CN1153062A - Human urinary trypsin inhibitor preparation and method for production thereof - Google Patents
Human urinary trypsin inhibitor preparation and method for production thereof Download PDFInfo
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- CN1153062A CN1153062A CN 96121137 CN96121137A CN1153062A CN 1153062 A CN1153062 A CN 1153062A CN 96121137 CN96121137 CN 96121137 CN 96121137 A CN96121137 A CN 96121137A CN 1153062 A CN1153062 A CN 1153062A
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Abstract
A human urinary trypsin inhibitor (HUTI) preparation, which is free from virus genome, and a process to produce HUTI, which is obtained by the following process: a HUTI solution with its viral infectivity deactivated sufficiently, treated under such conditions as not to deactivate HUTI, is subjected to filtration treatment by using porous hollow fibers 1-100nm in average pore size. According to the invention, due to the HUTI in the preparation can not be degraded, it can obtain a highly safe HUTI preparation, which is free from virus infectivity and has a high stability. In addition, this invention also provides a process which can produce the said preparation efficiently.
Description
The present invention relates to high human urinary trypsin inhibitor preparation of a kind of safety and production method thereof.
People such as Proksch at first from Urina Hominis with complete isolated in form and be purified into a kind of human urinary trypsin inhibitor (hereinafter referred HUTI) [J.Lab.Clin.Med., 79,491 (1972)].This human urinary trypsin is a kind ofly to contain tens percent the sialic acid and the glycoprotein of neutral hexose, and this proteic molecular weight approximately is 67KD behind gel filtration, and isoelectric point, IP is 2-3[J.Lab.Clin.Med., 79,491 (1972), Jap.J.Urol., 74,1627 (1983), Proteinase Inhibi tors, 12,389 (1986), Biochem.Biophys.Res.Commun., 109,1247 (1982)].
When HUTI suppresses trypsin in the pancreas enzyme and chymase especially consumingly, it does not resemble Antithrombin III (AT-III) or gabexate mesilate (gabexate mesylate) (FOY), almost or fully do not suppress cohesion and haemolysis brinase [Folia pharmacol.Japan, 81,235 (1983)].In view of the Stabilization of HUTI on lysosome membrane, it is generally acknowledged that it can suppress the production of lysosomal enzyme and myocardial depressant factor [Jap.J.Anes th., 33,137 (1984)].
Because HUTI has above-mentioned activity and effect, can use it for acute pancreatitis and acute circulatory failure, and use clinically and not have the HUTI preparation preparation of side effect greatly to be used to handle acute pancreatitis as a kind of, perform the operation and endotoxin shock.
There is the possibility that contains all contaminations virus in the protein formulation (be not only those preparations that prepared by body fluid, and also have those preparations of the material preparation of being produced by a kind of process recombinant technique) that comes from the people in raw material.In these pollutant viruses, had been found that hepatitis C virus (hereinafter referred HCV) in recent years, and its prevention and the treatment of infection intactly established.Although the HUTI preparation still may contain the genome of this virus, with regard to Virus Pollution, handle their inactivations substantially in the HUTI preparation by liquid heat.Though viral genome itself be do not have communicable, thereby it need be removed high-purity and the safety that guarantees preparation from preparation.
Therefore, an object of the present invention is to provide a kind of antiviral HUTI preparation, it is substantially free of viral genome and has very high safety, and a kind of production method with high efficiency and excellent operability also is provided.
According to the present invention, sent out at present to see and adopted the liquid heat processing method, make the virally inactivated and acidic protein enzyme deactivation of pollutant but do not make the HUTI inactivation basically, a kind of perforated membrane of reuse (average pore size 1nm-100nm) filters to produce and does not a kind ofly contain viral genome and have high-purity and the safer HUTI preparation of high stability.
HUTI preparation of the present invention is substantially free of viral genome, does not particularly contain the HCV genome.
The implication that " is substantially free of viral genome " is can not detect viral genome in preparation; Promptly, virus genomic content is no more than the 1PCR units per ml, wherein 1PCR unit refers to the Vol.32 by Transfusion, the PCR method described in the pp.824-828 (1992), the i.e. minimum of the detected RNA of Nested (Double) RT-PCR method.The method for optimizing of Nested (Double) RT-PCR method describes in detail in experimental example 1.
HUTI preparation of the present invention preferably has at least 2000 units/milligram albumen in preparation, more preferably the HUTI of 2000-4500 unit/proteic specific activity of milligram.Here the HUTI of 1 unit refers to when HUTI and the reaction of 2ug trypsin, and it suppresses the tryptic active HUTI amount of 1ug.Specific activity is expressed as the HUTI unit of per 1 milligram of total protein, and it can be measured by the Kjeldahl method
The HUTI that contains in the preparation of the present invention preferably has molecular weight 60000-70000 and isoelectric point, IP is about 2-3.
The raw material of HUTI preparation of the present invention is not specially limited, as long as it is the compositions that contains HUTI, it can contain and comes from urine, cultured cell, by genetic engineering any HUTI that prepare or other derivants.Used HUTI only comprises otherwise deactivated a kind of HUTI with excalation or the alternate aminoacid sequence of part among the present invention, has HUTI and other HUTI of one or more aminoacid being joined this aminoacid sequence.
The viral example that may contain in the raw material of HUTI preparation comprises HCV, hepatitis b virus (HBV), cytomegalovirus (CMV), parvovirus and other this viroids.
Method of the present invention is preferred for producing HUTI preparation of the present invention, this method may further comprise the steps: fully removing possible pollutant viral infectivity and do not making basically under the condition of HUTI inactivation, handle a kind of feedstock composition that contains HUTI, filter by a kind of perforated membrane (average pore size 1nm-100nm) again.Basically the condition that does not make the HUTI inactivation is with after the virally inactivated processing, makes the residual activity of HUTI be not less than 90%.
Possible pollutant viral infectivity be can fully remove and the preferred heat treated of processing method, particularly heat treated under liquid state of HUTI inactivation do not made basically.
When using this liquid heat to handle, fully removing possible pollutant viral infectivity and the solution that will contain HUTI under the condition of HUTI inactivation is heated, these conditions are that the scope of pH value is 5-7, and treatment temperature is 60 ℃-100 ℃, and the processing time is 3 minutes-15 hours.
After above-mentioned heat treated, preferably this solution was further heated 1-60 minute preferably approximately 30 minutes (when pH value is transferred to 2-5) under liquid state.This heat treated in described lower pH value scope can make the acid protease that makes degraded HUTI in the HUTI solution simultaneously and above-mentioned virally inactivated in high temperature deactivation.The inactivation of acid protease makes preparation have high stability and do not contain the HUTI of degraded in preparation.
The acid protease here comprises the acid protease with following character:
(i) particularly can decomposing H UTI in (in the scope of pH value at 2-4) under a kind of sour environment;
(ii) use pepstatin (a kind of aspartic acid inhibitor) or bestatin (a kind of amastatin) with its inhibition; With
(iii) it was handled 1 minute at 100 ℃, or in the scope of 60 ℃ of pH value, handled about 30 minutes at 2-4, can inactivation.
After liquid heat was handled, the solution that will contain HUTI was by perforated membrane such as porous hollow fiber and membrane filter filtration, preferred porous hollow fiber.This porous hollow fiber is a kind of many porous tubular filament that have, and periphery wall is run through from hollow parts inboard to the outside of air silk in described hole, and this periphery wall plays filter membrane.
The used perforated membrane average pore size of the present invention is 1nm-100nm.The virus of depolluting can be removed in the hole of this size from contain HUTI solution.With regard to porous hollow fiber, the average pore size in hole is 1nm-100nm on the used porous hollow fiber periphery wall of the present invention, preferred 10nm-50nm, more preferably 15+/-2nm.
In addition, the preferred 330+ of hollow parts internal diameter of porous hollow fiber/-30um.The preferred 27+ of the thickness of periphery wall (film thickness)/-3um.
When the material that constitutes perforated membrane is not subjected to particular restriction, preferred regenerated cellulose.Adopt microphase-separated method (Am.Chem.soc., 9,197-228 (1985)) can prepare a kind of porous hollow fiber of making by regenerated cellulose from cellulose cuoxam.
This porous hollow fiber preferably uses in a kind of assembly.For example, many porous hollow fibers are tied together in the mode that is parallel to each other, be contained in the tube also bonding with binding agent.
In filter process, the solution temperature that contains HUTI is 4 ℃-50 ℃, preferred 4 ℃-20 ℃.
Filtering used pressure is 0.1kgf/cm
2-1kgf/cm
2, preferred 0.4kgf/cm
2-0.9kgf/cm
2
Under said temperature and pressure condition, the solution that contains HUTI effectively can be filtered.
When the protein concentration of the solution that contains HUTI is 0.01W/V%-10W/V%, during preferred 0.1W/V%-4W/V%, this solution can be filtered effectively.
Used filter method comprises crossing filtering method (circulation method) and dead-end filtration method (acyclic method), and wherein the crossing filtering method is with the strain rate filtering solution, and the dead-end filtration method is not with the strain rate filtering solution.Preferred crossing filtering method or use the dead-end filtration method of an air pressure.
Before filtering under these conditions, preferably the solution that contains HUTI that is used for the inventive method is adopted a kind ofly to be different from doughnut of the present invention or membrane filter tentatively filters.
After liquid heat is handled, when the solution that will contain HUTI filters, can make that this solution is easier effectively to be handled this solution by filter.
After the filtration, adopt the solution that conventional method will contain HUTI to make a kind of liquid preparation or dry preparation.
HUTI preparation of the present invention can contain suitable medicated premix pharmaceutically acceptable commonly used, as, antiseptic, chelating agen, and thickening agent, isotonic agent and the pharmaceutical preparation necessary composition of filling a prescription.
Examples of preservatives comprises benzalkonium chloride, p-Hydroxybenzoate, and benzyl alcohol is to chloromethyl 2-methyl-3-biphenylmethanol (parachloromethaxenol), chlorocresol, phenethanol, sorbic acid and salt thereof, thiomersalate, chlorobutanol or the like; The example of chelating agen comprises sodium ethylene diamine tetracetate, sodium citrate, Vitrafos or the like; The example of thickening agent comprises polyvinylpyrrolidone, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, sodium polyacrylate or the like; The example of isotonic agent comprises aminoacid (as glycine), glycerol, Polyethylene Glycol, propylene glycol, sodium chloride, monosaccharide, disaccharide, sugar alcohol or the like.
According to the present invention fully remove possible pollutant viral infectivity and do not make basically handle under the condition of HUTI inactivation re-use a kind of perforated membrane filter can produce do not have the HUTI degraded in the preparation do not contain a kind of HUTI preparation that pollutant are viral and have high-purity, high security and high stability.The method of the described preparation of effective production also is provided in addition.
In embodiment below and the experimental example the present invention is explained in more detail, but they be not be used for limiting of the present invention.Embodiment 1 (1) raw material
According to J.Lab.Clin.Med., the method described in 79,491 (1972) adopts fresh Urina Hominis to prepare a kind of HUTI solution as the raw material of preparation.The concentration of this HUTI solution is about 2W/V%.(2) liquid heat is handled
The pH value of the HUTI solution in (1) is transferred to 5.5, this solution was heated 10 hours at 60 ℃.Then, pH value is transferred to 3.5, reheat 30 minutes.(3) filter
The HUTI solution of handling through liquid heat is carried out following filtration.
Containing BMM (the Ben Baige microporous membrane is made by Asahi Chemical) as porous hollow fiber.BMM is a kind of porous hollow fiber that makes according to cuprammonium process from regenerated fiber.
PLANOVA15 (trade mark, by Asahi Chemical Indus try Co., Ltd. makes) has the periphery wall of the multiple structure that is no less than 150 layers, makes the BMM assembly with it.The form of porous hollow fiber is as follows in assembly:
Average pore size 15+/-2nm
The internal diameter 330+ of doughnut/-2um
The thickness 27+ of film/-3um
This assembly is by above-mentioned porous hollow fiber, but a kind of polycarbonate plastic container of pressurized, heated and a kind of with its adherent polyurethane binder composition.This assembly is sterilized in a kind of autoclave, again the distilled water of injection is filled assembly.Prove the safety (selecting from the product description of BMM) of the various materials that constitute PLANOVA15 according to the method for determining in the Japanese Pharmacopoeia.
Filtering condition is: the temperature of HUTI solution is 10 ℃-15 ℃, and filtering pressure is 0.8kgf/cm
2According to the filtercondition of embodiment with the HUTI solution of 12L at every 1m
2The effective face of above-mentioned porous hollow fiber on handled 1 hour, wherein the effective gross area of face porous hollow fiber periphery wall plays a part film.After filtration treatment is finished, adjust HUTI solution tire and with this solution filtration sterilization.The HUTI solution of gained is mixed with liquid preparation.
Measure the virus genomic amount of hepatitis C in the preparation of gained by the method for introducing in the following experimental example 1.The amount that the result measures does not surpass detectable limit (1PCR units per ml).
Experimental example 1: the affirmation that virus is removed
With HCV projection verification experimental verification result.Specifically be that the HUTI solution example that will be added with the 2W/V% of the positive blood plasma of HCV under the filtercondition described in the embodiment 1 (3) filters, before and after filtering, with the HCV genome in the PCR method mensuration solution.
(a) from sample, extract HCV RNA
Guanidine, guanidine thiocyanate and sarcosil add and may contain in the sample solution of pollutant virus.Then, with phenol/chloroform to this solution deproteinization.Use the isoamyl alcohol precipitated rna.Every kind of reaction is all at room temperature carried out.
(b) prepare HCV cDNA with reverse transcriptase
Unordered hexamer is combined with the RNA of acquisition in (a), obtained HCV cDNA with reverse transcriptase in 1 hour 42 ℃ of reactions then.
(c) with Nes ted PCR method amplification cDNA
With HCV primer (using 5 ' the distolateral 5 '-GTGAGTACACCGGAATTGCC-3 ' and 5 ' that obtains-CACGGTCTACGAGACCTCCC-3 ' work first primer and 5 '-ACGACCGGGTCCTTTCTTGG-3 ' and 5 '-GCACTCGCAAGCACCCTATC-3 ' to make second primer) and Taq polymeric enzymatic amplification (HCV) cDNA from the genomic noncoding region of HCV.In the time of 94 ℃, carry out 30 seconds thermal denaturation, in the time of 55 ℃, carry out 2 minutes annealing, in the time of 72 ℃, carry out 2 minutes extension.With these step repetitive cycling 20 times or more times, obtain a kind of product.
(d) analysis of PCR product
The product that will obtain in (c) carries out the polyacrylamide gel electrophoresis of 6W/V% and handles and with ethidium bromide staining it is detected.
Result of the test shows that the genomic amount of HCV is 10 in the preceding sample solution of filtration
3The PCR units per ml is filtered its amount of back and is dropped to and be no more than detectable limit (1PCR units per ml).Experimental example 2: filtercondition
(1) filter pressure
Use 2W/V%HUTI solution and with embodiment 1 in used same components, filtering solution under following condition: temperature, 15 ℃, filter pressure, 0.2kgf/cm
2, 0.5kgf/cm
2And 0.8kgf/cm
2Measure the filtering solution amount of per minute.The results are shown in Table 1.
Table 1
| Processing pressure (kgf/cm 2) | ????0.2 | ????0.5 | ????0.8 |
| Filtering solution amount (ml/min) | ????0.55 | ????2.14 | ????3.57 |
(2) the preliminary filtration
Before the filtration, filter HUTI solution with a kind of Mycoderma (aperture 0.45um, membrane filter) that removes.This preliminary filtration can make filtration treatment more effective.Experimental example 3: the character of preparation and stability
(1) character
In embodiment 1, measure the activity of HUTI before and after filtering, the specific activity of HUTI, sugared content, the variation of pH value and thermal source (according to the pyrogenic test in the Japanese Pharmacopoeia).The results are shown in Table 2.In addition, measure the variation of filtering the front and back molecular weight distribution with HPLC.From these results, show that the response rate of HUTI is not less than 95% (comparing with the solution that contains HUTI as raw material), and before and after handling, do not find the activity of HUTI, the change of character such as molecular weight distribution.
Table 2
| Project | Reference material | Before BMM handles | After BMM handles | Productive rate (%) |
| Character | Colourless, transparent, do not have and smell or tasteless liquid | Colourless, transparent, do not have and smell or tasteless liquid | Colourless, transparent, do not have and smell or tasteless liquid | - |
| Active | 50000 units per ml or more than | 75100 units per ml | 71700 units per ml | 95.5 |
| Specific activity | 30000 unit/milligrams or more than | 3560 unit/milligrams | 3550 unit/milligrams | 99.7 |
| Sugar content | 11-15％ | 14％ | 14％ | 100.0 |
| ??pH | 5.5-7.0 | 5.9 | 6.0 | - |
| Thermal source | For the first time: body temperature increases＜0.6 ℃ of total body temperature and increases＜1.5 ℃ of second time: 0.6 ℃ or animal are more than 0.6 ℃ or be lower than 0.6 ℃ | Conformance with standard | Conformance with standard | - |
(2) stability test
The HUTI preparation of gained among the embodiment 1 was preserved 6 months down at 25 ℃, measured heat stability, the activity of molecular weight distribution and HUTI detects its stability.
The result has good stability, and molecular weight distribution etc. does not change.Experimental example 4:DNA negative test
Measure the amount of total DNA of the HUTI preparation of gained among the embodiment 1 with Threshold system (making) by Molecular Debices.Extract DNA according to its appended material with a kind of DNA extraction test kit (by Wako PureChemical Industries, Ltd. makes).The content that found that total DNA is no more than detectable limit (2pg/ml), proves that preparation is not subjected to viral pollution after filtration treatment of the present invention.
Claims (19)
1. a preparation that contains human urinary trypsin inhibitor is characterized in that said preparation is substantially free of the virus base
Because of group.
2. preparation according to claim 1, wherein viral genome is the genome of hepatitis C virus.
3. preparation according to claim 1, wherein human urine trypsin inhibitor have at least 2000 units/
The proteic specific activity of milligram.
According to claim 1 to any preparation described in the claim 3, it is to use a kind of perforated membrane
Filtration contains that the solution of human urinary trypsin inhibitor obtains, and described perforated membrane average pore size is 1nm-
100nm, described solution remove the infectiousness of possibility pollutant virus and do not make the people basically abundant
Handled under the condition of urinary trypsin inhibitor inactivation.
5. preparation according to claim 4, wherein perforated membrane is a kind of porous hollow fiber.
6. preparation according to claim 4, wherein filter and carry out under following condition: temperature is 4 ℃
-50 ℃ is 0.1kgf/cm with filter pressure
2-1kgf/cm
2
7. preparation according to claim 4, wherein the protein concentration that contains of solution is 0.01W/V%-
10W/V％。
8. preparation according to claim 4, wherein handling is heat treated.
9. preparation according to claim 8, wherein heat treated is to handle in liquid heat.
10. preparation according to claim 9, it is at pH5-7 and 60 ℃-100 ℃ process liquid
Heat treated obtained in 3 minutes-15 hours.
11. preparation according to claim 10, wherein liquid heat handle also comprise other pH value
Adjusting to the liquid heat of carrying out behind the 2-5 handles.
12. a method that is used to produce a kind of human urinary trypsin inhibitor preparation, it comprises uses a kind of porous
Membrane filtration contains the solution of human urinary trypsin inhibitor, and described perforated membrane average pore size is 1nm-
100nm, described solution remove the infectiousness of possibility pollutant virus and do not make the people basically abundant
Handled under the condition of urinary trypsin inhibitor inactivation.
13. according to the method for claim 12, wherein perforated membrane is a kind of porous hollow fiber.
14. according to the method for claim 12, wherein filter and carry out under following condition: temperature is 4 ℃
-50 ℃ is 0.1kgf/cm with filter pressure
2-1kgf/cm
2
15. method according to claim 12, wherein the protein concentration that contains of solution is 0.01W/V%-
10W/V％。
16. method according to claim 12, wherein handling is heat treated.
17. method according to claim 16, wherein heat treated is to handle in liquid heat.
18. method according to claim 17, wherein liquid heat is handled pH5-7 and 60 ℃-100
℃ carried out 3 minutes-15 hours.
19. method according to claim 18 also comprises other pH value is transferred after liquid heat is handled
Putting in order the liquid heat of carrying out behind the 2-5 handles.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96121137 CN1153062A (en) | 1995-10-04 | 1996-10-04 | Human urinary trypsin inhibitor preparation and method for production thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP257771/95 | 1995-10-04 | ||
| CN 96121137 CN1153062A (en) | 1995-10-04 | 1996-10-04 | Human urinary trypsin inhibitor preparation and method for production thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1153062A true CN1153062A (en) | 1997-07-02 |
Family
ID=5126767
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96121137 Pending CN1153062A (en) | 1995-10-04 | 1996-10-04 | Human urinary trypsin inhibitor preparation and method for production thereof |
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| CN (1) | CN1153062A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044554A (en) * | 2012-05-14 | 2013-04-17 | 旭华（上海）生物研发中心有限公司 | Human urinary trypsin inhibitor (hUTI) of reorganization-dimerization and preparation method and application thereof |
| CN103102409A (en) * | 2011-11-14 | 2013-05-15 | 上海枫华制药有限公司 | Method for inactivating virus contained in trypsin inhibitor extracted from human urine |
-
1996
- 1996-10-04 CN CN 96121137 patent/CN1153062A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103102409A (en) * | 2011-11-14 | 2013-05-15 | 上海枫华制药有限公司 | Method for inactivating virus contained in trypsin inhibitor extracted from human urine |
| CN103044554A (en) * | 2012-05-14 | 2013-04-17 | 旭华（上海）生物研发中心有限公司 | Human urinary trypsin inhibitor (hUTI) of reorganization-dimerization and preparation method and application thereof |
| CN103044554B (en) * | 2012-05-14 | 2014-08-27 | 旭华（上海）生物研发中心有限公司 | Human urinary trypsin inhibitor (hUTI) of reorganization-dimerization and preparation method and application thereof |
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