CN108795920B - Preparation method of pancreatin - Google Patents
Preparation method of pancreatin Download PDFInfo
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- 108010019160 Pancreatin Proteins 0.000 title claims abstract description 39
- 229940055695 pancreatin Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title abstract description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 48
- 102000016938 Catalase Human genes 0.000 claims abstract description 22
- 108010053835 Catalase Proteins 0.000 claims abstract description 22
- 210000000496 pancreas Anatomy 0.000 claims abstract description 12
- 238000005238 degreasing Methods 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 230000003213 activating effect Effects 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000000227 grinding Methods 0.000 claims abstract description 4
- 230000001376 precipitating effect Effects 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 230000005484 gravity Effects 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 3
- 241000894006 Bacteria Species 0.000 claims description 2
- 239000002207 metabolite Substances 0.000 claims description 2
- 241000700605 Viruses Species 0.000 abstract description 34
- 230000002779 inactivation Effects 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 7
- 241001465754 Metazoa Species 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- 230000000120 cytopathologic effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 239000000843 powder Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 208000035404 Autolysis Diseases 0.000 description 3
- 206010057248 Cell death Diseases 0.000 description 3
- 241000710188 Encephalomyocarditis virus Species 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000415 inactivating effect Effects 0.000 description 3
- 230000028043 self proteolysis Effects 0.000 description 3
- 210000003501 vero cell Anatomy 0.000 description 3
- XRHVZWWRFMCBAZ-UHFFFAOYSA-L Endothal-disodium Chemical compound [Na+].[Na+].C1CC2C(C([O-])=O)C(C(=O)[O-])C1O2 XRHVZWWRFMCBAZ-UHFFFAOYSA-L 0.000 description 2
- 108010067035 Pancrelipase Proteins 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 229940045258 pancrelipase Drugs 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000702619 Porcine parvovirus Species 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000001994 activation Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000937 inactivator Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000024691 pancreas disease Diseases 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000012502 risk assessment Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/94—Pancreatin
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- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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- Enzymes And Modification Thereof (AREA)
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Abstract
The invention relates to a preparation method of pancreatin, which comprises the steps of grinding pancreas, adding hydrogen peroxide to obtain a mixture, stirring for 1-8 h, adding catalase to react for 0.5-2 h, degreasing, activating, precipitating and drying to obtain the pancreatin, wherein the mass percentage concentration of the hydrogen peroxide in the mixture is 0.1-2%. The hydrogen peroxide can fully contact with the virus in a short time so as to achieve the purpose of virus inactivation, and in addition, the residual hydrogen peroxide is decomposed into water and oxygen by catalase, so that the pancreatin has no residual hydrogen peroxide, thereby greatly enhancing the virus safety of the medicine, and enabling the pancreatin product to meet the rigorous requirements in the aspects of pharmacopoeia of various countries and biochemical drug regulations of animal sources.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a preparation method of pancreatin.
Background
Pancreatin is a mixed enzyme preparation extracted from pancreas of mammals such as pig, cattle, sheep, etc., and mainly comprises trypsin, pancreatic amylase, pancreatic lipase, carboxypeptidase, chymotrypsin, elastase, kallikrein, ribonuclease, etc. As early as 1938, pancreatin products have been used for vesicular fibrosis and chronic pancreatitis, and most patients need to take for life. At present, pancreatin is a digestion-aiding medicine recorded in pharmacopoeias of various countries and is clinically used for treating dyspepsia, inappetence and digestive disorder caused by liver and pancreas diseases. Because the pancreatin contains various active substances, the pancreatin can be used as a raw material medicament to extract needed biochemical substances from the raw material medicament. In addition, pancreatin is also widely used in cell culture for the production of therapeutic biologicals such as mabs, cytokines, and the like.
Since pancreatin is derived from animal extracts, there is a risk of viral contamination in the raw materials thereof. Regulations in various countries such as FDA, CFDA, EMA, etc. are clearly stipulated, and virus inactivation and virus safety evaluation are required. In 2006, FDA published guidelines for Industry on exotic fashion efficacy Drug Products, where the following description was made of the viral safety of pancreatin Products (1) the manufacturer needed to perform a complete viral risk assessment on them (2) the virus removal/inactivation capacity of the production process was verified as required by ICH Q5A.
In the prior art, the production process of pancreatin comprises: the pancreatin is used as an API, cell culture raw material, and virus pollution risk is greatly increased by using the pancreatin as a raw material. The traditional virus inactivation methods such as strong alkali, high-temperature heating and irradiation have great influence on the enzyme activity.
In the patent "method for reducing or inactivating virus and microorganism content in the process of producing pancreatin" (CN 107849552 a) ", it is disclosed that pig pancreas is pretreated with peroxyethoxy acid, then residual peroxyacetic acid is washed away, and pancreatin is extracted from the treated glandular tissue. In the method of treating with peroxyacetic acid, since the virus is parasitic inside the cell, the method described in the patent can only inactivate microorganisms on the surface of glandular tissue, and has a very limited effect on inactivating the virus inside the cell, which has certain defects.
Treatment of pancreatin with an ultra high pressure of 4000, 5000 or 6000 bar for 5 minutes to inactivate viruses is disclosed in patent US 2011/0268844 a 1. The method has the defects that the inactivation effect of high-pressure treatment on certain viruses is uncertain, and the ultrahigh-pressure equipment is expensive in cost and high in production cost, so that the method is basically not desirable in production practice.
Disclosure of Invention
The invention aims to provide a preparation method of pancreatin with good virus inactivation effect.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of pancreatin comprises the steps of grinding pancreas, adding hydrogen peroxide to obtain a mixture, stirring the mixture for 1-8 hours, adding catalase to react for 0.5-2 hours, and then degreasing, activating, precipitating and drying to obtain the pancreatin, wherein the mass percentage concentration of the hydrogen peroxide in the mixture is 0.1% -2%.
Preferably, the pancreas is ground and autolyzed for 4-16 h, and then the hydrogen peroxide is added.
Preferably, the mixture is stirred at 2-15 ℃.
Preferably, 100-1000 u of catalase is added per 1mg of hydrogen peroxide.
Preferably, the catalase is a metabolite from bacteria or molds, for example, 50000U/ml liquid enzyme or 100000U/g enzyme powder of Pentobopa nanningensis from Taian Xindeli bioengineering, Inc.
Preferably, after the catalase is added, the reaction is carried out for 20-60 min at the temperature of 5-15 ℃.
After the pancreas is ground, active enzyme inside the cells permeates to the outside of the cells, so that autolysis on glands can be generated, the pancreas is dissolved into a flowing and uniform liquid state, and the full contact between an inactivator and viruses is facilitated. Therefore, the invention adds the hydrogen peroxide into the pancreas plasma after a certain autolysis, thereby inactivating the virus in the cells and leading the inactivation effect to be more thorough.
In addition, the hydrogen peroxide can be decomposed into water and oxygen under the action of catalase, so that the residual hydrogen peroxide in pancreatin can be avoided. The influence of the catalase on the pancreatin product is small, and in addition, most of catalase is removed in the subsequent degreasing, activation, precipitation and drying steps, so even though the catalase remains in the pancreatin, the residual quantity is small.
The steps of degreasing, activating, precipitating and drying in the invention are carried out by adopting a conventional method for preparing pancreatin.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the hydrogen peroxide can fully contact with the virus in a short time so as to achieve the purpose of virus inactivation, and in addition, the residual hydrogen peroxide is decomposed into water and oxygen by catalase, so that the pancreatin has no residual hydrogen peroxide, thereby greatly enhancing the virus safety of the medicine, and enabling the pancreatin product to meet the rigorous requirements in the aspects of pharmacopoeia of various countries and biochemical drug regulations of animal sources.
Drawings
FIG. 1 shows ST cells infected with PPV lesions;
FIG. 2 shows normal ST cells;
FIG. 3 is a normal Vero cell;
figure 4 Vero cells infected with EMCV lesions.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that these embodiments are provided to illustrate the basic principles, essential features and advantages of the present invention, and the present invention is not limited by the following embodiments. The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
Example 1, the preparation of pancreatin included the following steps carried out in sequence:
(1) after 100g of pancreas and 5g of duodenum are sliced, 20g of anhydrous acetone is added, stirred and mixed, and then ground by a colloid mill and autolyzed for 4 hours;
(2) adding 0.5g of hydrogen peroxide solution with the mass concentration of 30 percent sold in the market, and stirring for 8 hours at the temperature of 2 ℃;
(3) adding 100000u unit of catalase, and stirring for 2h at 5 ℃;
(4) putting the treatment liquid treated in the step (3) into a degreasing barrel, adding pre-cooled raw acetone with the temperature of 0-5 ℃ and the specific gravity density of less than or equal to 0.800, degreasing for 2 hours, and opening a valve to discharge the degreased acetone;
(5) adding calcium chloride as an activating agent into the treatment liquid treated in the step (4), uniformly stirring, and putting into an extraction tank, and activating at the temperature of 5 ℃ for 20 hours;
(6) separating the activated extracting solution by using a separator, filtering, collecting pancreatic milk filtrate, adding the pancreatic milk filtrate into a precipitation tank, adding acetone with the specific gravity of less than 0.850 and precooled to-7-0 ℃, stirring for 30min, and completing precipitation when the specific gravity of the precipitation solution is between 0.85 and 0.89 by using a specific gravity meter to obtain a precipitation solution;
(7) drying and crushing the precipitation solution to obtain pancreatin powder, wherein the pancreatin powder is 1500u/g, the pancrelipase powder is 10000u/g, and no contact enzyme residue is generated after detection.
Method for detecting virus inactivation effect
After the above step (1) and before the step (2), 6.5 log was added10TCID50/0.1ml titre of the indicator virus PPV (porcine parvovirus, virus solution added at 5% from the volume of the solution, approximately 5ml virus solution added to 100g pancreas).
Respectively taking out samples before adding hydrogen peroxide and after adding catalase reaction, respectively inoculating to ST cell culture, observing cytopathic effect (CPE), showing the influence of the samples before adding hydrogen peroxide on the cytopathic effect as shown in figure 1, showing the influence of the samples after adding catalase reaction on the cytopathic effect as shown in figure 2, calculating the virus titer and the reduction value of the virus titer, wherein the virus titer is less than or equal to 2.1 log104.4 log reduction in viral titer10。
Example 2
The same as example 1 except that: 8g of a 30% strength by mass hydrogen peroxide solution were added, and the amount of catalase added was 500000 u. The detection shows that the prepared pancreatin powder contains 1500u/g of trypsin and 10000u/g of pancrelipase and has no residual contact enzyme.
Method for detecting virus inactivation effect
After step (1) and before step (2), 6.5 log was added10TCID50/0.1ml titre of the indicator virus EMCV (encephalomyocarditis Virus, virus solution added at 5% from the volume of the solution, approximately 5ml of virus solution added to 100g of pancreas).
Respectively taking out samples before adding hydrogen peroxide and after adding catalase reaction, respectively inoculating the samples into Vero cell culture, observing cytopathic effect (CPE), showing the influence of the samples before adding hydrogen peroxide on the cytopathic effect in figure 4, showing the influence of the samples after adding catalase reaction on the cytopathic effect in figure 3, calculating the virus titer and the reduction value of the virus titer, wherein the virus titer is less than or equal to 1.1 log105.4 log reduction in viral titer10。
Comparative example 1
The same as example 1 except that: after the grinding in step (1), hydrogen peroxide is added without the gland autolysis.
The virus inactivation effect was measured by the same method as in example 1, and the virus titer was measured to be 4.5log101log reduction in viral titer10。
Comparative example 2
Basically the same as example 1, except that: the sequence of each step is (1), (4), (5), (2), (3), (6) and (7). Through detection, the pancreatin powder has residual catalase.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (3)
1. A method for preparing pancreatin is characterized in that: grinding pancreas, autolyzing for 4-16 h, adding hydrogen peroxide to obtain a mixture, stirring for 8h, adding catalase, reacting for 2h at 5-15 ℃, degreasing, activating, precipitating and drying to obtain pancreatin, wherein the mass percentage concentration of the hydrogen peroxide in the mixture is 0.1-2%; adding 100-1000 u of catalase into every 1mg of hydrogen peroxide; the degreasing step comprises the following steps: and (3) putting the treatment liquid treated by the catalase into a degreasing barrel, adding pre-cooled raw acetone with the temperature of 0-5 ℃ and the specific gravity density of less than or equal to 0.800, degreasing for 2 hours, and opening a valve to discharge the degreased acetone.
2. The process for producing pancreatin according to claim 1, wherein: the mixture is stirred at the temperature of 2-15 ℃.
3. The process for producing pancreatin according to claim 1, wherein: the catalase is a metabolite from bacteria or mould.
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| CN109810968B (en) * | 2019-03-13 | 2021-03-02 | 淮安麦德森制药有限公司 | Process for producing pancreatin |
| CN112442497A (en) * | 2019-09-04 | 2021-03-05 | 四川德博尔制药有限公司 | Preparation method of pancreatin |
Citations (4)
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|---|---|---|---|---|
| CN103215246A (en) * | 2013-04-11 | 2013-07-24 | 重庆奥力生物制药有限公司 | Novel production process of pancreatin |
| CN105400745A (en) * | 2015-12-04 | 2016-03-16 | 南京农业大学 | Porcine reproductive and respiratory syndrome virus (PRRSV) genetic engineering strain, inactivated vaccine thereof, and preparation method of inactivated vaccine |
| CN106399268A (en) * | 2016-09-30 | 2017-02-15 | 诺华生物科技（武汉）有限责任公司 | Method for inactivating recombinant baculoviruses |
| CN107849552A (en) * | 2015-05-19 | 2018-03-27 | 科学蛋白实验室有限责任公司 | Reduction or the method for inactivation of viruses and microorganism content during pancreatinum is produced |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8124397B2 (en) * | 2005-08-08 | 2012-02-28 | Oregon Health & Science University | Inactivating pathogens with oxidizing agents for vaccine production |
| EP2165717A1 (en) * | 2008-08-27 | 2010-03-24 | Nordmark Arzneimittel GmbH & Co.KG | Method for reducing viral and microbial load on biological extracts containing solids |
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| CN103215246A (en) * | 2013-04-11 | 2013-07-24 | 重庆奥力生物制药有限公司 | Novel production process of pancreatin |
| CN107849552A (en) * | 2015-05-19 | 2018-03-27 | 科学蛋白实验室有限责任公司 | Reduction or the method for inactivation of viruses and microorganism content during pancreatinum is produced |
| CN105400745A (en) * | 2015-12-04 | 2016-03-16 | 南京农业大学 | Porcine reproductive and respiratory syndrome virus (PRRSV) genetic engineering strain, inactivated vaccine thereof, and preparation method of inactivated vaccine |
| CN106399268A (en) * | 2016-09-30 | 2017-02-15 | 诺华生物科技（武汉）有限责任公司 | Method for inactivating recombinant baculoviruses |
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| Title |
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