WO2016090704A1 - 硫酸软骨素制备工艺及其设备 - Google Patents

硫酸软骨素制备工艺及其设备 Download PDF

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Publication number
WO2016090704A1
WO2016090704A1 PCT/CN2015/000078 CN2015000078W WO2016090704A1 WO 2016090704 A1 WO2016090704 A1 WO 2016090704A1 CN 2015000078 W CN2015000078 W CN 2015000078W WO 2016090704 A1 WO2016090704 A1 WO 2016090704A1
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storage tank
chondroitin sulfate
liquid storage
filtrate
liquid
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PCT/CN2015/000078
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English (en)
French (fr)
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张木良
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张木良
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Priority to US15/534,459 priority Critical patent/US20180044441A1/en
Publication of WO2016090704A1 publication Critical patent/WO2016090704A1/zh

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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
    • C08B37/006—Heteroglycans, 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
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0069—Chondroitin-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

Definitions

  • the invention relates to a preparation process of chondroitin sulfate, in particular to a solventless method for extracting 10,000 tons of chondroitin sulfate and a device thereof, and belongs to the field of extracting chondroitin sulfate.
  • CS Chondroitin sulfate
  • organic solvents which are determined by the physical properties of the product. Water is insoluble in organic solvents. Commonly used solvents are: acetone, ethanol, ether, chloroform and the like. Because of the toxic side effects of acetone, ether and chloroform, they are discarded. So far, the process technology for CS extraction and purification worldwide has been determined by solvent concentration. The solvents acetone and ethanol used are too low in boiling point of acetone solvent, which is volatile and dangerous. Therefore, CS manufacturers are basically extracted and purified with ethanol.
  • the construction period is at least 8 months; (2) The preparation process of the CS product by solvent extraction is long, which results in low product yield and unit cost. From raw material input to finishing, drying, and laboring, all solvent preparation The whole process of the method must be at least 50 hours; (3) due to the high solvent price, the proportion of the additional cost is large, so it is necessary to recycle and reuse.
  • This section is the bottleneck section in the production process, open-air operation, plus fireproof and explosion-proof, so it should be separated from other sections. Therefore, so far, the world has not been able to design a CS automatic or semi-automatic production line; (4) in the process of solvent extraction and purification of CS products, high energy consumption refers to the coal, electricity, water, solvent used for solvent recovery.
  • the wastewater generated during the solvent recovery process (COD is more than 80,000 units) is about 60 tons or more, and then the washing water is washed and the sanitary water is washed.
  • the waste liquid and waste water generated per ton of CS product are more than 100 tons (excluding air). Pollution and domestic sewage), so it is necessary to build sewage treatment equipment to deal with. Otherwise, the company is unable to start production due to environmental protection environmental assessment failure; (6)
  • the low product yield in the solvent process refers to the defects of its technical process.
  • yield refers to the weight of the CS product extracted from the same site of animal cartilage, 100 kg of dry material or fresh material
  • solvent extraction and purification process The product content is relatively low. In large-scale production, the content of CS products is generally below 95% (referring to CPC) content). Therefore, in its products, there is a certain amount of protein, solvent, hydrogen peroxide and the like.
  • the Chinese invention patent entitled “An Organic Solvent Extraction Process for Chondroitin Sulfate”, “CN 201210576946.3”, provides an organic solvent-free extraction process for chondroitin sulfate, including the following process steps: animal cartilage The powder boiled material is matured, protease is added, the enzyme is enzymatically hydrolyzed, the enzyme is warmed up, the enzyme solution is cooled to room temperature, and then filtered, the filtrate is adjusted to pH 5-8, the cation exchange resin column is passed, and the effluent A is collected.
  • the purified water was eluted, and the eluent B was collected, and the effluent A and the eluent B were mixed, concentrated by ultrafiltration, and spray-dried.
  • the process requires an inactivating step, which not only increases the process flow, but also increases the cost input.
  • the extraction step is lacking, and impurities are generated in the production process, such as large investment, long cycle, high energy consumption, and high pollution. .
  • the purpose of the design of the present invention is to provide a chondroitin sulfate preparation process and equipment thereof, and to change the uniqueness of the conventional solvent extraction method for the CS process; and to solve the CS extraction process, from the raw material input to the final product, the realization cannot be achieved.
  • Automated production problems changed the CS production and extraction process, large investment, long cycle, high energy consumption, high pollution, high cost, and side effects (referring to people allergic to proteins, organic solvents, hydrogen peroxide), resulting in product variety Less (so far there is no CS oral liquid grade series), market capacity and limited application areas; saving investment, compared with the same scale, can save more than 80% of investment.
  • the product quality is controllable at random, the content is from 60% to 105% (refers to According to the CPC method, other quality indicators can meet or exceed the current product quality standards; no pollution, zero emissions, green production.
  • Chondroitin sulfate preparation process including liquefaction, extraction enzymatic degradation, filtration, separation and post-treatment steps;
  • (1) liquefaction the raw material is liquefied by pressure cooking, and becomes a liquid state
  • the raw material of the step (1) is frozen cartilage powder or cartilage mud; the frozen cartilage powder is pulverized or ground in a frozen cartilage powder, and is stored in a block form; the frozen cartilage powder is preferably in a fresh state. And reaching the frozen cartilage powder without meat, oil, and quality;
  • the cooking temperature of the step (1) is 100 to 120 ° C;
  • the specific operation of extracting the enzymatic degradation in the step (2) is: liquefying the step (1) After the cartilage liquid is cooled to 25-35 ° C, the alkaline solution is extracted by adding 0.8-1.2% of the total volume of the liquid, and then 3 to 9 ⁇ of the enzymatic enzyme and the same amount of degrading enzyme are added respectively to carry out enzymatic hydrolysis and Degradation until the dissociation stratification, that is, the natural separation of CS and protein substances occurs, and a mixed liquid is obtained;
  • the filtering device is preferably a vacuum circulation filter; the filter is continuously filtered by a vacuum circulation filter, and the filtered filtrate is clear, transparent, free from turbidity and impurities;
  • the filtrate obtained in the step (3) is physically separated from a small molecule such as an amino acid protein to obtain a permeate and a concentrate; and the bone residue obtained in the step (3) is dried to obtain an animal.
  • the physical separation method is preferably a molecular sieve; the separated macromolecule having a molecular weight of 3000 or more is concentrated night, and the small molecule having a molecular weight of 3000 or less is a permeate;
  • Post-treatment The permeate obtained in the step (4) is subjected to dehydration concentration and drying to obtain an animal protein powder; and the concentrate obtained in the step (4) is dehydrated to obtain a chondroitin sulfate product of the present invention.
  • the product is packaged, barreled, sealed, and gimmicked.
  • the whole process time of the step (1) takes about 1 to 3 hours; the whole process time of the step (2) is about 6-8 hours; the whole process of the step (3) takes about 2 hours. Hour; the whole process of the step (4) takes about 2 to 3 hours; the whole process of the step (5) takes about 3 hours, the whole process time does not exceed 20 hours, and can be automated, semi-automatic continuous production The final product.
  • the equipment in the whole process of the steps (1) and (2) may be stainless steel, polypropylene or Teflon, but in terms of cost and service life, it is not as resistant to corrosion and acidity as the Teflon material.
  • Alkali The utility model has the advantages of long service life, economical and no static electricity reaction; the cooking equipment can be, for example, a Teflon reaction kettle; and the step (3) continuous filtration device can be, for example, a vacuum circulation filter; the steps (4) and (5)
  • the dried equipment can be, for example, a Teflon drying apparatus.
  • the above-mentioned equipments are connected by Teflon pipes and flanges, so that they can be automated and semi-automatically produced continuously, and the final products are obtained, and the degree of automation is high.
  • An apparatus for preparing the chondroitin sulfate preparation process comprising a reaction kettle, wherein the reaction vessel is preferably a Teflon reaction vessel, wherein the reaction vessel is connected with a vacuum circulation filter, a filtrate liquid storage tank and a molecular sieve in sequence.
  • the molecular sieves are respectively connected with a protein liquid storage tank and a CS liquid storage tank.
  • the raw material is firstly boiled, cooled, alkalized, enzymatically hydrolyzed and degraded in the reaction vessel to complete steps (1) and (2) of the above process, and then filtered through a vacuum circulation filter to complete the step (3) of the above process.
  • the filtrate is pumped into the filtrate liquid storage tank, and then the material is pumped into the molecular sieve by the filtrate liquid storage tank, the material separation is performed to complete the step (4) of the above process, and the separated products are separately pumped into the protein liquid storage tank and In the CS liquid storage tank, subsequent processing is performed to complete the step (5) of the above process.
  • a pump is arranged between the vacuum circulation filter and the filtrate liquid storage tank, and between the filtrate liquid storage tank and the molecular sieve, and the molecular sieve and the protein liquid storage tank and the CS liquid storage tank are provided with a circulation.
  • the pump, the outlet of the circulation pump is also connected to the inlet of the molecular sieve, so that multiple separations can be performed, and the separation effect is improved.
  • the protein liquid storage tank is connected to a dehydration device, or a dehydration device and a drying device to obtain an animal protein powder.
  • the CS liquid storage tank is connected to a dehydration device, or a dehydration device and a drying device to obtain a chondroitin sulfate product of the present invention.
  • waste liquid and waste water generated during the whole CS extraction and purification process can be recycled by simple physical treatment, without discharge or separate treatment, low pollution and green environmental protection;
  • the smelly gas can be treated by the air purifying device, discharged after reaching the standard, safe and environmentally friendly;
  • the product quality is in full compliance with or exceeds the current USP35 version and Western European EP7.0 and Chinese Pharmacopoeia standards, and the product quality is high;
  • the product produced by the process technology of the invention is used as a medical raw material medicine, which is beneficial to the further development and expansion of downstream products, such as CS sodium salt, calcium salt, potassium salt, zinc salt oral liquid and shark CS oral liquid and composite thereof.
  • downstream products such as CS sodium salt, calcium salt, potassium salt, zinc salt oral liquid and shark CS oral liquid and composite thereof.
  • the development of formulas such as oral liquids has broad prospects;
  • the output of the product can reach more than 10,000 tons, which is the first case, which is unmatched by the solvent process technology.
  • FIG. 2 is a block diagram of a device connection according to an embodiment of the present invention.
  • the raw material is frozen fresh cartilage powder or cartilage mud
  • frozen fresh cartilage powder refers to the cartilage produced by different animals (such as cattle, pigs, sheep, chickens, ducks, sharks, etc.) after being slaughtered, in the process of segmentation. Then processed to achieve no meat, no oil, no impurities, and then smash or mince, according to a certain weight (such as 10 ⁇ 20 kg / block) in a square container frozen storage (-5 ⁇ -20 ° C) storage , that is, a block of cartilage powder;
  • the mixed solution is obtained, and the whole process time is about 6-8 hours; wherein, the enzyme A, ie, the enzymatic enzyme and the B enzyme, that is, the degrading enzyme, can select the conventional enzyme for extracting chondroitin sulfate, which has no effect on the present invention;
  • the filtrate obtained in the step (3) is physically subjected to CS and small molecules such as amino acids.
  • the protein and other substances are separated to obtain a permeate and a concentrate, and the whole process is about 2 to 3 hours, wherein the permeate is a liquid containing an amino acid small molecule protein, and the concentrate is a liquid containing CS;
  • the obtained bone slag is dried to obtain animal bone powder, which is used for feed, realizes waste utilization, does not need to be discharged or treated separately, has low pollution, and is environmentally friendly;
  • the physical separation method is preferably molecular sieve;
  • the separated separation amount is ⁇ 3000
  • the molecule is a concentrated night, and the small molecule with a molecular weight of ⁇ 3000 is a permeate;
  • Post-treatment the permeate obtained in the step (4) is subjected to dehydration concentration and drying to obtain an animal protein powder; and the concentrate obtained in the step (4) is dehydrated to obtain the chondroitin sulfate product of the present invention, and the whole process is about Use for 3 hours.
  • the product is packaged, barreled, sealed, and gimmicked.
  • An apparatus for preparing the chondroitin sulfate preparation method of the above embodiment 1, comprising a reaction vessel, wherein the reaction vessel is preferably a Teflon reaction vessel, and the reaction vessel is sequentially connected with a vacuum circulation filter, a filtrate liquid storage tank, and A molecular sieve, the molecular sieve is respectively connected with a protein liquid storage tank and a CS liquid storage tank.
  • the raw material is firstly boiled, cooled, alkalized, enzymatically hydrolyzed and degraded in the reaction vessel to complete steps (1) and (2) of the above process, and then filtered through a vacuum circulation filter to complete the step (3) of the above process.
  • the filtrate is pumped into the filtrate liquid storage tank, and then the material is pumped into the molecular sieve by the filtrate liquid storage tank, the material separation is performed to complete the step (4) of the above process, and the separated products are separately pumped into the protein liquid storage tank and In the CS liquid storage tank, a subsequent treatment is performed to complete the step (5) of the above process;
  • a pump is arranged between the vacuum circulation filter and the filtrate liquid storage tank, and between the filtrate liquid storage tank and the molecular sieve, a circulation pump is arranged between the molecular sieve and the protein liquid storage tank and the CS liquid storage tank, and the outlet of the circulation pump is also connected to the inlet of the molecular sieve, thereby enabling multiple separations and improving the separation effect;
  • the protein liquid storage tank is sequentially connected with the dehydration device and the drying device to obtain the animal protein powder; the
  • the temperature is raised to 85 ° C, allowed to stand for 30 minutes, and then the temperature is lowered, and the process is carried out in the reaction vessel;
  • the filtrate enters the separation process, and the bone residue is dried or dried to form an animal bone powder, which can be used for feed;
  • the macromolecular (molecular weight ⁇ 3000) CS and the small molecule ( ⁇ 3000) amino acid protein are separated by molecular sieve to obtain CS concentrated liquid and permeate;
  • the CS concentrate is repeatedly concentrated until the substrate mass concentration ⁇ 30% is dried, and the CS product is obtained in 45 kg, and the yield is 7.5%;
  • the separated permeate was concentrated and dried to obtain 90 kg of animal protein powder, and the yield was 15%.
  • the above process can also be used to produce CS products using cartilage of pigs, sheep, chickens, ducks and the like as raw materials, in the same manner.
  • the quality of the product obtained by the invention (solvent-free method) is compared with the quality of the product obtained by the solvent method.
  • the comparison table is as follows:
  • the raw materials used in the present invention are all commonly used raw materials in the production of the art, and are all available from the market, and have no influence on the production result; various devices used in the present invention are conventionally used in the production process in the art.
  • the equipment, and the operation and parameters of each equipment are carried out according to the normal operation, and there is nothing special.

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Abstract

本发明公开了一种硫酸软骨素制备工艺及其设备，具体地说是一种无溶剂法万吨级硫酸软骨素的提取工艺，包括液化、提取酶解降解、过滤、分离和后处理等步骤，设备包括反应釜，所述反应釜优选为特氟龙反应釜，所述反应釜依次管道连接有真空循环过滤器、滤液储液罐和分子筛，所述分子筛分别管道连接有蛋白液储罐和CS液储罐；本发明的优点在于：节约了投资，同等规模相比，可节约投入资金80％以上。规模越大，相对投入越少；产能最大可达万吨以上，这是溶剂法工艺技术所无法比拟的，且能实现自动化连续生产；产品质量随意可控，含量从60％～105％(指CPC含量)，其他质量指标也能达到或超过现行的产品质量标准要求；无污染，零排放，绿色环保生产。

Description

硫酸软骨素制备工艺及其设备 技术领域
本发明涉及一种硫酸软骨素制备工艺，具体地说是一种无溶剂法万吨级硫酸软骨素的提取工艺及其设备，属于硫酸软骨素的提取领域。
背景技术
硫酸软骨素(简称CS)自1861年美国人从动物软骨中提取分离出来至今，其提取、提纯的工艺技术关键都离不开有机溶剂，原因是该产品的物理特性所决定的——溶于水而不溶于有机溶剂。常用的溶剂有：丙酮、乙醇、乙醚、氯仿等。又因丙酮、乙醚、氯仿有毒副作用，而被弃之不用。到目前为止，全世界CS提取和提纯的工艺技术，都是由溶剂浓度决定的。所采用的溶剂丙酮和乙醇，又因丙酮溶剂的沸点太低，易挥发、危险性大，所以CS的生产企业基本上都是用乙醇提取和提纯的。目前全世界CS的提取工艺与技术普通采用是：(1)稀碱提取工艺(见《生化工艺学》中具体描述)；(2)浓碱提取工艺(见《生化工艺学》属21世纪生物工程系列高等院校教材书，由陈来同编著，科学出版社2012年1月第五次印刷出版)；(3)稀碱-浓盐提取工艺；(4)酶解-树脂提取工艺等。
然而，采用上述溶剂法提取制备存在以下缺点：(1)用溶剂法新建CS提取、提纯生产企业，固定资产投入大，资金浪费严重，新厂建设周期长、见效慢，造成产品成本居高不下，消费市场难以扩容。以年产CS(指从原料做起全部自产)百吨规模的企业来说，占地面积不少于6000平方米，加上溶剂回收系统、加热系统、冷却系统、污水处理系统所用设备及土建工程，安全防火、防爆、 防雷设施及生产车间(精、烘、包车间)要达到GMP要求等，不包括办公区及生活区就得投入500万元以上。且环评也不一定能通过验收。建设周期至少在8个月以上；(2)因溶剂法提取、提纯CS产品制备工艺时间长，相对造成产品产量低，单位成本上升，从原料投入到精、烘、包工段完成，所有溶剂制备法整个工艺流程至少要在50小时以上；(3)因溶剂价格高，在附加成本中所占比例较大，所以要回收重复利用。该工段又是生产过程中的瓶颈工段，露天操作，再加上要防燃、防爆，所以要与其他工段之间隔开。因此，到目前为止，全世界没法设计出一条CS自动或半自动生产流水线；(4)溶剂法提取、提纯CS产品的过程中，高能耗是指溶剂回收耗用的煤、电、水，溶剂消耗，其工段所用工人工资等，仅此项每吨产品要增加成本10000元以上，且有安全隐患；(5)溶剂法工艺中的高污染是指要消耗大量的氢氧化钠(烧碱)和盐酸，1000公斤CS产品以鲜牛胸骨为例，收率按5％计算，需要20吨原料和20吨纯化水，共产生40吨液体。需要氢氧化钠(以稀碱——浓盐工艺为准)800公斤以上，盐酸1850公斤以上，氯化钠1000公斤以上，溶剂要消耗掉1500公斤左右。溶剂回收过程中产生的废水(COD在80000个单位以上)约60吨以上，再合并洗料水、冲洗卫生水等，每吨CS产品要产生的废液及废水在百吨以上(不含空气污染和生活污水)，所以必须要建污水处理设备来处理。否则，企业因环保环评不达标，而无法开工生产；(6)溶剂法工艺中的产品出率低，是指其技术工艺的缺陷所造成的。在提取、提纯过程中，因酶种单一，达不到内切、外切之目的，使酶在酶解、降解过程中不彻底，液体不分层，蛋白质不聚合，或降解不完全，造成过滤困难，因而影响了产品的收率和质量(收率是指相同部位的动物软骨，百公斤干料或鲜料计所提取得到的CS产品重量)；(7)溶剂法提取、提纯工艺中产品含量相对较低。规模化生产中，CS产品的含量一般在95％以下(指CPC 含量)。所以在其产品中，存有一定量的蛋白质、溶剂、过氧化氢等。作为原料药用的CS下游产品——硫酸软骨素片剂、胶囊、针剂、滴眼液等品种，对蛋白质和溶剂及过氧化氢有过敏反应的人群均无法使用。这也是目前为止全世界没有CS口服液品种的原因之一。CS中的水分很难达到≤1％，相对在一定的容积(如胶囊)和重量(片剂和胶囊)中，CS的质量就少了，进而影响到了产品的疗效。因其疗效慢而又长致使人们对其保健作用产生了怀疑，从而影响到整个行业销量很难增长(经济因素除外)，这也是全世界CS的消费量一直在5000吨左右徘徊的重要原因之一；(8)由于溶剂的使用，胰酶的使用(针对西欧和伊斯兰国家依其宗教信仰，不准用猪的产物而言)，再加上生产过程中产生的废弃物对环境污染严重，所以无法在国外建厂。达不到整合全球资源，变废为宝，使之产能达到万吨级以上。难以达到以量求利、以质求量、薄利多销之目的。使全世界人民身体健康受益，得到保健及治疗之目的。另外，溶剂法提取工艺过程中，80％以上产品中都含有过氧化氢(双氧水)。以鲜牛胸骨为例：每吨CS产品要消耗掉300～400公斤过氧化氢。且该物质有害于消费人群的身体健康。
例如，名称为“一种硫酸软骨素的无有机溶剂提取工艺”申请号为“CN 201210576946.3”的中国发明专利提供了一种硫酸软骨素的无有机溶剂提取工艺，包括如下工艺步骤：将动物软骨粉末煮料熟化，加入蛋白酶，进行生物酶酶解，升温灭酶，将灭酶料液冷却到室温后过滤，将滤液调节pH至5～8，过阳离子交换树脂柱，收集流出液A，用纯化水洗脱，收集洗脱液B，将流出液A与洗脱液B混和，再经超滤浓缩后喷雾干燥。但是，该工艺需要进行灭酶步骤，不但增量了工艺流程，而且增加了成本投入，另外，缺少提取步骤，在生产过程会有杂质污染等产生，投入大、周期长、高能耗，污染高。
发明内容
本发明设计的目的在于，提供了一种硫酸软骨素制备工艺及其设备，改变传统采用溶剂法提取CS工艺技术的唯一性；解决了CS提取工艺过程中，从原料投入到最终产品，不能实现自动化生产问题；改变了CS生产提取过程中，投入大、周期长、高能耗、高污染、高成本，且有副作用(指对蛋白质、有机溶剂、过氧化氢过敏人群而言)，致使产品品种少(至今没有CS口服液级系列品种)，市场容量和应用领域受限等问题；节约了投资，同等规模相比，可节约投入资金80％以上。规模越大，相对投入越少；产能最大可达万吨以上，这是溶剂法工艺技术所无法比拟的，且能实现自动化连续生产；产品质量随意可控，含量从60％～105％(指CPC法测定)，其他质量指标也能达到或超过现行的产品质量标准要求；无污染，零排放，绿色环保生产。
本发明的技术方案为：
硫酸软骨素制备工艺，包括液化、提取酶解降解、过滤、分离和后处理步骤；
具体操作步骤如下：
(1)液化：将原料经压力蒸煮后液化，变成液体状态；
其中，所述步骤(1)的原料为冷冻软骨粉或软骨泥；所述冷冻软骨粉为将冷冻软骨粉进行粉碎或绞碎，呈块状冷冻储存；所述冷冻软骨粉优选在新鲜状态下，且达到无肉、无油、不变质的冷冻软骨粉；
所述步骤(1)的蒸煮温度为100～120℃；
(2)提取酶解降解：将步骤(1)液化后的软骨液体降温到25～35℃后，加入碱进行碱解，再加酶解酶与降解酶，进行酶解和降解，直至到解离分层，即产生CS与蛋白类物质自然分离现象，得到混合液；
其中，所述步骤(2)提取酶解降解的具体操作为：将步骤(1)液化后的 软骨液体降温到25～35℃后，加入液体体积总量的0.8～1.2％的NaOH进行碱解提取后，再分别加3～9‰的酶解酶与等量的降解酶，进行酶解和降解，直至到解离分层，即产生CS与蛋白类物质自然分离现象，得到混合液；
(3)过滤：将步骤(2)的混合液通过过滤装置连续过滤，得到滤液和骨渣，使滤液的澄清度在0.001～0.10范围内；
其中，所述过滤装置优选为真空循环过滤器；通过真空循环过滤器连续过滤，过滤后的滤液达到清澈、透明，无浑浊、杂质；
(4)分离：将步骤(3)得到的滤液通过物理方法使CS与小分子如氨基酸类蛋白等物质分离，得到透过液和浓缩液；将步骤(3)得到的骨渣经干燥得到动物骨粉，用于饲料，实现了废物利用，无需排放或者单独处理，污染低，绿色环保；
其中，所述物理分离方法优选为分子筛；分离的分子量在3000以上的大分子为浓缩夜，分子量在3000以下的小分子为透过液；
(5)后处理：将步骤(4)得到的透过液进行脱水浓缩和干燥，得到动物蛋白粉；将步骤(4)得到的浓缩液进行脱水，得到本发明硫酸软骨素产品。
最后，产品经包装成型，装桶，封上口，贴上唛头。
其中，所述步骤(1)的整个过程时间约需1～3小时；所述步骤(2)的整个过程时间约在6～8小时内；所述步骤(3)的整个过程约需时间2小时；所述步骤(4)的整个过程约用2～3小时；所述步骤(5)的整个过程约用3小时，整个工艺流程时间不超过20小时，且能自动化、半自动化连续生产得到最终成品。
所述步骤(1)和(2)整个工艺过程中的设备材质可以是不锈钢、聚丙烯或特氟龙，但从造价和使用寿命来讲，都比不上特氟龙材料耐腐蚀、搞酸碱， 使用寿命长、经济实惠、无静电反应；蒸煮的设备例如可以是特氟龙反应釜；所述步骤(3)连续过滤的装置例如可以是真空循环过滤器；所述步骤(4)和(5)干燥的设备例如可以是特氟龙干燥设备。上述各设备通过特氟龙管道及法兰连接，从而能自动化、半自动化连续生产，得到最终成品，自动化程度高。
一种用于上述硫酸软骨素制备工艺的设备，包括反应釜，所述反应釜优选为特氟龙反应釜，所述反应釜依次管道连接有真空循环过滤器、滤液储液罐和分子筛，所述分子筛分别管道连接有蛋白液储罐和CS液储罐。原料首先在反应釜内煮料、降温、碱解、酶解和降解，完成上述工艺的步骤(1)和步骤(2)，然后通过真空循环过滤器进行过滤完成上述工艺的步骤(3)后，滤液泵入到滤液储液罐中，再由滤液储液罐将物料泵入分子筛中，进行物料分离完成上述工艺的步骤(4)，再将分离得到的产物分别泵入蛋白液储罐和CS液储罐中，进行后续处理，完成上述工艺的步骤(5)。
进一步地，所述的真空循环过滤器与滤液储液罐之间、滤液储液罐与分子筛之间均设有泵，所述的分子筛与蛋白液储罐和CS液储罐之间设有循环泵，所述循环泵的出口还与所述分子筛的入口相连，从而能够进行多次分离，提高了分离效果。
进一步地，所述的反应釜与真空循环过滤器之间设有高度差，通过高度差使物料自然流动，降低了生产成本。
进一步地，所述的蛋白液储罐与脱水装置，或脱水装置和干燥装置相连，得到动物蛋白粉。
进一步地，所述的CS液储罐与脱水装置，或脱水装置和干燥装置相连，得到本发明硫酸软骨素产品。
本发明的优点在于：
(1)不用溶剂即可得到CS产品；
(2)整个工艺流程时间不超过20小时，且能自动化、半自动化连续生产得到最终成品；
(3)整个工艺技术生产中，用酸碱量很少，其总量约为产品重量的15％～30％，投入成本低产能高，经济效益高；
(4)整个CS提取、提纯工艺过程中产生的废液和废水，通过简单地物理处理即可循环使用，无需排放或者单独处理，污染低，绿色环保；
(5)有味道的气体可通过空气净化装置来处理，达标后排放，安全环保；
(6)整个工艺流程自动化程度高，自产量在100吨以上的用工不超过15人，人工少，降低了生产成本；
(7)产品质量完全符合或超过现执行的美国USP35版和西欧EP7.0及中国药典标准，产品质量高；
(8)生产成本与溶剂法相比，成本降低约40％～70％，降低了生产成本，提高了经济效益，；
(9)采用本发明工艺技术产出的产品作为医用原料药，有利于下游产品的进一步开发和扩展，如CS钠盐、钙盐、钾盐、锌盐口服液及鲨鱼CS口服液及其复合配方口服液等产品品种的开发，前景广阔；
(10)产品产量完全能达到万吨以上，尚属首例，这是溶剂法工艺技术所无法比拟的。
下面结合附图和实施例对本发明作进一步说明。
附图说明
图1为本发明实施例的工艺流程图；
图2为本发明实施例的设备连接框图。
具体实施方式
以下对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
除非另有说明，本发明中所采用的百分数均为重量百分数。
实施例1
如图1所示，一种硫酸软骨素制备工艺，具体操作步骤如下：
(1)液化：将原料投入反应釜内，在100～120℃的温度下解冻蒸煮，经压力蒸煮后液化，变成液体状态，整个过程时间约需1～3小时；
其中，原料为冷冻鲜软骨粉或软骨泥；冷冻鲜软骨粉是指不同的动物(如牛、猪、羊、鸡、鸭、鲨鱼等)在其被宰杀后，分割过程中产出的软骨，然后经过处理，达到无肉、无油、无杂质，然后进行粉碎或绞碎，按一定的重量(如10～20公斤/块)在方型器皿内速冻冷藏(-5～-20℃)储存，即成块状软骨粉；
(2)提取酶解降解：将步骤(1)液化后的软骨液体降温到25～35℃后，加入液体体积总量的0.8～1.2％的NaOH进行碱解提取3小时后，再分别加3～9‰的A酶即酶解酶(外切酶)与等量的B酶即降解酶(内切酶)，进行酶解和降解，直至到解离分层，即产生CS与蛋白类物质自然分离现象，得到混合液，整个过程时间约在6～8小时内；其中，A酶即酶解酶与B酶即降解酶可以选用目前传统的硫酸软骨素提取用酶，对本发明没有影响；
(3)过滤：将步骤(2)的混合液通过真空循环过滤器连续过滤，将骨渣及没降解的大分子蛋白过滤出来，得到滤液和骨渣，使滤液的澄清度在0.001～0.10范围内，通过真空循环过滤器连续过滤，过滤后的滤液达到清澈、透明，无浑浊、杂质，整个过程约需时间2小时；
(4)分离：将步骤(3)得到的滤液通过物理方法使CS与小分子如氨基酸 类蛋白等物质分离，得到透过液和浓缩液，整个过程约用2～3小时，其中，透过液是含有氨基酸类小分子蛋白的液体，浓缩液是含有CS的液体；将步骤(3)得到的骨渣经干燥得到动物骨粉，用于饲料，实现了废物利用，无需排放或者单独处理，污染低，绿色环保；所述物理分离方法优选为分子筛；分离的分了量≥3000的大分子为浓缩夜，分子量＜3000的小分子为透过液；
(5)后处理：将步骤(4)得到的透过液进行脱水浓缩和干燥，得到动物蛋白粉；将步骤(4)得到的浓缩液进行脱水，得到本发明硫酸软骨素产品，整个过程约用3小时。
最后，产品经包装成型，装桶，封上口，贴上唛头。
实施例2
一种用于上述实施例1硫酸软骨素制备工艺的设备，包括反应釜，所述反应釜优选为特氟龙反应釜，所述反应釜依次管道连接有真空循环过滤器、滤液储液罐和分子筛，所述分子筛分别管道连接有蛋白液储罐和CS液储罐。原料首先在反应釜内煮料、降温、碱解、酶解和降解，完成上述工艺的步骤(1)和步骤(2)，然后通过真空循环过滤器进行过滤完成上述工艺的步骤(3)后，滤液泵入到滤液储液罐中，再由滤液储液罐将物料泵入分子筛中，进行物料分离完成上述工艺的步骤(4)，再将分离得到的产物分别泵入蛋白液储罐和CS液储罐中，进行后续处理，完成上述工艺的步骤(5)；所述的真空循环过滤器与滤液储液罐之间、滤液储液罐与分子筛之间均设有泵，所述的分子筛与蛋白液储罐和CS液储罐之间设有循环泵，所述循环泵的出口还与所述分子筛的入口相连，从而能够进行多次分离，提高了分离效果；所述的反应釜与真空循环过滤器之间设有高度差，通过高度差使物料自然流动，降低了生产成本；所述的蛋白液储罐依次与脱水装置和干燥装置相连，得到动物蛋白粉；所述的CS液储罐与脱 水装置，得到本发明硫酸软骨素产品。
以牛骨为原料生产CS产品实例
1、取冷冻储存的鲜牛鼻骨骨粉600公斤，逐块投入1000立升反应釜内，加水300公斤，加热到110℃，恒温蒸煮90分钟，然后降温处理；
2、温度降至35℃以下，先进行碱解反应3小时，再加入A酶(外切酶)酶解反应2小时，再加入B酶(内切酶)降解反应2小时，在管道反应器内进行；
3、降解反应结束后，升温至85℃，静置30分钟，然后降温，此过程在反应釜内进行；
4、温度降至70℃以下时，将降温后的混合液通过泵循环，进入真空过滤系统，进行真空过滤得到滤液和骨渣；
5、滤液进入分离工序，骨渣烘干或晒干即成动物骨粉，可做饲料用；
6、滤液进入分离工序后，通过分子筛，将大分子(分子量≥3000)的CS与小分子(＜3000)的氨基酸类蛋白质分开，得到CS浓缩液和透过液；
7、分开后的CS浓缩液再经过反复浓缩，直至底物质量浓度≥30％时进行干燥处理，即可得到CS产品45公斤，收率为7.5％；
8、分开后的透过液浓缩和干燥，得到动物蛋白粉90公斤，其收率为15％。
另外，还可以采用上述工艺，用猪、羊、鸡、鸭等动物的软骨作原料生产CS产品，方法相同。
采用发明方面(无溶剂法)所得产品质量与采用溶剂法所得产品质量进行对比，对照表如下所示：
(产品质量指标依美国USP35版标准要求为依据)
物料来源：牛鼻软骨(冷冻品)数量：100kg
Figure PCTCN2015000078-appb-000001
本发明中所用原料均为本领域生产中常用原料，均可从市场中得到，且对于生产结果不会产生影响；本发明中所采用的各种设备，均为本领域生产工艺中使用的常规设备，且各设备的操作、参数等均按照常规操作进行，并无特别之处。

Claims (10)

  1. 硫酸软骨素制备工艺，其特征在于，包括液化、提取酶解降解、过滤、分离和后处理步骤；
    具体操作步骤如下：
    (1)液化：将原料经压力蒸煮后液化，变成液体状态；
    (2)提取酶解降解：将步骤(1)液化后的软骨液体降温后，加入碱进行碱解，再加酶解酶与降解酶，进行酶解和降解，直至到解离分层；
    (3)过滤：将步骤(2)的混合液通过过滤装置连续过滤，得到滤液和骨渣，使滤液的澄清度在0.001～0.10范围内；
    (4)分离：将步骤(3)得到的滤液通过物理方法使CS与小分子蛋白物质分离，得到透过液和浓缩液，其中，透过液是含有氨基酸类小分子蛋白的液体，浓缩液是含有CS的液体；将步骤(3)得到的骨渣经干燥得到动物骨粉；
    (5)后处理：将步骤(4)得到的透过液进行浓缩和干燥，得到动物蛋白粉；将步骤(4)得到的浓缩液进行脱水，得到本发明硫酸软骨素产品。
  2. 根据权利要求1所述的硫酸软骨素制备工艺，其特征在于：所述步骤(1)的原料为冷冻软骨粉或软骨泥。
  3. 根据权利要求2所述的硫酸软骨素制备工艺，其特征在于：所述冷冻软骨粉为将冷冻软骨粉进行粉碎或绞碎，呈块状冷冻储存。
  4. 根据权利要求1所述的硫酸软骨素制备工艺，其特征在于：所述步骤(1)的蒸煮温度为100～120℃。
  5. 根据权利要求1所述的硫酸软骨素制备工艺，其特征在于，所述步骤(2)的具体操作为：将步骤(1)液化后的软骨液体降温到25～35℃后，加入液体体积总量的0.8～1.2％的NaOH进行碱解提取后，再分别加3～9‰的酶解酶与等量 的降解酶，进行酶解和降解，直至到解离分层，即产生CS与蛋白类物质自然分离现象，得到混合液。
  6. 根据权利要求1所述的硫酸软骨素制备工艺，其特征在于：所述步骤(4)的物理分离方法为分子筛；分离的分子量在3000以上的大分子为浓缩夜，分子量在3000以下的小分子为透过液。
  7. 一种用于如权利要求1-6任意一项所述的硫酸软骨素制备工艺的设备，其特征在于：包括反应釜，所述反应釜优选为特氟龙反应釜，所述反应釜依次管道连接有真空循环过滤器、滤液储液罐和分子筛，所述分子筛分别管道连接有蛋白液储罐和CS液储罐。
  8. 根据权利要求7所述的设备，其特征在于：所述的真空循环过滤器与滤液储液罐之间、滤液储液罐与分子筛之间均设有泵，所述的分子筛与蛋白液储罐和CS液储罐之间设有循环泵，所述循环泵的出口还与所述分子筛的入口相连。
  9. 根据权利要求7所述的设备，其特征在于：所述的反应釜与真空循环过滤器之间设有高度差。
  10. 根据权利要求7所述的设备，其特征在于：所述的蛋白液储罐与脱水装置，或脱水装置和干燥装置相连；所述的CS液储罐与脱水装置，或脱水装置和干燥装置相连。
PCT/CN2015/000078 2014-08-12 2015-02-04 硫酸软骨素制备工艺及其设备 WO2016090704A1 (zh)

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