CN101163510B

CN101163510B - Virus inactivation method, processing system and device used therein

Info

Publication number: CN101163510B
Application number: CN200680013880XA
Authority: CN
Inventors: 邹方霖; 陈春生; 王建霞
Original assignee: Chengdu Kuachang Medical Industrial Ltd
Current assignee: Chengdu Kuachang Science and Technology Co Ltd
Priority date: 2005-04-29
Filing date: 2006-04-29
Publication date: 2012-06-20
Anticipated expiration: 2026-04-29
Also published as: CN101163510A; WO2006116899A1

Abstract

A method of inactivating virus, at least comprising: A) providing bio-fluid; B) providing the treatment system; and C) contacting the bio-fluid with the treatment system, wherein the treatment system at least contains solid-phase medium and the chambers containing the solid-phase medium, which at least comprises: a) the adsorptive medium of the viral inactivator; and /or b) the viral inactivating medium, which comprises the viral inactivator and the adsorptive medium of the viral inactivator, which comprises: (a) deactivation adsorptive medium, which at least contains the adsorptive medium and the deactivator fixed on the surface of the medium; and/or (b) physical adsorptive medium, which comprises photosensitizer physically adsorptive medium as photosensitizer viral inactivator's adsorptive medium, and organic solvent physically adsorptive medium as organic solvent viral inactivator's adsorptive medium.

Description

A kind of virus inactivating method, used processing system and device wherein

Technical field

Relate generally to of the present invention handles, relates more specifically to method, processing system and the device of inactivation of virus to biofluid.

Background technology

Since nineteen seventies, because the pollution of the pathogen (pathogen) in the biological substance, the for example pollution of virus (virus), and cause the incident of serious medical treatment & health consequence, become the problem that the public is concerned about day by day.For this reason, scientific and technical boundary developed some deactivations or/remove the technology of these pathogen.The inactivation of virus that with inactivation of virus, particularly contains the solid-liquid phase reaction below is an example, and the problem that prior art waits to solve is described.

The existing inactivation of virus technology that contains the solid-liquid phase reaction is mainly based on organic solvent virus deactivation (Solvant-Detergent handles, and is called for short SD among the present invention and handles).Organic solvent virus deactivation medium contains organic solvent S (can contain detergent D in addition) and VIA adsorbent, for example activated carbon (with reference to Chinese patent 01123658.2).Other contains the inactivation of virus technology of solid-liquid phase reaction; Comprising also that the immobilization alkyl phosphorus compound is handled (makes adsorbent with inorganic adsorbent; With reference to German patent DE 4001099A1), immobilization iodinate (make adsorbent with containing silicon dried soil PVPP filter plate, introduce) with reference to German Shenk Company products, or the like.Prior art problems is, used activated carbon, inorganic adsorbent or contain silicon dried soil PVPP filter plate and have side effect (for example stronger protein adsorption ability, thrombin inactivation, plasma A PTT value significantly improve, or the like).

In the existing technology with the unwanted VIA of solid-phase media absorption removal, organic solvent virus inactivator adsorbing medium is respectively inorganic adsorbent (for example containing perlitic grease removal filter plate), affinity adsorbent (for example C-18 oleophilic resin), activated carbon.Prior art problems is, the affinity adsorbent cost is very high to be not suitable for disposable use, and used activated carbon and inorganic adsorbent have side effect (for example stronger protein adsorption ability, thrombin inactivation, plasma A PTT value significantly improve, or the like).

In the existing technology with the unwanted VIA of solid-phase media absorption removal, photosensitizer VIA adsorbing medium is respectively activated carbon (for example, PCT/US94/14227; US6159375; US08/347564), silicon dioxide and ion exchange resin (WO9103933), macroporous adsorbent resin (polystyrene-divinylbenzene, acrylic ester polymers, US6348309).Prior art problems is; Activated carbon, silicon dioxide and ion exchange resin have side effect (for example stronger protein adsorption ability, plasma A PTT value significantly improve, or the like); And macroporous adsorbent resin comes off easily and pollute biofluid, also can form side effect.

In a word, existing be used to handle method biofluid, that comprise viral inactivation treatment, the solid-phase media in the wherein used processing system has side effect more, and for example: protein conformation changes the loss with amount; The loss of platelet conformation change and amount; The loss of erythrocyte conformation change and amount, the introducing of impurity particle, or the like.In existing leucocyte removal technology, also there is similar phenomenon.Thereby, under present condition, develop a kind of existing effective efficiency (for example to the absorption of VIA or/and inactivation of virus), again the virus inactivating method of minimized side effect only arranged, be still the target that science and technology is pursued.

Summary of the invention

The object of the invention; Be to provide existing effective inactivation of virus function or/and effective VIA is removed function; Basically there is not or only has the virus inactivating method of minimized side effect again, and the processing system and the device that are used for method of the present invention.Among the present invention, statement " effectively inactivation of virus function " is the function of instigating one or more model virus more than 99.9% to be inactivated; Statement " effectively VIA is removed function " is the function of instigating one or more VIAs more than 90% to be removed.

The basic technical scheme of method of the present invention is: through using existing effective efficiency, again the solid-phase media of minimized side effect only being arranged, realize the object of the invention.This technical scheme comprises embodiment: 1. generally speaking, at adding passivator on the solid-phase media its side effect in inactivation of virus is minimized; 2. as far as specific VIA, selection function/side effect also can realize same purpose than maximized solid-phase media.

Virus inactivating method of the present invention comprises: A) at least. biofluid is provided; B). processing system is provided; With C). said biofluid is contacted with said processing system, and wherein said processing system comprises solid-phase media and the chamber that holds said solid-phase media at least, and wherein said solid-phase media comprises at least: a). the VIA adsorbing medium; And/or b). the inactivation of virus medium; Said inactivation of virus medium comprises VIA adsorbing medium and VIA fixed thereon; Wherein said VIA adsorbing medium comprises: (a). passivation adsorbing medium, said passivation adsorbing medium contain adsorbing medium at least and are fixed on the passivator on the adsorbing medium; Or/and (b). the physical absorption medium; Said physical absorption medium comprises: (i). as the photosensitizer physical absorption fiber of photosensitizer VIA adsorbing medium, said photosensitizer physical absorption fiber contains the organic polymer physical absorbent of photosensitizer VIA; (ii). as the organic solvent physical absorption medium of organic solvent virus inactivator adsorbing medium, said organic solvent physical absorption medium contains the organic polymer physical absorbent of organic solvent VIA.

Processing system of the present invention, it is the processing system described in the above-mentioned virus inactivating method of the present invention.Said processing system comprises solid-phase media and the chamber that holds said solid-phase media at least, and wherein said solid-phase media comprises at least: a). the VIA adsorbing medium; And/or b). the inactivation of virus medium; Said inactivation of virus medium comprises VIA adsorbing medium and VIA fixed thereon; Wherein said VIA adsorbing medium comprises: (a). passivation adsorbing medium, said passivation adsorbing medium contain adsorbing medium at least and are fixed on the passivator on the adsorbing medium; Or/and (b). the physical absorption medium; Said physical absorption medium comprises: (i). as the photosensitizer physical absorption fiber of photosensitizer VIA adsorbing medium, said photosensitizer physical absorption fiber contains the organic polymer physical absorbent of photosensitizer VIA; (ii). as the organic solvent physical absorption medium of organic solvent virus inactivator adsorbing medium, said organic solvent physical absorption medium contains the organic polymer physical absorbent of organic solvent VIA.

Device of the present invention, it contains above-mentioned processing system at least.

Embodiment of the present invention will be explained, can reach the object of the invention through method of the present invention, processing system or device.It is to be noted that method of the present invention, processing system or device also are particularly suitable for the disposable situation of solid-phase media except that the little advantage of its side effect.

The specific embodiment

The professional and technical personnel should be known in the term of following use, and only in order to describe concrete pattern of the present invention, perhaps content of the present invention is not limited to the definition of following explanation.

In the present invention, term " biofluid " is meant and contains the liquid that maybe possibly contain biological substance, for example blood and blood constituent, blood plasma and blood plasma derivant, biological product, bio-pharmaceutical, or the like.Among the present invention, term " single part blood constitutent " is meant from same person blood last or that repeatedly gather or/and the component of therefrom separating, comprise single part of blood, single part of blood plasma, single part of platelet, single part of erythrocyte, or the like.

In the present invention, term " effectively reduces pathogen hazard " and is meant and comprises effective inactivation of virus or/and a kind of processing procedure of leucocyte removal; Term " inactivation of virus " is meant through adding VIA (for example SD agent, photosensitizer VIA, or the like) or/and physical energy (for example heat, light, or the like), makes in the prepared product the active effectively process of reduction of infection of the virus that part at least possibly exist; Term " leucocyte removal " comprises the process that reduces leukocyte concentration of carrying out through to mechanism such as leukocytic absorption and size filtered; Statement " effectively " as far as inactivation of virus be instigate one or more model virus more than 99.9% to be inactivated, be to instigate the leukocyte more than 90% to be removed as far as leucocyte removal.

In the present invention, term " viral inactivation treatment " is to instigate VIA to contact the overall process that the VIA in biofluid is removed basically with biofluid.Virus comprises that film virus is or/and non-lipid-coated virus.Viral inactivation treatment contains the inactivation of virus process, also contains VIA under a lot of situation and removes process.In process of production, viral inactivation treatment and other processing are that order is carried out or/and carry out simultaneously, thereby also can partly experience or/and other processing beyond the associated virus deactivation (for example protein purification, or the like) in the above-mentioned viral inactivation treatment.

Among the present invention; Term " VIA " is meant anyly all or part of virus that possibly exist in the biofluid is had the inactivation of virus function but possibly be not limited to the additive of inactivation of virus function, the organic solvent virus inactivator during for example the photosensitizer VIA in photosensitizer VIA/photo-irradiation treatment, SD handle or organic solvent virus inactivator/detergent, or the like.VIA also has other function except the inactivation of virus function under many circumstances.For example psoralen is except inactivation of virus, also have deactivation to some other organisms (for example antibacterial), at this moment VIA be again the bacteria inactivation agent, or the like.Term " VIA derivant " is the derivant that VIA forms in viral inactivation treatment, the derivant (for example reddish black A and B) that for example produces when the photoactivation as the methylene blue of VIA in photosensitizer VIA/photo-irradiation treatment.

Among the present invention, the organic solvent virus deactivation comprises that the combination (being called for short SD) with organic solvent virus inactivator (being called for short S) or organic solvent virus inactivator and detergent is the inactivation of virus that VIA carries out.SD handles the SD processing method (U.S. Pat 4540573) comprise USA New York Blood Center invention, and afterwards through the deriving method (for example, only adding the shared viral inactivation treatment method of viral method of going out of S and S and ethanol etc.) of other people exploitation.Among the present invention, term " organic solvent virus inactivator (being called for short S among the present invention) " is meant the organic solvent that under the specified conditions of viral inactivation treatment, uses.These specified conditions include but not limited to: competitive Adsorption (for example, in the environment of biofluid, often containing influential photosensitizer adsorbed components, for example the lipid material in the human plasma); Reacting dynamics condition more unfavorable (for example, the concentration of VIA generally is not more than 1% (w/v) during the liquid phase inactivation of virus); Reaction condition conservative (for example, usually reaction temperature less than 38 ℃ pH between 4-10); Or the like.Thereby, say that from the angle of technical scheme the organic solvent virus inactivator among the present invention is different from organic solvent in general sense.The organic solvent virus inactivator comprises any solvent that is used for inactivation of virus, for example tributyl phosphate (being called for short TnBP among the present invention), formaldehyde, ether, or the like.What be worth explanation is that the organic solvent virus inactivator is often shared with detergent.Among the present invention, detergent comprises any detergent that is used for inactivation of virus, for example Tweens detergent (for example Tween-80) and Triton class detergent (for example Triton X 100).

Among the present invention, the photosensitizer inactivation of virus comprises that with the photosensitizer VIA be the inactivation of virus that VIA carries out; Term " photosensitizer VIA " is meant the photosensitizer that under the specified conditions of viral inactivation treatment, uses.These specified conditions include but not limited to: competitive Adsorption (for example, in the environment of biofluid, often containing influential photosensitizer adsorbed components, for example the lipid material in the human plasma); Reacting dynamics condition more unfavorable (for example, the concentration of VIA generally is not more than 1 μ mol/l during the liquid phase inactivation of virus); Reaction condition conservative (for example, usually reaction temperature less than 38 ℃ pH between 6-10); Or the like.Thereby, say that from the angle of technical scheme the photosensitizer VIA among the present invention is different from photosensitizer in general sense.Say from kind, the photosensitizer VIA include but not limited to dye class photosensitizer VIA, hypericin (hypericin) and psoralen class photosensitizer VIA, or the like.Usually, these photosensitizer VIAs suitably can have much higher inactivation of virus efficient under the rayed.Among the present invention; Term " dye class photosensitizer VIA " is meant and can be used as the dye class material that the photosensitizer VIA carries out inactivation of virus (for example photochemical virus deactivation); For example, phthalocyanine (U.S. Pat 5232844), sapphirine (sapphyrin) (U.S. Pat 5041078), phenothiazine dyestuff (Lambrecht et al., Vox Sang.60; 207-213, (1991) and cyanine dye (U.S. Pat 4915683), or the like; Term " psoralen class photosensitizer VIA " is meant can be in order to the psoralen class material (U.S. Pat 4169204,4294822,4328239 and 4727027) that carries out photosensitizer VIA inactivation of virus (for example photochemical virus deactivation), comprise psoralen (English Psoralen), psoralen derivant, or the like.The example of psoralen derivant have 8-methoxyproralen, 5-methoxy psoralen, S59psoralen, trioxsalen, aminomethyltrimethylpsorale, or the like.

Among the present invention; Term " side effect " is meant when using solid-phase media, processing system or device; They remove the ability that causes the bioactive unwanted variation of biofluid have useful function, also possibly have, for example following one or more variations: the reducing of total protein, to the interference of blood coagulation processing system, to the change of platelet form, to the raising of hemolytic, or the like.Among the present invention, term " specific adsorption " be meant the VIA adsorbing medium to the absorption of VIA or leucocyte-removing medium to leukocytic absorption; Term " non-specific adsorption " is meant that the VIA adsorbing medium is to the absorption to material beyond the leukocyte of the absorption of material beyond the VIA or leucocyte-removing medium.Non-specific adsorption comprises absorption useful to the needed character of biofluid (for example grease removal) and unwanted absorption (the for example minimizing of coagulation factor activity).The unwanted reactivity of solid-phase media comprise unwanted absorption and unwanted other reactivity (for example catalytic activity, enzyme activate active, participate in reactive activity in the biofluid, or the like).

In the present invention, term " solid-phase media " also is called for short medium, is meant and has certain function the solid phase material of (for example adsorption function, inactivation of virus function, or the like); Term " VIA adsorbing medium "; Sometimes be called for short adsorbing medium; Be meant have at least but possibly be not limited to VIA or/and the VIA derivant have adsorption function (for example sometimes it also can have filtering function, remove leukocyte function, or the like) and can be with VIA in the biofluid or/and the concentration of VIA derivant finally reduce to acceptable level (for example tributyl phosphate concentration less than 10ppm, methylene blue concentration less than 0.03 μ g/ml, or the like) solid phase material, adsorbing medium can be pure material (for example activated carbon powder, the wood fiber, or the like), also can be mixture (for example the filter material of cellulose, the filter material that contains activated carbon, C18 chromatography glue, or the like); Term " inactivation of virus medium " is meant to have at least but possibly be not limited to the solid-phase media of inactivation of virus function (for example it also can have filtering function sometimes), for example VIA/adsorbing medium complex; Term " leucocyte-removing medium " is meant any solid-phase media that can be used for leucocyte-removing.

In the present invention, term " VIA adsorbent " is meant under the specified conditions of viral inactivation treatment through adsorbing the adsorbent of effectively removing VIA.These specified conditions comprise: specific VIA; Specific absorption environment (for example, often containing influential adsorbed components in the biofluid, for example the lipid material in the human plasma); Specific adsorption dynamics adsorption kinetics condition (for example, like embodiments of the invention, the concentration of VIA is less in the biofluid, yet requires the concentration of the remaining VIA in absorption back extremely low, for example less than 10ppm or less than 0.01 μ mol/l); Specific adsorption reaction condition (for example, for keeping the activity of biofluid, adsorption temp is limited to 0-37 ℃ usually, and the absorption pH value is limited to 3.8-9.8 usually); Or the like.Thereby, say that from the angle of technical scheme the VIA adsorbent among the present invention is distinguished in adsorbent in general sense.

Among the present invention; Term " organic polymer chemosorbent " is meant through the one-tenth key group of the generation chemical bond of on organic polymer, introducing q.s (for example ionic group, coordinating group, or the like) and prepares thereby the one-tenth key group that mainly passes through to be introduced generates the reagent that chemical bond (for example ionic bond, coordinate bond, or the like) adsorbs, for example ion-exchange fibre, ion-exchange particles and chelating agen; " organic polymer affinity adsorbent " is meant through the affinity ligand of on organic polymer, the introducing q.s (end group of hydrazine for example; Or the Counterfeit Item of viral RNA or DNA is to the affine absorption of some photosensitizer VIA) prepare thereby reagent that the affinity ligand that mainly passes through to be introduced adsorbs, for example affine fiber, affine granule, or the like; " organic polymer physical absorbent " is meant the organic polymer adsorbent outside above-mentioned organic polymer chemosorbent and the organic polymer affinity adsorbent; For example Plant fiber, polyphenyl alkene, or the like, comprise and do not carry out special affinity groupsization or/and do not carry out the organic polymer of special ion-exchange group modification.It is pointed out that organic polymer does not comprise activated carbon.In the embodiment of the invention; The organic polymer physical absorbent does not comprise present known organic polymer affinity adsorbent and organic polymer ion exchange absorbent, and these functionalization organic polymers all pass through special affinity groupsization (for example affine fiber, affine granule) or/and special ion-exchange groupization (for example ion-exchange fibre, ion-exchange particles) modification.The organic polymer physical absorbent must be through at the ion-exchange group of introducing q.s on the organic polymer or organic ligand prepares thereby the reagent that mainly adsorbs through the effect of the weak interaction on the organic polymer (comprise Van der Waals force, dipole-dipole interaction, hydrogen strong, or the like) and (end group or/and on the chain substituent group below 5%) on a small quantity ionic group (the for example a small amount of acidic group on the Plant fiber) of in the preparation process, importing.

Among the present invention, the organic polymer in the term " organic polymer physical absorbent " comprises natural polymer, routine strong natural polysaccharide.In embodiments of the present invention, the said polysaccharide that gathers comprises following one or more materials: cellulose, glucosan, agarose, chitosan, starch.The example of cellulose derivative comprise celluloid, cellulose acetate, methylcellulose, carboxymethyl cellulose, or the like.Although gathering polysaccharide has been used to remove in the VIA as carrier; For example celluloid be used as the carrier of photosensitizer VIA part and be used for removing the photosensitizer VIA and remove leukocyte depletion filter (U.S. Pat 08/179567,08/204102,08/347564), contain the gel that gathers polysaccharide made the carrier of SD agent adsorbent (for example C18) and be used for removing the SD agent, or the like; The beyond thought result of another of the embodiment of the invention then is to gather the repeatably absorption of polysaccharide to enough strong, the dynamic stabilization of dyestuff (for example methylene blue) itself.In an embodiment of the present invention, some filter material (for example Seitz-Bio10, Seitz-Bio20, Seitz-bio40), some porous particle (for example Sephadex G10, Sephadex G25, Sephadex G50, Sepharose) all contain and gather polysaccharide.

Among the present invention, the organic polymer in the term " organic polymer physical absorbent " comprises synthetic high polymer, for example polyolefin, polyurethane, gather the alkane ester, or the like.In embodiments of the present invention, said synthetic high polymer comprises polyolefin, for example polystyrene, polrvinyl chloride, polyvinyl alcohol, or the like.In an embodiment of the present invention, some filter material (for example Seitz-Supradur100, Seitz-Supradur200, Seitz-Supradur 500), some porous particle (for example cross-linked acrylic acid macroporous adsorbent resin, crosslinked polystyrene macroporous adsorbent resin, polystyrene-poly acrylonitrile macroporous adsorbent resin, PMMA, polyisobutylene etc.) all contain polyolefin.

Among the present invention, term " passivator " is meant that to the unwanted reactivity on other constituent of solid-phase media or processing system (for example side effect) has passivation but possibly be not limited to the reagent of passivation.Among the present invention, term " complex " is meant that two or more composition connects the material that forms through absorption or other physical chemistry, chemistry or biological chemistry action.For example, term " passivator/adsorbing medium complex " is meant the complex of the passivator of minimum adsorbing medium that consists of VIA and adsorbing medium; Term " VIA/adsorbing medium/passivator complex " is meant the complex of the passivator of minimum adsorbing medium that consists of VIA, VIA and adsorbing medium.

In the present invention, processing system can be independently as a device (for example filter, chromatographic column, or the like) or as a formation of device (filter in for example single part of blood or the component blood processor, chromatographic column, or the like).In the present invention, term " device " is meant that minimum constituent is a structure above-mentioned processing system, that can be applied to handle biofluid, for example filter, chromatographic column, test kit (English Kit), or the like; Term " chamber " refers to a kind of hollow container that can hold solid-phase media at least, for example the hollow posts of the hollow filter cylinder of filter, chromatographic column, or the like.

Among the present invention, term " filter material " usually is meant the solid-phase media that can only allow the structural flow under the certain size to cross.Thereby the said filter material among the present invention for example has the filter material (being called for short the specific adsorption filter material) of adsorption function often as the immobile phase in the solid-liquid phase reaction to VIA.Whether a kind of filter material the specific adsorption filter material, except the information (for example active carbon filter plate) that manufacturer provides, mainly is to see whether whether it have the specific adsorption function in viral inactivation treatment.For example, the Seitz-Bio filter plate that it has been generally acknowledged that no adsorption function just is found to be a kind of dye class photosensitizer VIA adsorbing medium in an embodiment of the present invention.Filter material comprises absolute filtration filter material and in-depth filtration filter material.Filter material preferred version is the in-depth filtration filter material among the present invention.Although do not intend the entering theoretical discussion, fluid flow path is longer in the in-depth filtration filter material, and its function (for example absorption, inactivation of virus) is realized having material impact.Filter material has various ways, for example filter membrane, filter plate, filter stick, filter element, filter felt, or the like.

Among the present invention, term " filter " is meant the device that comprises filter material and having thereof at least, and it includes but not limited to known filter.Said having comprises the structure of said solid-phase media periphery with pressure seal, for example filter disc, filter cylinder, filter post, or the like.In the filter of following examples of the present invention; Said having usually comprises: hold the container of said solid-phase media, the last end structure of fixing said solid-phase media and lower end structure, reach the structure (for example, owing in the convex body that last end structure and lower end structure on exceed when sealing contact force to solid-phase media periphery solid-phase media sealed to avoid the pressure seal structure of leak of liquid) of solid-phase media periphery with pressure seal filtering material style solid-phase media.In addition, also can increase other functional structure, for example at last end structure or/and introduce structure that specific function is arranged (for example degerming filter membrane, or the like) on the lower end structure.The professional and technical personnel should be known in the filter formula device that uses following examples of the present invention, through making up with various structure, can prepare the filter that much has different use.

Among the present invention, term " dye seat " but be meant the structure of combination dye, comprise physical arrangement, physical chemistry structure, chemical constitution (for example group), or the like; Term " fiber " be meant length/diameter than greater than 10 and average diameter less than the material of 1mm; Term " fiber microstructure " (English Fibrets) is meant a kind of micro structure with fiber of a lot of irregular differential branches and very big surface area that fiber is processed to form through special production technology or special; This fiber microstructure is lacked (less than 1mm) and very thin (less than 50 μ m) very much, and for example Seitz-Bio10, Seitz-Bio20, Seitz-bio40 filter plate are with regard to the fibre-bearing micro structure.

First aspect of the present invention relates to virus inactivating method of the present invention.

Method of the present invention is based on beat all result in the embodiment of the invention:

1). about the application of purification adsorbing medium:

Because the permission residue of VIA very low usually (for example TnBP permits that residue is less than 10ppm in the European Pharmacopoeia) in the biofluid product standard, common view is: to adsorbing medium is unsuitable passivation.Surprisingly, in the embodiment of the invention some adsorbing mediums fixedly passivator form after adsorbing medium/passivator complex, still can be used for absorption and remove out VIA, and relatively have littler side effect with adsorbing medium.

In addition, owing to (require virus titer to descend 10 usually to the requirement of inactivation of virus is very high ³More than), common view is: to the inactivation of virus medium (particularly VIA not the solid-phase media on the long-chain adsorption group, for example SD-active carbon) carry out the deactivation efficient that passivation possibly reduce the inactivation of virus medium.Thereby, in the exploitation of inactivation of virus medium, all do not introduce Passivation Treatment.Yet embodiments of the invention will be explained, use the inactivation of virus medium that contains passivator, both protect the biological activity of the liquid phase medium that solid-phase media contacted effectively, carry out inactivation of virus again effectively, thereby reach the object of the invention.

In addition, the leucocyte-removing medium has leukocyte absorbability more or less usually, though common idea can think that adding passivator can suppress its side effect, also possibly reduce it to leukocytic adsorption.Yet it is shocking, in one embodiment of the invention, add passivator and suppressed its side effect, but still available its effectively removed leukocyte.In a preferred version, first kind of processing system of the present invention can be used for removing simultaneously VIA (or/and VIA derivant) and leukocyte.

2). about the application of physical absorption medium:

Generally speaking, removing additive through the solid-phase media that contains adsorbent is a kind of known technology to use for a long time.The professional and technical personnel should be known in through the solid-phase media that contains the VIA adsorbent can remove VIA.Since the solid-phase media of tool adsorption function generally speaking be very more than; And the kind that VIA comprises is also many; Thereby develop that to contain the particular procedure system that the specific virus inactivator is had a VIA adsorbing medium of imitating adsorption function be very difficult creative work always; Exploitation is provided the active adsorption of specific VIA and do not had the processing system of significant non-specific adsorption (for example, having basically no side effect) basically then is more difficult creative work.

About the application of photosensitizer physical absorption fiber, also based on the beyond thought result of the embodiment of the invention.For example, although: A) some dyestuff (for example methylene blue) is one of VIA the most frequently used in human blood or the human blood composition; B) contain have illicit sexual relations the seat the adsorbable dyestuff of fiber (for example natural fiber); C) in addition the filter material that contains natural fiber be used for biological product production for a long time, yet do not see up to now natural fiber directly as the adsorbing medium of dye class photosensitizer VIA.Can this perhaps be to know well not have to see, perhaps be the active adsorption shortage confidence that satisfy dye class photosensitizer VIA under the condition of concentration lower (usually less than 1 μ mol/ml), temperature not high (usually less than 36 ℃) to its absorbability.Yet according to embodiments of the invention, what moderns were taken aback is: utilize the synthetic fibers of natural fiber or nonionic exchange fiber to carry out effective removal of dyestuff VIA, realize unlike utilizing dyestuff fiber dyeed more difficult even more be prone to.For example, methylene blue is not used as the dyeing of natural fiber usually, but utilizes natural fiber can effectively remove the methylene blue VIA.According to embodiments of the invention, these fibers not only to what dye class photosensitizer VIA had absorbability and had characteristic meaning are: its absorption is enough strong (for example the concentration of absorption back methylene blue is reduced to below the 0.03 μ g/ml); Its absorption is dynamic stabilization (significant desorbing does not appear in the methylene blue that for example when biofluid continues to flow screen plate, adsorbs on it); Its absorption be repeatably (for example, under similarity condition its absorption repeatability be 100%); With its absorption be enough special (for example, having basically no side effect).

The present invention does not intend the entering theoretical discussion, is that example provides some observations with the fiber that contains organic Polymer Physics adsorbent only.Perhaps because such reasons, the weak interaction of organic polymer physical absorbent (the micro ion group of for example introducing in the production process, Van der Waals force, dipole-dipole interaction, hydrogen are strong) just enough removes active adsorption dye class photosensitizer VIA by force: 1). and the biofluid that " on dye (dyeup-take) " of dye class photosensitizer VIA be immobile phase with the fiber normally, contain dye class photosensitizer VIA is that mobile phase is preferably being carried out under the solid-liquid phase reaction condition; 2) remove dye class photosensitizer VIA and do not require levelling; 3). with regard to the quantity of used fiber, the total amount of dye class photosensitizer VIA to be adsorbed is not very big; 4). the structural complexity of fiber; Or the like.In a word; These weak interactions of organic polymer physical absorbent; It is that absorption is enough strong to the specific virus inactivator under the specified conditions; And be enough little to the side effect of the biofluid under the specified conditions, thereby have high relatively specific adsorption ability, thus can realize the object of the invention.

About the application of organic solvent physical absorption medium, also based on the beyond thought result of the embodiment of the invention.For example, although: A) organic solvent virus inactivator (for example TnBP) is one of VIA the most frequently used in human blood or the human blood composition; B) contain polyolefinic porous particle and can remove greasy dirt; C) even contain the removal that polyolefinic porous particle has been used for the dye class VIA, however do not see up to now with contain polyolefinic porous particle directly as the adsorbing medium of organic solvent virus inactivator, particularly in order to combine preparation inactivation of virus medium with the organic solvent virus inactivator.Similar with the situation of above-mentioned photosensitizer VIA; Can this perhaps be to know well not have to see, perhaps be the active adsorption shortage confidence that satisfy organic solvent virus inactivator under the condition of concentration lower (usually less than 1%w/v), temperature not high (usually less than 37 ℃) to its absorbability.Yet according to embodiments of the invention, what these porous particles not only had absorbability and had characteristic meaning the organic solvent virus inactivator is: its absorption is enough strong (for example the concentration of absorption back TnBP is reduced to below the 10ppm); Its absorption is dynamic stabilization (significant TnBP desorbing for example not occurring); Its absorption be repeatably (for example, under similarity condition its absorption repeatability be 100%); With its absorption be enough special (for example, having basically no side effect).

In an embodiment of virus inactivating method of the present invention; Said solid-phase media comprises organic solvent VIA adsorbing medium; And said organic solvent virus inactivator adsorbing medium contains said passivation adsorbing medium at least, or/and organic solvent physical absorption medium.

In an embodiment of virus inactivating method of the present invention; Said solid-phase media comprises organic solvent inactivation of virus medium, and said organic solvent virus deactivation medium contains organic solvent VIA and said passivation adsorbing medium at least or/and organic solvent physical absorption medium.

In an embodiment of virus inactivating method of the present invention, said organic solvent physical absorption medium comprises macroporous adsorbent resin or/and fiber.In an embodiment of the present invention; Used fiber (organic solvent physical absorption fiber) contains the organic polymer physical absorbent of organic solvent VIA, for example natural fiber (for example SeitzBio series filter plate), polyolefine fiber (for example Seitz Supradur 80, Seitz Supradur500, Seitz Eco1000, or the like), or the like.Big pore adsorption resin (organic solvent physical absorption resin) comprises granules of polystyrene (for example Amberlite XAD-7HP, Amberlite XAD-16), phenolic aldehyde condensation polymer type granule, polyacrylate granule and contains and gathers alkane ester macroporous adsorbent resin.In addition, said organic solvent physical absorption medium comprises that also inner surface contains the non-particulate material of said organic macromolecule porous.For example, polyolefin encapsulate pottery, or the like.

In an embodiment of virus inactivating method of the present invention, the organic polymer physical absorbent of said organic solvent virus inactivator comprises polyolefin.For example said polyolefins fiber, granules of polystyrene, polyacrylate granule.In a preferred version of an embodiment, said polyolefin comprises polystyrene, especially contains the macroporous adsorbent resin of polystyrene.

In an embodiment of virus inactivating method of the present invention, said solid-phase media comprises photosensitizer VIA adsorbing medium, and said photosensitizer VIA adsorbing medium contains said passivation adsorbing medium at least, or/and photosensitizer physical absorption fiber.In an embodiment of the present invention, used photosensitizer physical absorption fiber comprises natural fiber, cellulose base derivative fibre, non-functionalized synthetic fibers.

In an embodiment of virus inactivating method of the present invention, said photosensitizer physical absorption fiber comprises natural fiber.In an embodiment of the present invention, used natural fiber comprises Plant fiber, animal fiber (for example silkworm silk).Used Plant fiber comprises cotton fiber (for example not having the fat cotton), the wood fiber (in filter plate), flaxen fiber, paper pulp (for example paper).Said fiber also comprises cellulose base derivative fibre (for example, viscose rayon, acetate fiber, or the like).In an embodiment of virus inactivating method of the present invention, said natural fiber comprises the wood fiber.

In an embodiment of virus inactivating method of the present invention, said photosensitizer physical absorption fiber comprises synthetic fibers, preferred non-functionalized synthetic fibers.In an embodiment of the present invention; Used non-functionalized synthetic fibers comprise the synthetic fibers beyond affine fiber and the ion-exchange fibre, for example polyester fiber, polypropylene fibre (for example superfine polypropylene oil suction fibre), Silon, polyurethane fiber and other polyolefine fiber.In a preferred version, said fiber has following one or more characteristics: A). average diameter 0.01-20 μ m; B). crimpness 1-2; C). water absorption 25-50g/100g fiber.In addition, well-known, other structural parameters of fiber, the galvanic electricity layer current potential of for example high molecular vitrification point, fiber and isoelectric point, IP, or the like, also its absorbability is constituted influence.

In an embodiment of virus inactivating method of the present invention, said synthetic fibers comprise polyolefine fiber.In an embodiment of the present invention, some filter material (for example Seitz-Supradur100, Seitz-Supradur200, Seitz-Supradur 500) as photosensitizer physical absorption medium all contains polyolefine fiber.

In an embodiment of virus inactivating method of the present invention, said VIA adsorbing medium also contains granule in addition, and said granule contains the organic polymer physical absorbent of photosensitizer VIA.For example following processing system: in a chamber, photosensitizer VIA adsorbing medium comprises non-woven fabrics or the filter material that contains cinnamic organic polymer granule and the photosensitizer physical absorption fiber (for example polyolefine fiber) that is positioned at the granule below.

In an embodiment of virus inactivating method of the present invention, the concentration of said photosensitizer VIA is 0.55-3.0 μ mol/l when carrying out inactivation of virus.High photosensitizer inactivation of virus agent concentration helps reducing and goes out the virus time or/and use and help keeping the bioactive viral condition of going out (for example lower temperature, lower light intensity, or the like).In fact, the side effect that contains the solid-phase media of VIA adsorbing medium is a factor of restriction photosensitizer inactivation of virus agent concentration.In an embodiment, said inactivation of virus carries out under subambient temperature, for example between 4-19.5 ℃, between preferred 15-19.5 ℃, more preferably carry out between 15-17 ℃.

In an embodiment of virus inactivating method of the present invention, said solid-phase media comprises said organic solvent virus deactivation medium, organic solvent virus inactivator adsorbing medium or/and photosensitizer physical absorption fiber.This is a kind of dual virus inactivating method.

In an embodiment of virus inactivating method of the present invention, said solid-phase media comprises iodine inactivation of virus medium, and said iodine inactivation of virus medium contains iodine, iodine adsorbing medium and passivator at least.

In an embodiment of virus inactivating method of the present invention, said solid-phase media comprises the solid phase VIA and fixed passivator on it.In an embodiment of the present invention, the example of solid phase VIA is positive charge in-depth filtration filter material (the for example Zetaplus VR of a Cuno company filter plate).Wherein, the solid phase VIA is the solid phase VIA based on the positive charge effect.Although because the restriction of the quantity of existing product, only enumerate an example of this embodiment in the embodiment of the invention, be to spread to easily on other solid phase VIA yet those skilled in the art should be known in this method.

In an embodiment of above-mentioned virus inactivating method of the present invention, the height of said inactivation of virus medium greater than 2cm less than 6cm, and the height of said VIA adsorbing medium greater than 1cm less than 3cm.For safety, using excessive adsorbing medium is a kind of known way, yet excessive adsorbing medium increases the side effect risk again.

In an embodiment of virus inactivating method of the present invention, said solid-phase media comprises the in-depth filtration filter material, and said in-depth filtration filter material contains said VIA adsorbing medium, and has following characteristics: A). average density is greater than 0.25g/cm ³And B). ash is less than 1%.The root a tree name embodiment of the invention, the control ash minimizes for side effect and has great significance.In the filter material except that said fiber, can also contain adhesive, reinforcing agent (for example polyolefin), or the like.The filter material of higher density can have than high absorption capacity.In an embodiment, said solid-phase media comprises following a kind of filter material or their analog: Seitz-Bio10, Seitz-Bio20, Seitz-bio40, Seitz-Supradur100, Seitz-Supradur200, Seitz-Supradur500, Seitz-Supradur1000.In a preferred version, said filter material average density is greater than 0.30g/cm ³(for example Seitz-Supradur100, Seitz-Supradur200).In an embodiment of the inventive method, the total height of said in-depth filtration filter material is greater than 6mm.

Among the present invention, can contain in the passivation adsorbing medium one or more passivator, one or more adsorbing mediums, or the like.Adsorbing medium in the above-mentioned passivation adsorbing medium comprises: VIA adsorbing medium in VIA adsorbing medium, the inactivation of virus medium and leucocyte removal medium.In an embodiment of the present invention, said VIA adsorbing medium contains following one or more adsorbents: activated carbon, inorganic adsorbent, organic polymer chemosorbent, organic polymer affinity adsorbent, organic polymer physical absorbent.The organic polymer affinity adsorbent comprises particle or the fiber that is fixed with part (for example: C6-C18 carbochain, the end group that contains hydrazine or viral RNA or DNA Counterfeit Item).These adsorbents have adsorption function for VIA, but often also have stronger unwanted reactivity.

In an embodiment of virus inactivating method of the present invention, the adsorbing medium in the said passivation adsorbing medium comprises active carbon.In an embodiment of the present invention, activated carbon occurs with different form, for example activated carbon powder, activated carbon-fiber felt, contain activated carbon filter material, or the like.

In an embodiment of virus inactivating method of the present invention, the adsorbing medium in the said passivation adsorbing medium comprises ion exchange absorption medium.Ion exchange absorption medium comprises: kieselguhr, perlite, fibre glass, or the like inorganic adsorbent; Ion exchange resin, ion-exchange fibre, or the like the organic polymer chemosorbent.

In an embodiment of virus inactivating method of the present invention, the adsorbing medium in the said passivation adsorbing medium comprises above-mentioned physical absorption medium (organic solvent virus inactivator adsorbing medium, photosensitizer physical absorption fiber).To the passivation of physical absorption medium, might further reduce side effect.

In embodiments of the present invention, the preferred injectable of above-mentioned passivator is in the Organic substance of human body.The characteristic of these passivator is: 1). itself be the material of relative inert; 2). can be fixed on the solid-phase media and to suppress its side effect and its function is not had significant adverse effect; 3) even. be made up of from solid-phase media or other passivator of controlled amounts and drop to the biofluid, its safety in utilization to biofluid does not cause substantial infringement.

In an embodiment of virus inactivating method of the present invention, the passivator in the said passivation adsorbing medium comprises having hydrophilic group or/and lipophilic group and can reduce the Organic substance of said solid-phase media to the side effect of said biofluid.Have the Organic substance poorly water-soluble (for example natural oil, organic solvent virus inactivator) of lipophilic group and quite a lot ofly have hydrophilic group or have hydrophilic group and the Organic substance of lipophilic group is considered to absorption affinity relatively poor (for example surfactant, hydroxy compounds, aminoacid), lose passivator as solid-phase media.Beat all is that this type material can be used as passivator of the present invention in the embodiments of the invention, and satisfies the object of the invention.

In an embodiment of the present invention, the passivator content in the said solid-phase media is greater than 0.05 μ mol/cm ³, be preferably greater than 1 μ mol/cm ³As far as processing system of the present invention, in some situation, have only when the content of passivator is suitably big and could satisfy the object of the invention (for example side effect minimizes).Some unpredictable consequences are in the embodiment of the invention, and the content of some passivator on absorbent charcoal material is greater than 5 μ mol/cm ³The time, its absorption to VIA (for example methylene blue) is still enough strong.As for the upper limit of passivator content, then should optimize by known method according to the difference of its activity (specific adsorption ability or inactivation of virus ability) and required degree of passivation (for example possibly require different) to the biofluid degree of passivation that has or not thrombin.

In an embodiment of virus inactivating method of the present invention, said scarvenger comprises natural oil.Said natural oil comprises natural oil and natural oil derivant.These materials all have lipophilic group.In embodiments of the present invention, natural oil comprises vegetable oil and phospholipid, and wherein: vegetable oil comprises Oleum Ricini, soybean oil, Oleum Camelliae, glycerol; Phospholipid comprises cephalin, lecithin and plant phospholipid.The example of natural oil derivant comprise trials of emulsion of plant oil, fat milk, or the like.

In an embodiment of virus inactivating method of the present invention, said scarvenger comprises hydroxy compounds.Hydroxy compounds has hydrophilic group, and it comprises that alcohols (for example, ethanol, glycerol, glycerin and sodium chloride, or the like), saccharide are or/and their derivants separately.In an embodiment, said saccharide comprises monosaccharide, polysaccharide or/and gather polysaccharide, for example: glucose, mannitol (molecular formula C ₆H ₁₄O ₆), sorbitol, Glycerin Fructose, sucrose, hetastarch, lentinan, or the like.

In an embodiment of virus inactivating method of the present invention, said scarvenger comprises aminoacid.Aminoacid has hydrophilic group, and it comprises cystine, lysine, tyrosine, glycine, arginine, proline, serine and these polymer of amino acid or the like.The astonishing result of the embodiment of the invention, be glucide or/aminoacid with can be attracted to activated carbon surface and reduce the side effect of activated carbon biofluid.Polyamino acid also has similar effect.

In an embodiment of virus inactivating method of the present invention, said scarvenger comprises organic solvent.In embodiments of the present invention, organic solvent comprises the organic solvent VIA, for example: tributyl phosphate (TnBP), ether, glycerol, ethyl carbonate, ethyl lactate, benzyl benzoate, or the like.

In an embodiment of the present invention, said passivator comprises polypeptide.Polypeptide has hydrophilic group, for example albumin, serum and milk, and their derivants separately.

In an embodiment of the present invention, said passivator comprises surfactant.Surfactant has hydrophilic group and lipophilic group.The present invention finds that the surfactant that has hydrophilic group and lipophilic group in exhibiting high surface activating agent, the especially molecular structure simultaneously can be attracted to activated carbon surface and reduce the side effect of activated carbon to biofluid.Hydrophilic group comprises :-OH ,-OSO ₃,-(CH ₂CH ₂O) ₃,-N (CH ₃) ₂,-N (CH ₃) ₃,-CH ₂COO ,-NH ₂Lipophilic group comprises: organic cyclic group ,-(CH ₂) n-, or the like.The example of surfactant comprises: Triton class surfactant, Tweens surfactant, sodium cholate, tetrahydrofurfural polyglycol ether, dimethyl acetylamide, polyvinylpyrrolidone and dimethyl sulfoxide.The part surface activating agent is presented in an embodiment as the example of passivator.

In an embodiment of virus inactivating method of the present invention, said inactivation of virus medium is fixed with organic solvent virus inactivator and organic solvent passivator, and the total content of said organic solvent passivator and organic solvent virus inactivator is greater than 0.2 μ mol/cm ³, be preferably greater than 0.3 μ mol/cm ³Embodiments of the invention explanations, have only when organic solvent VIA (for example TnBP) content greater than a certain degree, organic solvent just can be not only carries out effective inactivation of virus, but also can be used as passivator side effect is minimized as VIA.The content of embodiments of the invention explanation organic solvent virus inactivator is greater than 0.2 μ mol/cm ³The time this characteristic can be arranged.In said solid-phase media, (for example content is greater than 0.01 μ mol/cm also can to contain an amount of detergent D ³) or other passivator (for example polysaccharide).When D content is enough big (for example greater than 0.2 μ mol/cm ³), D also not only can make viral inactivator auxiliary agent, but also can make passivator.

In an embodiment of the present invention, said passivator comprises the combination of two or more above-mentioned passivator, for example: Dextran 40/glucose, Dextran 40/albumin, albumin/glucose, TnBP/ tween 80/glucosan, or the like.

In an embodiment of virus inactivating method of the present invention, said processing system also contains the leucocyte-removing solid-phase media.For example, an embodiment of the inventive method, it comprises at least: A). single part of blood constitutent is provided; B). said processing system is provided, and said processing system also contains the leucocyte-removing solid-phase media; C). make said biofluid flow through that said processing system is carried out leucocyte removal and inactivation of virus or/and VIA absorption; D). from C) described in processing system collect and to be substantially free of said VIA and leukocytic single part of blood constitutent.In an embodiment of the inventive method, said leucocyte-removing solid-phase media contains said organic polymer physical absorbent.

In an embodiment of virus inactivating method of the present invention, said leucocyte-removing solid-phase media comprises said VIA adsorbing medium.

In an embodiment of virus inactivating method of the present invention, said biofluid comprises single part of blood constitutent.In an embodiment of virus inactivating method of the present invention; The content of organic solvent virus inactivator in the said organic solvent virus deactivation medium is equal to or less than 3 * (the volume ml of 10ppm * said single part of blood constitutent) or less than (the volume ml of 10ppm * said single part of blood constitutent).In fact, the content of restriction organic solvent virus inactivator has the detection that helps exempt organic solvent virus inactivator in the final products.

A kind of processing system that effectively reduces virus harm of the present invention, it is the processing system described in the above-mentioned virus inactivating method.

A kind of device that effectively reduces virus harm of the present invention, it contains above-mentioned processing system at least.Said device comprise pillar, filter, test kit, or the like.In embodiments of the present invention, some said devices contain also that VIA adds structure or/and inactivation of virus reacting environment or/and cleaning mixture.

In an embodiment of device of the present invention, installing is single part blood constitutent treatment kits.

Embodiment

Below the reference implementation example is described the present invention in more detail.But it should be understood that the embodiment of the invention only provides the example of the individual cases of the specific embodiment of the invention.The professional and technical personnel should be known in and the invention is not restricted to these given Implementation Modes (for example given process, parameter and combination).Because content of the present invention is clear and definite, but concrete process, parameter and combination then can be changeable.

In following examples, agents useful for same and material are market reagent on sale and material.Wherein, used adsorbing medium is respectively:

1). activated carbon: the used VIA adsorbing medium that contains activated carbon is respectively activated carbon powder, activated carbon-fiber felt (ZC-1200A, Chinese purple river charcoal fiber company limited) and activated carbon filter plate (AKS 5 and AKS 6, German Seitz company).

2). ion exchange absorbent: the used VIA adsorbing medium that contains ion exchange absorbent is respectively silicon oxide particles and fibre glass.The material of used oxide containing silicon particle is for containing perlitic filter plate (Zetaplus Delipid, Cuno company).

3). affinity adsorbent: the used VIA adsorbing medium that contains affinity adsorbent is C18 anti-phase gel (U.S. Water company).

4). the physical absorption medium.Wherein, used physical absorption medium is respectively:

(1). photosensitizer physical absorption fiber comprises natural fiber, cellulose base derivative fibre, non-functionalized synthetic fibers.Used natural fiber comprises Plant fiber, animal fiber (for example silkworm silk).Used Plant fiber comprises cotton fiber (for example not having the fat cotton), the wood fiber (in filter plate, for example Seitz Bio series filter plate), paper pulp (for example paper).Used non-functionalized synthetic fibers comprise the synthetic fibers beyond affine fiber and the ion-exchange fibre, for example polyester fiber, polypropylene fibre (for example superfine polypropylene oil suction fibre), Silon, polyurethane fiber (being non-woven fabrics).Especially polyolefine fiber, it is contained in the filter material that following examples are used as photosensitizer physical absorption medium, for example Seitz Supradur 80, Seitz Supradur500, Seitz Eco 1000, or the like.

(2). organic solvent physical absorption medium comprises fiber (organic solvent physical absorption fiber) and macroporous adsorbent resin (organic solvent physical absorption resin).Used fiber contains the organic polymer physical absorbent of organic solvent VIA, for example natural fiber (for example Seitz Bio series filter plate), polyolefine fiber (for example SeitzSupradur 80, Seitz Supradur500, Seitz Eco 1000, or the like), or the like.Big pore adsorption resin (organic solvent physical absorption resin) comprises granules of polystyrene (for example Amberlite XAD-7HP, Amberlite XAD-16), phenolic aldehyde condensation polymer type granule, polyacrylate granule and contains and gathers alkane ester macroporous adsorbent resin.Amberlite XAD-7HP is a polarity polystyrene macroporous adsorbent resin granule, and AmberliteXAD-16 is nonpolar polystyrene macroporous adsorbent resin granule.Particles used have following one or more characteristics: A). mean diameter 5-1000 μ m; B). specific surface area 100-2000m ²/ g dry powder; C). average pore size is less than 5- D). excluded volume is less than 50000 molecular weight.The globular protein matter exclusion lower limit molecular weight of the used porous particle solid-phase media of part is less than 5000.

In following examples, above-mentioned photosensitizer physical absorption fiber or organic solvent physical absorption fiber comprise cellosilk, non-woven fabrics, cloth and in-depth filtration filter material.The used in-depth filtration filter material that contains photosensitizer physical absorption fiber or organic solvent physical absorption fiber, average density is greater than 0.25g/cm ³, and ash less than 1%, comprise multiple German Seitz Company products (KS80, K900, Supradur 80, P30, Eco 1000, Permadur0/400A, T2600, Bio20, Bio40, Bio60, Supradur 100, or the like).In the present invention, prefix Seitz-is meant German Seitz Company products.The professional should be known in that the similar products of other company have similar adsorption property.The permeability of the used in-depth filtration filter material of part solid-phase media is less than 200L/m ²Min, they are respectively: Seitz-Supradur 100, Seitz-bio 10, Seitz-bio 40.

Among the following embodiment, used passivator comprises:

1) natural oil that has lipophilic group is or/and organic solvent, for example: Oleum Ricini, soybean oil, Oleum Camelliae, fat milk, tbp (being called for short TnBP among the present invention), ether.

2) has the surfactant of hydrophilic group and lipophilic group, for example: sodium cholate, Triton X100, Tween 80 and polyvinylpyrrolidone.

3). have the alkyl compound of hydrophilic group, for example: glycerol, glucose, maltose, glucosan (dextran), water-soluble cellulose, mannitol (molecular formula C ₆H ₁₄O ₆), sorbitol, hetastarch, lentinan.

4). have the aminoacid of hydrophilic group, for example: proline, arginine and glycine.

5). have the polypeptide of hydrophilic group, for example: human albumin (Beijing Tiantan Bio-pharmaceuticals goods joint stock company limited), biseko (German Biotest company) and milk.

6). the composite passivant of above-mentioned passivator, for example: Dextran 40/glucose, Dextran 40/albumin, albumin/glucose, TnBP/ tween 80/glucosan.The following embodiment according to the present invention, those skilled in the art use other similar passivator to reach the passivation purpose easily.

Among the following embodiment, used VIA comprises:

1). organic solvent virus inactivator or organic solvent virus inactivator/detergent, for example: tbp, ether, TnBP/ tween 80, TnBP/Triton X100, TnBP/ sodium cholate, ether/tween 80.

2). photosensitizer VIA, for example dye class VIA or psoralen viroid inactivator.Used dye class VIA is respectively methylene blue, crystal violet, toluidine blue.Used psoralen viroid inactivator is respectively psoralen and 8-methoxyproralen.The professional should be known in that other psoralen and used psoralen have adsorption property much at one.

3). iodine.Iodo-PVPP filter plate (Seitz company) particularly.

4). solid phase VIA, for example Zetaplus VR filter material (Cuno company).

In following embodiment, the implementation condition of inactivation of virus is generally speaking: pH is 2.0-12.0; Temperature is-5 to 60 ℃; Experiment comes preferred (for example, solid-phase media volume/biofluid volume is between 1% to 30%) according to inactivation of virus to contain the solid-phase media of VIA and the quantity of biofluid; Experiment comes preferred (for example linear flow rate 0.1-10cm/ minute, pressure 0.1-5 kilogram/cm to the inactivation of virus fluid dynamics condition according to inactivation of virus ²); Contain the solid-phase media of VIA adsorbing medium and the quantity of biofluid and remove experiment next preferred (for example, solid-phase media volume/biofluid volume is between 1% to 30%) according to VIA; Confirming of solid-liquid phase adsorption reaction condition, carry out preferably according to known rule basically, for example: it is big more that biofluid flows through linear velocity, and adsorption efficiency is more little; Or the like.

In following embodiment, (initial titer is greater than 10 with pattern lipid-coated virus VSV according to known method for inactivation of virus efficient ^4.8) and Sendai virus (initial titer is greater than 10 ^5.1) study.Among the following embodiment, various bioactive detections all adopt known method to carry out.Among the present invention, leukocyte removal efficiency is measured and is calculated by known method.

The device of following embodiment preparation comprises the device of the pathogen hazard that can be used for effectively reducing blood constitutent in single minute.It contains processing system of the present invention at least, and chamber wherein is conventional filter cylinder or chromatographic column.The filter of the pathogen hazard that effectively reduces blood constitutent in single minute of following embodiment preparation, generally speaking, internal diameter is 3cm, solid-phase media loading height 3-5cm, the filter port of export also have one deck 0.4 μ m filter membrane, in case the medium fragment spills.The pillar of the pathogen hazard that effectively reduces blood constitutent in single minute of following embodiment preparation, generally speaking, internal diameter is 1cm, solid-phase media loading height 3-5cm, the port of export of post also have one deck 0.4 μ m filter membrane, in case the medium fragment spills.

The preparation of embodiment 1 passivation solid-phase media of the present invention

Following embodiment provides some more detailed examples.

Embodiment 1.1 contains the VIA adsorbing medium of passivator

The solid-phase media for preparing in the present embodiment is adsorbing medium/passivator complex.

1.1.1 method for preparing

(1). preparation passivator distributed processing system

In the present embodiment, passivator is with preferred concentrations (for example, natural oil: 0.2-0.5%; Organic solvent: 0.3-2.0%; Surfactant: 1.0-3.0%; Polypeptide: 1.0-10.0%; Aminoacid: 3.0-10.0%; Or the like) be dispersed in the aqueous solution (for example PBS buffer).Yet notice, according to the character of used passivator, other medium (for example organic solvent virus inactivator) also can be used as the passivator disperse medium and prepares passivator distributed processing system (for example solution, suspension).At this moment, distributed processing system concentration (w/v) can be between 0.1%-50%.

The dispersion of low aqueous solubility Organic substance passivator can be adopted known technology.The dispersive method of natural oil in aqueous solution is a lot, for example emulsion process, remove the air method, or the like.A scheme of present embodiment also adds surfactant in disperse medium.The use of surfactant (for example Tween 80, Triton X 100) except that helping above-mentioned passivator, particularly natural oil or/and the dispersion of organic solvent virus inactivator in water, also can be used as eluant sometimes and control the absorption of above-mentioned passivator on adsorbing medium.

(2). passivator is fixed on the adsorbing medium

In the present embodiment, passivator on adsorbing medium fixedly or basically be through absorption carry out.But need know, also can select other fixed form (for example covalent bonding).For example, liquid passivator also can directly contact with adsorbing medium and carry out adsorption reaction.

If use powdery adsorbing medium (for example active carbon), then it is added in the passivator dispersion of above-mentioned preparation and carry out adsorption reaction.If use block adsorbing medium (for example active carbon filter plate), then the passivator dispersion with above-mentioned preparation is mobile phase, is the immobile phase adsorption reaction of flowing with the adsorbing medium.

All association reactions, all be to use optimization passivator/adsorbing medium ratio, under optimized reaction conditions, carry out.These optimizations are undertaken by known combination technology (for example adsorption technology).The condition of adsorption reaction comprises: the concentration of reactant addition, pH, temperature, time, some additive (for example surfactant, salt, or the like), flow rate of mobile phase (when flowing adsorption reaction), or the like.The professional and technical personnel should know through controlling these conditions and controls adsorption reaction, thereby obtain required result (for example adsorbance).The uniformity of adsorption reaction also is a top-priority factor of need.

This professional professional person should be known in through go up at solid phase carrier (for example chromatography glue) fixed virus inactivator adsorbent (for example C18) and then fixedly passivator also can prepare adsorbing medium/passivator complex.

(3). clean not conjugate

Fixing or a little less than be adsorbed on passivator and other material on the adsorbing medium, can select for use different cleaning mixture (for example the urea liquid of PBS buffer, preferred concentration, alcoholic solution, or the like) to clean or the washing of anticreep property according to different needs.

The part solid-phase media for preparing in the present embodiment is listed in the table 1.

The complex of above-mentioned preparation, particularly particulate matter can be used as solid-phase media (the for example A5-A30 in the table 1) separately, also can mix the back as the solid-phase media that contains adsorbing medium and passivator with other component (for example speedup thing, binding agent, solubilizing agent, or the like).For example in the table 1, the chromatography gel of A1 adsorbing medium/passivator complex and percent by volume 10% (Sepharose FF, Pharmacia Company products) mixes; The perlite that A2 contains adsorbing medium/passivator complex and percent by volume 10% mixes.Other component in the solid-phase media (for example speedup thing, binding agent, solubilizing agent, or the like); Can be according to the unwanted reactivity that it had; (for example carry out passivation according to actual needs; Form other solid phase components/passivator complex), or with carry out passivation (for example, forming solid-phase media/passivator complex) after adsorbing medium mixes.Passivating method in the method for preparing of their passivating method and above-mentioned adsorbing medium/passivator complex together.In the table 1, A1 forms solid phase components/passivator complex, the preparation of remix formation solid-phase media earlier; A2 mixes earlier to form solid-phase media, adds passivator again the different component passivation is prepared.

Table 1. part contains the VIA adsorbing medium of passivator

Complex	Adsorbing medium	Passivator	Complex	Adsorbing medium	Passivator
						A1	Activated carbon powder	Oleum Ricini	A21	AKS5	Tween 80
A2	Activated carbon powder	Dextran	A22	AKS5	Polyvinylpyrrolidone
						A3	ZC-1200A	Human albumin	A23	AKS5	TnBP
A4	AKS6	Proline	A24	AKS5	Oleum Ricini

A5	AKS6	Arginine	A25	AKS5	Soybean oil
						A6	AKS6	Glycine	A26	AKS5	Fat milk
A7	AKS6	Human albumin	A27	AKS5	TnBP/Triton?X100
						A8	AKS6	Glucosan	A28	AKS5	Dextran 40/glucose
A9	AKS5	Human albumin	A29	AKS5	Dextran 40/albumin
						A10	AKS5	Biseko	A30	AKS5	TnBP/ tween 80/glucosan
A11	AKS5	Arginine	A31	Amberlite XAD- 7HP	Dextran 40/glycine
						A12	AKS5	Glycine	A32	Amberlite XAD-1	Dextran 40/glycine
A13	AKS5	Glycerol	A33	Fibre glass	Human albumin
						A14	AKS5	Glucose	A34	Dacron	Human albumin
A15	AKS5	Glucosan	A35	Urethane fibers	Human albumin
						A16	AKS5	Maltose	A36	Zetaplus Delipid	Human albumin
A17	AKS5	Mannitol	A37	Zetaplus Delipid	Dextran 40/albumin
						A18	AKS5	Lentinan	A38	The C18 gel	Human albumin
A19	AKS5	Polyethylene Glycol	A39	The C18 gel	Dextran 40/albumin
						A20	AKS5	Triton X100	A40	The PVPP filter plate	Human albumin

In the table 1, the VIA adsorbing medium that part contains passivator is an organic solvent virus inactivator adsorbing medium, is again photosensitizer VIA adsorbing medium (person that for example contains the activated carbon with contain the macroporous adsorbent resin person).

1.1.2 identify

(1). passivator Determination on content in the solid-phase media

In the present embodiment, the passivator content of solid-phase media=(passivator adds total amount-loose passivation dosage)/solid-phase media amount.Wherein, loose passivation dosage obtains through known related assays technology.For example, the assay method of natural oil is for analysing light appearance method; The assay method of organic solvent virus inactivator is a gas chromatography; The assay method of surfactant is a gas chromatography; The assay method of polypeptide is a HPLC; Amino acid whose assay method is a HPLC; Or the like.In the solid-phase media of present embodiment preparation, in most cases the content of passivator is all greater than 0.05 μ mol/cm ³, individually greater than 0.4mmol/cm ³

(2). the mensuration of the specific adsorption of solid-phase media

Among the present invention, VIA specific adsorption amount=(VIA adds the inactivation of virus dosage of absorption of total amount-not)/solid-phase media volume.

In the present embodiment, organic solvent virus inactivator (TnBP) and photosensitizer VIA (methylene blue) are used to measure specific adsorption respectively.The mensuration of methylene blue is used known spectrophotometer method.The mensuration of TnBP is used known gas chromatography.The adsorbance of VIA is measured by known dynamic adsorption quantity measuring method.Measuring equipment therefor is that the solid-phase media of present embodiment preparation and the pillar container (volume 10ml) or the filter (volume 10ml) of control media, (the methylene blue concentration 100 μ g/ml of 100ml inactivation of virus agent solution during mensuration are housed respectively; TnBP concentration 10mg/ml) be that the 0.3cm/ branch flows through device with the linear velocity.

In the table 1: solid-phase media A1-A35 to the adsorbance of photosensitizer VIA (methylene blue) all greater than 0.01mmol/cm ³, individually greater than 0.02mmol/cm ³, indivedual even greater than 0.1mmol/cm ³(for example A1, A2, A32, or the like); Organic solvent virus inactivator (TnBP) adsorbance of solid-phase media A1-A30 and A36-A39 is all greater than 0.05mmol/cm ³, individually greater than 0.1mmol/cm ³, indivedual even greater than 0.3mmol/cm ³A1-A30 to the adsorbance of iodine greater than 1mmol/cm ³In addition, part above-mentioned solid phase medium (particularly contain the activated carbon person) to the specific adsorption of other photosensitizer VIA, for example psoralen, also has similar results.

In the table 1, A33-A35 also can be used as the leucocyte-removing medium.

(3). the mensuration of the side effect of solid-phase media

In the present embodiment, the mensuration of side effect comprises measures the non-specific adsorption amount or/and APTT (human plasma fraction's prothrombin activity).In the present embodiment, non-specific adsorption amount=(indicator adds the indicator total amount of absorption of total amount-not)/enclose the phase medium volume.

In the present embodiment, human albumin (sample C) (Tiantan Bio-pharmaceuticals goods joint stock company limited) is used as the non-specific adsorption indicator; The former active time of the partial prothrombinase of human plasma (sample D) (being called for short APTT among the present invention) is used as the indication parameter that the blood coagulation processing system changes.The APTT test kit is available from Chinese Academy of Medical Sciences's Chengdu blood transfusion institute.

Identical with the assay method of above-mentioned specific adsorption, the mensuration of side effect is also undertaken by known dynamic response assay method.The volume ratio of human albumin during mensuration (concentration 5%) or human plasma (protein concentration 5.5%) and solid-phase media is between 3: 1 to 5: 1.

The adsorbing medium for preparing in the present embodiment/passivator complex compares with the contrast adsorbing medium, and side effect obviously descends, and is presented as: A). albumin adsorbance (mg/cm ³) descend more than 25%, (for example albumin/adsorbing medium complex, vegetable oil/adsorbing medium complex, sugar/adsorbing medium complex, or the like) descends individually more than 50%; B). human plasma APTT lift-off value descends more than 30%, and (for example albumin/adsorbing medium complex, vegetable oil/adsorbing medium complex, sugar/adsorbing medium complex, or the like) descends individually more than 100%.

Embodiment 1.2 contains the inactivation of virus medium (1) of passivator

The solid-phase media for preparing in the present embodiment is organic solvent virus inactivator/adsorbing medium/passivator complex.

1.2.1 method for preparing

(1). prepare VIA/adsorbing medium complex from adsorbing medium

(A). preparation inactivation of virus agent solution or suspension

In the present embodiment, be decentralized photo, prepare inactivation of virus agent solution or suspension, for example: TnBP/Triton X 100/ aqueous solution (5%TnBP, 5%Triton X 100) by known technology with the PBS buffer; TnBP/ Tween 80/aqueous solution (3%TnBP, 10% Tween 80 concentration); Beta-propiolactone/Tween 80/aqueous solution (0.5% beta-propiolactone); Or the like.

(B). VIA is fixed on the adsorbing medium

Solid-liquid phase adsorption reaction condition through routine is carried out, and the VIA in the liquid phase is adsorbed on the solid phase adsorption medium.

(C). passivator is fixed on the adsorbing medium

Fixing means is identical with the method for " passivator is fixed on the adsorbing medium " among the embodiment 1.1.

(2). prepare VIA/adsorbing medium/passivation complex from VIA/adsorbing medium complex

The method for preparing of VIA in the present embodiment/adsorbing medium complex is with the method identical (for example iodo-PVPP filter plate) of " VIA is fixed on the adsorbing medium " in the present embodiment (1).And passivator is fixed to the method on VIA/adsorbing medium complex, then identical with the method for " passivator is fixed on the adsorbing medium " among the embodiment 1.1.

The part solid-phase media of present embodiment preparation is listed in the table 2.Organic solvent virus inactivator/adsorbing medium in the present embodiment/passivator complex (the for example B1-B3 in the table 2) can be separately as or mixes the back with other component (for example speedup thing, binding agent, solubilizing agent, or the like) and is used as the solid-phase media that contains VIA.Its passivating method also can mix forming that solid-phase media adds the passivator passivation again or the passivation different component makes their mix again earlier.

1.2.2 identify

The inactivation of virus medium of present embodiment preparation, the mensuration of its inactivation of virus efficient is carried out as stated above, is determined at room temperature and carries out, and linear flow rate is less than the 1ml/cm/ branch, and the volume ratio of biofluid and solid phase carrier is less than 100.VIA/adsorbing medium/passivator the complex of present embodiment preparation has effective inactivation of virus function.

The inactivation of virus medium of present embodiment preparation, the assay method of its passivator content, inactivation of virus agent content, solid-phase media side effect is identical with correlation method among the embodiment 1.

The inactivation of virus medium of present embodiment preparation in the table 2, the content of passivator is greater than 0.05 μ mol/cm ³, individually greater than 0.4mmol/cm ³Compare with contrast VIA/adsorbing medium complex, inactivation of virus efficient obviously changes because of passivation, and side effect obviously descends: A). albumin adsorbance (mg/cm ³) descend more than 15%, descend more than 30% individually; B). human plasma APTT lift-off value descends more than 20%, descends more than 50% individually.

It is to be noted especially, in the B7 or B8 of table 2: A). said VIA comprises the organic solvent VIA; B). said passivator comprises the organic solvent VIA; And C). the content of organic solvent virus inactivator is greater than 0.1mmol/cm in the said solid-phase media ³, even greater than 0.3mmol/cm ³(0.40mmol/cm for example ³).At this moment, the organic solvent virus inactivator can be not only as VIA carry out effective inactivation of virus, but also the passivator that can be used as VIA adsorbing medium (for example activated carbon) go to make side effect to minimize.

Embodiment 1.3 contains the inactivation of virus medium (2) of passivator

What present embodiment prepared is solid phase VIA/passivator complex.Used solid phase VIA is respectively Cuno-Zetaplus VR go out viral filter plate and Seitz-iodo-PVPP filter plate.Passivator is fixed to the method for solid phase VIA, identical with the method that " passivator is fixed on the adsorbing medium " among the embodiment 1.1.Prepared product is listed in the table 2.

The inactivation of virus medium of present embodiment preparation, the assay method of its inactivation of virus efficient, passivator content and side effect is identical with the embodiment corresponding method of determination respectively.

Solid phase VIA/passivator the complex of present embodiment preparation in the table 2, the content of passivator is greater than 0.05 μ mol/cm ³Compare with contrast solid phase VIA, inactivation of virus efficient obviously changes because of passivation, and side effect obviously descends: A). albumin adsorbance (mg/cm ³) descend more than 5%; B). human plasma APTT lift-off value descends more than 10%.

Table 2. part contains the solid-phase media of VIA

B13 ^*: SEITS PVPP iodine filter plate; PS ^*: polystyrene

Embodiment 1.4 contains the VIA adsorbing medium/leucocyte-removing solid-phase media of passivator

In the present embodiment, used leucocyte-removing medium-VIA adsorbing medium is respectively: fibre glass, cotton fiber, dacron, polyurethane (polyurethane) non-woven fabrics, Seitz-Supradur 100 polypropylene fibre filter plates; Used passivator is respectively above-mentioned passivator (for example, glycine, Dextran 40/glucose and their mixture).

Passivator/VIA adsorbing medium-leucocyte-removing solid-phase media the complex of present embodiment preparation; Its preparation method is identical with the method for preparing of adsorbing medium/passivator complex among the embodiment 1.1; Adsorption reaction is carried out between leucocyte-removing medium-VIA adsorbing medium and passivator; The assay method of passivator content and solid-phase media side effect wherein, respectively with embodiment 1.1 in corresponding method for measuring identical.

The prepared product of present embodiment, its leukocyte removal efficiency can reach more than 99%, and the serge blue clearance can reach more than 95%, and its side effect obviously reduces than the corresponding leucocyte-removing medium that does not combine passivator: A). albumin adsorbance (mg/cm ³) descend more than 15%; B). human plasma APTT lift-off value descends more than 20%.

The preparation (1) of embodiment 2. devices of the present invention

The device of present embodiment preparation, used solid-phase media are selected from embodiment 1, particularly wherein the passivation solid-phase media of embodiment 1.1-1.4 preparation.

The device of present embodiment obtains through two kinds of methods: A). and the passivation solid-phase media that will make is packed in the chamber; B). solid-phase media packed into, and reuse passivator is to its passivation in the chamber, and passivating method is identical with the method for " passivator is fixed on the adsorbing medium " among the embodiment 1.

The device of present embodiment preparation, its authentication method is identical with the corresponding authentication method of passivation solid-phase media among the embodiment 1.Generally speaking, its function (for example, specific adsorption ability, leukocyte removal efficiency, inactivation of virus efficient) is consistent with the function and the side effect of its contained passivation solid-phase media respectively with side effect.Be that function is not had a mind to the free burial ground for the destitute and reduced because of adding passivator, its side effect is obviously decline then.

Following embodiment provides some more detailed examples.

Embodiment 2.1 VIAs are removed device

Embodiment 2.1.1 VIA is removed filter

In the present embodiment, the solid-phase media in the filter is selected from passivator/VIA adsorbing medium (fiber is or/and filter material) complex.For example, passivator/styroflex complex, passivator/the gather third vinyl fiber complex, passivator/activated carbon filter plate complex, or the like.

Embodiment 2.1.2 VIA is removed post

In the present embodiment, the solid-phase media that VIA is removed in the post is selected from passivator/VIA adsorbing medium (granule) complex.For example, passivator/polystyrene macroporous adsorbent resin complex, passivator/activated carbon powder complex, or the like.

Embodiment 2.2 virus inactivating devices

Embodiment 2.2.1 inactivation of virus filter

In the present embodiment, the solid-phase media in the inactivation of virus filter is respectively: 1). be fixed with the inactivation of virus medium (for example high-load TnBP/ soil temperature 80/ activated carbon filter plate complex) of passivator; 2). be fixed with the inactivation of virus medium and the VIA adsorbing medium (for example high-load TnBP/ soil temperature 80/ activated carbon filter plate complex and sugar-aminoacid scarvenger/activated carbon filter plate complex) that is fixed with passivator of passivator; And 3). inactivation of virus medium and the VIA adsorbing medium (for example TnBP/ soil temperature 80/ activated carbon filter plate complex and sugar-aminoacid scarvenger/activated carbon filter plate complex) that is fixed with passivator.

Embodiment 2.2.2 inactivation of virus post

In the present embodiment, the solid-phase media in the inactivation of virus post is respectively: 1). be fixed with the inactivation of virus medium (for example high-load TnBP/ soil temperature 80/ contains cinnamic polymer adsorbent resin complex) of passivator; 2). be fixed with the inactivation of virus medium and the VIA adsorbing medium that is fixed with or does not have passivator (for example high-load TnBP/ soil temperature 80/ contains cinnamic polymer adsorbent resin complex and sugar-aminoacid scarvenger/activated carbon filter plate complex, or high-load TnBP/ soil temperature 80/ contains cinnamic polymer adsorbent resin complex and contains cinnamic polymer adsorbent resin) of passivator; And 3). inactivation of virus medium and the VIA adsorbing medium (for example contain cinnamic polymer adsorbent resin/TnBP/ soil temperature 80 complex and passivator/contain cinnamic polymer adsorbent resin complex) that is fixed with passivator.

Embodiment 2.3. leucocyte-removing/VIA is removed filter

In the present embodiment, the solid-phase media in the leucocyte-removing filter is selected from passivator/leucocyte-removing medium/VIA adsorbing medium complex.For example, one deck T 2600 filter plates of in filter cylinder, packing into, 4 layers of passivator/Seitz-Supradur 100 filter plate complex, the port of export has one deck 0.4 μ m filter membrane, pumps into passivation 1 hour with the circulation of 8% dextran then, and is subsequent use behind the dried disinfecting.This filter can be used for leucocyte-removing and VIA (for example methylene blue) is removed.

The preparation (2) of embodiment 3. devices of the present invention

The device of present embodiment preparation; Solid-phase media wherein contains above-mentioned photosensitizer physical absorption fiber, for example natural fiber, Silon, polyurethane fiber and filter plate (for example above-mentioned Supradur 100, Supradur 500, Eco 1000, Permadur 0/400A, T2600, Bio20, Bio40, Bio60, or the like).

The device of present embodiment preparation, its authentication method is identical with the authentication method of the related device of embodiment 2 preparations.Generally speaking; Compare with conventional device (for example with the device that contains active carbon or inorganic adsorbing medium); The device of present embodiment preparation has similar photosensitizer VIA to remove ability, and obviously lower side effect (for example, protein adsorption is hanged down more than 15% or/and APTT value lift-off value is low more than 15%) is arranged; Or obviously lower particle contamination (for example, flow through in the biofluid of processing system low more than 15% greater than the numbers of particles of 1 μ m at the visible diameter of microscopically) arranged.

Following embodiment provides some more detailed examples.

Embodiment 3.1 dye class are or/and psoralen class photosensitizer VIA is removed filter

The device of present embodiment (comprising 3.1.1 and 3.1.2) preparation, it is suitable for dye class or/and the removing of psoralen class photosensitizer VIA.In the present embodiment, used photosensitizer VIA is respectively serge blue, phthalocyanine dye, hypericin, cyanine dye and psoralen.

Embodiment 3.1.1 contains the VIA of photosensitizer VIA adsorbing fiber and removes filter

In the present embodiment, the VIA adsorbing fiber is to contain dye class or/and the fiber of the organic polymer physical absorbent of psoralen class photosensitizer VIA, and for example the superfine polypropylene oil suction fibre is or/and polyurethanes (polyurethane) fiber.Fiber filling thickness is 5cm.

Embodiment 3.1.2 contains the VIA of photosensitizer VIA adsorbing fiber and adsorption particle and removes filter

In the present embodiment; Adsorption particle is to contain dye class or/and the granule of psoralen class photosensitizer VIA, for example the resin of polypropylene-base (for example HP2MG series), contain cinnamic macroporous adsorbent resin (for example Amberlite XAD-7HP, Amberlite XAD-16), or the like.

In the present embodiment; Used fiber is contained in the used filter material, for example multiple German Seitz Company products (KS80, K900, Supradur 80, P30, Eco 1000, Permadur 0/400A, T2600, Bio20, Bio40, Bio60, Supradur 100, or the like).These filter plates are to the photosensitizer VIA, particularly the dye class photosensitizer has adsorption.The filter diameter is 1.5cm, and macroporous absorption particle packing thickness is 3cm, the filter plate of the thick 3.5mm of adsorption particle below filling a slice.These filter plates can prevent also that except that can further removing the VIA macroporous absorption particle detachment from polluting biofluid and having side effects.

Embodiment 3.2 dye class VIAs are removed filter

The device of present embodiment (comprising 3.2.1-3.2.4) preparation, it is suitable for removing dye class photosensitizer VIA, for example serge blue.

Embodiment 3.2.1 contains the VIA of polyolefine fiber filter plate and removes filter

In the present embodiment; The VIA adsorbing medium is selected from the filter material of the polyolefine fiber of the organic polymer physical absorbent that contains dye class photosensitizer VIA, for example above-mentioned Eco 1000, Permadur 0/400A, T2600, Supradur 80, Supradur 100, Supradur 500.The filter plate filling is more than 3 layers (each thick 3.5mm).

The VIA of embodiment 3.2.2 including natural fibers filter plate is removed filter

In the present embodiment, the VIA adsorbing medium is selected from the filter material of including natural fibers, for example multiple German Seitz Company products (for example, Bio20, Bio40, Bio60, or the like).The filter plate filling is more than 3 layers (each thick 3.5mm).

The VIA of embodiment 3.2.3 including natural fibers is removed filter

In the present embodiment, the VIA adsorbing medium is selected from natural fiber, for example degreasing cotton fiber, silkworm silk or the wood fiber.

Embodiment 3.2.4 contains the VIA of synthetic fibers and removes filter

In the present embodiment, the VIA adsorbing medium is selected from the synthetic fibers that contain organic Polymer Physics adsorbent, for example polyurethane fibre or styroflex.

Leukocyte depletion filter is removed/removed to embodiment 3.3 dye class VIAs

The partial devices of above-mentioned preparation also can be used for the removal of dye class VIA and removes leukocyte among the embodiment 3.In fact, cotton fiber, polyester, polyurethanes (polyurethane), or the like, be dye class photosensitizer VIA adsorbing medium in the present embodiment, be leucocyte-removing material material again.

The preparation of embodiment 4. devices of the present invention

The device of present embodiment preparation, solid-phase media wherein contains above-mentioned organic solvent physical absorption medium.

The device of present embodiment preparation, its authentication method is identical with the authentication method of the device of embodiment 2 preparations.Generally speaking; Compare with conventional device; The device of present embodiment preparation has similar VIA to remove ability or/and inactivation of virus efficient, and obviously lower side effect (for example comparing with the device that contains active carbon or inorganic adsorbing medium) is arranged: protein adsorption low 15% or more or/and APTT value lift-off value hangs down more than 15%.

Following embodiment provides some more detailed examples.

Embodiment 4.1 organic solvent virus inactivators are removed device

The present embodiment device is through preparing in above-mentioned organic solvent physical absorption medium is packed into lauter tub or the open tubular column.Used organic solvent physical absorption medium; Comprise fiber (for example, superfine polypropylene oil suction fibre), filter plate (for example) or/and macroporous adsorbent resin (for example Supradur 80), contain the porous particle (Amberlite XAD-7HP, Amberlite XAD-16, or the like) of polyphenyl alkene.

Embodiment 4.2 organic solvent virus inactivating devices

The present embodiment device, a kind of method for preparing is through preparing in organic solvent virus deactivation medium is packed into lauter tub or the open tubular column.In the present embodiment, organic solvent virus deactivation medium contains above-mentioned organic solvent physical absorption medium and is fixed on the organic solvent virus inactivator on the adsorbing medium.Used method for preparing in this method; Identical with the method that " VIA is fixed on the adsorbing medium " among the embodiment 1.2, wherein: used adsorbing medium is selected from above-mentioned organic solvent physical absorption medium (for example used organic solvent physical absorption medium among the embodiment 4.1); Used VIA is S (for example TnBP or beta-propiolactone) or S/D (for example TnBP/ soil temperature-80, TnBP/Triton X100 or TnBP/ ethanol).

Another kind of method for preparing is: above-mentioned organic solvent physical absorption medium is packed in lauter tub or the open tubular column; Reuse organic solvent dispersion flows through adsorbing medium with optimal speed (for example 0.1-1cm/min) the organic solvent virus inactivator is fixedly got on after the prewashing, washes out loose material then.The method for preparing of organic solvent dispersion is identical with the method for " preparation of organic solvent dispersion " among the embodiment 1.1.The example of organic solvent dispersion comprises the following solution of debita spissitudo ratio: TnBP/ soil temperature-80 solution, TnBP/TritonX100 solution, TnBP/ alcoholic solution, or the like.

But the content root a tree name different needs and the difference that contain organic solvent VIA in the above-mentioned inactivation of virus medium.For example, if the volume of handled biofluid is 250ml, the content of TnBP is greater than 7.5mg in the device that then has, and the content of TnBP is equal to or less than 7.5mg even is equal to or less than 2.5mg in the device that has.Its content that corresponds respectively to the organic solvent virus inactivator greater than 3 * (the volume ml of 10ppm * said single part of blood constitutent), be equal to or less than 3 * (the volume ml of 10ppm * said single part of blood constitutent) and be equal to or less than (the volume ml of 10ppm * said single part of blood constitutent).

Embodiment 4.3 organic solvent virus deactivation/organic solvent virus inactivator is removed device

The present embodiment device prepares through organic solvent virus deactivation medium and organic solvent virus inactivator adsorbing medium are respectively charged in lauter tub or the open tubular column.Two kinds of packing methods are arranged: A). organic solvent virus deactivation medium is contained in the porch near the chamber, and organic solvent virus inactivator adsorbing medium is contained near the exit; B) organic solvent virus inactivator adsorbing medium is contained near the porch of chamber with near the exit, and organic solvent virus deactivation medium is contained in therebetween.In addition, also can remove device through organic solvent virus inactivating device and organic solvent virus inactivator is connected in series.

In the present embodiment; Used solid-phase media is one of following combination: 1). contain above-mentioned organic solvent physical absorption medium and organic solvent virus deactivation medium that is fixed on the organic solvent virus inactivator on the adsorbing medium (reference implementation example 4.2) and above-mentioned organic solvent physical absorption medium (reference implementation example 4.1); 2). other organic solvent virus deactivation medium (the for example organic solvent virus deactivation medium of embodiment 1 preparation) and above-mentioned organic solvent physical absorption medium (reference implementation example 4.1); 3). contain above-mentioned organic solvent physical absorption medium and the organic solvent virus deactivation medium that is fixed on the organic solvent virus inactivator on the adsorbing medium (reference implementation example 4.2) and other organic solvent virus inactivator adsorbing medium (the for example organic solvent virus inactivator adsorbing medium of embodiment 1 preparation).

Embodiment 4.4 organic solvent virus deactivation/organic solvent virus inactivator removes/and the photosensitizer VIA removes device

The present embodiment device prepares through organic solvent virus deactivation medium, organic solvent virus inactivator adsorbing medium and photosensitizer VIA adsorbing medium (or organic solvent virus deactivation medium and organic solvent virus inactivator/photosensitizer VIA adsorbing medium) are respectively charged in lauter tub or the open tubular column.Two kinds of packing methods are arranged: A). organic solvent virus deactivation medium is contained in the porch near the chamber; B) organic solvent virus inactivator medium is contained in the middle part near the chamber.In addition, also can remove device, remove device and be connected in series through organic solvent virus inactivating device, organic solvent virus inactivator with the photosensitizer VIA.

In the present embodiment; Used solid-phase media is one of following combination: 1). contain above-mentioned organic solvent physical absorption medium and the organic solvent virus deactivation medium that is fixed on the organic solvent virus inactivator on the adsorbing medium (reference implementation example 4.2); Above-mentioned organic solvent physical absorption medium (reference implementation example 4.1) and above-mentioned photosensitizer physical absorption fiber (reference implementation example 3); 2). other organic solvent virus deactivation medium (the for example organic solvent virus deactivation medium of embodiment 1 preparation), above-mentioned organic solvent physical absorption medium (reference implementation example 4.1) and above-mentioned photosensitizer physical absorption fiber (reference implementation example 3) or other photosensitizer adsorbing medium (the for example photosensitizer VIA adsorbing medium of embodiment 1 preparation); 3). contain above-mentioned organic solvent physical absorption medium and the organic solvent virus deactivation medium that is fixed on the organic solvent virus inactivator on the adsorbing medium (reference implementation example 4.2); With other organic solvent virus inactivator adsorbing medium (the for example organic solvent virus inactivator adsorbing medium of embodiment 1 preparation) and photosensitizer adsorbing medium (the photosensitizer VIA adsorbing medium of for example above-mentioned photosensitizer physical absorption fiber or embodiment 1 preparation); 4). contain above-mentioned organic solvent physical absorption medium and the organic solvent virus deactivation medium that is fixed on the organic solvent virus inactivator on the adsorbing medium (reference implementation example 4.2); And photosensitizer/organic solvent virus inactivator adsorbing medium (for example, contain 1 preparation of cinnamic macroporous polymer adsorbent resin, embodiment passivator/activated carbon complex, or the like).

The preparation (4) of embodiment 5. devices of the present invention

The device of present embodiment preparation, solid-phase media wherein is the combination of the solid-phase media in the prepared different device of above embodiment.

When multiple solid-phase media makes up, polyphone relation or parallel connection relation being arranged between different solid-phase medias.Just list out the example of some solid-phase media series combination in this example: the combination of the combination of the combination of adsorbing medium/passivator complex and inactivation of virus medium, adsorbing medium/passivator complex and adsorbing medium/passivator complex, adsorbing medium/passivator complex and fibrous filter; Or the like.The series combination of solid-phase media can be contacted in same container, also can be through contacting in a plurality of containers.In this example, use the method for in same container, contacting.Table 3 is listed the partial devices of present embodiment preparation.

Table 3

Device	Solid-phase media 1	Solid-phase media 2	Function
				Filter F1	A9 (table 1)	Seitz-Bio?20	Remove SD agent/remove photosensitizer VIA and derivant thereof
Filter F2	A9 (table 1)	Seitz-Supradur 100	Remove SD agent/remove photosensitizer VIA and derivant thereof
				Filter F3	A9 (table 1)	Seitz-T2600	Remove SD agent/remove photosensitizer VIA and derivant thereof
Filter F4	A9 (table 1)	A12 (table 1)	Remove SD agent/remove photosensitizer VIA and derivant thereof
				Filter F5	A12 (table 1)	A21 (table 1)	Remove SD agent/remove photosensitizer VIA and derivant thereof
Filter F6	A15 (table 1)	A28 (table 1)	Remove SD agent/remove photosensitizer VIA and derivant thereof

Filter F7	A20 (table 1)	A28 (table 1)	Remove SD agent/remove photosensitizer VIA and derivant thereof
				Filter F8	A23 (table 1)	A24 (table 1)	Remove the SD agent
Filter F9	A9 (table 1)	Seitz-Bio 40, the polyester oil suction fibre	Remove SD agent/remove photosensitizer VIA and derivant thereof/remove leukocyte
				Filter G1	B6 (table 2)	B12 (table 2)	Dual inactivation of virus
Filter G2	B6 (table 2)	B14 (table 2)	Dual inactivation of virus
				Filter G4	B6 (table 2)	A23 (table 1)	Solid phase SD inactivation of virus
Filter G5	B12 (table 2)	A21 (table 1)	Solid phase SD VIA inactivation of virus
				Filter G6	B13 (table 2)	A29 (table 1)	Solid phase iodine inactivation of virus
Filter G7	C2	Seitz-Bio 20, polypropylene oil suction fibre	Solid phase SD VIA inactivation of virus
				Filter G8	C2	Seitz-Bio 40, the polyester oil suction fibre	Solid phase SD VIA inactivation of virus/leucocyte-removing
Filter K1	The S/D-PS adsorbent resin	The PS adsorbent resin of aminoacid passivation	Solid phase SD inactivation of virus

The function of the filter in the present embodiment and function and the side effect consistent (with reference to above-mentioned related embodiment) of side effect with its contained solid-phase media.

The example of embodiment 6. single part of blood constitutent test kits of the present invention

Among the present invention, term " single part of blood constitutent blood processor " is meant that single part of blood constitutent is the biofluid blood processor of biofluid.Single part blood constitutent blood processor of the present invention, comprise single part of blood-plasma virus killing apparatus, single part of plaque virus inactivating device (for example using Fructus Psoraleae to make viral inactivator), or the like.Based on said apparatus, also can derive some other devices.For example, through linking to each other, can form the higher device of integrated level with other processing system (for example blood collection and separation process system).

The test kit of present embodiment (comprising 6.1-6.3) preparation contains single part of blood constitutent blood processor at least, and it is a kind of device of the foregoing description preparation.

In some cases, test kit also contains VIA and adds structure, comprises that the liquid phase VIA adds structure or the solid phase VIA adds structure.Liquid phase VIA (for example photosensitizer inactivation of virus agent solution) adds example of structure: but the liquid phase VIA in the medical polystyrene plastics pipe, pipe and the enclosed construction (for example switch or frangible medical polystyrene plastics thin slice) of deblocking.

In some cases, test kit also contains inactivation of virus liquid phase reactor place, for example be used for the photosensitizer inactivation of virus transparent plastic bag, or the like.

In some cases, test kit also contain other structure (for example remove leukocyte depletion filter, washing liquid, washing liquid adding apparatus, or the like.Wherein, washing liquid (for example normal saline) is used for device, particularly column type device or/and the blood constitutent of being detained on the solid-phase media in the filter formula device washes out to reduce blood constitutent loss.

The function of the test kit in the present embodiment and side effect are with the function and the side effect consistent (with reference to above-mentioned related embodiment) of its contained device.In the test kit other can add the material that is selected from above-mentioned passivator according to actual needs and carry out passivation partly if unwanted reactivity is arranged.The mode of passivation comprises: 1) parts of required passivation are carried out passivation, are assembled into device again; 2) device that assembles is carried out passivation; 3) to the parts of required passivation carry out passivation, again be assembled into device, then the device that assembles is carried out passivation again.

6.1 single parts of blood constitutent inactivation of virus of embodiment test kit

Embodiment 6.1.1 contains single part of blood constitutent inactivation of virus test kit of VIA absorption processing system

The test kit of present embodiment preparation, it contains the VIA absorption processing system, i.e. the filter that contains the VIA adsorbing medium or the post of the foregoing description preparation.Test kit also contains VIA adding apparatus and inactivation of virus reacting environment.Its operation principle is: single part of blood constitutent contacts with the VIA that the VIA adding apparatus adds; Carry out the inactivation of virus reaction in inactivation of virus reacting environment; Reaction is accomplished artifact liquid and is flow through filter or the post that contains the VIA adsorbing medium with preferred flow velocity and remove VIA or/and its derivant if necessary also can add structure adding washing liquid through washing liquid the blood constitutent of being detained is washed out.

Embodiment 6.1.2 contains single part of blood constitutent inactivation of virus test kit of viral inactivation treatment system

The test kit of present embodiment preparation, it contains the viral inactivation treatment system, i.e. the filter that contains the inactivation of virus medium or the post of the foregoing description preparation.Its operation principle is: single part of blood constitutent is flow through the filter or the post that contain the inactivation of virus medium with preferred flow velocity and (is for example carried out inactivation of virus; Immobilization SD agent processing, immobilization iodinate or immobilization ion processing), if necessary also can add structure adding washing liquid the blood constitutent of being detained in the processing system is washed out through washing liquid.

Embodiment 6.1.3 contains single part of blood constitutent inactivation of virus test kit of inactivation of virus/VIA absorption processing system

The test kit of present embodiment preparation, it contains the viral inactivation treatment system, i.e. the filter or the post that contain inactivation of virus medium and VIA adsorbing medium of the foregoing description preparation.Its operation principle is: single part of blood constitutent is carried out inactivation of virus (for example, immobilization SD agent processing, immobilization iodinate or immobilization ion processing) with the inactivation of virus medium in preferred flow velocity flow filter or the post and flows through the VIA adsorbing medium guaranteeing that the blood constitutent of flowing out filter or post is substantially free of VIA.If necessary also can add structure adding washing liquid through washing liquid washes out the blood constitutent of being detained in the processing system.

Embodiment 6.1.4 contains single part of blood constitutent inactivation of virus test kit of dual viral inactivation treatment system

The test kit of present embodiment preparation, the device that it contains embodiment 5 preparations also contains VIA adding apparatus and the inactivation of virus reacting environment first time.Its operation principle is: single part of blood constitutent contacts with the VIA that the VIA adding apparatus adds; Carry out the inactivation of virus reaction in inactivation of virus reacting environment; Artifact liquid flows through embodiment 5 preparations with preferred flow velocity filter or post accomplished in reaction; Carry out inactivation of virus and VIA and remove, and make the blood constitutent of flowing out filter or post be substantially free of VIA.If necessary also can add structure adding washing liquid through washing liquid washes out the blood constitutent of being detained in the processing system.

6.2 single parts of blood constitutent inactivation of virus/leucocyte-removing test kits of embodiment

The test kit of present embodiment preparation; It contains leucocyte-removing and VIA absorption processing system, i.e. the filter or the post that contain leucocyte-removing and VIA adsorbing medium (or contain leucocyte-removing and inactivation of virus medium or contain leucocyte-removing and inactivation of virus medium and VIA adsorbing medium) of the foregoing description preparation.

Embodiment 7. virus inactivating methods of the present invention (1)

The method of present embodiment (comprising 7.1-7.4), it comprises at least: A). biofluid is provided; B). processing system is provided, and said processing system contains solid-phase media and the chamber that holds said solid-phase media at least, and at least partly said solid-phase media contains the passivation adsorbing medium; C). make said biofluid flow through said processing system and carry out inactivation of virus or VIA absorption.Used processing system is selected from the related device that contains the passivation adsorbing medium of embodiment 2,5 or 6 preparations in the present embodiment.

Embodiment 7.1 contains the method that processing is removed in VIA absorption

Single minute blood constitutent inactivation of virus of embodiment 7.1.1 example

In the present embodiment, used biofluid is a single part of platelet; Used VIA is psoralen (4 '-aminomethyl-4,5 ', a 8-TMP); Equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the device of embodiment 2.1 preparations, and it contains the psoralen viroid inactivator adsorbing medium (example is gone into polyester oil suction fibre, fibre glass and superfine polypropylene oil suction fibre) that is combined with passivator.

Virus inactivating method is in the present embodiment: through the VIA adding apparatus VIA is added in the biofluid; Carry out inactivation of virus (psoralen of debita spissitudo, room temperature, illumination 30 minutes) in inactivation of virus reacting environment; Make biofluid get into said apparatus then, through removing VIA with VIA adsorbing medium contact wherein.

The method that contains the similar installation of adsorbing medium commonly used (for example activated carbon) with use compares, and the method for present embodiment also can effectively be removed VIA (for example psoralen is removed more than 90%), and has littler side effect.For example, use in the contrast method of the device that contains activated carbon felt, the loss of proteins amount is 10-20%, platelet loss 7%, and platelet pattern mark descends 16%; And use the absorption filter of 2.1 preparations, and the loss of proteins amount is merely 5%, platelet loss 3%, and platelet pattern mark does not descend basically.

The inactivation of virus of other biofluid of embodiment 7.1.2

In the present embodiment; Used biofluid is respectively: 1. person-portion more than merge blood plasma, 2. contain human fibrinogen's human plasma separation component (component I or cryoprecipitate in the for example cold alcohol precipitation), 3. contain the human plasma separation component (for example cryoprecipitate) of people's blood coagulation eight factors, 4. contain the human plasma separation component (for example the DEAE-Sephadex of cryoprecipitate supernatant washes out component) of people's blood coagulation nine factors, 5. contain Human Factor's (PCC) human plasma separation component (for example the DEAE-Sephadex of cryoprecipitate supernatant washes out component), 6. contain the human plasma separation component (the component I I deposition in the for example cold alcohol precipitation) of gamma globulin, 7. reorganization Alpha interferon (interferon concentration 1,150,000 IU/ml, pH7.0), 8. positive human serum object of reference.

In the present embodiment, used VIA is S/D agent (for example, TnBP/Triton X100, TnBP/ Tween 80 or ether/Triton X100); Equipment therefor is selected from the absorption filter (difference of the quantity of its size root a tree name biofluid and difference) of embodiment 2.1 preparation, adsorbs in the filter and contains the organic solvent virus inactivator adsorbing medium (for example containing cinnamic macroporous polymer adsorbent resin or activated carbon filter plate) that is fixed with passivator.

Virus inactivating method in the present embodiment is: through the VIA adding apparatus VIA is added in the biofluid, carry out inactivation of virus (0.3-1%S or 0.3-1%S and 0.3-1%D in inactivation of virus reacting environment; 30 ℃; 4 hours), make biofluid get into said apparatus then, through removing the organic solvent virus inactivator with VIA adsorbing medium contact wherein.

The method that contains the similar installation of adsorbing medium commonly used (for example activated carbon) with use compares, and the method for present embodiment also can effectively be removed VIA (for example TnBP removes more than 90%), and it is much little that side effect is then wanted.For example; Compare with the existing method of using activated carbon; Virus inactivating method in the present embodiment makes the increase of plasma A PTT value will lack more than 30%, makes the loss rate of biological activity (for example Fibrinogen, the blood coagulation VIII factor, the blood coagulation IX factor, total protein) of other biofluid want little more than 30%.

Embodiment 7.2 contains the method for immobilization VIA viral inactivation treatment

The processing of embodiment 7.2.1 blood constitutent in single minute

In the present embodiment, used biofluid is a single part of blood plasma; Equipment therefor is selected from the test kit of embodiment 6 preparations; The virus inactivating device that wherein contains embodiment 2.2 preparation, it contains organic solvent VIA/adsorbing medium/passivator complex, Cuno-Zetaplus VR go out viral filter plate and Seitz-iodo-PVPP filter plate respectively.It is emphasized that the viral inactivation treatment in the present embodiment, can make blood plasma product factory after adopting slurry, promptly carry out one time inactivation of virus,, improve product virus safe property to reduce the viral pollution risk in blood plasma storage, fortune and production process.

Virus inactivating method is in the present embodiment: the biofluid under the room temperature is flow through said apparatus with preferred flow velocity (for example linear velocity 0.1-1.5cm/ branch), carry out inactivation of virus.If necessary, the device that comprises solid-phase media with the washing of Xian's liquid.

The method that contains the similar installation of adsorbing medium commonly used (for example activated carbon) with use compares; The method of present embodiment can be on an equal basis effective inactivation of viruses (for example model virus deactivation 4 more than the log); And (for example have littler unwanted reactivity; The increase of APTT value will be lacked more than 20%, and it is little more than 15% that the loss rate of Fibrinogen, the blood coagulation VIII factor, the blood coagulation IX factor, total protein is wanted).

The processing of other biofluid of embodiment 7.2.2

In the present embodiment, used biofluid is respectively: 1. the human plasma separation component (component I or cryoprecipitate in the for example cold alcohol precipitation), 3 that person-portion more than merges blood plasma, 2. contain the human fibrinogen contains Human Factor's (PCC) human plasma separation component (for example the DEAE-Sephadex of cryoprecipitate supernatant washes out component).In the present embodiment; Equipment therefor is selected from the virus inactivating device (the volume root a tree name biofluid volume of chamber is different and different) of embodiment 2.2 preparation, and it contains adsorbing medium/organic solvent virus inactivator/passivator complex, Cuno-Zetaplus VR go out viral filter plate and Seitz-iodo-PVPP filter plate respectively.

Virus inactivating method is identical with method among the embodiment 7.2.1 in the present embodiment, its with use contain adsorbing medium commonly used (for example activated carbon) similar installation method more also with embodiment 7.2.1 in more consistent.

Embodiment 7.3 contains the method for removing VIA and leukocyte step

In the present embodiment, used biofluid is a single part of blood plasma; Used VIA is selected from photosensitizer VIA (for example, 4 '-aminomethyl-4,5 ', 8-TMP; Used kit is selected from the test kit of embodiment 7 preparations, and the leucocyte-removing/VIA that wherein contains embodiment 2.4 preparations is removed filter.

Leucocyte removal in the present embodiment/VIA removal method is: through the VIA adding apparatus VIA is added in the biofluid; (for example carry out inactivation of virus in inactivation of virus reacting environment; The VIA of debita spissitudo, room temperature, illumination 30 minutes); Make biofluid get into said apparatus then, through removing VIA and its derivant with solid-phase media contact wherein.

The method that contains the similar installation of adsorbing medium commonly used (for example fibre glass) with use compares, and the method for present embodiment has equal leucocyte removal efficient, and side effect then obviously reduces.

Embodiment 8. virus inactivating methods of the present invention (2)

The method of present embodiment (comprising 8.1-8.3), it comprises at least: A). biofluid is provided; B). said biofluid is contacted with VIA and carry out inactivation of virus (for example, the VIA of debita spissitudo, room temperature, illumination 30 minutes), wherein said VIA comprises the photosensitizer VIA; C). processing system is provided, and said processing system contains VIA adsorbing medium and the chamber that holds said solid-phase media at least, and wherein said VIA adsorbing medium contains photosensitizer physical absorption fiber; D). make through B) biofluid of step process flows through said processing system and remove absorption of photosensitizer VIA and derivant thereof.

In the present embodiment, used biofluid is a single part of blood plasma; Used processing system is the device of embodiment 7 preparations, and it contains the device (filter or post) that is selected from embodiment 3 preparations.

The method that contains the similar installation of adsorbing medium commonly used (for example activated carbon) with use compares; The method of present embodiment can effectively be removed inactivation of viruses agent (for example more than 95%); And (for example have littler unwanted reactivity; The increase of APTT value will be lacked more than 20%, and it is little more than 15% that the loss rate of Fibrinogen, the blood coagulation VIII factor, the blood coagulation IX factor, total protein is wanted).

Embodiment 8.1 contains dye class or/and psoralen class photosensitizer VIA is removed the method for step

In the present embodiment, used VIA is selected from dye class or psoralen class photosensitizer VIA (for example, serge blue or 4 '-aminomethyl-4,5 ', 8-TMP); Equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the absorption filter of embodiment 3.1 preparations.

Embodiment 8.2 contains the method that dye class photosensitizer VIA is removed step

In the present embodiment, used VIA is selected from dye class photosensitizer VIA (for example serge blue); Equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the absorption filter of embodiment 3.2 preparations.

Embodiment 8.3 contains dye class photosensitizer VIA and removes/remove the method for leukocyte step

In the present embodiment, used VIA is selected from dye class photosensitizer VIA (for example serge blue); Equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the absorption filter of embodiment 3.3 preparations.

Embodiment 9. virus inactivating methods of the present invention (3)

Virus inactivating method in the present embodiment (comprising 9.1-9.3) comprises at least: A). biofluid is provided; B). processing system is provided; Said processing system contains solid-phase media and the chamber that holds said solid-phase media at least; Wherein said solid-phase media comprises the inactivation of virus medium or/and the VIA adsorbing medium; And: said inactivation of virus medium contains organic solvent physical absorption medium and organic solvent virus inactivator fixed thereon at least, and said VIA adsorbing medium comprises organic solvent physical absorption medium at least; C). make said biofluid flow through that said processing system is carried out inactivation of virus or/and VIA absorption.Used processing system is selected from the device of embodiment 4 preparations in the present embodiment.

Embodiment 9.1 contains the method that step is removed in organic solvent VIA absorption

Single minute blood constitutent inactivation of virus of embodiment 9.1.1 example

In the present embodiment, used biofluid is a single part of blood plasma; Equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the device of embodiment 4.1 preparations.

Virus inactivating method is identical among virus inactivating method in the present embodiment and the embodiment 7.1.1, and its VIA is removed efficient and reduced also identical with side effect.

The inactivation of virus example of other biofluid of embodiment 9.1.2

In the present embodiment, used biofluid is identical among used biofluid and the embodiment 7.2.2; Equipment therefor is selected from the filter or the post (the volume root a tree name biofluid volume of chamber is different and different) of embodiment 4.1 preparations.Virus inactivating method is identical among virus inactivating method in the present embodiment and the embodiment 7.1.2, and its VIA is removed efficient and reduced also identical with side effect.

Embodiment 9.2 contains the method for immobilization organic solvent virus inactivation step

Single minute blood constitutent inactivation of virus of embodiment 9.2.1 example

In the present embodiment, used biofluid is a single part of blood plasma; Equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the device of embodiment 4.2 preparations.Virus inactivating method is identical among virus inactivating method in the present embodiment and the embodiment 7.2.1, and its inactivation of virus efficient reduces also identical with side effect.

The inactivation of virus example of other biofluid of embodiment 9.2.2

In the present embodiment, used biofluid is identical among used biofluid and the embodiment 7.2.2; Equipment therefor is selected from the filter or the post (the volume root a tree name biofluid volume of chamber is different and different) of embodiment 4.2 preparations.Virus inactivating method is identical among virus inactivating method in the present embodiment and the embodiment 7.2.2, and its inactivation of virus efficient reduces also identical with side effect.

Embodiment 9.3 contains immobilization organic solvent virus deactivation/organic solvent virus inactivator and removes the method for step

Single minute blood constitutent inactivation of virus of embodiment 9.3.1 example

In the present embodiment, used biofluid is a single part of blood plasma; Equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the filter or the post of embodiment 4.3 preparations.

Virus inactivating method is in the present embodiment: the biofluid under the room temperature is flow through said apparatus with preferred flow velocity, carry out inactivation of virus and remove the organic solvent virus inactivator that possibly come off.

Inactivation of virus efficient in the present embodiment method is identical with embodiment 9.2.2 method with side effect, and the organic solvent content from the biofluid that the equipment therefor outlet is collected is less than 10ppm.

The inactivation of virus example of other biofluid of embodiment 9.3.2

In the present embodiment, used biofluid is identical among used biofluid and the embodiment 7.2.2; Equipment therefor is selected from the filter or the post (the volume root a tree name biofluid volume of chamber is different and different) of embodiment 4.3 preparations.

Virus inactivating method is in the present embodiment: the biofluid under the room temperature is flow through said apparatus with preferred flow velocity, carry out inactivation of virus and remove the organic solvent virus inactivator that possibly come off.Organic solvent content and embodiment 9.3.1 method in the present embodiment in the biofluid of inactivation of virus efficient, side effect and the collection of method are consistent.

Embodiment 10. virus inactivating methods of the present invention (4)

Virus inactivating method in the present embodiment (comprising 10.1 and 10.2) comprises at least: A). biofluid is provided; B). said biofluid is carried out the inactivation of virus first time; C). processing system is provided, and said processing system contains inactivation of virus medium and the chamber that holds said solid-phase media at least, and wherein said inactivation of virus medium contains organic solvent physical absorption medium and organic solvent virus inactivator fixed thereon at least; D). make through the first time inactivation of virus said biofluid flow through said processing system and carry out the inactivation of virus second time.In the present embodiment, used biofluid is a single part of blood plasma.In the present embodiment, equipment therefor is selected from the test kit of embodiment 6 preparations, wherein contains the device that is selected from embodiment 4.4 or embodiment 5 preparations.

In the present embodiment, use two kinds of different inactivation of virus mechanism, inactivation of virus efficient is higher.

Embodiment 10.1 contains the inactivation of virus of photosensitizer inactivation of virus and organic solvent virus inactivation step

In the present embodiment, used photosensitizer VIA is selected from dye class or psoralen class photosensitizer VIA (for example, serge blue or 4 '-aminomethyl-4,5 ', 8-TMP).In the present embodiment; Used processing yarn system is selected from the device of embodiment 4.4 or embodiment 5 preparations; Particularly contain photosensitizer VIA adsorbing medium, organic solvent virus deactivation medium and organic solvent virus inactivator adsorbing medium, wherein said inactivation of virus medium contains organic solvent physical absorption medium and organic solvent virus inactivator fixed thereon at least.

In the present embodiment; Virus inactivating method is: through the VIA adding apparatus photosensitizer VIA is added in the biofluid; Inactivation of virus reacting environment carry out the first time inactivation of virus (for example; The VIA of debita spissitudo, room temperature, illumination 30 minutes); Make biofluid get into said apparatus then, through removing the photosensitizer VIA with solid-phase media contact wherein and carrying out inactivation of virus and remove the photosensitizer VIA and the organic solvent virus inactivator second time.

In the present embodiment, owing to use the lower solid-phase media of side effect, side effect is controlled at the acceptable level.For example, single minute blood plasma is after above-mentioned viral inactivation treatment, and the APTT value remained in 47 seconds, and the loss rate of Fibrinogen, the blood coagulation VIII factor, the blood coagulation IX factor also is respectively less than 30%.

Embodiment 10.2 contains the inactivation of virus of thermal virus deactivation and organic solvent virus inactivation step

In the present embodiment, equipment therefor is selected from the test kit of embodiment 6 preparations, and it contains the filter or the post of embodiment 2.2 or 4.3 preparations, and it contains organic solvent inactivation of virus medium and organic solvent virus inactivator adsorbing medium.

Virus inactivating method is in the present embodiment: through the protective agent adding apparatus known blood plasma activity protecting agent (for example saccharide, sodium citrate, calcium, or the like) is added in the biofluid; (for example carry out inactivation of virus in inactivation of virus reacting environment; The protective agent of debita spissitudo, 52 ℃, 3 hours); Make biofluid get into said apparatus then, through carrying out the organic solvent virus deactivation and remove the organic solvent virus inactivator that possibly come off with solid-phase media contact wherein.

In the present embodiment, owing to use the lower solid-phase media of side effect, the side effect of inactivation of virus is less at least for the second time.

Embodiment 11. virus inactivating methods of the present invention (5)

Virus inactivating method in the present embodiment comprises at least: A). biofluid is provided; B). embodiment is provided the device of 2 preparations, and it contains said inactivation of virus medium or/and the VIA adsorbing medium; C). make said biofluid flow through that said processing system is carried out inactivation of virus or/and VIA absorption and leucocyte removal.

Should be understood that, for a person skilled in the art, obviously can make various changes and modification embodiment preferred of the present invention described here.Reaching without departing from the spirit and scope of the present invention under the situation that does not reduce its advantage, can carry out these modifications and change.Therefore, these modifications and change are included in the scope of appended claim.

Claims

1. virus inactivating method comprises at least:

A). biofluid is provided; B). processing system is provided; With C). said biofluid is contacted with said processing system, and wherein said processing system comprises solid-phase media and the chamber that holds said solid-phase media at least, and wherein said solid-phase media comprises at least: a). the VIA adsorbing medium; And/or b). the inactivation of virus medium; Said inactivation of virus medium comprises VIA adsorbing medium and VIA fixed thereon; It is characterized in that: wherein said VIA adsorbing medium comprises (a). the passivation adsorbing medium is or/and (b) physical absorption medium

Wherein:

1). said passivation adsorbing medium contains adsorbing medium at least and is fixed on the passivator on the adsorbing medium; Said passivator be injectable in human body, can reduce said solid-phase media to the side effect of said biofluid and contain hydrophilic group or/and the Organic substance of lipophilic group, wherein said passivator is selected from following group: (i). natural oil; (ii). hydroxy compounds; (iii) aminoacid; (iv). organic solvent;

2). said physical absorption medium comprises: (i). as the photosensitizer physical absorption fiber of photosensitizer VIA adsorbing medium, said photosensitizer physical absorption fiber contains the organic polymer physical absorbent of photosensitizer VIA; (ii). as the organic solvent physical absorption medium of organic solvent virus inactivator adsorbing medium, said organic solvent physical absorption medium contains the organic polymer physical absorbent of organic solvent VIA.

2. the described method of claim 1, wherein said solid-phase media comprises organic solvent VIA adsorbing medium, and said organic solvent virus inactivator adsorbing medium contains said passivation adsorbing medium at least, or/and organic solvent physical absorption medium.

3. the described method of claim 1; Wherein said solid-phase media comprises organic solvent inactivation of virus medium, and said organic solvent virus deactivation medium contains organic solvent VIA and said passivation adsorbing medium at least or/and organic solvent physical absorption medium.

4. the described method of claim 1, wherein said organic solvent physical absorption medium is that macroporous adsorbent resin is or/and fiber.

5. the described method of one of claim 1-4, the organic polymer physical absorbent of wherein said organic solvent virus inactivator is a polyolefin.

6. the described method of claim 5, wherein said polyolefin is a polystyrene.

7. the described method of claim 1, wherein said solid-phase media comprises photosensitizer VIA adsorbing medium, and said photosensitizer VIA adsorbing medium contains said passivation adsorbing medium at least, or/and photosensitizer physical absorption fiber.

8. claim 1 or 7 described methods, wherein said photosensitizer physical absorption fiber is a natural fiber.

9. the described method of claim 8, wherein said natural fiber is the wood fiber.

10. claim 1 or 7 described methods, be characterised in that: wherein said photosensitizer physical absorption fiber is synthetic fibers.

11. the described method of claim 10, wherein said synthetic fibers are polyolefine fiber.

12. the described method of claim 10, wherein said solid-phase media comprise said organic solvent virus deactivation medium and organic solvent virus inactivator adsorbing medium.

13. the described method of claim 1, wherein said solid-phase media comprise iodine inactivation of virus medium, said iodine inactivation of virus medium contains iodine, iodine adsorbing medium and passivator at least.

14. the described method of claim 13, wherein said solid-phase media comprises the in-depth filtration filter material, and said in-depth filtration filter material contains said VIA adsorbing medium, and has following characteristics: A). average density is greater than 0.25g/cm ³And B). ash is less than 1%.

15. the described method of claim 14, the adsorbing medium in the wherein said passivation adsorbing medium is an active carbon.

16. the described method of claim 14, the adsorbing medium in the wherein said passivation adsorbing medium are ion exchange absorption medium.

17. the described method of claim 1, wherein said natural oil is selected from: Oleum Ricini, soybean oil, Oleum Camelliae, glycerol, cephalin, lecithin, plant phospholipid.

18. the described method of claim 1, wherein said hydroxy compounds comprises alcohols, saccharide.

19. the described method of claim 1, wherein said aminoacid comprises cystine, lysine, tyrosine, glycine, arginine, proline, serine.

20. the described method of claim 1, wherein said organic solvent comprises the organic solvent VIA.

21. the described method of claim 20, wherein said inactivation of virus medium is fixed with organic solvent virus inactivator and organic solvent passivator, and the total content of said organic solvent passivator and organic solvent virus inactivator is greater than 0.2 μ mol/cm ³

22. the described method of claim 21, wherein said processing system also contains the leucocyte-removing solid-phase media.

23. the described method of claim 22, wherein said leucocyte-removing solid-phase media are said VIA adsorbing medium.

24. the described method of claim 1, wherein said processing system also contains the leucocyte-removing solid-phase media.

25. the described method of claim 24, the content of organic solvent virus inactivator in the wherein said organic solvent virus deactivation medium is less than 3 * (the volume ml of 10ppm * said single part of blood constitutent).

26. a processing system that effectively reduces virus harm, it is the processing system described in the said virus inactivating method of one of claim 1-25.

27. a device that effectively reduces virus harm, it contains right at least and requires 26 described processing systems.

28. the described device of claim 27, it is a single part of blood constitutent treatment kits.