica with a specific surface of 50 - Spherosyl KHOV 030 impregnated with a solution of diethylaminoethyldextran (DEAEdextran) at pH 11.5, TW ratio, wt.%: DEAEdec- 15 countries 15 (30 ml 5% - mineral oxide, the rest, and then dried in an oven to form a homogeneous powder, 20 Mp of 5% solution of 1 4-butanediol-20 glycidyl ether in diethyl ether are added, the mixture is stirred until complete evaporation of diethyl ether and achieving uniform impregnation with a diepoxy compound 25 (0.5% by weight of material).
    To obtain an anion exchanger, the mixture was adjusted to 80 ° C and removed at this temperature for 15 hours. After the final sieving, the sorbent was injected 30 dry into the column, washed, parts of 0.1 n. sodium hydroxide solution, then 1 liter of 1 M sodium chloride solution, and brought to equilibrium using the buffer solution used at jj.
    The capacity of the sorbent during protein fixation is 40–200 mg per 1 g of sorbent, depending on the chromatographic conditions. At the initial porosity of the sorbent 10 80, this capacity is constant.
    Example 2. South Spherosyl XBO 015 is impregnated at 65 ° C with 20 ml of a 65% solution of DEAE starch with a pH of 10 until the following ratio is obtained, wt%: DEAE Starch 13; mineral oxide else.
    The mixture is dried in a drying chamber50
    For about 15 hours until constant weight is obtained. The resulting powder is homogenized, if necessary, sieved for removed 1: possible apgomerates.55
    20 sp of 0.4% solution of 1,4-butanediol diglycer 1-odzphi-
    ra in ethyl ether (0.8% by weight of the material). The mixture was continuously stirred at 40 ° C until complete evaporation of the ethyl ether and uniform impregnation, then adjusted to 15 hours. After sieving, the carrier was placed in a dry state on a column, washed with 1 L of 0.1N. sodium alkali solution, then 1 l of 1 M NaCl solution and equilibrated with buffer solution used for the desired type of chromatography ..
    The protein fixing capacity is 40–200 mg per 1 g of carrier, depending on the chromatography conditions.
    Example 3. South spherosyl HOS 005 (porous silicon dioxide with a specific surface area of 10) is impregnated at 100 ° C with 20 ml of AQUEOUS solution of DEAEagarose at pH 9 in the following ratio Enine, wt.%: DEAEagarose 12; mineral oxide else
    The mixture is dried in a shaker chamber at 80 ° C for about 15 hours. The resulting powder is homogenized and sieved to remove possible agglomerates. After impregnation, 20 ml of a solution of epichlorohydrin or epibromohydrin in ethyl ether (0.6% of the mass of the material) is added to the carrier. The mixture is continuously stirred until complete evaporation of ethyl ether and the cross-linking agent is obtained, then adjusted to 40-120 ° C for about 15 hours. If necessary, the carrier is sieved and placed in a dry state in a column, washed with 1 L of 0.1 N. soda, then 1 l of 1M solution. NaCl and equilibrate with the buffer solution used for this chromatography.
    The capacity of protein fixation is 40–200 ml per 1 g of carrier, depending on the chromatographic conditions.
    Example 4. To the South of spherosyl XOV 030 (porous dioxide-silicon with a specific surface of 50) 30 M are added; 1% ketone acetate solution of cellulose with a concentration of 3% at room temperature. The impregnated carrier is dried in a stream of hot air, the resulting powder is dispersed in 1 l of sodium alkali solution at an ambient temperature for 15 hours, which leads to the hydrolysis of cellulose ester and to the regeneration of the original cellulose.
    In the second stage, the carrier, thus impregnated with cellulose, is treated with chlorotriethylamine hydrochloride in an alkaline medium with a pH of 10 ri. Material composition, wt.%: DEA Cellulose 9, silicon dioxide the rest.
    After drying in the drying chamber, to obtain a uniform powder, 20 ml of an O, 4% solution of butanediol diglyceride ester in ethyl ether are added (0.8% by weight of the material). The mixture was continuously stirred at 40 ° C until complete evaporation of the ethyl ether, then adjusted to 120 ° C for about 15 hours. After sieving, the carrier is placed in a dry state on a column, washed with 1 L of 0.1 N. sodium alkaline solution, then 1 l of 1 M NaCl solution, and equilibrated with buffer solution for chromatography.
    Example 5. 10 g of spherrzila KHOV 015 are removed and impregnated at 55 ° C with 20 ml of a DEAEagaroza solution with a concentration of 1.5% with a pH of 9. The mixture is dried in a drying oven at 5055 ° C for about 12 hours to achieve a constant weight.
    After sieving, the impregnated material has the following composition, wt.%; DEAE agarose 3, silicon dioxide the rest.
    To 10 g of spherosyl impregnated in this way, add 20 ml of a solution (concentration of 0.5%) of a diepoxide compound of
    CH3 CH2-j: H- (CH2) 2-N- (CH2VCH
    6
    in ethyl ether, which corresponds to a concentration of this compound of 1% relative to the impregnated material.
    The reaction mixture was stirred at 40 ° C until complete evaporation of the ethyl ether. The temperature is then raised to approximately within about 10 hours.
    After sieving, the carrier is packed dry in a column, washed with 1 L of 0.1 N. sodium hydroxide and then 1 l of 1 M NaCl and equilibrated with an appropriate buffer solution suitable for chromatography.
    Example 6. Weigh off 10 g of spherosyl HOS 005 and impregnate it
    20 ml of 10% aqueous solution of DEAEstarch heated to 75 ° C, pH 8.5. Then the mixture is dried in a drying oven for 15h. The resulting powder product is homogenized and sieved to remove agglomerates.
    Impregnated material has the following composition, wt.%: DEAEstarch 20, silicon dioxide else. 20 ml of a solution of epibromohydrin with a concentration of 2% in ethyl ether, pH 8.5, which corresponds to a concentration of epibromohydrin of 4% relative to the impregnated spherosyl, are added to 10 g of spherosyl thus impregnated. The mixture is continuously stirred at 40 ° C until complete evaporation of the ethyl ether. Then for about 15 h bring the TeNmepaTypy up to.
    After sieving with a dry carrier, the column is filled, washed with 1 L of 0.1 N. sodium hydroxide, then 1 l of 1 M NaCl and equilibrated with a buffer solution suitable for chromatography.
    Example 7. Direct cleaning of gamma globulins from serum or
    plasma of people and animals.
    Cycle diagram for 50 g of sorbent prepared in accordance with the examples given above:
    Bringing the column to equilibrium with a buffer solution with a pH between 6.3 and 8, for example, 6.8 (ROts buffer solution 0.01-0.02 M or Tris-HCl buffer solution 0.05 M, or sodium chloride solution with concentration 1-3 g / l) at a rate of 200 ml / cm -h.
    The introduction of 50 ml of plasma or shorts, pre-dialyzed against the buffer solution used in the chromatography, and filtered to eliminate the possibility
    colmatage (average feed rate 50-100 ml / cm h). In the case of sorbent, the preparation of which is described in Example 1, the amount of plasma or serum — per cycle — should be reduced to 25 ml.
    Washing the column with buffer solution used in chromatography.
    Collecting an output peak consisting of pure gamma globulins, the purity of which is checked by immunoelectrophoresis, with a yield of 50-100%
    depending on the buffer solutions used. The yield is higher at pH below 6.8 or at higher ionic strengths, and there is a danger that the product will not be sufficiently pure. This production of gammaglobulins releases them from pyrogenic substances and antigen associated with hepatitis B (AgHBs), which may be present in the initial material.
    Elution of other proteins held in the column with any buffer solution with pH 4 or with buffer solution used in chromatography, with the addition of 10-60 g / l of sodium chloride, or with citrate buffer solution of 0.05 M with pH 4-8 . The cycle lasts about 2 hours (when using simple automatics v. One day, you can spend a dozen cycles, that is, the output during processing is close to 10 liters of serum or plasma per 1 kg of porous inorganic oxide per day).
    Example 8. Removal of hemoglobin during the purification of albumin from placental blood and the concentration of other proteins.
    Fractionation of placental blood with alcohol according to the Koch method, passes through a stage of mass deposition of globulins at pH 6j8 in an environment of 20-25% ethanol. Under these conditions, albumin, some alpha-1, alpha-2 globulins and hemoglobin essentially remain in the upper layer of the solution. They are collected. by cold centrifugation, diluted with an equal volume of distilled water (to reduce the alcohol concentration), the pH is set between 6 and 7, and the liquid is clarified by filtration through cellulose ester membranes
    Cleaning cycle diagram for 50 g of sorbent:
    Equilibration of the column using a buffer phosphate solution of 0.01 M or Tris-HC1 0.05 M with a pH of 6-7 (preferably 6.5) at a feed rate of 200 ml / cm h
    Introduction at an average feed rate of 100 ml / cm2, h 1000 ml of the solution described above and to be purified.
    Washing the column with buffer solution, using 1) 1 m at chromatography at the same feed rate. Purified hemoglobin is removed from the column with a slight degree of dilution, while other proteins, such as albumin, remain fixed on the column.
    Elution of strains fixed on a column under conditions identical to those given in Example 2, with the peak containing concentrated proteins and
    JO practically devoid of hemoglobin. Cycle time 4 hours
    Example 9. The concentration of a solution of proteins diluted in an alcoholic medium, and the removal of alcohol.
    5 Fractionation of proteins according to the Koch method inevitably leads to the re-dissolution of alcohol precipitates during the various stages. For this, it is preferable to strongly dilute the precipitate in order to reduce the residual concentration of the resulting alcohol. After this, it is necessary, on the one hand, to remove alcohol, on the other hand, to concentrate the proteins present. This is usually accomplished by concentration in vacuo, lyophilization or dialysis, but the latter two methods are either very complicated or 0 are a source of depyrogenogen. Therefore, it is preferable to use the following simple, fast and economical way.
    An example is an albumin solution with a concentration of 2%, containing 10% alcohol.
    Scheme for cleaning and concentrating on 1 kg of sorbent:
    Bringing to equilibrium using 0.01 M phosphate buffer solution with pH 7, feed rate 200 ml / cm, h.
    The introduction of an alcohol solution of albumin with a pH of 7 by adding hydrochloric acid or sodium hydroxide, depending on the initial pH value, an average feed rate of 100 ml / cm h. Thus, 200 albumin can be fixed on this column (or 10 liters of solution per cycle) ; if albumin is poorly fixed on the column, it is only enough to dilute the stock solution with distilled water to reduce the ionic strength of the medium.
    权利要求:
    Claims (2)
    [1]
    Rinsing with distilled water, a feed rate of 200 ml / cm h and determination of the moment when albumin is not absorbed and the removal of alcohol is completed. Elution of albumin with one of the following buffer solutions: O, 1 M solution of sodium chloride or 0.05 solution of citrate with a pH of 6.8; in this case, as a rule, the final concentration of albumin is approximately 10-12 removal of alcohol is complete, the result is with this method is approximately 100%. This method is applicable to all proteins whose isoelectric point is below 6.5. If the isoelectric point of the proteins exceeds this value, the method is applicable provided that the pH of the buffer solution used in the chromatography is increased. All impurities present in these protein solutions can also be removed, provided they are electrically neutral (glucids and polysaccharides) or have a positive charge of the same type as the sorbent (cations). If impurities have a negative charge, there can be competition on a sorbent with negatively charged proteins that are desirable to fix. In this case, if the degree of affinity of the impurity to the sorbent is less than the degree of affinity of the protein, and if the solution can be diluted sufficiently with water to achieve ionic strength compatible with protein fixation on the sorbent, even anions can be removed. The example below illustrates such a separation. Example 10. Concentration and purification of albumin in sodium caprylate solution. In the fractionation methods, sodium caprylate is used to coagulate all proteins, with the exception of albumin, which remains in solution in the presence of caprylate. An example is the solution containing 15 g / l of albumin and 3 g / l of caprylate. Cycle scheme for 1 kg of sorbent prepared in accordance with Examples 2 and 3 (when using a sorbent, the preparation of which is described in Example 1, the amount of sorbent should be doubled): Equilibration with phosphate buffer solution 0.01 pH 6, feed rate 200 ml / cm.h. Introduction of albumin solution and caprylate with pH 6 (in case of excessively high ionic strength, dilution with water); The average feed rate is 100 ml / cm2. About 8 liters of solution can be introduced into the column. Washing the column with the buffer solution used in the chromatography, until any substances from the column are stopped. Elution of albumin in accordance with the method set forth in the preceding examples. A solution is obtained containing 10–20% albumin, which, after bringing its concentration to 20%, contains less than 2.5 g / l sodium caprylate. The total cycle time is approximately 4 hours. From this example, it can be seen that the method can be extended to purify and concentrate various biological molecules that have negative charges at certain pH values (nucleic acids, proteins, anionic surfaces, anionic glycolipids). The possibility of wide application of the method and the fact that this type of column supports, without any consequences, the passage of fluids of very different polarity, is shown in the following example. Example 11. Concentration and purification of gangliosides from aqueous extracts of the brain of animals. Gangliosides are glycolipids that play an important role in physiology and pathology at the level of cell septa as receptors and effectors. They contain more or less sialic acid and are therefore negatively charged at pH 3. From 1 kg of bovine brain, you can get about 7 liters of aqueous extract. The aqueous extracts are passed directly through a column of 50 g of sorbent prepared according to Example 3, previously brought to equilibrium with a Tris-HCf 0.05 M buffer solution, pH 6.8. The feed rate is 200 mp / cm h. All gangliosis-schy in these conditions are fixed on the column. Pre-rinsing was performed with the following materials in the sequence indicated: Tris-HCf 0.05 M, pH 6.8, 0.1 g. sodium hydroxide solution, water; chloroform-methanol-water in a 30:60:25 ratio, which removes numerous impurities. Thereafter, the ganglioside elution is performed in a concentrated and purified form at the same feed rate using chloroform-methanol — 0.1N. hydrochloric acid in a volume ratio of 30:60:25. After the elution, the collected peak is neutralized by adding O, 1N. The sodium hydroxide solution is evaporated and dissolved in any chromatographic system for analysis. The yield is 100%. The column can go from organic solvent to aqueous solution and vice versa. This can be used to eliminate the need for column cleaning, or to maintain sterile conditions in the column. Claim 1. Compositional material for anion exchanger based on porous mineral carrier and polymer binder, characterized by the fact that, in order to give the material high activity to proteins, it contains as a mineral carrier porous silicon dioxide with a specific surface of 10-50, and as a polymeric binder, diethylaminoethyl derivative collapse is small, Dextran, agarose, or csbluza in the following ratio of components, wt.%: Diethylaminoethyl derivative of starch, dextran, agarose, or ellyulozy3-20 Other porous silica, and further 0.5-4 wt.% of the material 1,4-butandiolglitsndilovogo ether epihlor (bromo) or hydrino iepoksisoedineni formula agilis CIS-CH- (CH2) (CH2 -CH-GNR / x
    [2]
    2. A method of producing a composite material for an anion exchanger by treating a mineral carrier with a polymeric binder, characterized in that, in order to impart high activity to proteins, silica is used as a mineral carrier with a specific surface of 10-50, as a binder is diethylaminoethyldextranum dextran, starch, agarose or cellulose, and the treatment is carried out by impregnation with a 1.5-10% solution of the binder at pH 8.5-11.5, followed by drying to constant weight at 50-120 seconds and additional processing 1.4 -butanediol glycidyl ether, epichloro (bromo) hydrin or a diepoxy compound of the formula CH2-CH (CH2l7-N- (CH VCH - pH2 in an amount of 0.5-4 wt.% material.
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    同族专利:
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    YU183476A|1983-04-30|
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    YU39773B|1985-04-30|
    IE44507L|1977-01-29|
    GB1544867A|1979-04-25|
    AR220302A1|1980-10-31|
    DK148617C|1986-01-20|
    AU509089B2|1980-04-17|
    CA1088007A|1980-10-21|
    NO762631L|1977-02-01|
    LU73094A1|1977-03-24|
    ES450832A1|1977-08-16|
    DE2633246A1|1977-02-17|
    BR7604920A|1977-08-09|
    DE2633246C2|1985-09-05|
    NO148250B|1983-05-30|
    DK340276A|1977-01-30|
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    NZ181607A|1978-12-18|
    RO71506A|1981-06-30|
    JPS5256087A|1977-05-09|
    NL7608388A|1977-02-01|
    NO148250C|1983-09-07|
    IT1064693B|1985-02-25|
    SU867284A3|1981-09-23|
    DK148617B|1985-08-19|
    US4673734A|1987-06-16|
    FR2319399A1|1977-02-25|
    AU1632676A|1978-02-02|
    BE844657A|1977-01-31|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    LU73094A|LU73094A1|1975-07-29|1975-07-29|
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