CN106146688A - Process for preparing heparinoid by heparin sodium waste materials - Google Patents

Process for preparing heparinoid by heparin sodium waste materials Download PDF

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CN106146688A
CN106146688A CN201610598231.6A CN201610598231A CN106146688A CN 106146688 A CN106146688 A CN 106146688A CN 201610598231 A CN201610598231 A CN 201610598231A CN 106146688 A CN106146688 A CN 106146688A
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precipitate
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heparan
ethanol
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田志鹏
赵焕荣
张素艳
白文举
王鹏飞
高树华
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河北常山生化药业股份有限公司
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0003General processes for their isolation or fractionation, e.g. purification or extraction from biomass
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0069Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/10Heparin; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00Polymer mixtures characterised by other features
    • C08L2205/02Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group

Abstract

The invention discloses a process for preparing heparinoid by heparin sodium waste materials. The waste materials produced in refined heparin sodium production serve as raw materials and are subjected to ethanol fractionation, crude heparinoid is obtained and then oxidized by ethanol fractionation and hydrogen peroxide to obtain positive specific rotation heparinoid and negative specific rotation heparinoid, and heparin substances in the crude heparinoid are degraded into low molecular heparin substances. The process solves the problem that dermatan sulfate existing in the market is low in purity for a long time, high-purity dermatan sulfate is prepared, raw materials can be provided for sulodexide, the substances have the functions of resisting thrombus and edema, moisturizing skins and the like, the waste materials are turned into wealth, additional values are created, and the prepared heparinoid has the functions of resisting thrombus, diminishing inflammation, relieving pain and the like. The process is simple in step, green, environmentally friendly and low in cost, no toxic and harmful substances are generated, and scale production is easily realized.

Description

肝素钠下脚料制备类肝素工艺 Preparation process waste heparin heparan

技术领域 FIELD

[0001]本发明涉及利用下脚料制备类肝素的方法,属于黏多糖生物制药技术领域。 [0001] The present invention relates to a method of utilizing waste heparan prepared, the field of biotechnology pharmaceutical mucopolysaccharide.

背景技术 Background technique

[0002]类肝素(heparinoid)即类似肝素的物质,是在化学结构上与肝素有一定程度的类似、具有抗凝血活性的酸性黏多糖类物质。 [0002] heparinoid (heparinoid) i.e., heparin-like substances, the chemical structure is similar to some extent to heparin having anticoagulant activity of acidic mucopolysaccharide substance. 类肝素具有抗血栓形成、消炎、止痛、改善患处血液循环、吸收渗出物、治愈水肿及浮肿、促进组织修复等作用。 Heparan having antithrombotic, antiinflammatory, analgesic, improve blood circulation lesion, absorb exudate, edema and edema healing, tissue repair promoting effect. 与肝素相比,类肝素的抗凝血作用弱而缓和,产生抗栓作用时出血可能性小,半衰期长等特点,用药安全,长期使用副作用少。 Compared with heparin, the anticoagulant effect of heparin-like weak and relaxation, the possibility of minor bleeding when antithrombotic effect produced, long half-life and other characteristics, medication safety, long-term use fewer side effects. 该产品广泛用于软膏制剂、口服保健品、化妆品等。 The products are widely used in ointment formulations, oral care products and cosmetics. 类肝素是一类混合物,它由乙酰肝素、硫酸皮肤素、肝素、硫酸软骨素和少量其他杂多糖组成,其中乙酰肝素和硫酸皮肤素为其主要成分。 Heparin is a class-based mixture, consisting of heparan, dermatan sulfate, heparin, chondroitin sulfate, and small amounts of other miscellaneous polysaccharides, wherein the heparan sulfate and dermatan as its main component. 各组分所占比例不同,所组成的类肝素质量特性不同,表现为比旋度与效价值有所差异。 The proportion of the components of different, different heparan quality characteristics composed, performance vary with the valence value of the specific rotation. 目前此产品主要销往欧洲市场,价格区间一般在700〜1600美元/公斤,其价格的高低与类肝素的比旋度和效价高低密切相关。 At present, this product mainly exported to European markets, the general price range of $ 700~1600 / kg, the price level is closely related to the level and type of heparin potency and specific rotation. 目前此种类肝素产品在市场上供不应求,具有很好的应用前景。 At present, this kind of heparin products on the market in short supply, has good prospects.

发明内容 SUMMARY

[0003]本发明提供一种利用肝素钠下脚料制备正比旋类肝素和负比旋类肝素的方法。 [0003] The present invention provides a method of preparing waste proportional spin-spin heparan and heparan negative than the use of heparin.

[0004]本发明目的是通过以下步骤实现的: [0004] The object of the present invention is achieved by the following steps:

a.粗分 a. The crude minutes

将肝素钠下脚料按湿重5〜30%w/v浓度加入纯化水后再加入2〜10%w/v氯化钠,氯化钠溶解后,调整药液PH4〜8后加入乙醇,当药液中乙醇浓度为30〜38%v/v时,在10〜30 °C下静置沉淀,沉淀2〜10小时后收集沉淀得到类肝素粗品; The wet weight heparin waste 5~30% w / v was added and then purified water was added to a concentration of 2~10% w / v sodium chloride, sodium chloride is dissolved, the ethanol was added to adjust the liquid PH4~8, when when the concentration of ethanol in liquid is 30~38% v / v, at 10~30 ° C the precipitate was allowed to stand, the precipitate was collected after precipitation 2~10 hours to obtain a crude heparan;

b.精制 b. Refined

将上述类肝素粗品按湿重5〜30%w/v浓度加入纯化水后再加入2〜10%w/v氯化钠,氯化钠溶解后,调整药液PH4〜8后加入乙醇,当药液中乙醇浓度为32〜35%v/v时,在10〜30°C下静置沉淀,沉淀2〜10小时后收集沉淀制得正比旋类肝素;在上清液中加入乙醇,当上清液中乙醇浓度为34〜43%v/v时,在10〜30°C下静置沉淀,沉淀2〜10小时后收集沉淀制得负比旋类肝素; The above crude heparan wet weight of 5~30% w / v was added and then purified water was added to a concentration of 2~10% w / v sodium chloride, sodium chloride is dissolved, the ethanol was added to adjust the liquid PH4~8, when when the concentration of ethanol in liquid is 32~35% v / v, the precipitate was allowed to stand at 10~30 ° C, the precipitate was collected after precipitation 2~10 hours to obtain proportional spin heparinoids; adding ethanol to the supernatant, when ethanol concentration of the supernatant 34~43% v / v, also left to settle at 10~30 ° C, the precipitate was collected to obtain a negative specific rotation heparan 2~10 hours after precipitation;

c.氧化脱色 c. Decoloration

将上述精制的正比旋类肝素湿品按湿重10〜50%w/v浓度加入纯化水溶解后,在25〜350C下调整药液pH9.0〜12.0后,加入0.5〜4.0%ν/ν过氧化氢进行反应; After the above-described rotary proportional purified heparanase wet product wet weight of 10~50% w / v concentration was added purified water were dissolved, under 25~350C adjusted liquid pH9.0~12.0, addition of 0.5~4.0% ν / ν hydrogen peroxide reaction;

将上述精制的负比旋类肝素湿品按湿重10〜50%w/v浓度加纯化水溶解后,在25〜35 °C下调整溶液pH9.0〜12.0后,加入0.5〜4.0%ν/ν过氧化氢进行反应; After adding the above purification purified heparanase negative specific rotation of wet product wet weight of 10~50% w / v concentration dissolved in water, adjusted pH9.0~12.0 solution at 25~35 ° C, was added 0.5~4.0% ν / ν hydrogen peroxide reaction;

d.沉淀 d. The precipitate

上述正比旋类肝素氧化反应8〜36小时后,按质量体积比向药液中加入I〜6%的氯化钠,氯化钠溶解后,调整药液pH4〜8,再加入1.5〜3.0倍药液体积的乙醇,然后在10〜30°C下静置沉淀,沉淀8〜24小时后收集沉淀物正比旋类肝素; After the above oxidation reaction is proportional to the spin heparan 8~36 hours, I~6% by mass of sodium chloride was added to the liquid in the volume ratio, the sodium chloride is dissolved, adjust the liquid pH4~8, 1.5~3.0 times added liquid volumes of ethanol, and then left to settle at 10~30 ° C, the precipitate was collected after spin 8~24 hours proportional heparinoid precipitate;

上述负比旋类肝素氧化反应8〜36小时后后,按质量体积比向药液中加入I〜6%的氯化钠,氯化钠溶解后,调整药液pH4〜8,再加入1.5〜3.0倍药液体积的乙醇,然后在10〜30°C下静置沉淀,沉淀8〜24小时后收集沉淀物负比旋类肝素; 8~36 hours after the reaction ratio of the above negative rotation heparan oxide, I~6% by mass of sodium chloride was added to the liquid in the volume ratio, the sodium chloride is dissolved, adjust the liquid pH4~8, added 1.5~ 3.0 times the liquid volume of ethanol, then left to settle at 10~30 ° C, the precipitate was collected the precipitate was 8~24 hours spin negative than heparinoids;

e.冷冻干燥 e. freeze-dried

将上述正比旋类肝素沉淀物按湿重30〜45%浓度加入纯化水溶解后降温,降温至-50〜-60°C时抽真空,当真空度彡15Pa后缓慢加热,加热至50〜55°C后保温,保温3〜5小时后制得比旋度为0°〜+ 40°、效价彡50.0 USPU/mg的正比旋类肝素; When the above-described vacuum proportional spin heparanase purified precipitate was dissolved in water was added after cooling by 30~45% concentration of wet weight, was cooled to -50~-60 ° C, when the degree of vacuum 15Pa San heated slowly warmed to 50~55 after incubation ° C, three to five hours after incubation of rotation is made larger than 0 ° ~ + 40 °, San titer proportional spin heparinoids 50.0 USPU / mg of;

将上述负比旋类肝素沉淀物按湿重30〜45%浓度加入纯化水溶解后降温,降温至-50〜-60°C时抽真空,当真空度彡15Pa后缓慢加热,加热至50〜55°C后保温,保温3〜5小时后制得比旋度为-15°〜0°、效价彡50.0 USPU/mg的负比旋类肝素。 When the above-described vacuum negative 30~45% by wet weight concentration ratio of heparinoid rotation purified precipitate was dissolved in water was added after cooling, cooling to -50~-60 ° C, when the degree of vacuum 15Pa San heated slowly heated to 50~ after 55 ° C incubation, after three to five hours of incubation the degree of rotation is made larger than -15 ° ~0 °, San titer 50.0 USPU / mg heparin-negative specific rotation.

[0005]本发明取得的技术进步: [0005] Technical advances made in the present invention:

本发明建立的方法主要是从肝素钠下脚料中通过乙醇分级沉淀,得到类肝素原料粗品;然后通过乙醇分级沉淀从类肝素原料中制备出正比旋类肝素和负比旋类肝素。 The method of the present invention is primarily established ethanol fractionation by precipitation from waste heparin, heparan give crude material; prepared is then proportional to the negative spin-spin heparinoid heparan and heparan feed ratio from fractionation by ethanol precipitation.

[0006]本发明采用从粗品肝素钠到精品肝素钠生产过程中产生的下脚料为原料,从下脚料中进一步深加工,采用乙醇分级沉淀获得比旋度为0°〜+ 40°、效价彡50.0 USPU/mg的正比旋类肝素和比旋度为-15°〜0°、效价彡50.0 USPU/mg的负比旋类肝素,实现了将下脚料变废为宝的过程,可以为企业创造出较大的额外收益,使企业年可获利2500万元,工艺步骤简易,绿色环保,不产生有毒有害物质,成本低廉,易于规模化生产。 [0006] The present invention uses the waste from the crude heparin Heparin Sodium production process as a raw material, waste from further processing, the precipitate was obtained by ethanol fractionation specific rotation of 0 ° ~ + 40 °, San titer 50.0 USPU / mg heparan proportional rotation and specific rotation of -15 ° ~0 °, San titer 50.0 USPU / mg heparan negative specific rotation, to achieve the turning waste into the waste process, the enterprise may be create significant additional revenue, the company annual profit 25 million yuan, simple process steps, environmental protection, does not produce toxic or harmful substances, low cost, easy-to-scale production.

具体实施方式 Detailed ways

[0007]下面结合实施例对本发明作进一步说明。 [0007] below with reference to embodiments of the present invention will be further described.

[0008]实施例l:a.粗分取生产肝素钠精品2kg下脚料湿品加纯化水溶解并定容至40L后,加入3.2kg氯化钠,氯化钠溶解后,再用3mol/L盐酸溶液调整溶液pH6.0后加入乙醇,使溶液中乙醇的浓度为37.5%L/L,然后在15 ± 1°C静置沉淀,沉淀8小时后收集沉淀得到类肝素粗品0.8kg ; [0008] Embodiment Example l:. A crude heparin was separated production scraps Toys 2kg wet product was dissolved purified water was added to the constant volume 40L after, 3.2kg of sodium chloride was added, to dissolve sodium chloride, and then 3mol / L after the hydrochloric acid solution in ethanol were added after adjusting the solution pH6.0, the concentration of ethanol in the solution was 37.5% L / L, and then left to settle at 15 ± 1 ° C, 8 hours the precipitate was collected precipitate was 0.8kg crude heparanase;

b.精制将上述0.8kg类肝素粗品加纯化水溶解并定容至1L,再加入0.8kg氯化钠,氯化钠溶解后,用3mol/L盐酸调整溶液pH6.0,再加入乙醇使溶液中乙醇的浓度为34.5%L/L,然后在15±1°C静置沉淀,沉淀8小时后收集沉淀得到0.3kg正比旋类肝素湿品;在上清液中补加乙醇,使得溶液中乙醇的浓度38%L/L,然后在15 ± 1°C静置沉淀,沉淀8小时后收集沉淀得到0.6kg负比旋类肝素湿品; b. Purification of the above plus 0.8kg heparin-purified crude dissolved in water and dilute to 1L, then added to 0.8kg of sodium chloride, sodium chloride was dissolved, the solution is adjusted pH6.0 with 3mol / L hydrochloric acid, and then the solution was added ethanol ethanol concentration was 34.5% L / L, and then left to settle at 15 ± 1 ° C, the precipitate was collected the precipitate obtained after 8 hours 0.3kg wet product is proportional to the spin heparinoids; in the supernatant was supplemented with ethanol, such that the solution the concentration of ethanol 38% L / L, and then left to settle at 15 ± 1 ° C, the precipitate obtained after 8 hours the precipitate was collected rotation heparanase negative than 0.6kg wet product;

将所制得的正比旋类肝素和负比旋类肝素分别取样测定比旋度和效价,测定结果为:正比旋类肝素比旋度为+7.8°,效价为69.5USPU/mg;负比旋类肝素比旋度为_6.9°,效价为56.0USPU/mg; The resulting rotation is proportional heparan and heparan negative specific rotation were sampled for potency and specific rotation, the measurement result is: proportional spin heparanase specific rotation of + 7.8 °, titer 69.5USPU / mg; Negative specific rotation heparanase specific rotation _6.9 °, titer 56.0USPU / mg;

取样检测如果正比旋类肝素若不能满足比旋度为O〜+40°,效价彡50.0 USPU/mg的标准,须重复上述正比旋类肝素沉淀过程;如果负比旋类肝素样品不能满足比旋度为-15〜0°,效价彡50.0 USPU/mg的标准,须重复上述负比旋类肝素沉淀过程,当正比旋类肝素样品和负比旋类肝素样品比旋度和效价符合要求后,则可进行以下氧化脱色; If the sample is proportional spin detecting heparanase If not meet specific rotation of O~ + 40 °, San titer 50.0 USPU / mg criteria shall be proportional to the spin repeat the precipitation procedure heparan; spin negative than if the sample does not satisfy the specific heparanase curl is -15~0 °, San titer 50.0 USPU / mg of standard shall repeat the rotation heparan negative than the precipitation process, when the sample is proportional to the spin heparan and heparan negative samples meet specific rotation than the rotation titers after the request, may be decolorized following oxidation;

c.氧化脱色将精制的0.3kg正比旋类肝素湿品加纯化水溶解并定容至IL后,将溶液温度调整为30土10C,再用3mol/L氢氧化钠溶液调整溶液pH1.2后,加入1ml 30%过氧化氢进行反应; C. After Decoloration Purified 0.3kg wet product is proportional to the spin heparan adding purified water to dissolve and dilute the IL, the temperature of the solution was adjusted to 30 soil 10C, then 3mol / L sodium hydroxide solution, the solution is adjusted pH1.2 was added 1ml 30% hydrogen peroxide reaction;

将精制的0.6kg负比旋类肝素湿品加纯化水溶解并定容至2L后,将溶液温度调整为30土10C,再用3mol/L氢氧化钠溶液调整溶液pH9.8,然后加入20ml 30%过氧化氢进行反应; Purified Purified water was added 0.6kg negative specific rotation heparan wet product is dissolved and the volume to 2L, the temperature of the solution was adjusted to 30 soil 10C, then 3mol / L sodium hydroxide solution to adjust the solution pH9.8, was then added to 20ml 30% hydrogen peroxide reaction;

d.沉淀 d. The precipitate

上述正比旋类肝素反应结束即反应10小时后,向药液中加入35g氯化钠,氯化钠溶解后用3mol/L盐酸溶液调整药液pH6.3,再加入2L乙醇,然后在15± I °(:静置沉淀,沉淀10小时后收集正比旋类肝素沉淀; After completion of the reaction is proportional to the spin heparan i.e. for 10 hours, 35g of sodium chloride was added to the drug solution, the drug solution pH6.3 adjusted with 3mol / L hydrochloric acid to dissolve sodium chloride solution, then 2L of ethanol and then in 15 ± I ° (: the precipitate was allowed to stand, the precipitate was collected after 10 hours the precipitate is proportional to the spin heparinoids;

上述负比旋类肝素反应结束即反应10小时后,向药液中加入70g氯化钠溶解,氯化钠溶解后用3mol/L盐酸溶液调整药液pH6.0,再加入4L乙醇,然后在15 土I °(:静置沉淀,沉淀1小时后收集负比旋类肝素沉淀; After the above reaction than negative i.e. heparan end rotation for 10 hours, 70g of sodium chloride was added to the dissolved drug solution, the drug solution pH6.0 adjusted with 3mol / L hydrochloric acid to dissolve sodium chloride solution, then 4L of ethanol was added, and then 15 soil I ° (: the precipitate was allowed to stand, the precipitate was collected precipitate was negative specific rotation heparan after 1 hour;

e.冷冻干燥 e. freeze-dried

向上述正比旋类肝素沉淀中加入500ml纯化水搅拌溶解后,补加纯化水定容至800ml,然后将药液装入冻干盘放入冻干机中,开始对药液降温,当制品温度降至_57°C后,对整个系统抽真空,当干燥箱内真空度为14Pa后对制品缓慢加热,当制品温度升至51°C后保温,保温3.5小时后停止冻干,制得正比旋类肝素86g,经检测,比旋度为+8.0°,效价为69.8USPU/mg; After 500ml of purified water was added to the precipitated heparan proportional spin while stirring, additional purified water volume to 800ml, and then lyophilized drug solution charged into the lyophilizer tray, the liquid begins to cool when the temperature of the article after bringing back to _57 ° C, evacuating the whole system, when the degree of vacuum drying oven heated slowly to 14Pa article, when the article temperature was raised to 51 ° C incubation, incubation is stopped after lyophilization 3.5 hours, obtain proportional rotary heparan 86g, after testing, the specific rotation was + 8.0 °, titer 69.8USPU / mg;

向上述负比旋类肝素沉淀中加入1200ml纯化水搅拌溶解后,补加纯化水定容至1500ml,然后将药液装入冻干盘放入冻干机中,开始对药液降温,当制品温度降至-55°C后,对整个系统抽真空,当干燥箱内真空度为12Pa后对制品缓慢加热,当制品温度升至53°C后保温,保温5小时后停止冻干,制得负比旋类肝素200g,经检测,比旋度为-7.1°,效价为56.5USPU/mg0 After stirring to dissolve, supplemented with purified 1200ml purified water was added to the above-described negative specific rotation heparan precipitate to water volume to 1500ml, and then lyophilized drug solution charged into the lyophilizer tray, liquid began to cool, when the article after the temperature was lowered to -55 ° C, evacuating the whole system, when the degree of vacuum of 12Pa an oven heated slowly to the article, the article when the temperature was raised to 53 ° C incubation, the incubation is stopped lyophilized to 5 hours, to obtain negative specific rotation heparan 200g, after testing, specific rotation -7.1 °, titer 56.5USPU / mg0

[0009]实施例2:本实施例与实施例1不同之处是, [0009] Example 2: This embodiment differs from the embodiment 1 is

a.粗分取生产肝素钠精品4kg下脚料湿品加纯化水溶解并定容至40L后,加入2.0kg氯化钠,氯化钠溶解后,再用3mol/L盐酸溶液调整溶液pH5.8后加入乙醇,使溶液中乙醇的浓度为35.4%L/L,然后在11 ± 1°C静置沉淀,沉淀6小时后收集沉淀得到类肝素粗品2.0kg; a. The crude was separated production scraps heparin 4kg wet product quality of purified water was added to dissolve and dilute 40L after, 2.0kg of sodium chloride was added, to dissolve sodium chloride, and then 3mol / L hydrochloric acid solution was adjusted pH5.8 after addition of ethanol, the concentration of ethanol in the solution was 35.4% L / L, and then left to settle at 11 ± 1 ° C, the precipitate was collected six hours heparan crude precipitate was 2.0kg;

b.精制将上述2.0kg类肝素粗品加纯化水溶解并定容至10L,再加入0.3kg氯化钠溶解后,用3mol/L盐酸调整溶液pH4.5,再加入乙醇使溶液中乙醇的浓度为32.7%L/L,然后在11 土TC下静置沉淀,沉淀10小时后收集沉淀得到0.9kg正比旋类肝素湿品;在上清液中补加乙醇,使得溶液中乙醇的浓度34.8%L/L,然后在11 ± TC下静置沉淀,沉淀1小时后收集沉淀得到1.4kg负比旋类肝素湿品; b. Purification of the above plus 2.0kg heparin-purified crude dissolved in water and dilute to 10L, 0.3kg of sodium chloride was added after dissolving, the solution is adjusted pH4.5 with 3mol / L hydrochloric acid, and then adding ethanol to a concentration of ethanol in the solution to 32.7% L / L, and then left to settle at 11 soil TC, the precipitate was collected after 10 hours the precipitate obtained is proportional to the spin heparan 0.9kg wet product; the supernatant supplemented with ethanol, such that the concentration of ethanol in the solution 34.8% L / L, and then left to settle at 11 ± TC, the precipitate obtained after 1 hour the precipitate was collected rotation heparanase negative than 1.4kg wet product;

将所制得的正比旋类肝素和负比旋类肝素分别取样测定比旋度和效价,测定结果为:正比旋类肝素比旋度为+6.5°,效价为60.4USPU/mg;负比旋类肝素比旋度为_7.4°,效价为54.2USPU/mg; The resulting rotation is proportional heparan and heparan negative specific rotation were sampled for potency and specific rotation, the measurement result is: proportional spin heparanase specific rotation of + 6.5 °, titer 60.4USPU / mg; Negative specific rotation heparanase specific rotation _7.4 °, titer 54.2USPU / mg;

取样检测如果正比旋类肝素若不能满足比旋度为O〜+40°,效价彡50.0 USPU/mg的标准,须重复上述正比旋类肝素沉淀过程;如果负比旋类肝素样品不能满足比旋度为-15〜0°,效价彡50.0 USPU/mg的标准,须重复上述负比旋类肝素沉淀过程。 If the sample is proportional spin detecting heparanase If not meet specific rotation of O~ + 40 °, San titer 50.0 USPU / mg criteria shall be proportional to the spin repeat the precipitation procedure heparan; spin negative than if the sample does not satisfy the specific heparanase curl is -15~0 °, San titer 50.0 USPU / mg of standard shall repeat the precipitation procedure heparanase negative spin ratio. 当正比旋类肝素样品和负比旋类肝素样品比旋度和效价符合要求后,则可进行以下氧化脱色; When the sample is proportional to the spin heparan and heparan negative specific rotation of the sample and the specific rotation of potency meet the requirements, the following can be oxidized decolorization;

c.氧化脱色将精制的0.9kg正比旋类肝素湿品加纯化水溶解并定容至4.5L后,将溶液温度调整为26±1°C,再用3mol/L氢氧化钠溶液调整溶液pHll.0后,加入90ml 30%过氧化氢进行反应; c. Decoloration Purified 0.9kg wet product is proportional to the spin heparanase purified water was added to dissolve and dilute to 4.5L After the temperature of the solution was adjusted to 26 ± 1 ° C, then 3mol / L sodium hydroxide solution, the solution is adjusted pHll after .0 added 90ml 30% hydrogen peroxide reaction;

将上述精制的1.4kg负比旋类肝素湿品加纯化水溶解后并定容至7L后,将溶液温度调整为26 ± 1°C,再用3mol/L氢氧化钠溶液调整溶液pH9.8后加入140ml 30%过氧化氢进行反应; After the above-described purified 1.4kg negative specific rotation plus purified heparanase wet product dissolved in water and dilute to 7L, temperature of the solution was adjusted to 26 ± 1 ° C, then 3mol / L sodium hydroxide solution, the solution is adjusted pH9.8 after addition of 140ml 30% hydrogen peroxide reaction;

d.沉淀 d. The precipitate

上述正比旋类肝素反应结束即反应12小时后,向药液中加入225g氯化钠,氯化钠溶解后用3mol/L盐酸溶液调整药液pH5.9,再加入12L乙醇,然后在11 土I °C下静置沉淀,沉淀8小时后收集正比旋类肝素沉淀; After completion of the reaction is proportional to the spin heparan i.e. 12 hours, 225g of sodium chloride was added to the drug solution, the drug solution pH5.9 adjusted with 3mol / L hydrochloric acid solution was dissolved sodium chloride, 12L of ethanol was added, and then the soil 11 the precipitate was allowed to stand at I ° C, the precipitate was collected after 8 hours precipitation proportional spin heparinoids;

上述负比旋类肝素反应结束即反应8小时后,向药液中加入350g氯化钠溶解,氯化钠溶解后用3mol/L盐酸溶液调整药液pH4.6,再加入18L乙醇,然后在11 土I °C下静置沉淀8小时后收集负比旋类肝素沉淀; After the above reaction than negative i.e. heparan end rotation for 8 hours, 350g of sodium chloride was added to the drug solution dissolved sodium chloride dissolved with 3mol / L hydrochloric acid solution to adjust the liquid pH 4.6, 18L of ethanol was added, and then after 8 hours at 11 [deg.] C soil stand precipitate was collected by the I negative specific rotation heparinoids precipitate;

e.冷冻干燥 e. freeze-dried

向上述正比旋类肝素沉淀中加入2000ml纯化水搅拌溶解后,补加纯化水定容至2500ml,然后将药液装入冻干盘放入冻干机中后,开始对药液降温,当制品温度降至-51°C后,对整个系统抽真空,当干燥箱内真空度为IlPa后,对制品缓慢加热,当制品温度升至54°C后保温,保温4小时后停止冻干,制得正比旋类肝素275g,经检测,比旋度为+6.4°,效价为60.8USPU/mg; After 2000ml purified water was added to the above proportional spin heparan precipitate dissolved with stirring, additional volume to 2500ml purified water, and then lyophilized drug solution charged into the lyophilizer tray, liquid began to cool, when the article after the temperature was lowered to -51 ° C, evacuating the whole system, when the degree of vacuum ILPA an oven, slowly heated to the article, when the article after incubation temperature was raised to 54 ° C, for 4 hours lyophilized stopped, Ltd. proportional to obtain 275 g of heparan spin, after testing, the specific rotation was + 6.4 °, titer 60.8USPU / mg;

向上述负比旋类肝素沉淀中加入3500ml纯化水搅拌溶解后,补加纯化水定容至4000ml,然后将药液装入冻干盘放入冻干机中,开始对药液降温,当制品温度降至-52°C后,对整个系统抽真空,当干燥箱内真空度为15Pa后,对制品缓慢加热,当制品温度升至55°C后保温,保温5小时后停止冻干,制得负比旋类肝素456g,经检测,比旋度为-7.6°,效价为54.5USPU/mg0 After stirring to dissolve, supplemented with purified 3500ml purified water was added to the above-described negative specific rotation heparan precipitate to water volume to 4000ml, and then lyophilized drug solution charged into the lyophilizer tray, liquid began to cool, when the article after the temperature was lowered to -52 ° C, vacuum pumping the entire system, when the degree of vacuum of 15Pa an oven, slowly heated to the article, the article when the temperature was raised to 55 ° C incubation, the incubation is stopped 5 hours lyophilized to prepare to give 456 g of heparan negative specific rotation, after testing, specific rotation -7.6 °, titer 54.5USPU / mg0

[0010]实施例3:本实施例与实施例1、实施例2不同之处是, [0010] Example 3: This Example Example 1, Example 2 except that,

a.粗分取生产肝素钠精品1kg下脚料湿品加纯化水溶解并定容至40L后,加入0.8kg氯化钠,氯化钠溶解后,再用3mol/L氢氧化钠溶液调整溶液pH7.0后加入乙醇,使溶液中乙醇的浓度为32.3%L/L,然后在20±1°C下静置沉淀,沉淀3小时后收集沉淀得到类肝素粗品5.2kg; a. The crude was separated production scraps plus heparin Toys 1kg wet product was dissolved purified water and dilute to 40L after, 0.8kg of sodium chloride was added, to dissolve sodium chloride, and then 3mol / L sodium hydroxide solution to adjust pH7 solution the precipitate was collected to give crude heparanase 5.2kg after adding ethanol to the concentration of ethanol in the solution is 0.05 to 32.3% L / L, and then left to settle at 20 ± 1 ° C, 3 hours the precipitate;

b.精制将上述5.2kg类肝素粗品加纯化水溶解并定容至20L,再加入0.4kg氯化钠溶解后,用3mol/L氢氧化钠调整溶液pH7.1后加入乙醇,当溶液中乙醇浓度为33.3%L/L时,在20±1°C下静置沉淀,沉淀4小时后收集沉淀得到2.1kg正比旋类肝素湿品;在上清液中补加乙醇,当上清液中乙醇浓度为42.4%L/L时,在20 土I °C下静置沉淀,沉淀4小时后收集沉淀得至IJ2.8kg负比旋类肝素湿品; b. Purification of the above plus 5.2kg heparin-purified crude dissolved in water and dilute to 20L, 0.4kg of sodium chloride was added after the dissolution, the solution was adjusted pH7.1 with 3mol / L sodium hydroxide was added ethanol, the ethanol solution when concentration was 33.3% L / L, the precipitate was allowed to stand at 20 ± 1 ° C, the precipitate was collected after 4 hours the precipitate obtained is proportional to the spin heparan 2.1kg wet product; supplemented with ethanol in the supernatant, the supernatant when when the ethanol concentration of 42.4% L / L, at 20 [deg.] C soil left to settle the I, the precipitate was collected to give a negative specific rotation IJ2.8kg heparan wet product precipitated after 4 hours;

将所制得的正比旋类肝素和负比旋类肝素分别取样测定比旋度和效价,测定结果为:正比旋类肝素比旋度为+8.5°,效价为72.4USPU/mg;负比旋类肝素比旋度为_5.5°,效价为58.3USP U/mg; The resulting rotation is proportional heparan and heparan negative specific rotation were sampled for potency and specific rotation, the measurement result is: proportional spin heparanase specific rotation of + 8.5 °, titer 72.4USPU / mg; Negative specific rotation heparanase specific rotation _5.5 °, titer 58.3USP U / mg;

取样检测如果正比旋类肝素若不能满足比旋度为O〜+40°,效价彡50.0 USPU/mg的标准,须重复上述正比旋类肝素沉淀过程;如果负比旋类肝素样品不能满足比旋度为-15〜0°,效价彡50.0 USPU/mg的标准,须重复上述负比旋类肝素沉淀过程。 If the sample is proportional spin detecting heparanase If not meet specific rotation of O~ + 40 °, San titer 50.0 USPU / mg criteria shall be proportional to the spin repeat the precipitation procedure heparan; spin negative than if the sample does not satisfy the specific heparanase curl is -15~0 °, San titer 50.0 USPU / mg of standard shall repeat the precipitation procedure heparanase negative spin ratio. 当正比旋类肝素样品和负比旋类肝素样品比旋度和效价符合要求后,则可进行以下氧化脱色; When the sample is proportional to the spin heparan and heparan negative specific rotation of the sample and the specific rotation of potency meet the requirements, the following can be oxidized decolorization;

C.氧化脱色 C. oxidative bleaching

将精制的2.1kg正比旋类肝素湿品加纯化水溶解并定容至5L后,将溶液温度调整为34土I °C,再用3mol/L氢氧化钠溶液调整溶液pH12.0后,加入150ml 30%过氧化氢进行反应; After the spin-purified heparanase proportional 2.1kg wet product was added dissolved in water and purified constant volume to 5L, the temperature of the solution was adjusted to 34 Soil I ° C, then 3mol / L sodium hydroxide solution to adjust the solution pH 12.0, was added 150ml 30% hydrogen peroxide for reaction;

将上述精制的2.8kg负比旋类肝素湿品加纯化水溶解后并定容至6.5L后,将溶液温度调整为34±1°C,再用3mol/L氢氧化钠溶液调整溶液pH12.0后加入195ml 30%过氧化氢进行反应; After the above-described spin-purified heparanase negative than 2.8kg wet product purified water was added to dissolve and dilute to 6.5L, temperature of the solution was adjusted to 34 ± 1 ° C, then 3mol / L sodium hydroxide solution to adjust the solution pH12. 0 after addition of 195ml 30% hydrogen peroxide reaction;

d.沉淀 d. The precipitate

上述正比旋类肝素反应结束即反应36小时后,向药液中加入50g氯化钠,氯化钠溶解后用3mo 1/L氢氧化钠溶液调整药液pH8.0,再加入7.5L乙醇,然后在20 土I °C下静置沉淀,沉淀24小时后收集正比旋类肝素沉淀; After completion of the reaction is proportional to the spin heparan i.e. 36 hrs, 50g of sodium chloride was added to the liquid, the liquid to dissolve sodium chloride pH8.0 adjusted with 3mo 1 / L sodium hydroxide solution, then added 7.5L of ethanol, the precipitate was then allowed to stand at 20 soil I ° C, the precipitate was collected after 24 hours the precipitate is proportional to the spin heparinoids;

上述负比旋类肝素反应结束即反应36小时后,向药液中加入65g氯化钠溶解,氯化钠溶解后用3mol/L氢氧化钠溶液调整药液pH8.0,再加入1L乙醇,然后在20± I °C下静置沉淀,沉淀24小时后收集负比旋类肝素沉淀; After the above reaction than negative i.e. heparan end rotation for 36 hours, 65g of sodium chloride was dissolved in the drug solution, the drug solution pH8.0 adjusted with 3mol / L sodium hydroxide solution, sodium chloride was dissolved, then added to 1L of ethanol, the precipitate was then allowed to stand at 20 ± I ° C, the precipitate was collected negative specific rotation heparan precipitate after 24 hours;

e.冷冻干燥 e. freeze-dried

向上述正比旋类肝素沉淀中加入6000ml纯化水搅拌溶解后,补加纯化水定容至7000ml,然后将药液装入冻干盘放入冻干机中,开始对药液降温,当制品温度降至-58°C后,对整个系统抽真空,当干燥箱内真空度为14Pa后,对制品缓慢加热,当制品温度升至55°C后保温,保温5小时后停止冻干,制得正比旋类肝素672g,经检测,比旋度为+8.7°,效价为72.8USPU/mg; After stirring to dissolve 6000ml purified water was added to the precipitate heparan proportional rotation, additional volume to 7000ml purified water, and then lyophilized drug solution charged into the lyophilizer tray, the liquid begins to cool when the temperature of the article after bringing back to -58 ° C, vacuum pumping the entire system, when the degree of vacuum of 14Pa an oven, slowly heated to the article, the article when the temperature was raised to 55 ° C incubation, stop after lyophilization incubated for 5 hours to obtain 672 g spin heparan proportional, after testing, the specific rotation was + 8.7 °, titer 72.8USPU / mg;

向上述负比旋类肝素沉淀中加入8000ml纯化水搅拌溶解后,补加纯化水定容至9000ml,然后将药液装入冻干盘放入冻干机中,开始对药液降温,当制品温度降至-55°C后,对整个系统抽真空,当干燥箱内真空度为13Pa后,对制品缓慢加热,当制品温度升至51°C后保温,保温3小时后停止冻干,制得负比旋类肝素905g,经检测,比旋度为-5.2°,效价为58.5USPU/mg0 After stirring to dissolve, supplemented with purified 8000ml purified water was added to the above-described negative specific rotation heparan precipitate to dilute to 9000 ml of water, and then lyophilized drug solution charged into the lyophilizer tray, liquid began to cool, when the article after the temperature was lowered to -55 ° C, vacuum pumping the entire system, when the degree of vacuum of 13Pa an oven, slowly heated to the article, the article when the temperature was raised to 51 ° C incubation, the lyophilized stopped after 3 hours incubation, Ltd. to give 905 g heparanase negative specific rotation, after testing, specific rotation -5.2 °, titer 58.5USPU / mg0

Claims (1)

1.一种肝素钠下脚料制备类肝素工艺,其特征在于包括以下步骤: a.粗分将肝素钠下脚料按湿重5〜30%w/v浓度加入纯化水后再加入2〜10%w/v氯化钠,氯化钠溶解后,调整药液PH4〜8后加入乙醇,当药液中乙醇浓度为30〜38%v/v时,在10〜30 °C下静置沉淀,沉淀2〜10小时后收集沉淀得到类肝素粗品; b.精制将上述类肝素粗品按湿重5〜30%w/v浓度加入纯化水后再加入2〜10%w/v氯化钠,氯化钠溶解后,调整药液PH4〜8后加入乙醇,当药液中乙醇浓度为32〜35%v/v时,在10〜30°C下静置沉淀,沉淀2〜1小时后收集沉淀制得比旋度为0°〜+ 40°、效价彡50.0 USPU/mg的正比旋类肝素;在上清液中加入乙醇,当上清液中乙醇浓度为34〜43%v/v时,在10〜30 °C下静置沉淀,沉淀2〜10小时后收集沉淀制得比旋度为-15°〜0°、效价彡50.0 USPU/mg的负比旋类肝素; c.氧化脱色将上述精制的正比旋类肝素湿 A heparin preparation heparan process waste, comprising the steps of:. A waste crude hours, wet weight heparin 5~30% w / v concentration was added and then purified water was added 2~10% w / v sodium chloride, sodium chloride is dissolved, the ethanol was added to adjust the liquid PH4~8, when the concentration of ethanol in liquid 30~38% v / v, at 10~30 ° C left to settle, after precipitation the precipitate was collected 2~10 hours to obtain a crude heparan;. b above heparanase purified crude wet weight of 5~30% w / v was added and then purified water was added to a concentration of 2~10% w / v sodium chloride after the precipitate collected was dissolved sodium, adjusted liquid PH4~8 ethanol was added, when the chemical concentration of ethanol 32~35% v / v, the precipitate was allowed to stand at 10~30 ° C, the precipitate 2~1 hours when ethanol was added to the supernatant, when the ethanol concentration of the supernatant 34~43% v / v; degree of rotation is made larger than 0 ° ~ + 40 °, San titer 50.0 USPU / mg proportional spin heparan , the precipitate was allowed to stand at 10~30 ° C, the precipitate was collected by precipitation 2~10 hours than curl of -15 ° ~0 °, San titer 50.0 USPU / mg heparin negative specific rotation type;. c oxide the above-described bleaching purified heparan proportional spin wet 品加入纯化水溶解后,在25〜35°C下调整药液pH9.0〜.12.0后,加入过氧化氢进行反应; 将上述精制的负比旋类肝素湿品加纯化水溶解后,在25〜35°C下调整溶液pH9.8〜.12.0后,加入过氧化氢进行反应; d.沉淀上述正比旋类肝素氧化反应8〜36小时后,按质量体积比向药液中加入I〜6%的氯化钠溶解后,调整药液pH4〜8,再加入1.5〜3.0倍药液体积的乙醇,然后在10〜30 °C下静置沉淀,沉淀8〜24小时后收集沉淀物正比旋类肝素; 上述负比旋类肝素氧化反应8〜36小时后后,按质量体积比向药液中加入I〜6%的氯化钠溶解后,调整药液pH4〜8,再加入1.5〜3.0倍药液体积的乙醇,然后在10〜30°C下静置沉淀,沉淀8〜24小时后收集沉淀物负比旋类肝素; e.冷冻干燥将上述正比旋类肝素沉淀物按湿重30〜45%浓度加入纯化水溶解后降温,降温至-50〜-60°C时抽真空,当真空度彡15Pa后 After the purified product was added dissolved in water, adjusted liquid pH9.0~.12.0 at 25~35 ° C, hydrogen peroxide was added for reaction; after the above-described rotation purified heparanase negative than adding purified water wet product was dissolved in at 25~35 ° C was adjusted pH9.8~.12.0, hydrogen peroxide was added for reaction; after precipitation of the above-described proportional spin d heparan oxidation 8~36 hours, a mass ratio of the volume of liquid added to the I~ the precipitate was collected after proportional 6% sodium chloride is dissolved, adjust the liquid pH4~8, 1.5~3.0 times the added liquid volume of ethanol, then left to settle at 10~30 ° C, the precipitate 8~24 hours rotary heparinoids; 8~36 hours after the reaction ratio of the above negative rotation heparan oxide, the mass ratio of the volume of sodium chloride are dissolved I~6% was added to the liquid, the adjusting liquid pH4~8, added 1.5~ 3.0 times the volume of liquid collected in ethanol, and then left to settle at 10~30 ° C, the precipitate 8~24 hours after the precipitate was negative specific rotation heparinoids;. e proportional to the above-described lyophilized pellet spin heparinoid wet weight when vacuum 30~45% concentration dissolved in water was added after cooling the purified, cooled to -50~-60 ° C, degree of vacuum after San 15Pa 慢加热,加热至50〜55°C后保温,保温3〜5小时后制得比旋度为0°〜+ 40°、效价彡50.0 USPU/mg的正比旋类肝素; 将上述负比旋类肝素沉淀物按湿重30〜45%浓度加入纯化水溶解后降温,降温至-50〜-60°C时抽真空,当真空度彡15Pa后缓慢加热,加热至50〜55°C后保温,保温3〜5小时后制得比旋度为-15°〜0°、效价彡50.0 USPU/mg的负比旋类肝素。 Slow heating, heated to 50~55 ° C incubation, after three to five hours of incubation the degree of rotation is made larger than 0 ° ~ + 40 °, San titer proportional spin heparinoids 50.0 USPU / mg; the above-mentioned negative specific rotation after heparinoid precipitate a wet 30~45 weight% concentration dissolved in water was added after cooling the purified, cooled to -50~-60 ° C during evacuation, when the degree of vacuum of 15Pa San heated slowly heated to 50~55 ° C incubation after three to five hours of incubation the degree of rotation is made larger than -15 ° ~0 °, San titer 50.0 USPU / mg heparin negative specific rotation class.
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US5922690A (en) * 1996-04-25 1999-07-13 Van Gorp; Cornelius L. Dermatan disulfate, an inhibitor of thrombin generation and activation
CN1445245A (en) * 2003-04-18 2003-10-01 山东大学 Dermatan sulfate with low molecule and its preparing method
CN1850864A (en) * 2006-05-29 2006-10-25 南京健友生物化学制药有限公司 Method for separating and purify dermatansulfate and low-molecular heparan sulfate from sodium heparan product
CN101885782A (en) * 2009-05-11 2010-11-17 深圳市海普瑞药业股份有限公司 Method for purifying dermatan sulfate from heparin byproduct

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922690A (en) * 1996-04-25 1999-07-13 Van Gorp; Cornelius L. Dermatan disulfate, an inhibitor of thrombin generation and activation
CN1445245A (en) * 2003-04-18 2003-10-01 山东大学 Dermatan sulfate with low molecule and its preparing method
CN1850864A (en) * 2006-05-29 2006-10-25 南京健友生物化学制药有限公司 Method for separating and purify dermatansulfate and low-molecular heparan sulfate from sodium heparan product
CN101885782A (en) * 2009-05-11 2010-11-17 深圳市海普瑞药业股份有限公司 Method for purifying dermatan sulfate from heparin byproduct

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