CN1876687A - Heparin sodium production process - Google Patents

Heparin sodium production process Download PDF

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Publication number
CN1876687A
CN1876687A CN 200610031887 CN200610031887A CN1876687A CN 1876687 A CN1876687 A CN 1876687A CN 200610031887 CN200610031887 CN 200610031887 CN 200610031887 A CN200610031887 A CN 200610031887A CN 1876687 A CN1876687 A CN 1876687A
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hours
resin
minutes
heparin sodium
throw out
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CN 200610031887
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胡世辉
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Abstract

The invention relates the technology of heparin sodium. The invention overcomes the defects of many procedures, big heparin sodium biological activity damage, little productivity and high residual quantity. The invention comprises the following steps: clearing raw material, extracting, flocculating and setting, ion exchanging, washing, carrying out elution, settling, dewatering and drying. The invention has the advantages of rational technology, improving quality, little active damage, little residual quantity, high purify, low cost, and good economic benefit.

Description

Heparin sodium production process
Technical field
The present invention relates to the extracting method that a kind of medical heparin is received, particularly a kind of heparin sodium production process.
Background technology
Heparin sodium belongs to macromolecular compound, and it is the salt of receiving of the different acidic mucopolysaccharide phase blended sulfuric acid glycosaminoglycan of 6000 to 8000 molecular weight, white powder, and water soluble is not soluble in ethanol and acetone and other organic solvent.Heparin sodium is not only mucopolysaccharide sulfuric acid ester anticoagulant in medicine, have reducing blood lipid simultaneously.Because heparin sodium is by the crude substance that extracts in the organism, it or not the product of chemosynthesis, have no side effect, in clinical use, be subjected to doctor and patient's favor, be widely used in the various cerebrovascular diseases of control, stop thrombogen to be transformed into fibrin monomer, prevent from hematoblasticly to gather and destroy, treat sudden thrombotic disease, arteriosclerosis and reducing cholesterol, prevent that the metastasis of cancer cells from all having definite curative effect.Heparin sodium is constantly popularized and expansion medical clinical application, and market demand is also in continuous increase.Along with the market requirement constantly increases, traditional in the past extraction production technology method, inapplicable growing output and quality.
At present, it is several that domestic method from chitterlings extraction heparin sodium mainly contains salt solution, alkaline hydrolysis method and enzymolysis process etc., wherein uses the most general with the salt solution.Heparin in the pig intestinal mucosa normally with other mucopolysaccharides and protein bound together, with the salt solution make heparin under alkaline condition with receive ionic reaction and generate heparin sodium, thereby with separate in the proteinic mixture, the heparin negative ion is adsorbed from dissociation solution with strongly basic anion exchange resin, the heparin negative ion that will be adsorbed on the resin with salt solution elutes again, drying obtains finished product.Though this technology simple and stable, the crude heparin sodium yield that obtains is lower, and is very big to the biological activity influence of heparin sodium, the heparin sodium activity of loss 5-7%, and proteinic residual quantity is higher, tires to be difficult to reach more than the 90USPu/mg difficult quality control and latent fixed.Therefore, the protein separation process method that innovative development is new effectively improves and the output and the quality of stable heparin sodium product, reduce the loss of activity of heparin sodium finished product, reduce raw-material consumption, reduce production and operation cost, become the technical barrier that crude heparin sodium is produced.
Summary of the invention
It is reasonable to the purpose of this invention is to provide a kind of design technology, and cost of manufacture is low, heparin sodium crude yield height, and the heparin sodium loss of activity is little, steady quality, the heparin sodium production process of minimizing refining step.
The technical solution adopted for the present invention to solve the technical problems is:
1) with fresh intestinal mucosa removal of contamination, enter the freezer storage, allow it thaw naturally again, soaked 6 hours in well water or distilled water, clear Xian is clean, advances archenteron-scrapping machine to system, operation firmly evenly, casing, intestines skin and intestinal mucosa are separately deposited, and intestinal mucosa is discharged into to be deposited in the pond, quantitatively is discharged in the reactor;
2) intestinal mucosa is put into reactor, puts into sodium-chlor and alkali lye then in reactor, and sodium-chlor is controlled at 5% degree, basicity stirred 10 minutes at PH=9, opened the steam valve ventilation, the steam off valve was warming up to 50 ℃ at 30 minutes for the first time again, was incubated 1 hour, for the second time be warming up to 60 ℃, be incubated 3 hours, be warming up to 90 ℃ at 40 minutes for the third time, constant temperature discharging after 10 minutes, drag for dereaction pot top waste liquid, with 90-120 order nylon net cloth extracted twice filter residue, extracted twice filtrate merges stand-by;
3) filtrate cooling back adds the sedimentation pot, and the proportioning by 0.2% adds flocculating setting agent, stirs 30 minutes standing sedimentations, 6 hours time, clarification again, elimination sediment;
4) clear filtrate is put into adsorption tank, add 2-3Kg ROHM AND HAAS resin, salinity is controlled at below 15 °, and whip attachment 12 hours is filtered and extracted resin, discards filtrate, and the resin of collection is washed till basicity PH=7 in water;
5) resin after the cleaning is put into cleaning pot, the 5% proportioning weak brine agitator treating that the usefulness weight resin is 1.2 times 2 times, and each 1 hour, flush away resin surface impurity and Low molecular heparin after the filtration, discarded washings;
6) with the resin of washing, use the 17-18% strong brine of 1.2 times of weight resins to stir wash-out 2 times, inferior 4 hours of head, secondary 2 hours regathers twice elutriant, and hybrid filtering is removed particulate contamination;
7) filtering elutriant is put into clarifying kettle, adds 50 ° of alcohol of effluent volume 95%, stirs 5 minutes, seals, and staticly settles 24 hours, and elimination top alcohol is collected the throw out of bottom;
8) throw out is poured in the container, the alcohol that adds throw out volume 95%, staticly settled 24 hours, elimination top alcohol, extraction vessel inner bottom part throw out is put to B and is vacuumized, and adds acetone and stir into pasty state to B, dehydration, triplicate places the thermostatic drying chamber inner drying to constant weight the throw out after the dehydration, gets product.
The invention has the beneficial effects as follows: 1, design technology is reasonable, in the dissociation solution that generates heparin sodium, add flocculating settling agent, make plurality of impurities such as protein and other mucopolysaccharides, heparitin in conjunction with producing precipitation, simultaneously by its superior flocculation function, with water-fast micro-solid residue cohesion larger particles and the sedimentation together of other throw outs in the dissociation solution, make the solid-liquid separation of dissociation solution more complete, obtain the higher heparin sodium finished product of purity.
The present invention and the traditional technology method comparison sheet of tiring
Leading indicator (u/mg) tires Weight loss on drying (%) Absorbancy Protein
260nm 280nm
Traditional technology 80-110 <10 1.5 0.8 Do not have (trace)
The present invention 100-120 8.4 1.4 0.75 Trace
2, absorption rate of recovery height, starting time is fast.The macropore strong base vinylbenzene resin anion(R.A) that adopts U.S. Rhom and Hass to produce, exchange capacity is better than D 254With 1299 * 9 wait other resins, physical strength is good, is difficult for stopping up the duct, starting time is short, resin is difficult for being polluted by dissociation solution, effectively prolongs regeneration of resin cycle and time limit of service.
The present invention and traditional technology method yield comparison sheet
Leading indicator (u/mg) tires Yield (the secondary small intestine of u/) Anionite-exchange resin
Consumption Regeneration period Time limit
Traditional technology 80-110 56926.9 150kg 5-7 days 2 years
The present invention 100-120 61111.1 72kg 3 months 6 years
3, optimize and revise the corresponding process operation parameter of production process, the cancellation refining step is simplified technical process, reduces and produces consumable material, reduces production and operation cost, has improved quality product.
The present invention and traditional technology method consumptive material comparison sheet
Consume Small intestine (pair) Salt (Kg) Alkali (Kg) Ethanol (Kg) Hydrochloric acid (Kg) Resin (Kg)
Traditional technology 2000 270 100 231 50 150
The present invention 1800 150 42 200 0 72
Specific embodiment
The fresh pig small intestine is cleaned, and removal of contamination enters the freezer storage.When arriving some amount, take out chitterlings and be soaked in water 6 hours, allow it thaw naturally, clean up Deng chitterlings.Again chitterlings are delivered to multifunctional stainless steel and carry out striking, firmly want evenly during the postcibal diarrhea operation, scrape the casing, intestines skin and the intestinal mucosa that make and answer pile up separately, in time cleaning to the intestines machine.Intestinal mucosa should be unified to be discharged into and deposits the pond, guarantees the freshness of intestinal mucosa.Add sodium-chlor and alkali lye then in reactor, salinity is controlled at about 5%, and basicity is controlled at PH=9, pours intestinal mucosa into, stirs 10 minutes, keeps pH value constant.If intestinal mucosa for pickling, also answers water to be diluted to the 0.8-1N that specific gravity hydrometer or baum measurement reach standard, redilution 4-5 doubly, basicity is controlled at PH=9.Open the steam valve ventilation of reactor, aperture can not be too big, in order to avoid it is too fast to heat up.Be warming up to about 50 ℃ at 30 minutes for the first time, be incubated 1 hour, be warming up to 60 ℃ for the second time, be incubated 3 hours, in 40 minutes, be warming up to 90 ℃ rapidly for the third time, constant temperature discharging in 10 minutes, drag for oil and impurity that the dereaction pot floats over top, filter with 90-120 order nylon net cloth.Filter residue is carried out extracted twice, and twice filtrate merges stand-by.Cooled filtrate is poured the sedimentation pot into, and the proportioning adding SH-I mixed flocculation precipitation agent by every pot of volume about 0.2% stirs standing sedimentation after 30 minutes, and the time can not be less than 6 hours, after the clarification, and the elimination throw out.Filtrate after the clarification is put into adsorption tank, add handled well 2-3Kg ROHM AND HAAS resin, whip attachment 12 hours.Stirring will notice that evenly the time is abundant, can not use inferior materials and turn out substandard goods.Salinity is controlled at below 15 degree during desorption.After absorption is finished, filter and extract resin, discard filtrate, the resin of collecting is washed till basicity PH=7 in water.Resin after the cleaning is put into cleaning pot, and 5% proportioning of pressing 1.2 times of weight resins adds the weak brine agitator treating 2 times, and each 1 hour, the impurity molecule of flush away resin surface and Low molecular heparin discarded washings after the filtration.Resin after the washing, 18% proportioning of pressing 1.2 times of weight resins adds strong brine and stirs wash-out 2 times, head times 4 hours, secondary 2 hours, purpose is that the heparin wash-out with the resin internal adsorption comes out, and collects twice elutriant mixing after-filtration, removes particulate contamination.Put into clarifying kettle after elutriant filters, press elutriant volume 95% and add 50 ℃ of alcohol, stirred 5 minutes, seal, staticly settle 24 hours after, elimination top alcohol, the throw out bottom the collection.Again throw out is poured in the container, press throw out volume 95% and add alcohol, staticly settled 24 hours, elimination top alcohol, the extraction throw out is put to B and is vacuumized, after waiting to drain moisture, add acetone and to funnel, stir into pasty state, dewater, triplicate utilizes acetone that the moisture in the throw out is sloughed, collecting dehydration postprecipitation thing places thermostatic drying chamber to be dried to constant weight, if there is not thermostatic drying chamber, also can carry out drying with siccative, dried throw out promptly is a heparin sodium crude.

Claims (2)

1, a kind of heparin sodium production process is characterized in that:
1) with fresh intestinal mucosa removal of contamination, enter the freezer storage, allow it thaw naturally again, soaked 6 hours in well water or distilled water, clear Xian is clean, advances the archenteron-scrapping machine striking, operation firmly evenly, casing, intestines skin and intestinal mucosa are separately deposited, and intestinal mucosa is discharged into to be deposited in the pond, quantitatively is discharged in the reactor;
2) intestinal mucosa is put into reactor, puts into sodium-chlor and alkali lye then in reactor, and sodium-chlor is controlled at 5% degree, basicity stirred 10 minutes at PH=9, opened the steam valve ventilation, the steam off valve was warming up to 50 ℃ at 30 minutes for the first time again, was incubated 1 hour, for the second time be warming up to 60 ℃, be incubated 3 hours, be warming up to 90 ℃ at 40 minutes for the third time, constant temperature discharging after 10 minutes, drag for dereaction pot top waste liquid, with 90-120 order nylon net cloth extracted twice filter residue, extracted twice filtrate merges stand-by;
3) filtrate cooling back adds the sedimentation pot, and the proportioning by 0.2% adds flocculating setting agent, stirs 30 minutes standing sedimentations, 6 hours time, clarification again, elimination sediment;
4) clear filtrate is put into adsorption tank, add 2-3Kg ROHM AND HAAS resin, salinity is controlled at below 15 °, and whip attachment 12 hours is filtered and extracted resin, discards filtrate, and the resin of collection is washed till basicity PH=7 in water;
5) resin after the cleaning is put into cleaning pot, the 5% proportioning weak brine agitator treating that the usefulness weight resin is 1.2 times 2 times, and each 1 hour, flush away resin surface impurity and Low molecular heparin after the filtration, discarded washings;
6) with the resin of washing, use the 17-18% strong brine of 1.2 times of weight resins to stir wash-out 2 times, inferior 4 hours of head, secondary 2 hours regathers twice elutriant, and hybrid filtering is removed particulate contamination;
7) filtering elutriant is put into clarifying kettle, adds 50 ° of alcohol of effluent volume 95%, stirs 5 minutes, seals, and staticly settles 24 hours, and elimination top alcohol is collected the throw out of bottom;
8) throw out is poured in the container, the alcohol that adds throw out volume 95%, staticly settled 24 hours, elimination top alcohol, extraction vessel inner bottom part throw out is put to B and is vacuumized, and adds acetone and stir into pasty state to B, dehydration, triplicate places the thermostatic drying chamber inner drying to constant weight the throw out after the dehydration, gets product.
2, heparin sodium production process according to claim 1 is characterized in that: this producing and manufacturing technique can processing in the equipment of any adaptation.
CN 200610031887 2006-06-27 2006-06-27 Heparin sodium production process Pending CN1876687A (en)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101649336B (en) * 2008-08-25 2012-05-02 四川天成生化科技有限公司 Novel process for producing sodium heparin
CN101735340B (en) * 2010-01-18 2012-08-22 叶青理 Method for preparing heparin sodium by combining enzymolysis and salt decomposition
CN101544999B (en) * 2009-04-10 2012-09-05 湖北五瑞生物工程有限公司 Method for producing and purifying high purity and low molecular weight sodium heparin
CN102746421A (en) * 2012-05-23 2012-10-24 杭州龙扬生物科技有限公司 Impurity removing technology of crude heparin sodium
CN104844731A (en) * 2015-05-07 2015-08-19 内蒙古泰亨肠衣制品有限公司 Heparin sodium crude product extraction method
CN106519077A (en) * 2016-11-17 2017-03-22 江苏联众肠衣有限公司 Preparation process of high-potency heparin sodium
CN108299573A (en) * 2018-01-15 2018-07-20 中盐金坛盐化有限责任公司 The method of comprehensive utilization of casing factory waste water
CN108576364A (en) * 2018-03-16 2018-09-28 潢川县鹏升畜产品有限公司 A kind of technique of extraction intestine membrane protein
CN110218269A (en) * 2019-06-25 2019-09-10 广元市海鹏生物科技有限公司 A kind of heparin process for producing sodium of short-term crude product
CN110305236A (en) * 2019-05-16 2019-10-08 东莞市德鸿肠衣有限公司 A kind of heparin production method of high yield
CN110437349A (en) * 2018-05-02 2019-11-12 山阳县恒瑞肉制品有限公司 A kind of novel postcibal diarrhea of heparin sodium, enzymatic hydrolysis, elution process

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101649336B (en) * 2008-08-25 2012-05-02 四川天成生化科技有限公司 Novel process for producing sodium heparin
CN101544999B (en) * 2009-04-10 2012-09-05 湖北五瑞生物工程有限公司 Method for producing and purifying high purity and low molecular weight sodium heparin
CN101735340B (en) * 2010-01-18 2012-08-22 叶青理 Method for preparing heparin sodium by combining enzymolysis and salt decomposition
CN102746421A (en) * 2012-05-23 2012-10-24 杭州龙扬生物科技有限公司 Impurity removing technology of crude heparin sodium
CN102746421B (en) * 2012-05-23 2014-03-12 杭州龙扬生物科技有限公司 Impurity removing technology of crude heparin sodium
CN104844731A (en) * 2015-05-07 2015-08-19 内蒙古泰亨肠衣制品有限公司 Heparin sodium crude product extraction method
CN106519077A (en) * 2016-11-17 2017-03-22 江苏联众肠衣有限公司 Preparation process of high-potency heparin sodium
CN108299573A (en) * 2018-01-15 2018-07-20 中盐金坛盐化有限责任公司 The method of comprehensive utilization of casing factory waste water
CN108576364A (en) * 2018-03-16 2018-09-28 潢川县鹏升畜产品有限公司 A kind of technique of extraction intestine membrane protein
CN110437349A (en) * 2018-05-02 2019-11-12 山阳县恒瑞肉制品有限公司 A kind of novel postcibal diarrhea of heparin sodium, enzymatic hydrolysis, elution process
CN110305236A (en) * 2019-05-16 2019-10-08 东莞市德鸿肠衣有限公司 A kind of heparin production method of high yield
CN110218269A (en) * 2019-06-25 2019-09-10 广元市海鹏生物科技有限公司 A kind of heparin process for producing sodium of short-term crude product

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