• 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:
    The invention relates to the chemistry of high molecular weight compounds, specifically to the production of mucopolysaccharides by the depolymerization of heparin, which has biological properties, which makes it possible to use them for specific control of blood coagulation. The invention allows to simplify the process and increase their anticoagulant activity due to the fact that heparin is treated with sodium nitrite in an aqueous medium in the presence of hydrochloric or acetic acid at a pH of 2.2-2.75 and a mass ratio of heparin and sodium nitrite 1: (0.158-0.172 ) followed by neutralization of the solution and precipitation of the target product with ethanol. The target product can be further treated with potassium borohydride or potassium permanganate at a mass ratio of depolymerized heparin and potassium borohydride, 47: 7 or depolymerized heparin and potassium permanganate 20: 1 at pH 8.5. 2 hp f-ly, 2 tab. cl
    公开号:SU1658820A3
    申请号:SU813360355
    申请日:1981-11-20
    公开日:1991-06-23
    发明作者:Лормо Жан-Клод；Петиту Морис；Шоай Жан
    申请人:Шоай С.А. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the chemistry of high molecular weight compounds, specifically to the production of mucopolysaccharides by the depolymerization of heparin, which has biological properties, which makes it possible to use them for specific control of blood coagulation.
    The aim of the invention is to simplify the process of obtaining mucopolysaccharides and increase their anticoagulant activity.
    Example. 60 g of heparin, related to the Yun-Wessler indicator characterizing the ability of active products to cause Xa blood inhibition by antithrombin III inhibition (AT III), is dissolved to the indicator characterizing the ability of active products to inhibit total blood or plasma coagulation (USP) (USP), close to 1, and the USP index is 160 U / mg in 3 liters of distilled water at 4 ° C. Sodium nitrite is added in an amount sufficient to obtain a 0.05 M solution (10.35 g; mass ratio heparin: sodium nitrite — 1 0.172), then the pH is adjusted to 2.5 using pure hydrochloric acid, the solution at 4 ° C shaken for 10 minutes The pH is then adjusted to 7.5 with 5N. soda solution. Adding 5 volumes of pure etao
    OP 00 00
    N o
    S
    nopa (15500 ml) the reaction products precipitate. The precipitate is recovered by centrifugation. It is washed with ethanol and dried at 60 ° C under a high vacuum. Collect 60 g of the product with the following characteristics: USP indicator 17 U / mg, SE index 240 U / mg.
    Heparin is used as a starting material, having a USP ratio of 165 U / mg, and a SE / USP ratio of about 1. Dissolve 3 g of heparin in 150 ml of distilled water at 4 ° C, then add 517 mg of sodium nitrite to the reaction medium ( mass ratio heparin: sodium nitrite 1: 0.172). After completion of the treatment carried out in accordance with the above description, 2.8 g of the product is extracted with a UXR indicator of 24 U / mg and an activity index of SE 250 U / mg.
    50 g of heparin is used with a USP of 158 U / mg and a SE / USP ratio close to 1. The indicated amount of heparin is dissolved in 2500 ml of distilled water and 8.625 g of sodium nitrite is added at 4 ° C (mass ratio heparin: nitrite sodium 1: 0.172). After the completion of the treatment, 46 g of product are obtained, which has the following characteristics: USP indicator 13 U / mg, activity index SE 270 U / mg.
    EXAMPLE 2 At ambient temperature, 47 g of the product obtained in Example 1 are dissolved in 1200 ml of distilled water. With stirring, 7 g of potassium borohydride are added. Stirring is continued for 2 hours at ambient temperature, and then acetic acid is added to the reaction medium in order to lower the pH to 4.0 and thereby destroy unused potassium borohydride. The mixture is stirred for 30 minutes, then the pH is increased to 7.5 with the help of 5 n soda solution. 5 volumes of alcohol are added to the reaction mixture. The resulting precipitate is collected, dried, washed with pure ethanol and dried under vacuum at 60 ° C. This gives 46.5 g of a product with the following characteristics: USP indicator 17 U / mg, activity index SE 250 250 U / mg.
    PRI me R 3. Dissolve 40 g of the product obtained in example 1 in 400 ml of distilled water at ambient temperature. The pH value is provided at 8.5 using 5 n. soda solution, then 2 g of potassium permanganate KMn04, dissolved in 40 ml of water, are added. The reaction CRPM is stirred in
    for 15h During this stirring, the pH of the mixture is constantly maintained at 8.5 with the help of 5N. soda solution. After 15 hours, 0.2 volumes of alcohol are added.
    (90 ml) in order to remove KMp04 that did not participate in the reaction.
    The reaction mixture is allowed to settle for 1 hour. The resulting MnO2 precipitate is removed by centrifugation. Precipitation
    0 ethanol extract the reaction products, washed and dried. Thus, 35 g of the product is obtained, which has the following characteristics: USP indicator 12 U / mg, activity index SE 270 U / mg.
    5 Example 4. Dissolve 3 g of heparin in 150 ml of distilled water at 4 ° C. 517 mg of sodium nitrite is added to obtain a 0.05 M solution. The pH is set to 2.2 by adding pure acid.
    0 HCl and stir the solution at 4 ° C for 10 min. The pH is then adjusted to 7.5 with 5 n. sodium hydroxide. The resulting product is precipitated by adding 5 volumes of pure ethanol. The resulting dock is separated by centrifugation, washed with ethanol and dried at 60 ° C under vacuum. 2.8 g of product are obtained.
    Using the same starting material, the reaction is carried out at a pH of 2.5; 2, 6
    0 and 2.75. The product yield of 2.8 g. The characteristics of the obtained products are summarized in table. 1. Example 5. Dissolve 10 g of commercial heparin (YW / USP ratio of about 1; USP titer 160 U / mg) in 1 distilled
    5 water at 4 ° C. Sufficient sodium nitrite NaN02 is added to produce a 0.02 M solution, i.e. 1.58 g (ratio of heparin to sodium nitrite 1: 0.138), then adjusted to pH 2.5 using pure
    0 hydrochloric acid. Stir at 4 ° C for 10 min and adjust the pH to 7.5 with 5 n. alkali sodium. By adding 5 volumes of pure ethanol (i.e. 5 L), the reaction products are precipitated. Recover
    5 precipitate by centrifugation, then washed with pure ethanol and dried at 60 ° C under high vacuum.
    10 g of product are obtained having the following characteristics:
    0 Titer of USP 15 mE / mg
    The titer of Yuin-Wessler is 253 U / mg. The titer of APTT is 11 U / mg. Comparative data on the properties of the products obtained by the proposed and well-known methods are given in Table. 2
    Simplification of the process is achieved by obtaining products that can be directly used in therapy without further purification.
    In a known method, the target product requires purification using adsorption chromatography.
    权利要求:
    Claims (3)
    [1]
    Claim 1. Method for producing mucopolysaccharides by treating heparin with a depolymerization agent, characterized in that, in order to simplify the process and get a desired product with increased anticoagulant activity, sodium nitrite is used as a depolymerization agent, and the treatment is carried out in an aqueous medium in the presence of hydrochloric or acetic acid at pH 2.2-2.75 and mass
     -
    ten
    15
    the ratio of heparin and sodium nitrite 1: (0,138-0,172), followed by neutralization of the solution and precipitation of the target product with ethanol
    [2]
    2. A method according to claim 1, characterized in that the target product is further treated with potassium borohydride with a weight ratio of depolymerized heparin to potassium borohydride 47: 7.
    [3]
    3. A method according to claim 1, characterized in that the target product is further treated with potassium permanganate at a weight ratio of depolymerized heparin and potassium permanganate 20: 1 at a pH of 8.5.
    Table
    Table 2
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    DD157561A5|1982-11-17|
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    EP0037319A1|1981-10-07|
    DE3176086D1|1987-05-14|
    JPH0231081B2|1990-07-11|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8006282A|FR2478646B2|1980-03-20|1980-03-20|
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