CN103183746B - Process for extracting heparin sodium comprehensively by small intestines of pigs - Google Patents
Process for extracting heparin sodium comprehensively by small intestines of pigs Download PDFInfo
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- CN103183746B CN103183746B CN201210347347.4A CN201210347347A CN103183746B CN 103183746 B CN103183746 B CN 103183746B CN 201210347347 A CN201210347347 A CN 201210347347A CN 103183746 B CN103183746 B CN 103183746B
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Abstract
The invention relates to the technical field of heparin sodium production, and provides a process for extracting heparin sodium comprehensively by small intestines of pigs. The process comprises the main steps as follows: pre-processing, casing bundle soaking, enzymolysis, adsorption, washing, elution, precipitation and drying. According to the process for extracting heparin sodium comprehensively by the small intestines of pigs, casings and precipitate intestinal mucosa are combined to prepare heparin sodium, so that the utilization rate of the small intestines of pigs is improved, the additional value of the small intestines of pigs is increased, only about 1400 small intestines of pigs are required for producing one hundred million international units of heparin sodium crude products, the product purity is high, and the titer of heparin sodium is larger than 110 U/mg. Meanwhile, residual intestine skins can be utilized effectively.
Description
Technical field
The present invention relates to technical field of heparin sodium production, particularly a kind of chitterlings comprehensively extract the technique of heparin sodium.
Background technology
Heparin sodium, also known as heparin, is a kind of natural anticoagulative substance of acid mucopolysaccharides containing sulfate.Heparin sodium is white or off-white powder, and odorless, tasteless has and draws moist, soluble in water, is insoluble to the organic solvents such as ethanol, acetone, dioxane.
Heparin sodium is extensively present in Mammals liver, lung, intestinal mucosa, how to become complex body to exist with protein bound.The separable heparin sodium of enzymolysis protein, heparin sodium is the mucopolysaccharide of sulfur acid, amino, glyconic acid.When pH8-9, electronegative, ion-exchange can be carried out with anionite, carry out roughing out, polysaccharide liquid precipitate in high concentration ethanol carry out consummate.Heparin sodium is antithrombotics best during blood chemistry measures.Heparin sodium is a kind of mucopolysaccharide of sulfur acid group, molecular weight is 1.5 ten thousand, and its anticoagulant mechanism is together with anti-freezing enzyme II, in lower concentration energy supressor Ⅸ a, effect between VIII and PF3, and antithrombin Ⅲ deactivation serine protease can be strengthened, thus zymoplasm is stoped to be formed; Also have the self-catalysis of Trombin inhibiting and the effect of supressor X.
The enzymolysis production method of traditional heparin sodium often with the intestinal mucosa of chitterlings for raw material extracts, casing is often abandoned and is done its use, the defect existed is: chitterlings cannot effectively utilize, and the production cycle is long, and energy consumption is large, yield is low, produce the mucous membrane that 100,000,000 international unit heparin sodium crudes need 2800-3000 root chitterlings, product purity is low, and tiring of heparin sodium is at most 80U/mg, and produce a large amount of intestines slags and waste water, contaminate environment.A kind of method utilizing bio-fermentation process to produce heparin sodium of the disclosure of the invention of CN1308088A.The method adopts 2709 proteolytic enzyme as catalyzer, and D204 strongly basic anion exchange resin as ion exchange resin, and adopts 150-180 order multilayer cloth screen to filter.There is following defect in the method: product yield, purity are also lower, and produce a large amount of intestines slags and waste water, contaminate environment; Chitterlings after getting intestinal mucosa remaining casing, intestines skin cannot effectively utilize to obtain heparin sodium, the utilising efficiency of chitterlings is low.
Summary of the invention
The object of the invention is to the above-mentioned defect overcoming prior art existence, a kind of chitterlings are provided comprehensively to extract the technique of heparin sodium, can fully utilize chitterlings, improve the utilization ratio of chitterlings, with short production cycle, product yield, purity are higher, decrease the discharge of intestines slag and waste water, are beneficial to environmental protection.
The technical solution adopted for the present invention to solve the technical problems is:
Chitterlings comprehensively extract a technique for heparin sodium, and described processing step is as follows:
(1)
pre-treatment:chitterlings are put into archenteron-scrapping machine, obtains pig intestinal mucosa slurries stand-by, residue casing, intestines skin, intestines skin is separately for extracting heparin sodium.
The technique that intestines skin extracts heparin sodium adopts method disclosed in the notification number CN101891842A patent of invention of contriver's earlier application to carry out.
(2)
casing bubble handle:by casing around a formation casing handle, then casing is soaked 4-5 hour putting into soak solution first time, taking-up drains, use casing special-purpose salt to casing pickling process, afterwards, casing is soaked 6-8 hour putting into soak solution secondary, and the soak solution that first time soaks is saturated nacl aqueous solution, and the soak solution that secondary soaks is the sodium chloride solution of salinity 15 °-18 °; When immersion for the first time and secondary soak, every 1000L soak solution all soaks 160 ± 5 casing handle, and the leach liquor collecting first time immersion is stand-by, the soak solution that the leach liquor after collection secondary soaks soaks first time as casing when extracting next time.The soak solution that first time soaks is identical with the volume of the soak solution that secondary soaks.
Chitterlings are after archenteron-scrapping machine process, the casing obtained still can remain small portion intestinal mucosa (heparin sodium cannot be extracted and cause waste), and also containing part heparin sodium in casing, in the past direct by the raw material use of casing just when making sausage after simply pickling, so often cause casing effectively to utilize, reduce the yield that chitterlings obtain heparin sodium.
The present invention was soaked by first time, the heparin sodium that major part exists in casing can be extracted (comprising in intestinal mucosa), the leach liquor that first time soaks is for regulating the raw material of pig intestinal mucosa slurries salinity during next step enzymolysis, without the need to additional sodium chloride solution, save the consumption of sodium chloride solution, also containing part heparin sodium in the leach liquor that first time soaks, the heparin sodium that can obtain with enzymolysis converges, without the need to respective purification operations.Such saving step, if the leach liquor that first time soaks has unnecessary can temporarily storage for extracting next time.
First time soak after to casing pickling process, the rear casing of processing can meet the demand cooking sausage like this.Again secondary immersion is carried out to casing, heparin sodium stripping remaining in casing, the yield of heparin sodium can be increased.Pickle the casing after process containing a large amount of salinities, therefore only need control the soak solution that secondary soaks is salinity 15 °-18 °, adds the casing after pickling process soaking, and the soak solution that secondary soaks can reach capacity the degree of salt solution, such salt can repeatedly utilize, and has saved the consumption of salt.
The soak solution that leach liquor (saturated brine namely containing small portion heparin sodium) after secondary soaks soaks first time as casing when extracting next time, by such operation, the raw material that secondary soaks and soak solution can also utilize again, without the need to newly joining the soak solution that saturated nacl aqueous solution soaked as first time, greatly save the consumption of salt.After secondary soaks, remaining casing can be sold as the raw material of processing sausage.
(3)
enzymolysis:pig intestinal mucosa slurries are added enzymatic vessel, pig intestinal mucosa slurries are pig intestinal mucosa: the mixture of the weight ratio of water=1:2.5-4, the leach liquor adding the first time immersion that step (2) is collected in enzymatic vessel regulates salinity to 5 ± 0.5 ° of feed liquid in enzymatic vessel, controls the pH of feed liquid 8.5 ± 0.5; Then the enzyme amount adding 1.2 ± 0.4kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, and control feed temperature at 53 ± 3 DEG C, salinity 4.2 ± 0.2 °, pH 7.0 ± 0.5 keeps 3 ± 0.5 hours; Finally be warming up to 85-88 DEG C, keep 20-25min to obtain enzymolysis solution, cross elimination residue.
When the last enzymolysis solution of this step crosses elimination residue, often adopt Bag filter to remove residue, such efficiency is often lower, contriver, by practical exploration, has invented and has adopted vibratory screening apparatus to cross the mode of elimination residue, substantially increased filtration velocity, improve production efficiency, is the good method replacing Bag filter.
(4)
absorption:enzymolysis solution is inputted adsorption tanks, is cooled to 57 ± 3 DEG C, add water and regulate salinity to 3.0 ± 0.5 °, control pH 7.0-7.5, adds the amount of resin of 3-8kg by every 1000L enzymolysis solution, add ROHM AND HAAS FPA98CL type resin in adsorption tanks, after whip attachment 6-8 hour, collect resin.
(5)
washing:the resin of collection is washed with water to pH for neutral, then resin is put into the sodium chloride solution of salinity 4 ± 1 °, temperature 55-60 DEG C, stir and wash at least 1 hour, wherein, resin: sodium chloride solution=1:1.3-1.7(w/v).Control sodium chloride solution temperature at 55-60 DEG C, be convenient to the dirt settling of resin surface lipid to clean up, be convenient to wash-out.
(6)
wash-out:resin after step (5) being washed is poured in wash-out tank and is carried out twice wash-out, wherein, first time, wash-out was: resin joined salinity is 21 ± 1 °, stir at least 3 hours, resin in the sodium chloride solution of temperature 55-60 DEG C: sodium chloride solution=1:1-1.4(w/v); Second time wash-out is: the resin after first time wash-out joined salinity is 21 ± 1 °, stir at least 3 hours, resin in the sodium chloride solution of temperature 55-60 DEG C: sodium chloride solution=1:0.8-1.2(w/v); Merge the elutriant of twice collection.
Sodium chloride solution temperature when controlling twice wash-out wash-out, at 55-60 DEG C, is convenient to sebaceous heparin sodium to elute from resin, increases yield.
(7)
precipitation:the elutriant that step (6) is collected is poured in setting tank, in setting tank, the alcohol of alcoholic strength 85 ± 5 ° is added under agitation condition, alcohol consumption is as the criterion to 45 °-60 ° with the alcoholic strength of surveying mixed solution in setting tank, staticly settles more than 15 hours, collecting precipitation thing.
(8)
dry:the alcohol that the throw out that step (7) obtains adds alcoholic strength more than 85 ° carries out dehydration 1-3 hour, does drying and processing and namely obtain heparin sodium product after being filtered dry.
W/v in the present invention is that mass volume ratio is specially: kg:L.
Casing is combined with intestinal mucosa and is produced heparin sodium by the present invention, improve the utilization ratio of chitterlings, add the added value of chitterlings, produce 100,000,000 international unit heparin sodium crudes and only need about 1400 chitterlings, product purity is high, the > 110U/mg that tires of heparin sodium.Meanwhile, remaining intestines skin also can be utilized effectively.
As preferably, in step (2), casing is around being specially: the length of casing by 1 ± 0.2 meter folded back and forth, tie up formation casing handle after fold in centre, every 100 ± 1 meters of casing synthesize one casing handle; Casing, in twice immersion process, all fills air with air pump and makes the upper and lower Rolling flow of soak solution in soak solution.
By casing around handle, the convenient process to casing, the casing of formation soaks in fermentation vat adopting the mode of hanging.In twice immersion process, all in soak solution, fill air with air pump and make the upper and lower Rolling flow of soak solution, heparin sodium residual in casing is fully washed out, adds the content of heparin sodium in soak solution, effectively improve the yield of heparin sodium.
As preferably, pickle process and be specially: the first step smears salt in step (2): by casing special-purpose salt uniform application on casing surface, the consumption of casing special-purpose salt is every 1 casing handle salt 1-1.2kg; The first step is smeared after salt completes and is pickled more than 48 hours, then carries out second step double salt: by casing special-purpose salt, uniform application is on casing surface again, and the consumption of casing special-purpose salt is every 1 casing handle salt 0.5-0.6kg; 12-14 hour is pickled after second step double salt completes.
The present invention is different from and traditional simply pickles process, and adopt two-step approach to pickle process, the first the first step smears salt, meets the requirement that casing cooks sausage; Second step double salt again, can ensure that the color and luster of casing is good, and toughness is better, improves the quality processed raw material as sausage, adds economic benefit.
As preferably, step (3) processes the enzymolysis solution that obtains under the rotating speed of 6000-8000 rev/min, after centrifugal treating 20-40min, then enters next step absorption.
Milkiness shape liquid is obtained after enzymolysis; whizzer is entered after elimination residue; start whizzer; enzymolysis solution is under centrifugal action, and after making milkiness shape enzymolysis solution enter centrifuge drum, solid particulate or the larger liquid (containing albumen) of density are to rotatory drum wall sedimentation; form sediment; the heparin sodium decomposed solution that density is less is assembled to rotary drum center position, flow to overflow port and discharges, become parting liquid.Sediment is squeezed out sediment by worm drive from slag-drip opening, parting liquid is discharged from discharge port by whizzer, is transported in adsorption tanks and carries out next step resin absorption operation.
In decomposition workshop section, directly remove partial impurities after increasing this step, make the resin energy fully adsorbing liquaemin in absorption process, improve resin absorption validity.In decomposition process, directly carry out the separation of impurity, improve the purity of the finished product.Control centrifugal speed and time, ensure the effect of centrifugation.
As preferably, after step (4) is collected resin, remaining feed liquid is delivered to adsorption tanks again, control temperature is at 57 ± 3 DEG C, pH 7.0-7.5, the amount of resin adding 2-3kg by every 1000L feed liquid adds after ROHM AND HAAS FPA98CL type resin adsorbs 6-8 hour again in adsorption tanks, collect resin, after the resin then collected with step (4) merges, enter next step washing step.
Feed liquid after resin absorption is re-started absorption by this step, can improve the yield of heparin sodium, cut the waste, and can reduce the content of albumen in waste liquid simultaneously, be beneficial to wastewater treatment.
As preferably, re-use after the resin activated process of described ROHM AND HAAS FPA98CL type, activation treatment is: resin 50-60 DEG C warm water soaking is rinsed well with clear water after more than 20 hours and drained, add again mass concentration be 10% sodium hydroxide solution stir more than 1 hour, it is neutral for finally rinsing to washing lotion pH with clear water, and the add-on of described sodium hydroxide solution is the gauge that every kilogram resin adds 1L sodium hydroxide solution; Resin after activation is under the rotating speed of 4000-5000 rev/min, and centrifugal treating 10-30min, is used further to absorption.
Resin to be used after activation treatment is entered whizzer by whizzer opening for feed.Start whizzer, resin is under the rotating speed effect of 4000-5000 rev/min, and after resin enters centrifuge drum, solid particulate resin, to rotatory drum wall sedimentation, sticks in bulging wall.The liquid that centrifugation throws away or the less material of density are assembled to rotary drum center position, flow to overflow port and discharge, become refuse.Collect the resin staying bulging wall, prepare to be used for absorption process.In this step resin hole, moisture is fully dried, and to increase the adsorption space of resin, improves the adsorptive power of resin.
As preferably, enter next step precipitation after the elutriant that step (6) is collected enters ultrafilter ultrafiltration again, the ultra-filtration membrane aperture of ultrafilter is at 0.45 μm-0.6 μm; Or the elutriant that step (6) is collected is under the rotating speed of 8000-10000 rev/min, after centrifugal treating 10-20min, then enter next step precipitation.
Through ultrafiltration, the waste water in elutriant and impurity can be got rid of, effectively improve the purity of product, and the alcohol usage quantity that next step wine sinks in technique can be reduced, cost-saving.
Elutriant is entered whizzer by whizzer opening for feed; start whizzer; elutriant decomposed solution centrifugal force (8000-10000 rev/min) effect under; after making milkiness shape elutriant enter centrifuge drum; solid particulate or the larger liquid (containing albumen) of density are to rotatory drum wall sedimentation, and form sediment, the heparin sodium elutriant that density is less is assembled to rotary drum center position; flow to overflow port to discharge, become parting liquid.Sediment is squeezed out sediment by worm drive from slag-drip opening, parting liquid is discharged from discharge port by whizzer, is transported in setting tank and carries out next step alcohol precipitation operation.This step increases the operation centrifugal to elutriant, thus directly removes partial impurities and albumen in elution procedure, thus the purity of raising the finished product, and can reduce the alcohol usage quantity that next step wine sinks in technique, cost-saving.
As preferably, after step (7) collecting precipitation thing, remaining supernatant liquor inputs in another sky setting tank, in another sky setting tank, add saturated nacl aqueous solution stir, and regulate pH to be 9-10, the volume ratio of supernatant liquor and saturated nacl aqueous solution is 1:0.5-0.7, after staticly settling 8-12 hour, collecting precipitation, enters next step drying step after the throw out then obtained with step (7) merges.
This step first time wine is sunk after supernatant liquor again carry out wine and sink, effectively can improve the yield of heparin sodium, cut the waste, be beneficial to wastewater treatment.
More preferred, carry out before the throw out after above-mentioned merging being entered next step drying
heavy molten redeposition:by throw out: the weight ratio mixing of water=1:8-10, fully dissolve and form throw out solution, in throw out solution, add casing special-purpose salt, stir, the consumption of casing special-purpose salt is the 1-3% of throw out solution quality; The alcohol adding alcoholic strength 85 ± 5 ° again precipitates again, and alcohol consumption is as the criterion to 45 °-60 ° with the alcoholic strength of surveying mixed solution in setting tank, staticly settles more than 15 hours, collecting precipitation thing, then enters next step drying.By adding heavy molten redeposition step, effectively can solve the alcohol of high density and elutriant and easily forming salt-pepper noise and be mixed in heparin sodium product the problem causing product purity lower.
As preferably, the temperature of step (8) drying and processing is 60-80 DEG C.
As preferably, collect step (3) enzymolysis solution and filter the residue obtained, the sodium chloride solution of salinity 5 ± 0.5 ° is added in enzymatic vessel, then residue is rejoined in enzymatic vessel, the weight ratio of the sodium chloride solution of residue and salinity 5 ± 0.5 ° is 1:5-6, controls the pH of feed liquid 8.5 ± 0.5, and the enzyme amount then adding 1.0-1.2kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, control feed temperature at 55 ± 1 DEG C, insulation 6-7 hour; Finally be warming up to 88-90 DEG C, keep 20-25min, then obtain enzymolysis solution after leaving standstill 20-30min, enzymolysis solution, under the rotating speed of 6000-8000 rev/min, after centrifugal treating 20-40min, enters next step absorption.
In existing technique, the remaining residue of enzymolysis and intestines slag are often given it up, so comparatively waste and add the burden of environment.And the present inventor is through practical exploration for many years, invent the processing step that effectively recycles residue, by the enzymolysis processing again to residue, can further residue decomposition, extract heparin sodium, add the yield of heparin sodium, decrease waste discharge, be beneficial to environmental protection.
The invention has the beneficial effects as follows:
1, casing is combined with intestinal mucosa and is produced heparin sodium by the present invention, improve the utilization ratio of chitterlings, add the added value of chitterlings, produce 100,000,000 international unit heparin sodium crudes and only need 1300-1400 root left and right chitterlings, product purity is high, the > 110U/mg that tires of heparin sodium.Meanwhile, remaining intestines skin also can be utilized effectively.
2, the enzymolysis and extraction again of residue, can further residue decomposition, extracts heparin sodium, adds the yield of heparin sodium, decrease waste discharge, be beneficial to environmental protection.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail.
In the present invention, if not refer in particular to, the raw material adopted and equipment etc. all can be buied from market or this area is conventional.Method in following embodiment, if no special instructions, is the ordinary method of this area.
Resin activated process:
By new ROHM AND HAAS FPA98CL type resin (commercially available import resin, dealer Beijing Bosaisi Biotech. Co., Ltd.) to rinse well with clear water after 20 hours with 50 DEG C of warm water soaking and to drain, add again mass concentration be 10% sodium hydroxide solution stir more than 1 hour, it is neutral for finally rinsing to washing lotion pH with clear water, and the add-on of described sodium hydroxide solution is the gauge that every kilogram resin adds 1L sodium hydroxide solution.Research shows, the warm water temperature adopted in resin activated process is between 50-60 DEG C, and soak time, between 16-24 hour, is equivalent to the activation treatment effect of resin, does not do repeating one by one at this.Resin after activation is under the rotating speed of 4000-5000 rev/min, and centrifugal treating 10-30min, is used further to absorption.
Embodiment 1:
(1)
pre-treatment:chitterlings are put into archenteron-scrapping machine (China fortune board 280B type archenteron-scrapping machine), obtain pig intestinal mucosa slurries (pig intestinal mucosa: the mixture of the weight ratio of water=1:2.5) stand-by, residue casing, intestines skin, intestines skin is separately for extracting heparin sodium.
(2)
casing bubble handle:the length of casing by 1 ± 0.2 meter is folded back and forth, tie up in centre after having folded and form casing handle, every 100 ± 1 meters of casing synthesis one is casing handle, then casing is soaked 4 hours putting into saturated nacl aqueous solution first time, taking-up drains, use casing special-purpose salt to casing pickling process: the first step smears salt: by casing special-purpose salt uniform application on casing surface, the consumption of casing special-purpose salt is every 1 casing handle salt 1kg; The first step is smeared after salt completes and is pickled 48 hours, then carries out second step double salt: by casing special-purpose salt, uniform application is on casing surface again, and the consumption of casing special-purpose salt is every 1 casing handle salt 0.6kg; 12 hours are pickled after second step double salt completes; Afterwards, casing is soaked 6 hours the sodium chloride solution secondary putting into salinity 15 °-18 °, when first time immersion and secondary soak, every 1000L soak solution all soaks 160 ± 5 casing handle, the soak solution that first time soaks is equal with the soak solution volume that secondary soaks, the leach liquor collecting first time immersion is stand-by, collects the soak solution that the leach liquor after secondary immersion soaks first time as casing when extracting next time.After secondary soaks, remaining casing can be sold as the raw material of processing sausage.Casing, in twice immersion process, all fills air with air pump and makes the upper and lower Rolling flow of soak solution in soak solution.
(3)
enzymolysis:2000L pig intestinal mucosa slurries are added enzymatic vessel, and the leach liquor adding the first time immersion that step (2) is collected in enzymatic vessel regulates salinity to 5 ± 0.5 ° of feed liquid in enzymatic vessel, controls the pH of feed liquid about 8; Then the enzyme amount adding 0.8kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, and control feed temperature at 56 DEG C, salinity 4.2 ± 0.2 °, pH 6.5 keeps 2.5 hours; Finally be warming up to 85 DEG C, keep 25min to obtain enzymolysis solution, cross elimination residue; Then enzymolysis solution is under the rotating speed of 6000 revs/min, after centrifugal treating 40min, then enters next step absorption.
Collect enzymolysis solution and filter the residue obtained, the sodium chloride solution of salinity 5 ± 0.5 ° is added in enzymatic vessel, then residue is rejoined in enzymatic vessel, the weight ratio of the sodium chloride solution of residue and salinity 5 ± 0.5 ° is 1:5, control the pH of feed liquid about 8, then the enzyme amount adding 1.0kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, controls feed temperature at 56 DEG C, is incubated 6 hours; Finally be warming up to 88 DEG C, keep 25min, then obtain enzymolysis solution after leaving standstill 30min, enzymolysis solution, under the rotating speed of 6000 revs/min, after centrifugal treating 40min, enters next step absorption.
(4)
absorption:enzymolysis solution is inputted adsorption tanks, is cooled to 54 DEG C, add water and regulate salinity to 3.0 ± 0.5 °, control pH 7.0, adds the amount of resin of 3kg by every 1000L enzymolysis solution, add ROHM AND HAAS FPA98CL type resin in adsorption tanks, and whip attachment, after 8 hours, collects resin; Feed liquid remaining after collection resin is delivered to adsorption tanks again, control temperature is at 54 DEG C, pH 7.0, the amount of resin adding 2kg by every 1000L feed liquid adds after ROHM AND HAAS FPA98CL type resin adsorbs 8 hours again in adsorption tanks, collect resin, then, after the resin collected with absorption enzymolysis solution merges, next step washing step is entered.
(5)
washing:the resin of collection is washed with water to pH for neutral, then resin is put into the sodium chloride solution of salinity 4 ± 1 °, temperature 55 DEG C, stir and wash for 3 hours, wherein, resin: sodium chloride solution=1:1.3(w/v);
(6)
wash-out:resin after step (5) being washed is poured in wash-out tank and is carried out twice wash-out, wherein, first time wash-out be: resin joined salinity is 21 ± 1 °, stir 5 hours in the sodium chloride solution of temperature 55 DEG C, resin: sodium chloride solution=1:1(w/v); Second time wash-out is: the resin after first time wash-out joined salinity is 21 ± 1 °, stir 5 hours in the sodium chloride solution of temperature 55 DEG C, resin: sodium chloride solution=1:0.8(w/v); Merge the elutriant of twice collection;
Enter next step precipitation after the elutriant collected enters ultrafilter ultrafiltration again, the ultra-filtration membrane aperture of ultrafilter is at 0.45 μm-0.6 μm.
(7)
precipitation:poured into by elutriant in setting tank, add the alcohol of alcoholic strength 80 ° under agitation condition in setting tank, alcohol consumption is as the criterion to 45 ° with the alcoholic strength of surveying mixed solution in setting tank, staticly settles 20 hours, collecting precipitation thing; After collecting precipitation thing, remaining supernatant liquor inputs in another sky setting tank, in another sky setting tank, add saturated nacl aqueous solution stir, and regulate pH to be 9, the volume ratio of supernatant liquor and saturated nacl aqueous solution is 1:0.5, after staticly settling 12 hours, collecting precipitation, then precipitates the drying entering next step after the throw out obtained merges with elutriant.
(8)
dry:the alcohol adding alcoholic strength 85 ° to throw out carries out dehydration 3 hours, is filtered dry latter 60 DEG C and dries and obtain heparin sodium product.
After testing, produce 100,000,000 international unit heparin sodium crudes and only need about 1400 chitterlings, the > 110U/mg that tires of heparin sodium.
Embodiment 2:
(1)
pre-treatment:chitterlings are put into archenteron-scrapping machine (China fortune board 280B type archenteron-scrapping machine), obtain pig intestinal mucosa slurries (pig intestinal mucosa: the mixture of the weight ratio of water=1:4) stand-by, residue casing, intestines skin, intestines skin is separately for extracting heparin sodium.
(2)
casing bubble handle:the length of casing by 1 ± 0.2 meter is folded back and forth, tie up in centre after having folded and form casing handle, every 100 ± 1 meters of casing synthesis one is casing handle, then casing is soaked 5 hours putting into saturated nacl aqueous solution first time, taking-up drains, use casing special-purpose salt to casing pickling process: the first step smears salt: by casing special-purpose salt uniform application on casing surface, the consumption of casing special-purpose salt is every 1 casing handle salt 1.2kg; The first step is smeared after salt completes and is pickled 48 hours, then carries out second step double salt: by casing special-purpose salt, uniform application is on casing surface again, and the consumption of casing special-purpose salt is every 1 casing handle salt 0.5kg; 12 hours are pickled after second step double salt completes; Afterwards, casing is soaked 8 hours the sodium chloride solution secondary putting into salinity 15 °-18 °, when first time immersion and secondary soak, every 1000L soak solution all soaks 160 ± 5 casing handle, the soak solution that first time soaks is equal with the soak solution volume that secondary soaks, the leach liquor collecting first time immersion is stand-by, collects the soak solution that the leach liquor after secondary immersion soaks first time as casing when extracting next time.After secondary soaks, remaining casing can be sold as the raw material of processing sausage.Casing, in twice immersion process, all fills air with air pump and makes the upper and lower Rolling flow of soak solution in soak solution.
(3)
enzymolysis:1000L pig intestinal mucosa slurries are added enzymatic vessel, and the leach liquor adding the first time immersion that step (2) is collected in enzymatic vessel regulates salinity to 5 ± 0.5 ° of feed liquid in enzymatic vessel, controls the pH of feed liquid about 9; Then the enzyme amount adding 1.6kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, and control feed temperature at 50 DEG C, salinity 4.2 ± 0.2 °, pH 7. 5 keeps 3.5 hours; Finally be warming up to 88 DEG C, keep 20min to obtain enzymolysis solution, cross elimination residue; Then enzymolysis solution is under the rotating speed of 8000 revs/min, after centrifugal treating 20min, then enters next step absorption.
Collect enzymolysis solution and filter the residue obtained, the sodium chloride solution of salinity 5 ± 0.5 ° is added in enzymatic vessel, then residue is rejoined in enzymatic vessel, the weight ratio of the sodium chloride solution of residue and salinity 5 ± 0.5 ° is 1:6, control the pH of feed liquid about 9, then the enzyme amount adding 1.2kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, controls feed temperature at 54 DEG C, is incubated 7 hours; Finally be warming up to 90 DEG C, keep 20min, then obtain enzymolysis solution after leaving standstill 20min, enzymolysis solution, under the rotating speed of 8000 revs/min, after centrifugal treating 20min, enters next step absorption.
(4)
absorption:enzymolysis solution is inputted adsorption tanks, is cooled to 60 DEG C, add water and regulate salinity to 3.0 ± 0.5 °, control pH7.5, adds the amount of resin of 8kg by every 1000L enzymolysis solution, add ROHM AND HAAS FPA98CL type resin in adsorption tanks, and whip attachment, after 6 hours, collects resin; Feed liquid remaining after collection resin is delivered to adsorption tanks again, control temperature is at 60 DEG C, pH 7.5, the amount of resin adding 3kg by every 1000L feed liquid adds after ROHM AND HAAS FPA98CL type resin adsorbs 6 hours again in adsorption tanks, collect resin, then, after the resin collected with absorption enzymolysis solution merges, next step washing step is entered.
(5)
washing:the resin of collection is washed with water to pH for neutral, then resin is put into the sodium chloride solution of salinity 4 ± 1 °, temperature 60 C, stir and wash for 1 hour, wherein, resin: sodium chloride solution=1:1.7(w/v);
(6)
wash-out:resin after step (5) being washed is poured in wash-out tank and is carried out twice wash-out, wherein, first time wash-out be: resin joined salinity is 21 ± 1 °, stir 3 hours in the sodium chloride solution of temperature 60 C, resin: sodium chloride solution=1:1.4(w/v); Second time wash-out is: the resin after first time wash-out joined salinity is 21 ± 1 °, stir 3 hours in the sodium chloride solution of temperature 60 C, resin: sodium chloride solution=1:1.2(w/v); Merge the elutriant of twice collection;
The elutriant collected, under the rotating speed of 8000 revs/min, after centrifugal treating 20min, then enters next step precipitation.
(7)
precipitation:poured into by elutriant in setting tank, add the alcohol of alcoholic strength 90 ° under agitation condition in setting tank, alcohol consumption is as the criterion to 60 ° with the alcoholic strength of surveying mixed solution in setting tank, staticly settles 15 hours, collecting precipitation thing; After collecting precipitation thing, remaining supernatant liquor inputs in another sky setting tank, in another sky setting tank, add saturated nacl aqueous solution stir, and regulate pH to be 10, the volume ratio of supernatant liquor and saturated nacl aqueous solution is 1:0.7, after staticly settling 8 hours, collecting precipitation, then precipitates the drying entering next step after the throw out obtained merges with elutriant.
(8)
dry:the alcohol adding alcoholic strength 90 ° to throw out carries out dehydration 1 hour, is filtered dry latter 80 DEG C and dries and obtain heparin sodium product.
After testing, produce 100,000,000 international unit heparin sodium crudes and only need about 1400 chitterlings, the > 110U/mg that tires of heparin sodium.
Embodiment 3:
(1)
pre-treatment:chitterlings are put into archenteron-scrapping machine (China fortune board 280B type archenteron-scrapping machine), obtain pig intestinal mucosa slurries (pig intestinal mucosa: the mixture of the weight ratio of water=1:3) stand-by, residue casing, intestines skin, intestines skin is separately for extracting heparin sodium.
(2)
casing bubble handle:the length of casing by 1 ± 0.2 meter is folded back and forth, tie up in centre after having folded and form casing handle, every 100 ± 1 meters of casing synthesis one is casing handle, then casing is soaked 4.5 hours putting into saturated nacl aqueous solution first time, taking-up drains, use casing special-purpose salt to casing pickling process: the first step smears salt: by casing special-purpose salt uniform application on casing surface, the consumption of casing special-purpose salt is every 1 casing handle salt 1.1kg; The first step is smeared after salt completes and is pickled 50 hours, then carries out second step double salt: by casing special-purpose salt, uniform application is on casing surface again, and the consumption of casing special-purpose salt is every 1 casing handle salt 0.5kg; 14 hours are pickled after second step double salt completes; Afterwards, casing is soaked 7 hours the sodium chloride solution secondary putting into salinity 15 °-18 °, when first time immersion and secondary soak, every 1000L soak solution all soaks 160 ± 5 casing handle, the soak solution that first time soaks is equal with the soak solution volume that secondary soaks, the leach liquor collecting first time immersion is stand-by, collects the soak solution that the leach liquor after secondary immersion soaks first time as casing when extracting next time.After secondary soaks, remaining casing can be sold as the raw material of processing sausage.Casing, in twice immersion process, all fills air with air pump and makes the upper and lower Rolling flow of soak solution in soak solution.
(3)
enzymolysis:1500L pig intestinal mucosa slurries are added enzymatic vessel, and the leach liquor adding the first time immersion that step (2) is collected in enzymatic vessel regulates salinity to 5 ± 0.5 ° of feed liquid in enzymatic vessel, controls the pH of feed liquid about 8.5; Then the enzyme amount adding 1.2kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, and control feed temperature at 53 DEG C, salinity 4.2 ± 0.2 °, pH about 7.0 keeps 3 hours; Finally be warming up to 86 DEG C, keep 22min to obtain enzymolysis solution, cross elimination residue; Then enzymolysis solution is under the rotating speed of 7000 revs/min, after centrifugal treating 30min, then enters next step absorption.
Collect enzymolysis solution and filter the residue obtained, the sodium chloride solution of salinity 5 ± 0.5 ° is added in enzymatic vessel, then residue is rejoined in enzymatic vessel, the weight ratio of the sodium chloride solution of residue and salinity 5 ± 0.5 ° is 1:5.5, control the pH of feed liquid 8.5, then the enzyme amount adding 1.1kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, controls feed temperature at 55 DEG C, is incubated 6.5 hours; Finally be warming up to 89 DEG C, keep 22min, then obtain enzymolysis solution after leaving standstill 25min, enzymolysis solution, under the rotating speed of 7000 revs/min, after centrifugal treating 30min, enters next step absorption.
(4)
absorption:enzymolysis solution is inputted adsorption tanks, is cooled to 57 DEG C, add water and regulate salinity to 3.0 ± 0.5 °, control pH about 7.0, adds the amount of resin of 5kg by every 1000L enzymolysis solution, add ROHM AND HAAS FPA98CL type resin in adsorption tanks, whip attachment, after 7 hours, collects resin; Feed liquid remaining after collection resin is delivered to adsorption tanks again, control temperature is at 57 DEG C, pH about 7.0, the amount of resin adding 2.5kg by every 1000L feed liquid adds after ROHM AND HAAS FPA98CL type resin adsorbs 7 hours again in adsorption tanks, collect resin, then, after the resin collected with absorption enzymolysis solution merges, next step washing step is entered.
(5)
washing:the resin of collection is washed with water to pH for neutral, then resin is put into the sodium chloride solution of salinity 4 ± 1 °, temperature 58 DEG C, stir and wash for 2 hours, wherein, resin: sodium chloride solution=1:1.5(w/v);
(6)
wash-out:resin after step (5) being washed is poured in wash-out tank and is carried out twice wash-out, wherein, first time wash-out be: resin joined salinity is 21 ± 1 °, stir 4 hours in the sodium chloride solution of temperature 58 DEG C, resin: sodium chloride solution=1:1.2(w/v); Second time wash-out is: the resin after first time wash-out joined salinity is 21 ± 1 °, stir 4 hours in the sodium chloride solution of temperature 58 DEG C, resin: sodium chloride solution=1:1(w/v); Merge the elutriant of twice collection;
The elutriant collected, under the rotating speed of 10000 revs/min, after centrifugal treating 10min, then enters next step precipitation.
(7)
precipitation:poured into by elutriant in setting tank, add the alcohol of alcoholic strength 85 ° under agitation condition in setting tank, alcohol consumption is as the criterion to 50 ° with the alcoholic strength of surveying mixed solution in setting tank, staticly settles 18 hours, collecting precipitation thing; After collecting precipitation thing, remaining supernatant liquor inputs in another sky setting tank, in another sky setting tank, add saturated nacl aqueous solution stir, and regulate pH to be 9, the volume ratio of supernatant liquor and saturated nacl aqueous solution is 1:0.6, after staticly settling 10 hours, collecting precipitation, then precipitates the drying entering next step after the throw out obtained merges with elutriant.
As preferably step (7) finally being merged the throw out obtained: the weight ratio mixing of water=1:8-10, abundant dissolving forms throw out solution, in throw out solution, add casing special-purpose salt, stir, the consumption of casing special-purpose salt is the 1-3% of throw out solution quality; The alcohol adding alcoholic strength 85 ± 5 ° again precipitates again, and alcohol consumption is as the criterion to 45 °-60 ° with the alcoholic strength of surveying mixed solution in setting tank, staticly settles more than 15 hours, collecting precipitation thing, then enters next step drying.By adding heavy molten redeposition step, effectively can solve the alcohol of high density and elutriant and easily forming salt-pepper noise and be mixed in heparin sodium product the problem causing product purity lower.
(8)
dry:the alcohol adding alcoholic strength 85 ° to throw out carries out dehydration 2 hours, is filtered dry latter 80 DEG C and dries and obtain heparin sodium product.
After testing, produce 100,000,000 international unit heparin sodium crudes and only need about 1400 chitterlings, the > 110U/mg that tires of heparin sodium.
Above-described embodiment is one of the present invention preferably scheme, not does any pro forma restriction to the present invention, also has other variant and remodeling under the prerequisite not exceeding the technical scheme described in claim.
Claims (5)
1. chitterlings comprehensively extract a technique for heparin sodium, it is characterized in that: described processing step is as follows:
(1)
pre-treatment:chitterlings are put into archenteron-scrapping machine, obtains pig intestinal mucosa slurries stand-by, residue casing, intestines skin, intestines skin is separately for extracting heparin sodium;
(2)
casing bubble handle:by casing around a formation casing handle, then casing is soaked 4-5 hour putting into soak solution first time, taking-up drains, use casing special-purpose salt to casing pickling process, afterwards, casing is soaked 6-8 hour putting into soak solution secondary, and the soak solution that first time soaks is saturated nacl aqueous solution, and the soak solution that secondary soaks is the sodium chloride solution of salinity 15 °-18 °; When immersion for the first time and secondary soak, every 1000L soak solution all soaks 160 ± 5 casing handle, and the leach liquor collecting first time immersion is stand-by, the soak solution that the leach liquor after collection secondary soaks soaks first time as casing when extracting next time;
(3)
enzymolysis:pig intestinal mucosa slurries are added enzymatic vessel, pig intestinal mucosa slurries are pig intestinal mucosa: the mixture of the weight ratio of water=1:2.5-4, the leach liquor adding the first time immersion that step (2) is collected in enzymatic vessel regulates salinity to 5 ± 0.5 ° of feed liquid in enzymatic vessel, controls the pH of feed liquid 8.5 ± 0.5; Then the enzyme amount adding 1.2 ± 0.4kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, and control feed temperature at 53 ± 3 DEG C, salinity 4.2 ± 0.2 °, pH 7.0 ± 0.5 keeps 3 ± 0.5 hours; Finally be warming up to 85-88 DEG C, keep 20-25min to obtain enzymolysis solution, cross elimination residue;
(4)
absorption:enzymolysis solution is inputted adsorption tanks, is cooled to 57 ± 3 DEG C, add water and regulate salinity to 3.0 ± 0.5 °, control pH 7.0-7.5, adds the amount of resin of 3-8kg by every 1000L enzymolysis solution, add ROHM AND HAAS FPA98CL type resin in adsorption tanks, after whip attachment 6-8 hour, collect resin;
(5)
washing:the resin of collection is washed with water to pH for neutral, then resin is put into the sodium chloride solution of salinity 4 ± 1 °, temperature 55-60 DEG C, stir and wash at least 1 hour, wherein, resin: sodium chloride solution=1kg:1.3-1.7L;
(6)
wash-out:resin after step (5) being washed is poured in wash-out tank and is carried out twice wash-out, wherein, first time, wash-out was: resin joined salinity is 21 ± 1 °, stir at least 3 hours, resin in the sodium chloride solution of temperature 55-60 DEG C: sodium chloride solution=1kg:1-1.4L; Second time wash-out is: the resin after first time wash-out joined salinity is 21 ± 1 °, stir at least 3 hours, resin in the sodium chloride solution of temperature 55-60 DEG C: sodium chloride solution=1kg:0.8-1.2L; Merge the elutriant of twice collection;
(7)
precipitation:the elutriant that step (6) is collected is poured in setting tank, in setting tank, the alcohol of alcoholic strength 85 ± 5 ° is added under agitation condition, alcohol consumption is as the criterion to 45 °-60 ° with the alcoholic strength of surveying mixed solution in setting tank, staticly settles more than 15 hours, collecting precipitation thing;
(8)
dry:the alcohol that the throw out that step (7) obtains adds alcoholic strength more than 85 ° carries out dehydration 1-3 hour, does drying and processing and namely obtain heparin sodium product after being filtered dry;
In step (2), casing is specially around handle: the length of casing by 1 ± 0.2 meter folded back and forth, ties up form casing handle after having folded in centre, and every 100 ± 1 meters of casing synthesis one is casing handle; Casing, in twice immersion process, all fills air with air pump and makes the upper and lower Rolling flow of soak solution in soak solution;
Pickle process in step (2) to be specially: the first step smears salt: by casing special-purpose salt uniform application on casing surface, the consumption of casing special-purpose salt is every 1 casing handle salt 1-1.2kg; The first step is smeared after salt completes and is pickled more than 48 hours, then carries out second step double salt: by casing special-purpose salt, uniform application is on casing surface again, and the consumption of casing special-purpose salt is every 1 casing handle salt 0.5-0.6kg; 12-14 hour is pickled after second step double salt completes;
After step (4) is collected resin, remaining feed liquid is delivered to adsorption tanks again, control temperature is at 57 ± 3 DEG C, pH 7.0-7.5, the amount of resin adding 2-3kg by every 1000L feed liquid adds after ROHM AND HAAS FPA98CL type resin adsorbs 6-8 hour again in adsorption tanks, collect resin, then, after the resin collected with step (4) merges, next step washing step is entered;
After step (7) collecting precipitation thing, remaining supernatant liquor inputs in another sky setting tank, in another sky setting tank, add saturated nacl aqueous solution stir, and regulate pH to be 9-10, the volume ratio of supernatant liquor and saturated nacl aqueous solution is 1:0.5-0.7, after staticly settling 8-12 hour, collecting precipitation, enters next step drying step after the throw out then obtained with step (7) merges;
Collect step (3) enzymolysis solution and filter the residue obtained, the sodium chloride solution of salinity 5 ± 0.5 ° is added in enzymatic vessel, then residue is rejoined in enzymatic vessel, the weight ratio of the sodium chloride solution of residue and salinity 5 ± 0.5 ° is 1:5-6, control the pH of feed liquid 8.5 ± 0.5, then the enzyme amount adding 1.0-1.2kg by every 1000L feed liquid adds 2709 Sumizyme MPs in enzymatic vessel, controls feed temperature at 55 ± 1 DEG C, insulation 6-7 hour; Finally be warming up to 88-90 DEG C, keep 20-25min, then obtain enzymolysis solution after leaving standstill 20-30min, enzymolysis solution, under the rotating speed of 6000-8000 rev/min, after centrifugal treating 20-40min, enters next step absorption.
2. chitterlings according to claim 1 comprehensively extract the technique of heparin sodium, it is characterized in that: step (3) processes the enzymolysis solution that obtains under the rotating speed of 6000-8000 rev/min, after centrifugal treating 20-40min, then enters next step absorption.
3. chitterlings according to claim 1 comprehensively extract the technique of heparin sodium, it is characterized in that: re-use after the resin activated process of described ROHM AND HAAS FPA98CL type, activation treatment is: resin 50-60 DEG C warm water soaking is rinsed well with clear water after more than 20 hours and drained, add again mass concentration be 10% sodium hydroxide solution stir more than 1 hour, it is neutral for finally rinsing to washing lotion pH with clear water, and the add-on of described sodium hydroxide solution is the gauge that every kilogram resin adds 1L sodium hydroxide solution; Resin after activation is under the rotating speed of 4000-5000 rev/min, and centrifugal treating 10-30min, is used further to absorption.
4. chitterlings according to claim 1 comprehensively extract the technique of heparin sodium, it is characterized in that: enter next step precipitation after the elutriant that step (6) is collected enters ultrafilter ultrafiltration again, the ultra-filtration membrane aperture of ultrafilter is at 0.45 μm-0.6 μm; Or the elutriant that step (6) is collected is under the rotating speed of 8000-10000 rev/min, after centrifugal treating 10-20min, then enter next step precipitation.
5. chitterlings according to claim 1 comprehensively extract the technique of heparin sodium, it is characterized in that: the temperature of step (8) drying and processing is 60-80 DEG C.
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| CN106967185A (en) * | 2017-03-22 | 2017-07-21 | 潢川县鹏升畜产品有限公司 | The method of comprehensive utilization of liquaemin is extracted from chitterlings |
| CN110437347A (en) * | 2018-05-02 | 2019-11-12 | 山阳县恒瑞肉制品有限公司 | The method for extracting heparin sodium from chitterlings |
| CN109280098A (en) * | 2018-05-18 | 2019-01-29 | 山阳县恒桓生物科技有限公司 | A kind of preparation method of heparin sodium |
| CN109517092A (en) * | 2019-01-22 | 2019-03-26 | 胡晓辉 | The heparin process for producing sodium of pig intestinal mucosa |
| CN118546273B (en) * | 2024-06-07 | 2025-01-24 | 浩泰健康济盛(吉林)生物科技有限公司 | A method for producing heparin sodium using pig small intestine |
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| CN101851301A (en) * | 2010-06-02 | 2010-10-06 | 喻延安 | Method for extracting crude product of heparin sodium |
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