CN1371992A - Method for removing organic solvent used as virus inactivator and/or detergent - Google Patents
Method for removing organic solvent used as virus inactivator and/or detergent Download PDFInfo
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- CN1371992A CN1371992A CN 01104343 CN01104343A CN1371992A CN 1371992 A CN1371992 A CN 1371992A CN 01104343 CN01104343 CN 01104343 CN 01104343 A CN01104343 A CN 01104343A CN 1371992 A CN1371992 A CN 1371992A
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Abstract
The method for removing organic solvent and/or detergent from aqueous solution by using solid phase material containing active carbon as adsorbent to make adsorption is characterized by that said method can be used for removing organic solvent including TNbp and/or detergent including Tween detergent and Triton detergent from aqueous solution including blood plasma, plasma product, gene engineering product and other biological product for injection.
Description
The present invention relates to a kind of method of from the aqueous solution, removing as the organic solvent and/or the stain remover of virus inactivating agent.
The mixture (being called for short S/D usually) of organic solvent (being called for short S usually) and organic solvent and stain remover (being called for short D usually) is mixed in the aqueous solution and is given special industrial use.A common example is that organic solvent (for example TNbp) or organic solvent/stain remover mixture (for example TNbp/Tween 80) are used as the virus inactivating agent of the aqueous solution.These materials are (for example inactivation of viruses) after the specific function of finishing them, it must be removed from the aqueous solution usually.The method of having reported at present of removing S and S/D virus inactivating agent has following several:
1) vegetable oil extraction method: European patent 0239859 (1987) discloses a kind of method with vegetables oil extraction S/D virus inactivating agent, wherein vegetables oil is added in the aqueous solution that contains the S/D agent, stirring and evenly mixing, lipid material enters oil phase (leaving standstill the upper strata that is positioned at water-soluble liquid phase), and two-phase is by leaving standstill or centrifugal method separates.Yet this separation method is to stain remover (for example Tween 80) poor effect.Even to organic solvent, need extract repeatedly usually also that could to reduce to acceptable to content low-level.For example, be 1% TNbp to original concentration, must before and after carry out three vegetables oil extractions of 20%, 10% and 5%, its content can be reduced to≤level of 10ppm.
2) size chromatography: this method is based on the kinetics size difference of other molecule in S or the S/D agent molecule and the aqueous solution, and thus the S/D agent molecule is separated (B.Horowitz, M.E.Wiebe, A.Lippin and M.H.Stry Ker, Transfusion, 25 (1985) 516).Yet this method only is only effective when preparation target molecule and S/D molecule have tangible chromatography size difference, thereby range of application greatly limits.
3) C
18The reversed phase chromatography method: this method is that one of present method in common (people such as A.M.Prince, Blood, F9 (1992) 826 for B.Horowitz, R.Bonomo) mainly is to utilize the C that grafts on the silica gel particle
18The affinity interaction of the S/D agent in the chain and the aqueous solution is separated the S/D agent from the aqueous solution.Yet this method needs chromatographic apparatus, invests greatlyyer, and the price of carrier is higher, not very economical.
4) oleophylic chromatography: this method utilizes the chromatography carrier of a kind of SDR-HyperD of being referred to as to remove the S/D agent.HyperD is framework material with the silica gel particle, with silica gel surface and to be attached to three-dimensional cross-linked acrylate copolymer on the silica gel particle be oleophylic medium people such as (, J.Chromatogr 664 (1995) 119) L.Gueffier.But same C
18Chromatography is the same, and this method needs chromatographic apparatus, and the price of carrier is higher, not very economical.
Therefore, the purpose of this invention is to provide a kind of cost low, use simple, efficient is high removes the S/D agent method.
According to an aspect of the present invention, it provides a kind of method of removing organic solvent and/or stain remover from the aqueous solution by absorption, wherein uses to contain the gac solid formation and adsorb as sorbent material.This gac solid formation is meant and contains activity charcoal powder and/or the activated carbon fiber solid material as active substance.
In the method for the invention, can comprise TNbp by removed organic solvent, and stain remover comprises Tween class stain remover and Triton class stain remover.
Method of the present invention is applicable to the removal of organic solvent in the aqueous solution and/or stain remover, and this aqueous solution for example is aqueous solution for injection.And aqueous solution for injection includes but not limited to traditional Chinese medicine injection, blood plasma and blood plasma product, recombinant product and other biological products.
Another exercise question in our application is the patent application (application on December 26th, 2000 of " as the tensio-active agent and the active carbon desorption method thereof of new-type desorbent ", application number is 00120625.7) in, our table of discovery surface-active agent has the effect of charcoal absorption material (for example methylene blue) desorb that some document has been reported, and the more deep research of this invention makes us find that gac itself has stronger adsorption to some stain remover (D).Simultaneously, we more are surprised to find, and gac all has strong adsorption for the organic solvent that is generally used for viral inactivation treatment (S), organic solvent/stain remover mixture (S/D), can be used for the removal of these materials behind the inactivation of virus.
S, D and S/D agent there are adsorbing absorbent charcoal material,, include but not limited to activity charcoal powder, activated carbon fiber and contain activity charcoal powder or the mixture of activated carbon fiber, for example gac/diatomite mixture, gac filter plate etc. according to our research.
Adsorbable organic solvent in the absorbent charcoal material surface (S) after deliberation is TNbp general in the aqueous solution inactivation of virus.
Adsorbable stain remover in the absorbent charcoal material surface (D) after deliberation is tween-80 (Tween-80), Triton X45 and Triton X100 general in the aqueous solution inactivation of virus.
After deliberation adsorbable is TNbp/Tween-80, TNbp/Triton X45 and TNbp/Triton X100 general in the aqueous solution inactivation of virus in the lip-deep S/D of absorbent charcoal material system.The concentration range of S and D is 0.3%～2.5%.
Absorbent charcoal material is to the absorption of S, D and S/D, can carry out under temperature for-10 ℃ to 40 ℃, pH is 3.5～10.0 condition.
Below will describe the present invention in more detail, but scope of the present invention never only limits to these embodiment by embodiment.Embodiment 1S, D and the S/D absorption on gac
The different solid phase material with the gac active substance (the seeing Table 1) diameter of packing into is 6mm, highly is in the stainless steel chromatography post on the HPLC instrument of 5mm.After the distilled water balance, 10ml is contained the aqueous solution (2-8 ℃) the input horizon analysis system of S, D or S/D agent (seeing Table 1), and then reclaim the sample analysis S by chromatography column, the residual quantity of D.Liquid phase flow rate is 0.5ml/min in the whole process, and gained HPLC typical curve as shown in Figure 1.The adsorptive capacity of each S, D or S/D agent sees the following form shown in 1.
Table 1:S, D and the absorption of S/D on absorbent charcoal material
*: the activity charcoal powder mixture: activity charcoal powder 50%+ diatomite 50%**: gac filter plate: the S/D agent removes in SEITZ AKS5 (Seitzshenk company, Germany) the embodiment 2S/D inactivation of virus blood plasma
| System | Adsorbed material and original concentration | Residual concentration | ||||
| Activity charcoal powder | Activated carbon fiber | The activity charcoal powder mixture * | The gac filter plate ** | |||
| ??D | ????TNbp(20000ppm) | ＜10ppm | ＜10ppm | ＜10ppm | ＜10ppm | |
| ?S | ???Tween?80(0000ppm) | 350ppm | 280ppm | 420ppm | ?380ppm | |
| ??Triton?X45(10000ppm) | ＜20ppm | ＜20ppm | ＜20ppm | ＜20ppm | ||
| ??Triton?X100(10000ppm) | ＜20ppm | ＜20ppm | ＜20ppm | ＜20ppm | ||
| ?S/D | ??0.3％TNbp+ ??1.0％Tween ????80 | ???TNbp ?(3000ppm) | ＜10ppm | ＜10ppm | ＜10ppm | ＜10ppm |
| ?Tween?80 ?(1000ppm) | ＜20ppm | ＜20ppm | ＜20ppm | ＜20ppm | ||
| ??0.3％TNbp+ ??1.0％Triton ????X45 | ???TNbp ?(3000ppm) | ＜10ppm | ＜10ppm | ＜10ppm | ＜10ppm | |
| ?Triton?X45 ?(10000ppm) | ＜20ppm | ＜20ppm | ＜20ppm | ＜20ppm | ||
| ??0.3％TNbp+ ??1.0％Triton ????X100 | ???TNbp ?(3000ppm) | ＜10ppm | ＜10ppm | ＜10ppm | ＜10ppm | |
| ?Triton?X100 ?(10000ppm) | ＜20ppm | ＜20ppm | ＜20ppm | ＜20ppm | ||
| ??1.0％TNbp+ ??1.0％Triton ????X45 | ????TNbp ?(10000ppm) | ＜10ppm | ＜10ppm | ＜10ppm | ＜10ppm | |
| ?Triton?X45 ?(10000ppm) | ＜20ppm | ＜20ppm | ＜20ppm | ＜20ppm | ||
| ??1.0％TNbp+ ??1.0％Triton ????X100 | ???TNbp ?(10000ppm) | ＜10ppm | ＜10ppm | ＜10ppm | ＜10ppm | |
| ?Triton?X100 ?(10000ppm) | ＜20ppm | ＜20ppm | ＜20ppm | ＜20ppm | ||
Add TNbp and Triton X100 and be respectively 1% to ultimate density in the 100ml human plasma, stirring is 4 hours under 30 ℃, temperature is reduced to 2-8 ℃ then.The gac filter plate of getting blood plasma diameter that 40ml contains the S/D agent and be 6cm, thickness and be 3.6mm filters, and gets the content that supernatant liquor is measured TNbp and Triton X100.The 10000ppm of the concentration of TNbp from original solution drops in the supernatant liquor＜10ppm.And the 10000ppm of the concentration of Triton X100 from original solution drops in the supernatant liquor＜10ppm.The S/D viricide removes in the embodiment 3 human plasma components
Add TNbp (1%) and Triton X100 (1%) in the human plasma, stirred 4 hours down, produce albumin and sphaeroprotein respectively through cold ethanol method then at 30 ℃.Get the refining postalbumin of 150ml (temperature-2.5 ℃, pH4.70, alcohol 8%, protein concentration 1.5%) and 50ml precipitation II lysate (4 ℃ of temperature, pH7.30, protein concentration 2%) be that 6cm, thickness are gac filter plate (SEITZ AKS5, the Seitzshenk company of 3.6 ± 2mm with diameter respectively, Germany) filter, get then and filter supernatant liquor measurement TNbp and Triton X100 content.It the results are shown in shown in the following table 2.
Table 2
The S/D viricide removes in embodiment 4 antibody
| Filter plate | Refining postalbumin | Component I I resolution of precipitate liquid | ||||||
| Before the filter | After the filter | Before the filter | After the filter | |||||
| ??TNbp | ??Triton | ????TNbp | ??Triton | ???TNbp | ?Triton | ??TNbp | Triton | |
| ??AKS?4 | ??23ppm | ??155ppm | ??＜10ppm | ??＜20ppm | ??150ppm | ?270ppm | ＜10ppm | ＜20ppm |
| ??AKS?5 | ??23ppm | ??155ppm | ??＜10ppm | ??＜20ppm | ??150ppm | ?270ppm | ＜10ppm | ＜20ppm |
At 100ml pH is to add TNbp/Triton X100 mixed solution in 4.5 the human plasma gamma-globulin (protein concentration 10%) to make the concentration of TNBP in solution be 0.3%, and the concentration of Triton X100 is 1%.Stirring reaction is 8 hours under 20-25 ℃ of condition, and then the strainer (including the 5g activated carbon fiber) by containing activated carbon material.Gained the results are shown in shown in the following table 3.
Table 3
The removal of S/ID virus inactivating agent in embodiment 4 blood coagulations eight factors
| The protein loss | ????＜2％ |
| The TNBP residual volume | ????3ppm |
| Triton X100 residual volume | ????13ppm |
Add the S/D agent in 3 times of 10ml dissolving human plasma cryoprecipitate lysate and 10ml recombinate eight factor solution, ultimate density is 0.3%TNBP and 1%Triton X100.Make this mixture at room temperature reaction after 8 hours, be cooled to 4 ℃ then, then by the pretreated strainer that contains activated carbon material of a process distilled water, this strainer includes SEITZ AKS5 filter plate (the Seitzshenk company that diameter is 6cm, Germany), and, collect sample at last and analyze S and the residual volume of D with the flushing of 40ml aquae destillata.It the results are shown in following table 4.
Table 4
The removal of the S/D agent in embodiment 5 medicinal plants
| Sample | Concentration in the aqueous solution | Concentration after activated carbon treatment | |
| Human blood eight factors | Eight factors of recombinating | ||
| ????TNbp | ????3000ppm | ????6ppm | ????4ppm |
| ??Triton?X100 | ???10000ppm | ????15ppm | ????13ppm |
In the work in-process of 100ml Radix Astragali injection production, add TNbp and Triton X100 and be respectively 0.3% and 1% to ultimate density.At room temperature stirred then 8 hours, and carried out S/D and handle.After stirring is finished temperature is reduced to 2-8 ℃.The gac filter plate of getting sample diameter that 40ml contains the S/D agent and be 6cm, thickness and be 3.6mm filters (AKS 5 filter plates, Seitzshenk company, Germany).Filtering supernatant is also measured TNbp and Triton X100 Determination on content.The 3000ppm of the concentration of TNbp from original solution drops in the supernatant liquor＜10ppm.And the 10000ppm of the concentration of Triton X100 from original solution drops in the supernatant liquor＜20ppm.
Claims (6)
1, a kind of method of removing organic solvent and/or stain remover from the aqueous solution by absorption is wherein used to contain the gac solid formation and adsorb as sorbent material.
2, method according to claim 1, wherein said organic solvent comprises TNbp.
3, method according to claim 1, wherein stain remover comprises Tween class stain remover and Triton class stain remover.
4, method according to claim 1, wherein the gac solid formation is to comprise activity charcoal powder and/or the activated carbon fiber solid material as active substance.
5, the method for claim 1, the wherein said aqueous solution are aqueous solution for injection.
6, method as claimed in claim 5, wherein aqueous solution for injection comprises blood plasma and blood plasma product, recombinant product and is the drug for injection of raw material with the plant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01104343 CN1230526C (en) | 2001-02-27 | 2001-02-27 | Method for removing organic solvent used as virus inactivator and/or detergent |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01104343 CN1230526C (en) | 2001-02-27 | 2001-02-27 | Method for removing organic solvent used as virus inactivator and/or detergent |
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| CN1371992A true CN1371992A (en) | 2002-10-02 |
| CN1230526C CN1230526C (en) | 2005-12-07 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1302009C (en) * | 2005-09-05 | 2007-02-28 | 武汉海特生物制药股份有限公司 | Technology of preparing rat nerve growth factor using organic solvent virus deactivation method |
| US7662411B2 (en) | 2004-06-29 | 2010-02-16 | Reliance Life Sciences Pvt. Ltd. | Process for removal of solvent and detergent from plasma |
| CN1796546B (en) * | 2004-11-18 | 2011-08-10 | 奥索临床诊断有限公司 | Optimal placement of a robust solvent/detergent process post viral ultrafiltration of an immune gamma globulin |
| CN107988192A (en) * | 2009-07-31 | 2018-05-04 | 百深有限责任公司 | For purify restructuring ADAMTS13 and other oroteins method with and combinations thereof |
-
2001
- 2001-02-27 CN CN 01104343 patent/CN1230526C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7662411B2 (en) | 2004-06-29 | 2010-02-16 | Reliance Life Sciences Pvt. Ltd. | Process for removal of solvent and detergent from plasma |
| CN1796546B (en) * | 2004-11-18 | 2011-08-10 | 奥索临床诊断有限公司 | Optimal placement of a robust solvent/detergent process post viral ultrafiltration of an immune gamma globulin |
| CN1302009C (en) * | 2005-09-05 | 2007-02-28 | 武汉海特生物制药股份有限公司 | Technology of preparing rat nerve growth factor using organic solvent virus deactivation method |
| CN107988192A (en) * | 2009-07-31 | 2018-05-04 | 百深有限责任公司 | For purify restructuring ADAMTS13 and other oroteins method with and combinations thereof |
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| Publication number | Publication date |
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| CN1230526C (en) | 2005-12-07 |
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