CN100560139C - Be adsorbed with mylar of blood constituent pathogen inactivator and preparation method thereof - Google Patents
Be adsorbed with mylar of blood constituent pathogen inactivator and preparation method thereof Download PDFInfo
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- CN100560139C CN100560139C CNB2006100272232A CN200610027223A CN100560139C CN 100560139 C CN100560139 C CN 100560139C CN B2006100272232 A CNB2006100272232 A CN B2006100272232A CN 200610027223 A CN200610027223 A CN 200610027223A CN 100560139 C CN100560139 C CN 100560139C
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Abstract
The present invention relates to clinical infusion with blood or blood constituent in the composition and method of making the same technical field of carrying out the bloodborne pathogens inactivator that photochemistry uses when pathogen inactivated.The mylar that is adsorbed with the blood constituent pathogen inactivator of the present invention, but the compositions be made up of the adjuvant of pathogen inactivated photosensitizer of blood or blood constituent and venoclysis of inactivator wherein, mylar is medicinal mylar.The mylar compositions that is adsorbed with the blood constituent pathogen inactivator of the present invention can be preserved more than 2 years, and its content reduction is no more than 3%; The dosage of the pathogen inactivator of monolithic compositions is accurate, can reach the 95-105% of labelled amount; Aseptic, apyrogeneity, no insolubility microgranule, but reach the requirement of used for intravenous injection, thus solved science preparation and interpolation problem that present blood plasma or blood constituent carry out the pathogen inactivated pathogen inactivator of photochemistry.
Description
Technical field
The present invention relates to clinical infusion with blood or blood constituent in the composition and method of making the same technical field of carrying out the bloodborne pathogens inactivator that photochemistry uses when pathogen inactivated.
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.The pathogen inactivated method of whole blood that patent of the present invention is mentioned or blood constituent is meant a kind ofly adds pathogen inactivator-photosensitizer in whole blood or blood constituent, after rayed, filtering photosensitizer again, be prepared into the photochemistry bloodborne pathogens ablation method of safe blood constituent, what patent of the present invention related generally to is the composition and method of making the same that adsorbs pathogen inactivator with mylar.
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 in blood constituent, add methylene blue, riboflavin, benefit bone ester or derivatives thereof etc. can with the bonded photosensitizer of pathogenic microorganism nucleic acid or peplos in the blood, after rayed, sensitiser absorption luminous energy, electron transfer can take place or excite to 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.My center is in 1998 patents of invention of having declared " method of blood-plasma virus killing and device thereof ", and obtained patent right on July 2nd, 2003, China Patent No. is " 98121328.6 ", and this patent 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.
The method that adds pathogen inactivator at present both at home and abroad is directly to add low-concentration liquid pathogen inactivator or solid type pathogen inactivator, liquid pathogen inactivated photosensitizer agent can very fast degraded when low concentration and lose pathogen inactivated effect, the solid type pathogen inactivator exists 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 a kind of not only can keep stable in the pathogen inactivator 2 years, but also the adding dosage that can make pathogen inactivator accurately, meet the mylar that is adsorbed with the blood constituent pathogen inactivator of intravenous drip instructions for use.
Another object of the present invention provides the above-mentioned this preparation method that is adsorbed with the mylar of blood constituent pathogen inactivator.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is:
A kind of mylar that is adsorbed with the blood constituent pathogen inactivator, but wherein inactivator is made up of the pathogen inactivated photosensitizer of blood or blood constituent and the adjuvant of venoclysis, and mylar is medicinal mylar.
But the venoclysis adjuvant that adds has filling, bonding and wetting action, adjuvant best in quality be the photosensitizer quality 2-10 doubly.
The mylar that is adsorbed with the blood constituent pathogen inactivator of the present invention, the inactivator of load is 0.25-12.5ug/mm on its mylar monolithic
2, 0.5-5ug/mm preferably
2
Medicinal mylar of the present invention, the mylar that most preferably meets national standard (Q/320483CSY002-2001), this film performance is stable, impermeable to the pathogen photosensitizer, do not adsorb, chemical reaction does not take place, do not influence every quality testing, the quick eluting when not influencing pathogen inactivated photosensitizer and using can guarantee pathogen inactivator up-to-standard in storage period.
Bloodborne pathogens deactivation photosensitizer of the present invention, mainly contain methylene blue, riboflavin, benefit bone ester or derivatives thereof etc. can with the bonded photosensitizer of pathogenic microorganism nucleic acid or peplos in the blood, " methylene blue, benefit bone ester and derivant thereof, most preferably the photosensitizer of Shi Yonging is a methylene blue to preferred use photosensitizer.
But the pharmaceutic adjuvant that venoclysis of the present invention is used, but can be that pharmaceutic adjuvant that venoclysis is used is meant arbitrary single component in glucose, mannitol, hetastarch and the dextran of injection stage or its two kinds and two or more mixture etc.
The present invention is adsorbed with the preparation method of the mylar of blood constituent pathogen inactivator, and its step is as follows:
A, 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;
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 inactivator, 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;
C, under hundred grades of clean zones above-mentioned midbody solution being dripped on the clean mylar that was cleaning in the desired amount, under hundred grades of cleaning conditions, dry then.
Used solvent can be one or both the mixture in water for injection, ethanol, acetone and the ether among the step a, is preferably water for injection and alcoholic acid single or mixed solvent, most preferably is water for injection or water for injection and alcoholic acid mixed solution.
The concentration of inactivator midbody solution preferably is controlled at 0.5mg/ml-50mg/ml among the step b, and most preferred is 2mg/ml-20mg/ml.The 3%-10% adding that the use amount of active carbon is pressed the gross weight of photosensitizer agent and adjuvant gets final product.
Mylar cleaning treatment method used among the step c is: the first step is to soak, and mylar is twisted with the fingers opened, and adds smart filterable 95% ethanol, and jolting or ultrasonicly scatter fully to film is left standstill then, changes the ethanol 1～3 time in the container; In second step, before using mylar 1～3 hour, it was qualified to wash to the filtered water clarity with ready smart flushing device washing and filtering, mylar is transferred in the smart filterable ethanol stand-by at last.
Dripping the inactivator midbody solution among the step c to the method on the mylar is: under 100 grades of clean zones, concentration according to pathogen inactivated agent solution, drip the pathogen inactivator midbody solution with 10-50ul microsyringe or point sample rifle to film central authorities, after point sample finishes, pallet is dried under 100 grades of districts, standby.
Points for attention when dripping solution:
(1) strict with the dropping volume dropping that gives, positive negative error should be less than 1%.
(2) dripping should be in the central authorities of film depression.
(3) should notice whether water for injection volatilizes before the dropping, as not volatilize, can not drip.
(4) note the syringe needle liquid of whether having a surplus, the droplet of tuck can not be arranged.
The mylar that is adsorbed with the blood constituent pathogen inactivator is contained in the container when using, but the container of the upper and lower covers formula blood supply liquid stream warp that container is pharmaceutically useful macromolecular material to be made.Should notice during use that medicine and container on the mylar are dry, container also should be avoided producing plastic grain impurity.
The full review of sampling, the container that mylar is housed after the assay was approved can be used in combination with hematoplasmopathy substance inactivating device (China Patent No. is " 98121328.6 ").
Beneficial effect of the present invention: the mylar compositions that is adsorbed with the blood constituent pathogen inactivator of the present invention's preparation, the inactivator good stability on it can be preserved more than 2 years, and its content reduction is no more than 3%; The dosage of the pathogen inactivator of monolithic compositions is accurate, can reach the 95-105% of labelled amount; Pathogen inactivator and relevant auxiliary materials thereof have been adopted the preparation technology of high temperature depyrogenation, aseptic filtration, composition sterile, apyrogeneity, no insolubility microgranule, but reach the requirement of used for intravenous injection, thereby solved science preparation and interpolation problem that present blood plasma or blood constituent carry out the pathogen inactivated pathogen inactivator of photochemistry.
The specific embodiment
Below the used mylar of each embodiment be medicinal, used supplementary material is the injection stage standard, meet China 2005 editions pharmacopeia requirements.
Embodiment 1
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 |
| 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 |
Preparation method: 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.
Clean mylar by following step: the first step is to soak, and manual sth. made by twisting of mylar opened, and puts into the 500ml container for each ten thousand, adds smart filterable 95% ethanol of 300ml, and violent repeatedly jolting, ultrasonic is scattered fully to film.Leave standstill, the ethanol in the container is changed 2 times repeatable operation; Second step, using mylar preceding two hours, wash with ready smart flushing device washing and filtering, be washed till the filtered water clarity qualified till.Mylar is transferred in the smart filterable ethanol, stand-by.It is standby to go out 10000 clean of mylars with above-mentioned disposal methods.
Get clean upper and lower covers container 10000 covers, under 100 grades of laminar flow hood, dry standby; In lower cover, place thin film.According to the concentration of pathogen inactivated agent solution, drip the pathogen inactivator midbody solution to film central authorities with 10-50ul microsyringe or point sample rifle.Every mylar drips pathogen inactivator intermediate 10ul, dries under 100 grades of laminar flow hood, builds loam cake then, that is, through content, aseptic, pyrogen, microgranule etc. after the assay was approved, with the use that connects together of blood or the pathogen inactivated device of blood constituent.
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 verification the verifying results of the mylar absorption methylene blue compositions of this embodiment preparation sees following table two for details:
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
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 |
| 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 |
Preparation method: 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, 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 the no microgranule after the filtration adds to the 200ml standardize solution, standby; It is standby to handle out 10000 clean of mylars by mylar cleaning treatment method provided by the invention; Get and handle clean upper and lower covers 10000 covers well, under 100 grades of laminar flow hood, dry standby; Way by placement thin film provided by the invention places thin film in lower cover; Add pathogen inactivator by the method that pathogen inactivator midbody solution provided by the invention is attached on the mylar, every mylar drips pathogen inactivator intermediate 20ul, under 100 grades of laminar flow hood, dry, build loam cake then, promptly, through content, aseptic, pyrogen, microgranule etc. after the assay was approved, with the use that connects together of blood or the pathogen inactivated device of blood constituent.
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 verification the verifying results of the mylar absorption methylene blue compositions of this embodiment preparation sees following table four for details:
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
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 |
Preparation method is with embodiment 2
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 verification the verifying results of the methylene blue of this embodiment preparation sees following table six for details:
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
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 |
Preparation method: with embodiment 2, but the active carbon addition increases to 1.8g.
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 verification the verifying results of the mylar absorption combination of riboflavin of this embodiment preparation sees following table eight for details:
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
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 |
Preparation method: with embodiment 2
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 verification the verifying results that bone ester derivant compositions is mended in the mylar absorption of this embodiment preparation sees following table ten for details:
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, two pharmacopeia appendix ixC regulation that detection of particulates meets 2005.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 (6)
1, a kind of mylar that is adsorbed with the blood constituent pathogen inactivator, but the chemical compound formed by the adjuvant of pathogen inactivated photosensitizer of blood or blood constituent and venoclysis of inactivator wherein, mylar is medicinal mylar; Said photosensitizer is meant methylene blue, riboflavin, benefit bone ester or derivatives thereof, and the inactivator of load is 0.25-12.5 μ g/mm on the mylar monolithic
2
2, the mylar that is adsorbed with the blood constituent pathogen inactivator as claimed in claim 1 is characterized in that: the quality of adjuvant is 2-10 a times of photosensitizer quality.
3, the mylar that is adsorbed with the blood constituent pathogen inactivator as claimed in claim 1 is characterized in that: the inactivator of load is 0.5-5 μ g/mm on the mylar monolithic
2
4, as the described arbitrary mylar that is adsorbed with the blood constituent pathogen inactivator of claim 1～3, it is characterized in that: said medicinal mylar is the mylar that meets national standard Q/320483CSY002-2001.
5, as the described arbitrary mylar that is adsorbed with the blood constituent pathogen inactivator of claim 1～3, it is characterized in that: said photosensitizer is meant methylene blue.
6, as the described arbitrary mylar that is adsorbed with the blood constituent pathogen inactivator of claim 1～3, it is characterized in that: but the pharmaceutic adjuvant that said venoclysis is used is meant arbitrary single component or its two kinds and two or more mixture in glucose, mannitol, hetastarch and the dextran of injection stage.
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| CNB2006100272232A CN100560139C (en) | 2006-06-01 | 2006-06-01 | Be adsorbed with mylar of blood constituent pathogen inactivator and preparation method thereof |
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| WO2009018309A2 (en) * | 2007-08-01 | 2009-02-05 | Caridianbct Biotechnologies, Llc | Pathogen inactivation of whole blood |
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