CN100413542C - Pathogen inactivator composition for blood or blood component and its compounding process - Google Patents
Pathogen inactivator composition for blood or blood component and its compounding process Download PDFInfo
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- CN100413542C CN100413542C CNB2006100272247A CN200610027224A CN100413542C CN 100413542 C CN100413542 C CN 100413542C CN B2006100272247 A CNB2006100272247 A CN B2006100272247A CN 200610027224 A CN200610027224 A CN 200610027224A CN 100413542 C CN100413542 C CN 100413542C
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Abstract
The present invention relates to the technical field of an inactivator for pathogens in blood constituents or blood for clinical blood transfusion and a preparing method thereof. The present invention provides a composition of a blood pathogen inactivator, which is composed of a photosensitizer for inactivating pathogens in blood or blood constituents, and auxiliary material for intravenous infusion, wherein the quality of the auxiliary material for intravenous infusion is 2 to 10 times of that of the photosensitizer. The pathogen inactivator in the composition of the present invention is solid, so that the stability of the pathogen inactivating photosensitizer guaranteed. Besides, the preparing technology of pyrogen removal at high temperature and aseptic filtration is carried out to the pathogen inactivator and the relevant auxiliary material thereof, so that the scientific preparing and adding problems of pathogen inactivators for the existing photochemical inactivation of pathogens in blood plasma or blood constituents are solved.
Description
Technical field
The present invention relates to clinical blood transfusion with blood or blood constituent pathogen inactivator and compound method technical field thereof.
Background technology
Blood transfusion is the important support means of modern medicine, the whole blood of clinical infusion is a kind of generalized connective tissue that is made of blood plasma and various hemocyte, can be with physical method with blood constituents such as separation of whole blood protoerythrocyte, platelet, granulocyte, blood plasma and cryoprecipitates, the blood transfusion method that blood constituent is respectively applied for the various disease treatment is called component blood transfusion.Owing to compare with the whole blood infusion, component blood transfusion has that clinical effectiveness is remarkable, adverse reaction rate is low, be easy to preserve and save advantages such as blood resource, thereby is widely adopted, and becomes the principal mode of clinical blood transfusion.
Utilizing the research of pathogen that comprises virus in the photochemical method deactivation blood is to transfuse blood in recent years in the medical domain by the research direction of extensive concern, its principle is for adding pathogen inactivator-photosensitizer in whole blood or blood constituent, after rayed, sensitiser absorption luminous energy, electron transfer can take place or excite produce the singlet molecular oxygen, the framing structure that forms covalency additive compound or destruction nucleic acid in the nucleic acid specific region is to reach pathogen inactivated effect, last filtering photosensitizer is prepared into safe blood constituent.China Patent No. is that " method of blood-plasma virus killing and device thereof " patent of invention of 98121328.6 has elaborated the application of methylene blue photochemical method in blood-plasma virus killing.This pathogen inactivated method is promoted the use of in a big way in the whole nation, in use we to the degree of accuracy of the carrier of photosensitizer, photosensitizer consumption, add photosensitizer quality control etc. optimize again.
2004 the 17th reports such as volume supplementary issue p185 " application of methylene blue solid dosage forms in blood-plasma virus killing " Huang Yuwen of document " China's blood transfusion magazine ", prior art mainly is the operation of liquid methylene blue, its major defect: serge blue is understable in liquid, meets light chemical reaction easily takes place; The liquid serge blue is not suitable for long preservation and transportation; The liquid serge blue has carried out dilution once more to blood plasma; The exploitation and the production of serge blue-multi-joint bag system have been limited.The main method that adds at present both at home and abroad pathogen inactivator is directly to add the low-concentration liquid pathogen inactivator, and liquid pathogen inactivated photosensitizer agent can very fast degraded when low concentration and lose pathogen inactivated effect; Also have and use the solid type pathogen inactivator, exist single dose inaccurate, inhomogeneous, and be difficult to solve pathogen inactivator and add aseptic, the apyrogeneity of adjuvant and the difficult problem of no insoluble microgranule.
Summary of the invention
The object of the present invention is to provide and a kind ofly not only can keep stable in the pathogen inactivator 2 years (photosensitizer content be not less than labelled amount 90%), but also can make the adding dosage of pathogen inactivator accurate, and pathogen inactivator and adjuvant apyrogeneity thereof, aseptic, do not have an insoluble microgranule, meet the blood of intravenous drip instructions for use or the collocation method of blood constituent pathogen inactivator, this that makes kind of pathogen inactivator carries out fully pathogen inactivated the time blood or blood constituent, do not introduce ectogenic pollution, the person does not cause side reaction to accepting the infusion.
The compound method of blood of the present invention or blood constituent pathogen inactivator may further comprise the steps:
The first step: get recipe quantity photosensitizer (folding remove moisture and impurity level) but and photosensitizer quality 2-10 venoclysis doubly be dissolved in the useable solvents with adjuvant, and it is complete to make it dissolving;
Second step: be heated to 40-80 ℃, in solution, add activated needle-use activated carbon then, insulated and stirred 20～40 minutes, filtered while hot, it is 0.1mg/ml-1g/ml that filtrate adds identical solvent to the concentration of photosensitizer, fine straining to midbody solution does not have the microgranule more than the 25um repeatedly, and the no microgranule intermediate after the filtration is standby after pyrogen test is qualified;
The 3rd step: midbody solution is dripped in the desired amount on the carrier of cleaning, under hundred grades of cleaning conditions, dry.
In the step 2, preferably in the concentration range of 0.5mg/ml-50mg/ml, most preferred concentration is in the 2mg/ml-20mg/ml scope for the content of photosensitizer in the described midbody solution.The 3%-10% that the use amount of active carbon is generally pressed photosensitizer and adjuvant gross weight adds.The aperture of the hole filter membrane that uses during filtration is preferably less than 0.22um.
Used solvent can be water for injection, ethanol, acetone or ether in step 1 and the step 2, or two kinds mixed liquor wherein, is preferably water for injection or ethanol, most preferably is water for injection or water for injection and alcoholic acid mixed solution.
Used carrier can be medicinal macromolecular material such as mylar etc. in the step 3, is preferably mylar.Its effect is with the photosensitizer solution absorbs in the above, dries then, and the blood disease inactivator composition addition that forms like this behind the solid is more accurate, disperses also very even.
Photosensitizer be meant can with the bonded photosensitizer of pathogenic microorganism nucleic acid or peplos in the blood, as methylene blue, riboflavin, benefit bone ester or derivatives thereof etc., preferably use methylene blue, mend bone ester and derivant thereof, most preferably use methylene blue.
But venoclysis is selected from glucose with adjuvant, mannitol, fructose, Nulomoline, maltose, sorbitol, crystalline maltose, erythrose, lactose, galactose and various vegetable polysaccharides, polyglucose, oxypolygelatin (polygeline, succinylated gelatin), carboxymethyl starch, hetastarch 706, Dextran 10,20,40,70, polyvinyl pyrrolidone, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, cetomacrogol 1000,2000, the L-leucine, the L-proline, the L-isoleucine, the L-phenylalanine, the L-lysine acetate, the L-threonine, the L-methionine, the L-tryptophan, L-histidine (N-acetyl-L-tryptophan 0.52), L-tyrosine, the L-valine, the L-alanine, the L-serine, glycine, the L-arginine, the L-aspartic acid, the L-cysteine hydrochloride, but veins such as L-glutamic acid are with supplementary material or its mixture, and most preferably the adjuvant of Shi Yonging is the glucose of injection stage, mannitol, the single component in hetastarch or the dextran or the compositions of multiple composition.Beneficial effect of the present invention: the pathogen inactivator in the present composition is solid-state, not only guaranteed the stability of pathogen inactivated photosensitizer, and pathogen inactivator and relevant auxiliary materials thereof adopted the preparation technology of high temperature depyrogenation, aseptic filtration, thereby science preparation and interpolation problem that present blood plasma or blood constituent carry out the pathogen inactivated pathogen inactivator of photochemistry have been solved.
The specific embodiment
Embodiment 1
The methylene blue and the glucose of recipe quantity are joined in the 50ml water for injection, fully dissolving, be heated to 70 ℃, in solution, add activated needle-use activated carbon 0.12g again, insulated and stirred 30 minutes, filtered while hot, filtration uses the aperture of microporous filter membrane less than 0.22um, after the good water for injection of midbody solution reuse fine straining of no microgranule adds to the 100ml standardize solution after filtering, standby.Medicinal mylar every cleaning drips above-mentioned pathogen inactivator midbody solution 10ul then, under 100 grades of laminar flow hood, dry, through content, aseptic, pyrogen, microgranule etc. after the assay was approved, promptly make solid blood or blood constituent pathogen inactivator composition, use with carrier to can be applicable to the bloodborne pathogens inactivating device.Concrete prescription sees Table one:
Table one
| Title | Recipe quantity | Be somebody's turn to do the effect of product in the prescription |
| Methylene blue (anhydride) | 230mg | Principal agent |
| Glucose | 1.7g | Excipient |
| Mylar | 10000 (∮=5,5mm) | Carrier |
| Water for injection | In right amount | Solvent and abluent |
| Medicinal alcohol | In right amount | Solvent and abluent |
The content of the mylar absorption methylene blue compositions of this embodiment preparation is the 20.8ug/ sheet after testing, and aseptic, pyrogen test is qualified, and two pharmacopeia appendix ixC regulations that detection of particulates meets 2005 meet the injection requirement.
The pathogen inactivated authentication method and the effect of the mylar absorption methylene blue compositions of this embodiment preparation see Table two:
Table two
| Model virus | Verification method | Effect is judged |
| VSV | The cytopathy political reform | ＞6lgTCID 50 |
| SINDBIS | The cytopathy political reform | ＞6lgTCID 50 |
| HCV | Detection of nucleic acids | The free nucleic acid amplified production |
Embodiment 2
The methylene blue and the glucose of recipe quantity are joined in the 200ml volumetric flask, the medicinal alcohol 100ml of adding 50%, fully dissolving is heated to 45 ℃, fully dissolving, be heated to 45 ℃, in solution, add activated needle-use activated carbon 0.8g, insulated and stirred 30 minutes again, filtered while hot, filtration uses the aperture of microporous filter membrane less than 0.22um, and is after the 50% good ethanol of midbody solution reuse fine straining of no microgranule adds to the 200ml standardize solution after filtering, standby.Medicinal mylar every cleaning drips above-mentioned pathogen inactivator midbody solution 20ul then, under 100 grades of laminar flow hood, dry, through content, aseptic, pyrogen, microgranule etc. after the assay was approved, promptly make solid blood or blood constituent pathogen inactivator composition, use with carrier to can be applicable to the bloodborne pathogens inactivating device.Concrete prescription sees Table three:
Table three
| Title | Recipe quantity | Be somebody's turn to do the effect of product in the prescription |
| Methylene blue (anhydride) | 830mg | Pathogen inactivator |
| Glucose | 4.0g | Excipient |
| Mannitol | 4.0g | Excipient |
| Mylar | 10000 (∮=8mm) | Carrier |
| Water for injection | In right amount | Solvent and abluent |
| Medicinal alcohol | In right amount | Solvent and abluent |
The content of the mylar absorption methylene blue compositions of this embodiment preparation be the 79.5ug/ sheet after testing, and is aseptic, pyrogen test is qualified, and detection of particulates meets 2005, and two pharmacopeia appendix ixC stipulate, meet the injection requirement.
The pathogen inactivated authentication method and the effect of the mylar absorption methylene blue compositions of this embodiment preparation see Table four:
Table four
| Model virus | Verification method | Effect is judged |
| VSV | The cytopathy political reform | ＞6lgTCID 50 |
| SINDBIS | The cytopathy political reform | ＞6lgTCID 50 |
| HCV | Detection of nucleic acids | The free nucleic acid amplified production |
Embodiment 3
Preparation method is with embodiment 2, and concrete prescription sees Table five:
Table five
| Title | Recipe quantity | Be somebody's turn to do the effect of product in the prescription |
| Methylene blue (anhydride) | 1750mg | Principal agent |
| Hetastarch | 11.2g | Excipient |
| Mylar | 10000 (∮=11mm) | Carrier |
| The macromolecule enclosing cover | 10000 covers | Complexes carrier |
| Water for injection | In right amount | Solvent and abluent |
| Medicinal alcohol | In right amount | Solvent and abluent |
The content of the mylar absorption methylene blue compositions of this embodiment preparation be the 168.2ug/ sheet after testing, and is aseptic, pyrogen test is qualified, and detection of particulates meets 2005, and two pharmacopeia appendix ixC stipulate, meet the injection requirement.
The pathogen inactivated authentication method and the effect of the mylar absorption methylene blue compositions of this embodiment preparation see Table six:
Table six
| Model virus | Verification method | Effect is judged |
| VSV | The cytopathy political reform | ＞6lgTCID 50 |
| SINDBIS | The cytopathy political reform | ＞6lgTCID 50 |
| HCV | Detection of nucleic acids | The free nucleic acid amplified production |
Embodiment 4
Preparation method: with embodiment 2, but the active carbon addition increases to 1.8g.Concrete prescription sees Table seven:
Table seven
| Title | Recipe quantity | Be somebody's turn to do the effect of product in the prescription |
| Riboflavin (anhydride) | 8g | Principal agent |
| Glucose | 19.8g | Excipient |
| Mylar | 10000 (∮=20mm) | Carrier |
| The macromolecule enclosing cover | 10000 covers | Complexes carrier |
| Water for injection | In right amount | Solvent and abluent |
| Medicinal alcohol | In right amount | Solvent and abluent |
The content of the mylar absorption combination of riboflavin of this embodiment preparation is the 768ug/ sheet after testing, and aseptic, pyrogen test is qualified, and two pharmacopeia appendix ixC regulations that detection of particulates meets 2005 meet the injection requirement.
The pathogen inactivated authentication method and the effect of the mylar absorption methylene blue compositions of this embodiment preparation see Table eight:
Table eight
| Model virus | Verification method | Effect is judged |
| VSV | The cytopathy political reform | ＞6lgTCID 50 |
| SINDBIS | The cytopathy political reform | ＞6lgTCID 50 |
| HCV | Detection of nucleic acids | The free nucleic acid amplified production |
Embodiment 5
Preparation method is with embodiment 2.Concrete prescription sees Table nine:
Table nine
| Title | Recipe quantity | Be somebody's turn to do the effect of product in the prescription |
| Mend bone ester derivant (anhydride) | 450mg | Pathogen inactivator |
| Glucose | 4.0g | Excipient |
| Mannitol | 3.0g | Excipient |
| Mylar | 10000 (∮=8mm) | Carrier |
| The macromolecule enclosing cover | 10000 covers | Complexes carrier |
| Water for injection | In right amount | Solvent and abluent |
| Medicinal alcohol | In right amount | Solvent and abluent |
The content that bone ester derivant compositions is mended in the mylar absorption of this embodiment preparation be the 45.4ug/ sheet after testing, and is aseptic, pyrogen test is qualified, and detection of particulates meets 2005, and two pharmacopeia appendix ixC stipulate, meet the injection requirement.
The pathogen inactivated authentication method and the effect of the mylar absorption methylene blue compositions of this embodiment preparation see Table ten:
Table ten
| Model virus | Verification method | Effect is judged |
| VSV | The cytopathy political reform | ＞6lgTCID 50 |
| SINDBIS | The cytopathy political reform | ＞6lgTCID 50 |
| HCV | Detection of nucleic acids | The free nucleic acid amplified production |
More than the sample of 5 embodiment preparation through the test that keeps sample of 6 months accelerated tests and 18 months room temperatures, its pathogen inactivator main constituent content is all between the 90%-110% of labelled amount, aseptic, pyrogen test is all qualified, the microgranule inspection all meets the standard of injection preparation.Analysis after testing, virus checking and practical application, its pathogen inactivated rate reaches 99.9%, and dissolving in use is rapid, handled easily and use.
Claims (10)
1. the compound method of the compositions of a bloodborne pathogens inactivator, this method may further comprise the steps:
But a, get photosensitizer and the photosensitizer quality 2-10 venoclysis doubly that folding removes the recipe quantity of moisture and impurity level and be dissolved in the useable solvents, and make it dissolving fully with adjuvant;
B, be heated to 40-80 ℃, in solution, add activated needle-use activated carbon then, insulated and stirred 20～40 minutes, filtered while hot, it is 0.1mg/ml-1g/ml that filtrate adds identical solvent to the concentration of photosensitizer, fine straining to midbody solution does not have the microgranule more than the 25 μ m repeatedly, and it is standby after pyrogen test is qualified to filter the midbody solution that does not have the above microgranule of 25 μ m in the back;
C, midbody solution is dripped in the desired amount on the carrier of cleaning, under hundred grades of cleaning conditions, dry.
2. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 1 is characterized in that: among the step b in the said midbody solution content of photosensitizer be 0.5mg/ml-50mg/ml.
3. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 2 is characterized in that: among the step b in the said midbody solution content of photosensitizer be 2mg/ml-20mg/ml.
4. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 1 is characterized in that: the use amount of said active carbon is the 3%-10% of photosensitizer and adjuvant gross weight among the step b.
5. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 1 is characterized in that: used solvent is water for injection, ethanol, acetone or ether among step a and the step b, or two kinds mixed liquor wherein.
6. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 5 is characterized in that: used solvent is water for injection or water for injection and alcoholic acid mixed solution among step a and the step b.
7. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 1 is characterized in that: used carrier is meant medicinal mylar among the step c.
8. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 1 is characterized in that: said photosensitizer be meant can with the bonded photosensitizer of pathogenic microorganism nucleic acid or peplos in the blood.
9. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 1 is characterized in that: said photosensitizer is meant methylene blue, riboflavin, benefit bone ester or derivatives thereof.
10. the compound method of the compositions of bloodborne pathogens inactivator as claimed in claim 1 is characterized in that: but the adjuvant of said venoclysis is the single component in glucose, mannitol, hetastarch or the dextran of injection stage or the compositions of multiple composition.
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| CNB2006100272247A CN100413542C (en) | 2006-06-01 | 2006-06-01 | Pathogen inactivator composition for blood or blood component and its compounding process |
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| CN100413542C true CN100413542C (en) | 2008-08-27 |
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| CN107843469B (en) * | 2017-09-15 | 2021-03-02 | 中生北控生物科技股份有限公司 | Stable biochemical composite calibrator and preparation method thereof |
| CN107736363A (en) * | 2017-11-03 | 2018-02-27 | 漯河医学高等专科学校 | A kind of blood component pathogen inactivator and preparation method thereof |
| CN113230214A (en) * | 2018-06-20 | 2021-08-10 | 上海市公共卫生临床中心 | Animal non-inactivated vaccine freeze-drying protective agent and use method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5908742A (en) * | 1992-03-02 | 1999-06-01 | Cerus Corporation | Synthetic media for blood components |
| CN1249952A (en) * | 1998-10-07 | 2000-04-12 | 上海市血液中心 | Blood plasma virus deactivating method and apparatus |
| US20030219712A1 (en) * | 2002-02-01 | 2003-11-27 | Laura Goodrich | Addition of glycolysis inhibitor to a pathogen reduction and storage solution |
| CN2664661Y (en) * | 2003-10-30 | 2004-12-22 | 许亚勇 | Disposable blood virus inactivation device |
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2006
- 2006-06-01 CN CNB2006100272247A patent/CN100413542C/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5908742A (en) * | 1992-03-02 | 1999-06-01 | Cerus Corporation | Synthetic media for blood components |
| CN1249952A (en) * | 1998-10-07 | 2000-04-12 | 上海市血液中心 | Blood plasma virus deactivating method and apparatus |
| US20030219712A1 (en) * | 2002-02-01 | 2003-11-27 | Laura Goodrich | Addition of glycolysis inhibitor to a pathogen reduction and storage solution |
| CN2664661Y (en) * | 2003-10-30 | 2004-12-22 | 许亚勇 | Disposable blood virus inactivation device |
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