CN107177010A - The screening technology of liquaemin special enzyme preparation - Google Patents

The screening technology of liquaemin special enzyme preparation Download PDF

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Publication number
CN107177010A
CN107177010A CN201610138425.8A CN201610138425A CN107177010A CN 107177010 A CN107177010 A CN 107177010A CN 201610138425 A CN201610138425 A CN 201610138425A CN 107177010 A CN107177010 A CN 107177010A
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Prior art keywords
solution
hours
liquaemin
ethanol
stirring
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陈文龙
张宏
宋磊
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Nantong Youlong Casings Food Co Ltd
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Nantong Youlong Casings Food Co Ltd
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Priority to CN201610138425.8A priority Critical patent/CN107177010A/en
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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
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

The invention discloses a kind of screening technology of liquaemin special enzyme preparation, make refined heparin sodium molecular weight between 15000-19000 dalton, and the ratio of molecular weight ratio is not less than 1.0 between the molecular weight ratio and 16000-24000 dalton of 8000-16000 dalton.Technical scheme is that the consumption for using regulation trypsase and pepsin in enzymolysis process decomposes the macromolecule liquaemin in liquaemin, the purification step repeatedly precipitated by ethanol again, aoxidized realizes that the impurity such as liquaemin and other ribonucleic acid is completely separated, refined heparin sodium yield reaches that other quality standards meet Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia and West Europe States Pharmacopoeia specifications to more than 90%, Xa potency for 0.9-1.1 with IIa potency ratio.

Description

The screening technology of liquaemin special enzyme preparation
Technical field
The present invention relates to a kind of screening technology of liquaemin special enzyme preparation of biological technical field.
Background technology
Liquaemin is a kind of biochemical drug extracted from pig intestinal mucosa, is irreplaceable, redemption life in operation , market can not be out of stock choice drug.Since being used for clinic from nineteen forties, its application constantly expands, Especially since nineteen nineties, the product clinic is mainly used in preventing thrombosis, treatment cardiovascular disease, blood Disease, uremia etc..Western countries are had started to study preventive and therapeutic effect of the liquaemin to cancer, and its new application is continuously increased.
Since nineteen seventies, China's heparin process for producing sodium is updated, as the production of world's liquaemin Measure maximum country.The heparin sodium product of international market has more than 70% from China.Refined heparin sodium is produced by permanganic acid Potassium oxidizing process develops into hydrogen peroxide oxidation method, and partition method is washed with reference to alcohol, and substantial amounts of impurity is taken away with ethanol.2 months 2008 11, there are 4 death, 350 many cases adverse reactions, as " the liquaemin thing for causing a sensation the world because of injecting heparin sodium in the U.S. Part ".Therefore the annual standard upgrading all to liquaemin of Bureau of Drugs Supervision of the U.S., next year is by the standard upgrading of liquaemin molecular weight.
The content of the invention
The invention provides a kind of method that enzymatic isolation method decomposes the high component in liquaemin, the present invention uses following technical side Case is achieved：
A kind of method that enzymatic isolation method decomposes the HMW in liquaemin, it is characterised in that：Adjust trypsase and stomach cardia The consumption of enzyme and gradation time decompose the macromolecule liquaemin in liquaemin in the technical scheme of invention, also with Lower technical characteristic：Methods described comprises the following steps：
First, extract
1st, dissolving crude product：
Water valve is opened, drinking water is added, then heparin sodium crude is added in retort, is added when stirring, by raw material and drinking water 1 ：(6-7) ratio dissolves, and stirs 5-10 hours to whole dissolvings.
2nd, digest：
By previous step lysate, first adjust PH7.0-8.0 with hydrochloric acid solution, be warming up to 50-55 DEG C between when add pepsin The unit of 5-12g/hundred million, adds the unit pancreatin of 10-20g/hundred million, after 50-55 DEG C of insulation 4 hours, 4 hours, then adds stomach egg The unit of white enzyme 3-5g/hundred million, while adding the trypsase of the unit of 5-12g/hundred million, 50 DEG C are continued to be incubated 4 hours；
3rd, rise suddenly temperature：
Previous step enzymolysis liquid was warming up to 85-90 DEG C in 30~40 minutes, it is static 10-30 minutes, stirring is opened, is passed through and follows Ring water cools, when temperature is down to 50-55 DEG C, and PH10.0-12.0, static point are adjusted with 2-6mol/L sodium hydroxide solutions Layer 20-30 hours.
4th, the impurity centrifugation of bottom precipitation：Siphon supernatant, with 40-100 mesh sock filtrations, the solution after filtering is divided into Supernatant and lower sediment, stay supernatant to be precipitated, and lower sediment, which is put, stays upper strata centrifugate after centrifuge, centrifugation；
2nd, refine
1st, precipitate for the first time：
Treat that above-mentioned supernatant and centrifugate temperature are down to 20-30 DEG C, add after 20-30g/L sodium chloride, stirring and dissolving, Filtrate is adjusted into PH10.0-12.0 with hydrochloric acid, when stirring plus concentration be 95~97% ethanol solution so that the concentration of ethanol 45~50% are reached at 20 DEG C, is precipitated 10-12 hours.
2nd, aoxidize for the first time：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will with sodium hydroxide solution Solution adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours.
3rd, second of precipitation：Solution is added after 20-30g/L sodium chloride, stirring and dissolving, and being adjusted with hydrochloric acid solution will be molten Liquid PH6.0-7.0, when stirring plus concentration be 95~97% ethanol solution so that the concentration of ethanol reaches at 20 DEG C 45~50%, precipitate 10-12 hours.
4th, second of oxidation：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will with sodium hydroxide solution Solution adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours.
5th, third time is precipitated：Solution adds 20-30g/L sodium chloride, and solution is adjusted into PH10.0- with hydrochloric acid solution 12.0, when stirring plus ethanol solution that concentration is 95~97% so that the concentration of ethanol reaches 45 at 20 DEG C~ 50%, precipitate 10-12 hours.
6th, third time is aoxidized：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will with sodium hydroxide solution Solution adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours.
7th, the 4th precipitation：If previous step solution has sediment precipitation, with centrifuge, do not separate out then direct 20-30g/L sodium chloride is added, solution is adjusted into PH6.0-7.0 with hydrochloric acid solution, solution is let cool -10 is refrigerated in storehouse DEG C -- 5 DEG C, while stirring Bian Jia -10 DEG C -- 5 DEG C of acetone so that the weight/mass percentage composition that acetone accounts for solution is 40-45%, -5 DEG C -0 DEG C is incubated 24-30 hours, then discards waste acetone, stays bottom sediment purified water to dissolve, solution is added 20-30g/L sodium chloride, is adjusted solution PH 6.0-7.0 with hydrochloric acid solution, when stirring plus ethanol, makes concentration of alcohol at 20 DEG C When be 45-50%, precipitate 10-12 hours.
8th, by sediment with purified water by the dissolving of the unit of 2-5L/hundred million after, with aperture 0.22-0.3 micron membrane filter sheet frames Machine micro-filtration, with ethanol precipitation, makes concentration of alcohol reach 75-80%, adds 23-26% sodium chloride solution, every 1 liter molten Liquid adds 6-10ml sodium chloride solutions, quiescent setting 10-12 hours.
9th, upper strata ethanol is discarded, adds absolute ethyl alcohol dehydration, add when stirring, it is 97-99%, static 24- to make concentration of alcohol 30 hours, upper strata ethanol is discarded, stainless steel core rod is put in the product, with vavuum pump by pipeline and filtering flask remaining Ethanol is drained, to be dried.
10th, the product drained uniformly is placed in stainless steel disc, is placed in vacuum drying chamber and vacuumizes, with recirculated water plus Temperature, 35-60 DEG C of temperature is dried 70-80 hours.
11st, pack：Product is taken out, weighed, makes every packaging bag 5kg, is sealed with sealing machine, is placed on to be tested in Aluminum Drum.
In the technical scheme of invention, also with following technical characteristic：
[1), the solution after the 4th precipitation carries out QA sample examinations, surveys absorbance：260nm ＜ 0.1；400nm ＜ 0.02。
2), molecular weight is between 15000-19000 dalton, and the molecular weight ratio of 8000-16000 dalton The ratio of molecular weight ratio is not less than 1.0 between 16000-24000 dalton.
3), refined heparin sodium yield reaches more than 90%.
4), Xa potency and IIa potency ratio are 0.9-1.1.
Embodiment
Present disclosure is further described with reference to specific embodiment：
Embodiment
2nd, extract
1st, dissolving crude product：
Water valve is opened, drinking water is added, then heparin sodium crude is added in retort, is added when stirring, by raw material and drinking water 1 ：(6-7) ratio dissolves, and stirs 5-10 hours to whole dissolvings.
2nd, digest：
By previous step lysate, first adjust PH7.0-8.0 with hydrochloric acid solution, be warming up to 50-55 DEG C between when add pepsin The unit of 5-12g/hundred million, adds the unit pancreatin of 10-20g/hundred million, after 50-55 DEG C of insulation 4 hours, 4 hours, then adds stomach egg The unit of white enzyme 3-5g/hundred million, while adding the trypsase of the unit of 5-12g/hundred million, 50 DEG C are continued to be incubated 4 hours；
3rd, rise suddenly temperature：
Previous step enzymolysis liquid was warming up to 85-90 DEG C in 30~40 minutes, it is static 10-30 minutes, stirring is opened, is passed through and follows Ring water cools, when temperature is down to 50-55 DEG C, and PH10.0-12.0, static point are adjusted with 2-6mol/L sodium hydroxide solutions Layer 20-30 hours.
4th, the impurity centrifugation of bottom precipitation：Siphon supernatant, with 40-100 mesh sock filtrations, the solution after filtering is divided into Supernatant and lower sediment, stay supernatant to be precipitated, and lower sediment, which is put, stays upper strata centrifugate after centrifuge, centrifugation.
2nd, refine
1st, precipitate for the first time：
Treat that above-mentioned supernatant and centrifugate temperature are down to 20-30 DEG C, add after 20-30g/L sodium chloride, stirring and dissolving, Filtrate is adjusted into PH10.0-12.0 with hydrochloric acid, when stirring plus concentration be 95~97% ethanol solution so that the concentration of ethanol
45~50% are reached at 20 DEG C, is precipitated 10-12 hours.
2nd, aoxidize for the first time：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will with sodium hydroxide solution Solution adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours.
3rd, second of precipitation：Solution is added after 20-30g/L sodium chloride, stirring and dissolving, and being adjusted with hydrochloric acid solution will be molten Liquid PH6.0-7.0, when stirring plus concentration be 95~97% ethanol solution so that the concentration of ethanol reaches at 20 DEG C 45~50%, precipitate 10-12 hours.
4th, second of oxidation：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will with sodium hydroxide solution Solution adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours.
5th, third time is precipitated：Solution adds 20-30g/L sodium chloride, and solution is adjusted into PH10.0- with hydrochloric acid solution 12.0, when stirring plus ethanol solution that concentration is 95~97% so that the concentration of ethanol reaches 45 at 20 DEG C~ 50%, precipitation
10-12 hours.
6th, third time is aoxidized：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will with sodium hydroxide solution Solution adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours.
7th, the 4th precipitation：If previous step solution has sediment precipitation, with centrifuge, do not separate out then straight Connect addition 20-30g/L sodium chloride, solution is adjusted into PH6.0-7.0 with hydrochloric acid solution, solution is let cool in storehouse be refrigerated to- 10 DEG C -- 5 DEG C, while stirring Bian Jia -10 DEG C -- 5 DEG C of acetone so that the weight/mass percentage composition that acetone accounts for solution is 40- 45%, -5 DEG C -0 DEG C is incubated 24-30 hours, then discards waste acetone, stays bottom sediment purified water to dissolve, solution 20-30g/L sodium chloride is added, is adjusted with hydrochloric acid solution by solution PH 6.0-7.0, when stirring plus ethanol, makes concentration of alcohol
It is 45-50% at 20 DEG C, precipitates 10-12 hours.
8th, by sediment with purified water by the dissolving of the unit of 2-5L/hundred million after, with aperture 0.22-0.3 micron membrane filter sheet frames Machine micro-filtration, with ethanol precipitation, makes concentration of alcohol reach 75-80%, adds 23-26% sodium chloride solution, every 1 liter molten Liquid adds 6-10ml sodium chloride solutions, quiescent setting 10-12 hours.
9th, upper strata ethanol is discarded, adds absolute ethyl alcohol dehydration, add when stirring, it is 97-99% to make concentration of alcohol, static 24-30 hours, upper strata ethanol is discarded, stainless steel core rod is put in the product, with vavuum pump by pipeline and filtering flask surplus Remaining ethanol is drained, to be dried
10th, the product drained uniformly is placed in stainless steel disc, is placed in vacuum drying chamber and vacuumizes, with recirculated water plus
Temperature, 35-60 DEG C of temperature is dried 70-80 hours.
11st, pack：Product is taken out, weighed, makes every packaging bag 5kg, is sealed with sealing machine, is placed on to be tested in Aluminum Drum.
In the technical scheme of invention, also with following technical characteristic：
[1), the solution after the 4th precipitation carries out QA sample examinations, surveys absorbance：260nm ＜ 0.1；400nm ＜ 0.02。
2), molecular weight is between 15000-19000 dalton, and the molecular weight ratio of 8000-16000 dalton The ratio of molecular weight ratio is not less than 1.0 between 16000-24000 dalton.
3), refined heparin sodium yield reaches more than 90%.
4), Xa potency and IIa potency ratio are 0.9-1.1.

Claims (7)

1. a kind of screening technology of liquaemin special enzyme preparation, makes refined heparin sodium molecular weight in 15000-19000 dalton Between, and between the molecular weight ratio and 16000-24000 dalton of 8000-16000 dalton molecular weight ratio ratio Value is not less than 1.0；It is characterized in that：Using in enzymolysis process by adjust trypsase and pepsin consumption and point The secondary time decomposes the macromolecule liquaemin in liquaemin.
2. the screening technology of the liquaemin special enzyme preparation according to claim 1, it is characterised in that adjusted in enzymolysis process The consumption for saving trypsase and pepsin decomposes the macromolecule liquaemin in liquaemin；Its step includes：
First, extract
1）, dissolving crude product：
Water valve is opened, drinking water is added, then heparin sodium crude is added in retort, is added when stirring, by raw material and drinking water 1 ：(6-7) ratio dissolves, and stirs 5-10 hours to whole dissolvings；
2）, enzymolysis：
By previous step lysate, first adjust PH to 7.0-8.0 with hydrochloric acid solution, be warming up to 50-55 DEG C between when add pepsin The unit of 5-12g/hundred million, adds the unit pancreatin of 10-20g/hundred million, after 50-55 DEG C of insulation 4 hours, 4 hours, then adds stomach egg The unit of white enzyme 3-5g/hundred million, while adding the trypsase of the unit of 5-12g/hundred million, 50 DEG C are continued to be incubated 4 hours；
3）, rise suddenly temperature：Previous step enzymolysis liquid was warming up to 85-90 DEG C in 30~40 minutes, it is static 10-30 minutes, Start stirring, be passed through circulating water cooling, when temperature is down to 50-55 DEG C, adjusted with 2-6mol/L sodium hydroxide solutions PH10.0-12.0, static layering 20-30 hours；
4）, bottom precipitation impurity centrifugation：Siphon supernatant, with 40-100 mesh sock filtrations, the solution after filtering is divided into Clear liquid and lower sediment, stay supernatant to be precipitated, and lower sediment, which is put, stays upper strata centrifugate after centrifuge, centrifugation；2nd, it is smart System 1）, for the first time precipitate：
Treat that above-mentioned supernatant and centrifugate temperature are down to 20-30 DEG C, add after 20-30g/L sodium chloride, stirring and dissolving, use Filtrate is adjusted PH10.0-12.0 by hydrochloric acid, when stirring plus concentration be 95~97% ethanol solution so that the concentration of ethanol 45~50% are reached at 20 DEG C, is precipitated 10-12 hours；
2）, for the first time aoxidize：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will be molten with sodium hydroxide solution Liquid adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours；
3）, second precipitate：Solution is added after 20-30g/L sodium chloride, stirring and dissolving, is adjusted with hydrochloric acid solution by solution PH6.0-7.0, when stirring plus concentration be 95~97% ethanol solution so that the concentration of ethanol reaches 45 at 20 DEG C ~50%, precipitate 10-12 hours；
4）, second aoxidize：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will be molten with sodium hydroxide solution Liquid adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours；
5）, third time precipitate：Solution adds 20-30g/L sodium chloride, and solution is adjusted into PH10.0- with hydrochloric acid solution 12.0, when stirring plus concentration be 95~97% ethanol solution so that the concentration of ethanol reaches 45~50% at 20 DEG C, Precipitation 10-12 hours；
6）, third time aoxidize：Upper strata waste ethanol is discarded, lower sediment thing purified water dissolves, will be molten with sodium hydroxide solution Liquid adjusts PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, aoxidizes 10-12 hours；
7）, the 4th precipitation：If previous step solution has sediment precipitation, with centrifuge, do not separate out and then directly add Enter 20-30g/L sodium chloride, solution is adjusted into PH6.0-7.0 with hydrochloric acid solution, solution is let cool -10 DEG C is refrigerated in storehouse -- 5 DEG C, while stirring Bian Jia -10 DEG C -- 5 DEG C of acetone so that the weight/mass percentage composition that acetone accounts for solution is 40-45%, -5 DEG C - 0 DEG C is incubated 24-30 hours, then discards waste acetone, stays bottom sediment purified water to dissolve, solution adds 20- 30g/L sodium chloride, is adjusted solution PH 6.0-7.0 with hydrochloric acid solution, when stirring plus ethanol, makes concentration of alcohol at 20 DEG C For 45-50%, precipitate 10-12 hours；
8）, by sediment with purified water by the dissolving of the unit of 2-5L/hundred million after, with aperture 0.22-0.3 micron membrane filter board and frame machines Micro-filtration, with ethanol precipitation, makes concentration of alcohol reach 75-80%, adds 23-26% sodium chloride solution, every 1 liter of solution adds 6-10ml sodium chloride solutions, quiescent setting 10-12 hours；
9）, upper strata ethanol discarded, add absolute ethyl alcohol dehydration, add when stirring, it is 97-99% to make concentration of alcohol, static 24-30 hours, upper strata ethanol is discarded, stainless steel core rod is put in the product, pipeline and filtering flask handle are passed through with vavuum pump Remaining ethanol is drained, to be dried；
10）, the product drained uniformly is placed in stainless steel disc, be placed in vacuum drying chamber and vacuumize, with recirculated water plus Temperature, 35-60 DEG C of temperature is dried 70-80 hours；
11）, packaging：Product is taken out, weighed, makes every packaging bag 5kg, is sealed with sealing machine, is placed on to be tested in Aluminum Drum.
3. the method for the HMW in enzymatic isolation method separation liquaemin according to claim 2, it is characterised in that：4th Solution after secondary precipitation carries out QA sample examinations, surveys absorbance：260nm ＜ 0.1；400nm ＜ 0.02.
4. the method for the HMW in enzymatic isolation method separation liquaemin according to claim 2, it is characterised in that：Molecule Amount is between 15000-19000 dalton, and the molecular weight ratio and 16000-24000 of 8000-16000 dalton The ratio of molecular weight ratio is not less than 1.0 between dalton.
5. the method for the HMW in enzymatic isolation method separation liquaemin according to claim 2, it is characterised in that：Heparin Sodium fine work yield reaches more than 90%.
6. the method for the HMW in enzymatic isolation method separation liquaemin according to claim 2, it is characterised in that：Xa Potency is 0.9-1.1 with IIa potency ratio.
7. the method for the HMW in enzymatic isolation method separation liquaemin according to claim 2, it is characterised in that：Sulfuric acid The content of dermatan is less than 1%.
CN201610138425.8A 2016-03-11 2016-03-11 The screening technology of liquaemin special enzyme preparation Pending CN107177010A (en)

Priority Applications (1)

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Application Number Priority Date Filing Date Title
CN201610138425.8A CN107177010A (en) 2016-03-11 2016-03-11 The screening technology of liquaemin special enzyme preparation

Publications (1)

Publication Number Publication Date
CN107177010A true CN107177010A (en) 2017-09-19

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Country Status (1)

Country Link
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Application publication date: 20170919