CN1284896A - Flow device for the reduction of compounds from biological compositions and methods of use - Google Patents

Flow device for the reduction of compounds from biological compositions and methods of use Download PDF

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Publication number
CN1284896A
CN1284896A CN98813772A CN98813772A CN1284896A CN 1284896 A CN1284896 A CN 1284896A CN 98813772 A CN98813772 A CN 98813772A CN 98813772 A CN98813772 A CN 98813772A CN 1284896 A CN1284896 A CN 1284896A
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adsorbent
blood
biological
equipment
resin
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CN1136042C (en
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D·J·赫
M·S·克拉克
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Cerus Corp
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Cerus Corp
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Priority claimed from PCT/US1998/000531 external-priority patent/WO1998030327A1/en
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28026—Particles within, immobilised, dispersed, entrapped in or on a matrix, e.g. a resin
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0236—Mechanical aspects
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0278—Physical preservation processes
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/02—Blood transfusion apparatus
    • A61M1/0209—Multiple bag systems for separating or storing blood components
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/02—Blood transfusion apparatus
    • A61M1/0209—Multiple bag systems for separating or storing blood components
    • A61M1/0218—Multiple bag systems for separating or storing blood components with filters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/20—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising free carbon; comprising carbon obtained by carbonising processes
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
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    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28016—Particle form
    • B01J20/28019—Spherical, ellipsoidal or cylindrical
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28028—Particles immobilised within fibres or filaments
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
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    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28057—Surface area, e.g. B.E.T specific surface area
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention provides methods and devices for reducing the concentration of low molecular weight compounds in a biological composition containing cells while substantially maintaining a desired biological activity of the biological composition. The device comprises highly porous adsorbent particles, and the adsorbent particles are immobilized by an inert matrix.

Description

Reduce the flow device and the using method of chemical compound in the biological composition
Related application
The application is that the serial number of on January 6th, 1998 application is the part continuity of 09/003113 common pending application, and its full content is incorporated herein by reference.
Technical field
The application relates to the method and apparatus that reduces chemical compound in the biological composition.The molecular weight of these chemical compounds is the about 30000g/mol of about 100g/mol-.
Background technology
Big quantity research all concentrates on removes material from blood products.Great majority all cause leucocytes reduction in this research.Referring to, people's such as people's such as M.N.Boomgaard people's such as Transfusion34:311 (1994), F.Bertolini Vox Sang 62:82 (1992) and A.M.Joustra-Dijkhuis Vox Sang 67:22 (1994) for example.Filter platelet and be and be used for reducing the leukocytic common methods of platelet concentrate.Referring to, people's such as M.Bock Transfusion 31:333 (1991) (Sepacell PL-5A for example, Asahi, Tokyo, Japan), people's such as J.D.Sweeney Transfusion 35:131 (1995) (LeukotrapPL, Miles Inc., Covina, CA) and people's such as M.van Marwijk Transfusion30:34 (1990) (Cellselect, NPBI, Emmer-Compascuum, TheNetherlands; Immugard Ig-500, Terumo, Tokyo, Japan).Yet these filter machinery and can not remove the relatively low chemical compound of molecular weight at present, other chemical compound commonly used when comprising for example psoralen, psoralen photoproducts and handling biofluid.
Adsorption method has been used for separation selectivity blood constitutent on the phospholipid polyalcohol.For example, several copolymers with different electric charges and the interaction of blood constitutent are estimated, comprised thrombocyte adhesiveness and protein adsorption.People's such as K.Ishihara J.Biomed.Mat.Res.28:1347 (1994).But these polymer design are not used to adsorb low molecular weight compound.
Various dialysis apparatuss can be removed low molecular weight compound from blood plasma and whole blood.For example, low-molecular-weight toxin and medical compounds can be successfully removed in dialysis.Therefore, dialysis can be used for, for example from blood products, remove psoralen and psoralen photoproducts.Unfortunately, dialysis procedure needs very complicated and expensive equipment at present.Therefore, it is just unrealistic dialysis machinery to be used for depolluting of a large amount of blood products.
Use polystyrene divinylbenzene, silica dioxide gel and acryloyl ester polymer absorption methylene blue had been described in the past.For example, PCT publication number WO91/03933 described free absorbent resin batch research (for example, Amberlite (Rohm and Haas (and Frankfurt, Germany) and Bio Beads (Bio-Rad Laboratories (Munich, Germany)).But, in being exposed to blood products, very carefully these absorbent resins are removed afterwards, so these methods have caused transferring the danger of resin particle.
In addition, equipment and the method for removing leucocyte-removing and virus inactivating agent (for example, psoralen, hypericin and for example dyestuff of methylene blue, toluidine blue and crystal violet) also disclosed.Specifically, PCT publication number WO95/18665 has described the filter of the fabric web that comprises laying, and this fabric web contains the polymeric matrices of mechanically stable.This net itself contains interlock fabric fiber that forms the substrate with gap and the fibril grain that distributes in this gap.But this equipment reduces factor XI activity greatly.
Therefore need simpler, safer and more economical device,, kept the biological activity of the biological composition of celliferous processing simultaneously basically to reduce the concentration of low molecular weight compound in the celliferous biological composition.
Invention is described
The invention provides the equipment that reduces compound concentration in the biological composition.The molecular weight of chemical compound is the about 30000g/mol of about 100g/mol-.This equipment is flow device.An example of flow device is shown among Figure 12.Flow device is known in the literature, for example states in the open WO96/40857 of PCT, and the document is incorporated herein by reference.Flow device can make the concentration such as low molecular weight compound in the material of blood products reduce, and it is realized through this equipment perfusion by blood products.
The illustration chemical compound comprises pathogen inactivated chemical compound, dyestuff, mercaptan, plasticizer and complement activation.The equipment that is provided comprises by the fixed three-dimensional network absorbent particles of inert base.This immobilization has reduced the bleed danger of blood products of loose absorbent particles.And, simplified the operation that reduces the problem that accompanies with the loose absorbent particles of processing by inert base fixed absorbent granule.
The invention provides the concentration method that reduces biological respinse modifier in the biological composition, wherein this method has kept the required biological activity of biological composition basically.This method relates to this biological composition of a kind of device processes.
In one embodiment, this equipment comprises the inert base that contains a large amount of absorbent particles, and wherein the diameter range of absorbent particles is at the about 200 μ m of about 1 μ m-, and wherein this equipment is used for flow-type processing.
In another embodiment, this biological respinse modifier is a complement activation.
In another embodiment, this biological composition is a blood plasma.
In another embodiment, the length of this sorbent material is littler three times than width.
In another embodiment, absorbent particles comprises super crosslinked polystyrene network.
In another embodiment, absorbent particles is an activated carbon granule, and wherein the surface area of activated carbon granule is greater than about 1200m 2/ g.
In another embodiment, activated carbon granule is that steam activation by coconut husk forms.
In another embodiment, the network of fibers of the inert base of this equipment for forming by cellulose.
In another embodiment, inert base is a particle network, and this particle network is that the polyethylene particle by super high molecular weight forms with super crosslinked polystyrene network particle sintering.
In another embodiment, this method also reduces psoralen derivant in the biological composition, acridine derivatives, the concentration of dyestuff or quencher.
The accompanying drawing summary
Fig. 1 illustrates the perspective view of an embodiment of fiber, has shown its internal core and outer sheath, and they have formed the network of fibers of fixed absorbent medium.
Fig. 2 illustrates the part of an embodiment of Fibrized resin of the present invention.
Fig. 3 illustrates the cross-sectional view that the adsorbent pearl is fixed on an embodiment of the Fibrized resin that constitutes Fibrized resin in the fiber.
Fig. 4 illustrates in the fiber that the adsorbent pearl is fixed on Fibrized resin and the cross-sectional view of an embodiment of the Fibrized resin of Fibrized resin sample is surrounded in heat-sealing.
Fig. 5 is for Dowex  XUS-43493 and the loose adsorbent pearl of Amberlite  XAD-16 HP and the Fibrized resin that the contains Amberlite  XAD-16 sketch map except that the comparison of the adsorption dynamics adsorption kinetics of the psoralen that deaminizes from platelet.
Fig. 6 is for p (HEMA)-Dowex  XUS-43493 pearl coating and uncoated sketch map of comparison except that the adsorption dynamics adsorption kinetics of the psoralen that deaminizes from platelet.
Fig. 7 is the sketch map of the glycerol content of preprocessing solution to the comparison of the influence of the relative absorbability of amino psoralen of Amberlite  XAD-16 and Dowex  XUS-43493.
Fig. 8 be Wetting Solution to Amberlite  XAD-16 in 100% blood plasma (below) and Dowex  XUS-43493 (above) 4 '-(4-amino-2-oxa-) butyl-4 of dry adsorbent, 5 ', the comparison sketch map of the influence of 8-trimethylpsoralen absorbability, the sample of moistening is not designated as " No Tx " in alcoholic solution.Absorbability is reported as the percentage rate with respect to the optimal wet adsorbent power.
Fig. 9 for the Amberlite  XAD-16 that uses moistening in several different solutions from blood plasma through adsorbing the comparison sketch map of amino psoralen in 3 hours.
Figure 10 is through adsorbing dynamic (dynamical) relatively sketch map of methylene blue in 2 hours from blood plasma.
Figure 11 illustrates acridine, acridine orange, 9-aminoacridine and 5-[(β-carboxyethyl) amino] chemical constitution of acridine.
Figure 12 has described the flow structure of immobilization adsorption plant (IAD).
Figure 13 has described the experimental provision of whole blood perfusion research.
Figure 14 is the exploded view of the circular disk configuration assembly made according to the present invention.
Figure 15 is the exploded view of the drip chamber assembly made according to the present invention.
Implement best mode of the present invention
The invention provides the equipment that reduces compound concentration in the life assemblage thing. The molecular weight of compound is the about 30000g/mol of about 100g/mol-. This equipment is flow device. An example of flow device is shown among Figure 12. Flow device is known in the literature, for example states in the open WO96/40857 of PCT, and the document is incorporated herein by reference. Flow device can make the concentration such as low molecular weight compound in the material of blood product reduce, and it is realized through this equipment perfusion by blood product.
The illustration compound comprises pathogen inactivated compound, dyestuff, mercaptan, plasticizer and complement activation. The equipment that provides comprises the three-dimensional network of the adsorbent particle of being fixed by inert base. Should fixedly reduce the bleed danger of blood product of loose adsorbent particle. And, simplified the operation that reduces the problem that accompanies with the loose adsorbent particle of processing by inert base fixed absorbent particle.
Definition
Term " acridine derivative " refers to contain tricyclic structure acridine (dibenzo [b, e] pyridine; The 10-naphthazine) compound. These compounds have affinity to nucleic acid, and can adhere on the nucleic acid by inserting non-covalently. Term " aminacrine " refers to that these acridine compounds have one or more nitrogen-containing functional groups. The example of aminacrine comprises 9-aminoacridine and acridine orange (shown in Figure 11).
Term " adsorbent particle " broadly refers to arbitrarily natural or synthetic material, it can with liquid in interaction of molecules, therefore this molecule is removed from liquid. The example of naturally occurring adsorbent includes but not limited to active carbon, silica, diatomite and cellulose. The example of synthetic adsorbent includes but not limited to polystyrene, polyacrylic acid and carbon-bearing adsorbent. The adsorbent particle is generally porous, usually has high surface, and can affect how interactional functional group (for example ion, hydrophobic, acid, the alkalescence) modification of this adsorbent and molecule with various.
Term " aromatic series ", " aromatic compound " etc. broadly refer to have the compound of the former subring of delocalized electron. This monocyclic compound benzene (C6H 6) be common aromatic compounds. But, electron delocalization can occur on more than one adjacent ring (for example, naphthalene (2 rings) and anthracene (3 rings)). Dissimilar aromatic compounds includes, but not limited to aromatic halide (aryl halide), heteroaromatic compounds, aromatic hydrocarbon (aromatic hydrocarbons) and aromatic nitro compound (aromatic nitro-compound).
Term " biocompatible coated " broadly refers to hydrophilic polymer covering surfaces (for example polystyrene bead surface), when this hydrophilic polymer contacts with blood product, can not cause being harmful to, poisonous or immune response, and by reducing cell adherence power, reducing protein adherence power or improve the cell function and give this surface larger biocompatibility. Suitable coated be biocompatible, even they have faint impact (if any) to the biomaterial that is in contact with it. " faint " impact meaning is not see compared with the control large biology difference. In preferred embodiments, the biocompatible coated surperficial blood compatibility that has improved paradigmatic structure. For example, poly-(HEMA) (pHEMA) is often used in the coated of Medical Devices (for example blood filter).
Term " biocompatible container (housing) " broadly refers to the fiberboard box, container, bag, pipe, storage of suitable dress biological material such as blood plasma etc. Suitable container is biocompatible, even they have faint impact (if any) to the biomaterial that comprises wherein. " faint " impact meaning is to compare in the blood product function with described contrast herein for example blood plasma not to be seen large difference. Therefore, blood product can be preserved in biocompatible container before the receptor in blood transfusion.
Term " biology liquid " comprise human body or non-human body whole blood, blood plasma, blood platelet, red blood cell, white blood cell, serum, lymph, saliva, breast, urine from or contain the arbitrarily product of above-mentioned single or mixture, have or do not have chemical addition agent solution. Preferably, this liquid is blood or the blood product that contains or do not contain chemical addition agent solution, more preferably blood plasma.
Term " blood bag " refers to a class blood product container.
Term " blood product " refers to by the liquid of systemic circulatory system and/or relevant Cell Component etc. (such as red blood cell, white blood cell, blood platelet etc.); Blood product includes, but not limited to blood cell, blood platelet mixture, serum and blood plasma. Term " blood platelet mixture " refers to a class blood product, and wherein this Cell Component mainly or only has blood platelet. Blood platelet concentrate (PC) is a class blood platelet mixture, and wherein these blood platelets are attended by than the less part of normal plasma part. In blood product, synthetic media can remedy the shared volume of normal plasma; For example, the blood platelet concentrate can limit platelet suspension in 35% blood plasma/65% synthetic media. Often, this synthetic media contains phosphate.
Term " blood separator " broadly refers to blood to be separated into equipment, machinery of blood product (for example, blood platelet and blood plasma) etc. Separation property blood transfusion system is a class blood separator. Separation property blood transfusion system generally includes blood separation equipment, complicated pipeline and filter network, collects the computerized device of bag, anti-coagulants and control all components.
Term " through crosslinked " broadly refers to be connected to each other and forms the linear molecule of bidimensional or three-dimensional network. For example, divinylbenzene (DVB) is as the crosslinking agent that forms styrene diethylene benzene copoly mer. This term also comprises " super crosslinked ", wherein through super crosslinked network be with or solution in or for the linear polystyrene chain of solvent swelling state and difunctionality reagent is crosslinked makes. Various difunctionality reagent can be used for crosslinked (for example, referring to Davankov and Tsyurupa, Reactive Polymers 13:24-42 (1990); The people such as Tsyurupa, Reactive Polymers 25:69-78 (1995)).
Term " cycle compound " is meant have one (that is monocyclic compound) or the chemical compound of (that is polycyclic compound) annular atoms more than.This term is not limited to contain the chemical compound of the ring of specific quantity atom.Although the contained ring of most of cycle compounds is 5 or 6 atoms, the ring of other quantity atom (for example 3 or 4 atoms) is also admitted by the present invention.Although atom mainly is a carbon atom in the ring, without limits to the concordance of these atoms.In general, the ring of polycyclic compound is adjacent one another are, and still, term " multi-ring " chemical compound comprises that those contain the chemical compound of a plurality of rings not adjacent to each other.
Term " dyestuff " broadly is meant the chemical compound of giving color.Dyestuff contains the chromophore that is connected on one or more cycle compounds and the group of auxochrome usually.Color is owing to chromophore, yet dyeing affinity is because auxochrome.Dyestuff has been divided into many classes, comprises azine dye (for example, dimethyl diaminophenazine chloride, safranine and azocazmine B); Azo dye; The azocazmine dyestuff; Take off the phenylmethane dyestuff; Fluorescent yellow dye; The ketimide dyestuff; Rosaniline dyes; Triphenhlmethane dye; Phthalocyanine dye; And hypericin.Should think can be with method and apparatus of the present invention through putting into practice and combining for the dyestuff of cycle compound arbitrarily.
Term " Fibrized resin " typically refers to fixed sorbent material, for example comprises, is embedded in the network of fibers or attached to the resin on the network of fibers.In one embodiment, this network of fibers is made up of polymer fiber.In another embodiment, these fibers are to be made up of the polymer core (for example, polyethylene terephthalate [PET]) of the higher melting temperature of being surrounded by the polymer sheath of relatively low melting temperature (for example, nylon or modified PET).Fibrized resin can be made by this network of fibers of heating under the condition that produces negative effect significantly at the absorbability that does not cause resin.Contain the place of pearl at this resin, heat in case the adsorbent pearl attached to producing " fibrosis pearl " on the outer polymer sheath.By producing the Fibrized resin that every definition area contains dose known amounts adsorbent pearl, can be by the Fibrized resin of cutting definition area, rather than the adsorbent pearl of weighing obtains (for example to be used to remove cycle compound, psoralen, particularly amino psoralen) and the Fibrized resin sample of other products.
Term " filter " broadly is meant and can makes equipment by being detained other component simultaneously of some component in the mixture, material etc.For example, filter can comprise that the aperture allows blood products (for example blood plasma) by keeping for example net of other component of resin particle simultaneously.Term " filter " is not limited to keep the device of some component.
Term " adapter of flowing " is meant the device of the flow that can control predetermined substance such as blood products.Mobile adapter can be carried out additional function, as prevents that the absorbent resin material fragment from passing through.
Term " heterocyclic compound " is meant that broadly one of them or several ring contain the cycle compound of more than one atoms.Usually, carbon atom is main atom, and other atom for example comprises nitrogen, sulfur and oxygen atom simultaneously.The example of heterocyclic compound comprises furan, pyrroles, thiophene and pyridine.
Term " high-temperature activation process " is meant typically because the pyroprocess that raw material pyrolysis and/or oxidation cause the surface chemistry of surface area, porosity and treated material to change.
Term " immobilization adsorption plant (IAD) " is meant and is embedded in the inert base or attached to the fixed absorbent material on the inert base.At inert base is the place of network of fibers, and term IAD can use with term Fibrized resin exchange ground.
Term " inert base " is meant synthetic arbitrarily or naturally occurring fiber or fibrous material, they can be used for fixing absorbent particles, and not influence the required biological activity of blood products basically.Although this substrate is to absorption or remove almost not contribution of process, it may be favourable to the concentration that reduces less organic compound.In addition, this inert base can interact with cell or protein component, makes cell remove (for example leukocyte eliminating) or removes deproteinize or other molecule.This substrate can be subjected to surface treatment or bag by to improve degree of functionality.For example, this substrate can obtain hydrophobicity bag quilt or glow discharge is handled to increase biocompatibility, strengthens wettability, and/or promote to pour into.
Term " post in pipeline " is meant and is generally columniform to have the container of input and outfan, and wherein contained material can make the concentration of the little organic compound in the blood products reduce.
Term " separation " is meant isolates a kind of material from the mixture that contains more than one components.For example, can from whole blood, isolate platelet.Isolating product needs not to be this product to be separated from other component fully.
Term " macropore " meaning usually is that the aperture is greater than about 500 .The term micropore is meant that the aperture is less than about 20 .The term mesopore be meant the aperture greater than about 20 less than about 500 .
Term " macropore " is used to describe the pore structure of a large amount of apertures greater than about 500 .
Term " macroreticular " is a relative terms, and the meaning is to have degree of physical porous (that is, having big metering-orifice) structure, and the existing macropore of porous adsorbent structure has micropore again.
Term " net closure ", " mesh bag " etc. are meant and are processed into closure, bag, bag or the analog that contains a plurality of openings.For example, the present invention uses a kind of bag, and it is equipped with the fixed absorbent granule, and its hole dimension makes blood products can contact fixed absorbent particles, but fixed absorbent particles is retained in the bag.
Term " photoproducts " be meant psoralen or other dyestuff (for example methylene blue, phthalocyanine dye) through the photochemical reaction that being exposed to ultraviolet radiation product extremely.
Term " polyvinyl aromatic compound " is meant the polymer that contains aromatic radical in main chain, and polyethylene terephthalate for example, or as the polymer of side group as polystyrene, or had not only contained aromatic radical but also as the polymer of side group in main chain.
Term " polystyrene network " broadly is meant and contains styrene (C 6H 5CH=CH 2) polymer of monomers; These polymer can be linear, are made up of single covalency alkane chain and phenyl substituent, or through crosslinked, common and-or right-phenylene residue or other difunctionality or super cross-linked structure are crosslinked, thereby formation two-dimensional polymer main chain or three-dimensional network.
Term " psoralen remover " is meant a kind of material or the equipment that can remove greater than about 80% psoralen from blood products for example; Preferably, greater than about 90%; More preferably greater than about 99%.The psoralen remover can also be removed other component in the blood products, for example psoralen photoproducts.
Phrase " reduction concentration " is meant removes a part of low molecular weight compound from biological composition.It is about 70% that the reduction of concentration simultaneously is preferably greater than, and more preferably from about 90%, most preferably from about 99%.
Phrase " is removed described freely chemical compound part (for example psoralen, psoralen derivant, isopsoralen, acridine, acridine derivatives or dyestuff) in nearly all solution " and preferably is meant and removes greater than this chemical compound freely in about 80% the solution, more preferably remove greater than about 85%, be preferably greater than approximately 90% again, most preferably remove greater than about 99%.
Term " resin " is meant a kind of solid carrier (for example granule or pearl etc.), it can with solution or liquid (for example blood products) in comprise that the various little organic compound of psoralen interacts and absorption, has therefore reduced the concentration of these compositions in the solution.This process of removing is not limited in the mechanism of any specific.For example, can remove psoralen by hydrophobic or ionic interaction (that is affine interaction).Term " absorbent resin " broadly is meant natural organic matter and synthetic and composition thereof.
Term " sintered medium " is meant by applying heat and pressure for powder or mixture of powders, thereby makes this powder or the formed structure of mixture of powders partial melting, has liquid flow path like this in this structure.Loose structure can be made by following: the polymer powder that fusing point is low relatively mixes, and they is heated to this plastic particle partial melting, but still is penetrated in the porous material with the fluid approach.The sintering adsorbent medium similarly can be by carbon or other is high or not fused absorbent particles with low-melting powder mixes and heat and make.The method of production porous plastic material is described among the US3975481,4110391,4460530,4880843 and 4925880, is incorporated herein by reference.This method makes the powder particle fusion form the porosu solid structure.By in sintering process, polymer powder being placed in the shaping jig and this sintered medium can being formed different shape.Before carrying out sintering process, mix and absorbent particles can be added in the sintered medium with the powder thermoplastic polymer beads by absorbent particles.
Term " stabilizing agent " is meant the chemical compound or the compositions of the absorbability that can optimize some resin.In general, acceptable stabilizing agent should be able to water-soluble and ethanol (or other wetting agent), and is non-volatile with respect to water and ethanol, and can be safely with a small amount of conveying.The example of stabilizing agent includes, but not limited to glycerol and low-molecular-weight PEG.The difference of " wetting agent " and " stabilizing agent " is that the former is considered to open once more the adsorbent hole without super crosslinked resin (that is non-big net resin).Wetting agent can not prevent that generally the hole subsides under the drying condition, yet stabilizing agent can.The general discussion of moistening and wetting agent has statement in people's such as Pall US5501795, be incorporated herein by reference here.
Phrase " the required biological activity that has kept biological composition basically " is meant the characteristic that has kept biological composition basically, it is believed that the potential performance of the clear said composition of these property lists in treatment is adjusted.For example, for blood plasma, if thrombin, as factor I, II, V, VII, VIII, IX, X, XI level or PT and the variation of PTT time are retained in the blood plasma of handling by methods described herein basically, and activity in vivo is not destroyed or not significant so reduces.For example, the thrombin of the blood plasma of handling, as factor I, II, V, VII, VIII, IX, X, the variation of XI level should be less than about 10%.Blood plasma PT and the variation of PTT time handled can be, for example, and less than about 3 seconds and greater than 1 second; Be preferably for 1.5 seconds.Should think that also phrase " keeps the every kind performance relevant with described blood products basically " and also can comprise the acceptable value of those skilled in the art described in the document, the document comprises for example KleinH.G., ed.Standards for Blood Banks and Transfusion Services, 17 ThEd., Bethesda, MD:American Association of Blood Banks, 1996, be incorporated herein by reference.
Term " its coordinate " is meant function and the suitable equipment of biological activity that keeps biological composition when it is used for equipment of the present invention.For example, " on an equal basis " equipment or the substrate that contains absorbent particles is similarly kept cell viability or suitable thrombin level a kind of.
Term " low molecular weight compound " is meant the organic or biomolecule of molecular weight ranges at the about 30000g/mol of about 100g/mol-.Low molecular weight compound includes, but not limited to following chemical compound: little organic compound such as psoralen, acridine or dyestuff; Quencher is as glutathion; Plasticity extractable, for example plasticizer; Biological instrumentality as complement activation, has the molecular weight of the about 30000g/mol of about 100g/mol-; And polyamine derivatives.
Term " biological composition of suitable infusion " is meant that biological composition has kept its necessary biological property (for example platelet form), contain enough low-level any unwanted chemical compound (for example deactivation compounds, reaction instrumentality) simultaneously, so that infusion provides the function of wanting, but there is not harmful side effect.
Term " contrast " is meant the test of the relative effect research of carrying out different condition when it for example is used for the phrase of " relative comparison ".For example, in the place that biological composition is handled with a kind of equipment, " untreated contrast " should be meant the biological composition of this device processes of no use.It also can refer to two kinds of comparisons between the dissimilar equipment.
Term " 4 '-(4-amino-2-oxa-) butyl-4,5 ', 8-trimethylpsoralen " also is called " S-59 ".
Term " N-(9-acridinyl)-Beta-alanine " also is called " 5-[(β-carboxyethyl) amino] acridine ".It is also called " S-300 ".
Term " XUS-43493 " is also called Optipore 493 ".
Term " non-fiber adsorbing substance material " is meant basically by length or the longest dimension sorbent material less than the granulometric composition of five times of its width or narrow dimensions.
Absorbent particles
In order to reduce the required biological activity that compound concentrations in the biological composition keeps biological composition simultaneously basically, be provided for the absorbent particles in a kind of equipment.Typically, these chemical compounds that reduced in biological composition have the molecular weight of the about 30000g/mol of about 100g/mol-.
Absorbent particles can be to make it join any regular in the inert base or irregularly shaped, but is preferably roughly spherical.These particulate diameters are greater than about 1 μ m; Preferably, when with sintered medium during as the substrate of adsorbent these particulate diameters greater than about 10 μ m; More preferably, when with sintered medium during as substrate these particulate diameters between the about 150 μ m of about 50 μ m-.When with the wet-laying fiber medium during as the substrate of adsorbent, these particulate diameters are preferably between the about 200 μ m of about 1 μ m-, more preferably between the about 50 μ m of about 1 μ m-.
In a preferred embodiment, these absorbent resins are by active carbon natural or that synthetic source obtains.The non-limitative example of active carbon comprises: can from PICA USA Inc. (Columbus, OH) the Picatiff Medicinal  of Huo Deing can be from Norit Americas, Inc. (Atlanta, GA) the Norit  ROX0.8 of Huo Deing can be from Rohm﹠amp; Haas (Philadelphia, the Ambersorb  572 that PA) obtains and can be from PICA (Columbus, OH) the G-277  of Huo Deing.
Preferred active carbon be through particular purification and/or meet USP standard.And surface area is greater than 950m 2The active carbon of/g is preferred, because the surface area of the active carbon that general low molecular weight compound can utilize is big more, the adsorption of active carbon is good more.The active carbon that is formed by steam activation is tending towards having more hydrophobic surface, so for more hydrophobic low molecular weight compound, the charcoal of these steam activations usually has preferably binding capacity and these charcoals are preferred.The feasible selectivity to low molecular weight compound of lower macroporosity surpasses the bioactive larger protein of mediation, therefore has the active carbon that hangs down macroporosity, and for example the active carbon of being made by coconut husk also is preferred.
In a preferred embodiment, these granules are Norit A Supra, and it can derive from Norit Americas, and Inc. (Atlanta, GA).Norit A Supra is a kind of USP level active carbon that is formed by the steam activation of coconut husk.This active carbon has very high total surface area (2000m 2/ g) and be very micro porous.
In another preferred embodiment, these granules can be hydrophobic resins.The non-limitative example of hydrophobic resin comprises following polyaromatic adsorbent: Amberlite  adsorbent (for example, Amberlite  XAD-2, XAD-4 and XAD-16), and can be from Rohm﹠amp; (Philadelphia PA) obtains Haas; Can be from Toso Haas (TosoHass, Montgomeryville, PA) the Amberchrom  adsorbent of Huo Deing; Diaion  //Sepabeads  adsorbent (for example Diaion  HP20), can be from MitsubishiChemical America, (White Plains NY) obtains Inc.; Hypersol-Macronet  absorbent resin (for example Hypersol-Macronet  absorbent resin MN-200, MN-150 and MN-400) can (Bala Cynwyd PA) obtains from Purolite; With Dowex  adsorbent (for example Dowex  XUS-40323, XUS-43493 and XUS-40285), can be from Dow Chemical Company (Midland, MI) acquisition.
Preferred granule is the hydrophobic resin that contains the polyaromatic adsorbent of super crosslinked polystyrene network, for example Dowex  XUS-43493 (being Optipore  L493 or V493 on the known commercial) and Purolite MN-200.
Super crosslinked polystyrene network as Dowex  XUS-43493 and Purolite MN-200 is nonionic macropore and macroreticular resin.Nonionic macroreticular and macropore Dowex  XUS-43493 be to comprising for example 4 '-(4-amino-2-oxa-) butyl-4,5 ', and the psoralen of 8-trimethylpsoralen has high affinity, and it has good wettability.Phrase " good wettability " meaning is that dried (for example substantially anhydrous) adsorbent needn't used wetting agent (for example ethanol) moistening for the concentration that reduces the medium and small organic compound of blood products effectively with before blood products contacts.
For example preferred its of the super crosslinked polystyrene network of Dowex  XUS-43493 and Purolite MN-200 is shaped as the spheroidal particle of diameter range at the about 1300 μ m of about 200 μ m-.Comprise that for example the absorbent particles of Dowex  XUS-43493 preferably has king-sized internal surface area and relative little hole (for example 46 ).Particulate internal surface area can be at the about 1100m of about 300- 2/ g; 1100m preferably 2/ g.Particulate aperture can be greater than 25 and less than 800 ; Preferred about 25 -Yue 150 ; 25 -Yue 50 most preferably from about.When in the mechanism of not planning to limit the present invention to the reduction of carrying out little organic compound, the dominant mechanism that hydrophobic interaction is considered to adsorb.Its permeability can be by making micromolecule enter relative macromole (that is protein) thereby and the surface area of the more vast scale of cell optionally authorize adsorption process.Purolite  has many and the similar characteristic of Dowex  XUS-43493, and for example to high affinity of psoralen and good wettability, and it also is best absorbent particles.
Can polystyrene be divided into ⅰ according to its synthesis mechanism and physics and functional characteristic) legacy network and ⅱ) super cross-linked network.Preferred adsorbent has big surface area, the hole that does not subside, and do not need moistening.In addition, preferred adsorbent has a small amount of extractible residual monomer, cross-linking agent and other organic extractable.
This legacy network mainly is a styrene diethylene benzene copoly mer, and wherein divinylbenzene (DVB) is as cross-linking agent (that is the reagent that the linear polystyrene chain is linked together).These converging networks comprise " gel-type " polymer.This gel-type polymer is even, the atresia styrene-DVB copolymer that obtains by monomer copolymerizable.Macroporous adsorbent is represented the second quasi-tradition network.They are to obtain by copolymerization monomer in the presence of the diluent of the polystyrene chain that generates in precipitation.The polystyrene network that forms by this step has big relatively internal surface area (every gram polymer up to hundreds of square metre); Amberlite  XAD-4 is produced by this step.
Compare with above-mentioned legacy network, preferred adsorbent of the present invention (for example, Dowex  XUS-43493) is super cross-linked network.These networks are by with the linear polystyrene chain or with solution or with solvent swelling state and difunctionality reagent is crosslinked makes; Preferred difunctionality reagent produces the cross-bridge of conformation constraint, it is believed that to have prevented that like this hole subsides when this adsorbent is in substantially anhydrous (that is, " drying ") state.
Super cross-linked network it is believed that to have and other three key properties of legacy network phase region.At first, because these bridges make polystyrene chain keep separating, so the density of polymer chain is low.As a result, adsorbent has big relatively aperture surface area and aperture usually.Secondly, these networks can expand, that is, its volume increases when polymer phase contact organic molecule.It is " directly " when at last, this super cross linked polymer is in drying regime; That is, the rigidity of drying regime network has stoped the attraction of chain and chain.But, these chain relaxations when adsorbent is wetted, this has increased network expansible ability in liquid medium.Davankov and Tsyurupa, Reactive Polymers13:27-42 (1990); People Reactive Polymers 25:69-78 (1995) such as Tsyurupa, this paper is incorporated herein by reference.
Successfully utilize the bridge between several cross-linking agent production polystyrene chains, comprise dichloro-xylol (XDC), monochloro-dimethyl ether (MCDE), 1,4-two-chloromethyl biphenyl (CMDP), 4,4 '-two-(chloromethyl) biphenyl (CMB), dimethyl methyl acetal (DMF), p, p '-two-chloromethyl-1,4-diphenyl butane (DPB) and three-(chloromethyl)-mesitylene (CMM).Be reflected at these bridges of formation between the polystyrene chain by one of these cross-linking agent and styrene phenyl ring by Friedel-Crafts reaction.Therefore, the gained bridging is connected on the styrene phenol ring that occurs on two different polystyrene chains.Referring to for example US3729457, be incorporated herein by reference here.
Because these bridges have been eliminated the needs to " moistening " agent usually, so these bridges are particular importances.That is, these bridges have prevented that the hole subsides when adsorbent is in anhydrous basically (promptly " doing ") state, therefore adsorbent with needn't open once more with wetting agent before blood products contacts.In order to prevent that the hole from subsiding, should form the bridge of conformation constraint.The conformation that some difunctionality reagent limit as DPB does not cause; For example, DPB contains four continuous MU (methylene unit) of conformation being reset sensitivity.Therefore, DPB is used for preferred difunctionality reagent of the present invention.
The structure dependent characteristic of some of above-mentioned absorbent particles is listed in the Table A.
Table A
Resin Chemical property Average surface area (m 2/g) Average pore size () Hole dimension (μ m)
Amberlite  adsorbent-Rohm and Haas
XAD-2 Polyaromatic 300 90 20-60
XAD-4 Polyaromatic 725 40 20-60
XAD-7 Polymethacrylates 450 90 20-60
XAD-16 Polyaromatic 800 100 20-60
XAD-1180 Polyaromatic 600 300 20-60
XAD-2000 Polyaromatic 580 42 20-60
XAD-2010 Polyaromatic 660 280 20-60
Amberchrom  adsorbent-Toso Haas
CG-71m Polymethacrylates 450-550 200-300 50-100
CG-71c Polymethacrylates 450-550 200-300 80-160
CG-161m Polyaromatic 800-950 110-175 50-100
CG-161c Polyaromatic 800-950 110-175 80-160
Diaion  //Sepabeads  adsorbent-Mitsubishi Chemical
HP20 Polyaromatic 500 300-600 20-60
SP206 Brominated styrene 550 200-800 20-60
SP207 Brominated styrene 650 100-300 20-60
SP850 Polyaromatic 1000 50-100 20-60
HP2MG Polymethacrylates 500 200-800 25-50
HP20SS Polyaromatic 500 300-600 75-150
HP20MS Polyaromatic 500 300-600 50-100
Dowex  adsorbent-Dow Chemical Company
XUS-40285 Functionalized 800 25 20-50
XUS-40323 Polyaromatic 650 100 16-50
XUS-43493 Polyaromatic 1100 46 20-50
The processing absorbent particles
Can further process to remove subparticle, salt, potential extractable and endotoxin these absorbent particles.These can extract removing typically by using organic solvent, steam or treatment with supercritical fluid to realize of component.Preferably these granules are through sterilization.
The absorbent particles of the commercially available acquisition of " purification " (promptly finished) type is sold by present several company.Except these absorbent particles (for example resin) were processed, these adsorbents were tested by these companies, and final adsorbent guarantees aseptic (USP XXI), apyrogeneity (LAL) and do not have detectable extract (DVB and total organic matter).
Hot-working (for example steam) is a kind of effective ways of processing absorbent particles.F.Rodriguez，Principles?Of?Polymer?Systems，(HemispherePublishing?Corp.)，pp.449-53(3 rd.Ed.，1989)。(Bellefonte PA) uses a kind of solvent-free, hot proprietary process to purify Dowex  XUS-43493 and Amberlite adsorbent in Supelco company.Use the main benefit of steam to be in adsorbent, not add any potential extractable.But a big defective is that this process can seize moisture from the hole of resin bead; The effective performance of some adsorbents needs the quilt moistening once more before the contact blood products of these pearls.
Wetting agent and stabilizing agent are used with absorbent resin
Can use certain methods to prevent the forfeiture of particle drying and absorbability, for example Amberlite  loses some absorbabilitys down in some condition (for example dry).
In one approach, granule, material or equipment can be processed under airtight and the wetting state that can not become dry.This method is attended by several major defects.The level of extractable may increase in the material owing to go beyond the time limit, so the pot-life of these products may shorten.Because the moistening polymer does not typically pass through gamma-irradiation, therefore sterilization may be limited in steam course.The processing request assembly keeps the equipment of moisture state more difficult than dry processing equipment usually; For example, if time-lag is oversize between device assembles and the final sterilization, may consider biological load and endotoxin.
The second method that prevents the absorbability forfeiture is to use the adsorbent of being free from side effects through super-dry.As mentioned above, the macroreticular adsorbent (for example, Dowex  XUS-43493 and Purolite  MN-200) with highly cross-linked pore structure does not need wetting agent usually, and this is because this crosslinked hole that stoped subsides.Do not resemble Amberlite  XAD-16, these macroreticular adsorbents have kept very a high proportion of initial activity when it is dried.
In the third method, in the presence of non-volatile wetting agent by making Amberlite  XAD-16 and related adsorbent (for example, Amberlite  XAD-4) become hydrate can prevent forfeiture because of exsiccant absorbability.For example, when using Amberlite  XAD-16 as adsorbent, this adsorbent pearl can be partly dry in operation, sterilization and storage before using.When the moisture subcritical level of these adsorbents, the quick forfeiture (may because hole " subside ") of absorbability takes place; Therefore, in order to reach optimum efficiency, these holes have to " open " with wetting agent again before use.
When some absorbent resin is exposed to drying condition following time, stabilizing agent is effective near its maximum to keeping absorbability.It is believed that and use stabilizing agent to prevent that the adsorbent hole from subsiding.
Acceptable stabilizing agent should be water soluble and ethanol, and the second alcohol and water is non-volatile relatively, and to transfer safety on a small quantity.Glycerol and low molecular poly (for example PEG-200 and PEG-400) are the examples with stabilizing agent of these characteristics.Glycerol has positive blood compatibility history.In the chilled storage of erythrocyte goods, often it is added in the blood as antifreezing agent.Referring to people Transfusion 26:341-45 (1986) such as for example Chaplin; People Am.J.Vet.Res.42 (9) 1590-94 (1981) such as Valeri.The solution that will contain up to 1% glycerol transfers routinely, glycerite can be commercially available (Glyerolite 57 Solution for example, FenwalLaboratories, Deerfield, IL).The adsorbent pearl that resembles Amberlite  XAD-16 can be through stable in ethanol and glycerol.
The low molecular poly that is often used as the medicine base material also can be used as stabilizing agent.PEG is chemical general formula H (OCH 2CH 2) nThe liquid state of OH and solid polymer, wherein n is more than or equal to 4.The PEG goods are followed the quantity of corresponding its mean molecule quantity usually; For example, the molecular weight of PEG-200 is 200, and molecular weight ranges is 190-210.PEG is can many goods (for example Carbowax, Poly-G and Solbase) commercially available.
Be used for granulopectic inert base
By inert base fixed absorbent granule.This inert base can be by synthetic or natural polymer preparation.This inert base can be sintered polymer.Other assembly of this inert base and this equipment is preferably can be biocompatible, and can side effect not arranged because of the biological activity that contacts material basically.
In the embodiment of using synthetic fibers, these synthetic fibers are polyester fiber (AirQuality Filtration (AQF), Hoechst Celanese place (Charlotte, N.C.)).Other preferred example of synthetic fibers is polyethylene or Fypro.Other illustration synthetic fibers comprise polyolefin, polyvinyl alcohol and polysulfone fibre.
In a preferred embodiment, this synthetic polymeric fibers comprises dystectic first polymer core that has that sheath with low fusion temperature surrounds.This polymer core can be polyester (polyethylene terephthalate).This sheath can be nylon or modified poly ester.Fiber can (Osaka be Japan) with Hoechst Trevira GmbH﹠amp from Unitika; Co. (Augsberg, Germany) commercially available.
For fibre substrate, the most preferred embodiment is used cellulose fibre.These cellulose fibres can derive from the cellulose fibre of separate sources, and for example there are Corchorus olitorius L., kozu, kraft paper and abaca in these sources.To synthesize or the network of natural polymerization fibres is used to prepare the filter described in US4559145 and 5639376, this paper is incorporated herein by reference.
Agglomerating substrate also is embodiment preferred.The synthetic polymer of this sintered particles of suitable configurations is high density polyethylene (HDPE), ultra-high molecular weight polyethylene, polypropylene, polyvinyl fluoride, politef, nylon 6.More preferably this sintered particles is a polyolefin, as polyethylene.
Aforesaid polymer fiber can be the absorbent resin that does not adhere to absorbent particles.These fibers can be formed on the network of fibers that network of fibers maybe can be fixed in sorbent fibers still less.The present invention comprises these fibers; These fibers preferably contain greatly, the surface area of porous, adsorptivity or be easy to reduce other adsorptivity instrument of low molecular weight compound concentration.
Particulate fixing
In one embodiment, absorbent particles is fixed by inert base, thereby makes the adsorbing medium that is used to reduce the medium and small organic compound substrate concentration of material.This inert base can be to contain three-dimensional network synthetic or natural fiber network and fixing absorbent particles wherein.
Preferably, this adsorbing medium contains the aperture absorbent particles with highly porous structure and very large internal surface area, as mentioned above, is fixed by this inert base.Preferably, when biomaterial was contacted with adsorbing medium, adsorbing medium was free from side effects basically to biological activity or other performance of material.
The adsorbent pearl is fixed on the technology that constitutes air filter on the network of fibers has description in US5486410 and US5605746, be incorporated herein by reference.As described in Figure 1, the polymer fiber 600 of network of fibers is made up of the polymer core with higher melt 602 (for example, polyethylene terephthalate (PET)) of polymer sheath 604 (for example, the nylon) encirclement with low relatively fusion temperature.Referring to people's such as Heagle US5190657, this paper is incorporated herein by reference.Fibrized resin by in network of fibers at first uniform distribution adsorbent pearl make.Next, with this network Fast Heating (for example, 180 ℃ * 1min.) make the polymer sheath fusion of fiber 600 and stick to adsorbent pearl 606 and other fiber on, thereby form crosslinked network of fibers, as shown in Figure 2.As (not to scale (NTS)) as described in Fig. 3 and Fig. 4, in general, this network of fibers contains three layers: two skin 607 and not too thick internal layers 609 that contain adsorbent pearl 606 and less fiber 600 that are wrapped in fiber 600 densely.In a preferred embodiment, the edge of Fibrized resin can be with polyurethane or other polymeric seal.Perhaps, as described in Fig. 3 and Fig. 4, can in the gained Fibrized resin, prepare heat seal 608 with predetermined space; For example, can in Fibrized resin, prepare heat seal with square pattern.Afterwards, can be by these heat seal with the cutting of this Fibrized resin, contain required adsorbent pearl quality (for example, preferably less than 5.0g and be more preferably less than 3.0g) and suitable size and be placed on resin sample in the blood products container thereby form.These heat seal are used to prevent that the Fibrized resin that cuts is worn and helps the fixed absorbent pearl.But, do not need to use these heat seal in order to put into practice the present invention.In a selectivity embodiment, as described in Figure 4, the adsorbent pearl is not fixed on these fibers originally on one's body, but still be fixed on fiber denser outer 607 between and have a heat seal 608; This embodiment also can be by making the fibrotic mediators sample contain a certain amount of adsorbent after these heat seal cuttings.
The present invention also attempts using adhesive agent (for example, binding agent) that absorbent resin is fixed on the fiber.And, although preferably the adsorbent pearl chemically is adhered on the network of fibers, also can physically be limited in these pearls in the network of fibers; This can realize so that make these pearls be in the appropriate location by for example surrounding these pearls with enough fibers.
Also attempted these absorbent particles to be fixed on other method in the network of fibers.Can use dried shop method to fix these granules, described in US5605746 and 5486410 (AQF patent), this paper is introduced into as a reference.Can use wet shop method to fix these granules, described in US4559145 and 4309247, this paper is introduced into as a reference.Can use the melt-blown method to fix these granules, described in US5616254, this paper is introduced into as a reference.When using wet shop method to make up substrate by the natural polymerization fibres, this inert base preferably includes bonding agent so that the adsorbent pearl is attached on the fiber.The non-limitative example of bonding agent comprises melamine, polyamine and polyamide.This substrate typically contains 1% or these bonding agent still less.
Using absorbent particles when agglomerating synthetic polymer particle makes up inert base, it is very important that absorbent particles has higher melting temperature than substrate.
In a preferred embodiment, absorbent particles is fixed in the fibre substrate that the heat bonding by the biological components network of fibers forms.Another embodiment relates to absorbent particles is fixed in the abiotic component fibre and working strength resin system, adhesive agent or other fusible fibers, thereby forms bonding between fiber and absorbent particles.The non-limitative example of useful fiber comprises polyester, nylon and polyolefin.(supplier who is used for the fiber of nonwoven industry lists in " AGuide to Fibers for Nonwovens; " Nonwovens Industry, June 1998, and 66-87.) example of wet-strength resins system comprises melamine/formaldehyde, chloropropylene oxide base resin, polyamine and polyamide.But use meldable fibre to be fixed in the fibre substrate granule open.Referring to for example US4160059.
Preferably, gained adsorbing medium unit are contains the adsorbent of known quantity.The adsorbent of unit are is about 300g/m 2-Yue 1100g/m 2, preferably from about 500g/m 2-Yue 700g/m 2Like this, can measure the adsorbent (that is, need not claim Fibrized resin) of the appropriate amount of attempting to be used for specific purpose simply by the predetermined area of cutting fibre resin.
The preferred bio-compatible of this adsorbing medium (that is, not producing poisonous, harmful or immunoreation); Performance to the material of for example blood products (for example, blood plasma) has minimum influence; And without poisonous extractable.Adsorbing medium fixed absorbent particles preferably have high mechanical stability (that is, do not have subparticle produce).Adsorbing medium contains the adsorbent of about 20-70wt%, preferred 30-50wt%.If use fibre substrate, then adsorbing medium preferably contains the absorbent particles of about 30wt%.If use agglomerating particle matrix and ground polymeric adsorbant granule, then adsorbing medium preferably contains the absorbent particles of about 50wt%.
Bag is adsorbed the agent granule
The surperficial blood compatibility of granule, substrate or adsorbing medium can be improved by its surface by using the hydrophilic polymer bag.The hydrophilic polymer of illustration comprises poly-(methacrylic acid 2-hydroxyl ethyl ester) (pHEMA), it can be from for example Scientific Polymer Products, Inc. (Ontario, NY) obtain, and cellulose-based polymer, ethyl cellulose for example, it can (Midland MI) obtains from Dow Chemical.Referring to people such as for example Andrade, Trans.Amer.Soc.Artiif.Int.Organs XVII:222-28 (1971).Other example of bag quilt comprises Polyethylene Glycol and polyethylene glycol oxide, also can be from Scientific PolymerProducts, and Inc. obtains.This polymer coating can increase the blood compatibility and reduce because mechanical breakdown produces short grained danger.
This adsorbent surface also can be regulated with fixed heparin.In addition, can regulate reinforcing YIN-essence ion exchange polystyrene divinylbenzene adsorbent through heparin absorption.Heparin, a kind of polyanion will be adsorbed on the surface of the adsorbent with reinforcing YIN-essence ion exchange property very securely.The polystyrene divinylbenzene adsorbent that the various quaternary ammoniums of commercially available acquisition are regulated.
Can use a large amount of diverse ways to wrap quilt, comprise the radio frequency glow discharge polymerization described in US5455040, this paper is incorporated herein by reference with Wurster and wraps by method (by International Processing Corp. (Winchester KY) finishes).
In one embodiment, can be by absorbent particles (passing through air pressure usually) being suspended in the chamber so that for example the hydrophilic polymer of pHEMA can evenly be injected on the whole surface of absorbent particles and implements this Wurster bag by method.As described in embodiment 3, the Dowex  XUS-43493 that evenly sprays with pHEMA demonstrate that the platelet yield increases and with the bag of recruitment by change has produced unforeseeable effect to the platelet shape.Found that this Wurster bag is optionally wrapped the outer surface that is adsorbed the agent surface by method, to almost not influence of inner bore surface.
In a preferred embodiment, fixing adsorbing medium can be immersed in and wrap in the hydrophilic polymer by (referring to embodiment 2).This method is simpler and cost is lower than spray absorbent particles with hydrophilic polymer.
This method is not limited in the method for any this adsorbing medium of special time endoperidium.For example, in one embodiment, after making adsorbing medium but before this adsorbing medium of heat-sealing, carry out pHEMA bag quilt.In another embodiment, this adsorbing medium is at first sealed, carry out this pHEMA bag quilt then.Except wrapping, will use sintering process together with pHEMA and be used to remove discrete particles and fiber by this adsorbing medium.
Along with package amount increases, some chemical compounds are arrived particle surface by bag will become more difficult, and this makes absorption power reduce.Therefore, along with package amount increases, must use usually the adsorbent of recruitment reach adsorbent with the bag quilt identical remove power.In one embodiment, the optimum level of pHEMA bag quilt is the minimum bag quilt that can observe the protective effect of blood plasma function.
These bag quilts may be to the sensitivity of sterilizing.For example, the γ sterilization may cause bag to be crosslinked and/or split.Therefore, type of sterilization (E-beam and γ irradiation) and dosage may influence the performance of the adsorbent of the quilt that wraps.Usually, preferred E-beam.
Equipment
The invention provides the equipment that reduces compound concentration in the biological composition.The molecular weight of chemical compound is the about 30000g/mol of about 100g/mol-.This equipment is flow device.An example of flow device is shown among Figure 12.Flow device is known in the literature, for example states in the open WO96/40857 of PCT, and the document is incorporated herein by reference.
Flow device can make the concentration such as low molecular weight compound in the material of blood products reduce, and it is realized through this equipment by the blood products perfusion.
The adsorbing medium of flow device is preferably that about 3-30mm is thick not to have big pressure drop with the smooth flow that promotes biofluid.The preferred about 3-15mm of this medium is thick.More preferably the about 5-8mm of this medium is thick.
In one embodiment, this equipment is the circular disk configuration flow device.The circular disk configuration flow device as shown in figure 14, Figure 14 is the exploded view of this device instance.Desire is with the flow through connection tube (1) of container entrance of the biological composition of this device processes.Flow through IAD (immobilization adsorption plant) container entrance (2) and enter IAD medium (3) of this biological composition then, this medium reduces the concentration of low molecular weight compound in the biological composition.This biological composition prefilter (4) of can flowing through then, this chooses wantonly.It flows through film (5) remove particulate matter from compositions then.At last, treated biological composition leaves this equipment by IAD container outlet (6).
In another embodiment, this equipment is drip chamber structure (Porex IAD).Drip chamber structure flow device as shown in figure 15.Figure 15 is an exploded view.Desire is with the biological composition of this device processes IAD (immobilization adsorption plant) container entrance (60) of flowing through.This biological composition flows into IAD container (drip chamber) (50) then.Enter IAD medium (40) again, this medium reduces the concentration of low molecular weight compound in the biological composition.This biological composition prefilter (30) of can flowing through then, this chooses wantonly.It flows through film (20) remove particulate matter from compositions then.At last, treated biological composition leaves this equipment by IAD container outlet (10).
The preferred embodiment that is used for biological composition
In some embodiments, the invention provides the equipment that reduces compound concentrations in the biological composition.These equipment comprise adsorbing medium and have flow structure.The molecular weight of chemical compound is the about 30000g/mol of about 100g/mol-.Biological composition with can keep its biological activity substantially after such equipment contacts.
Shown that biological respinse modifier (for example, activatory complement) as milphosis toxin C 3a and terminal membrane attack complex SC5b-9 is by handling (for example bleed filter leukocyte, singly adopt, recovery etc.) and storage production to whole blood and its component.In the rough sledding of operation and blood transfusion, these biological respinse modifiers have been involved.
In some embodiments, equipment of the present invention reduces the concentration of complement activation in the biological composition.Compare with the compositions of this device processes of no use, when with this device processes said composition, wherein the concentration of complement activation is lowered.In one embodiment, be exposed to and make the terminal component of C3a complement fragment and SC5b-9 reduce about 30% at least in this equipment compared with the control.In another embodiment, be exposed to and make the terminal component of C3a complement fragment and SC5b-9 reduce about 50% at least in this equipment compared with the control.In another embodiment, be exposed to and make the terminal component of C3a complement fragment and SC5b-9 reduce about 90% at least in this equipment compared with the control.
In one embodiment, the invention provides a kind of equipment that is used for reducing the biological composition compound concentrations that contains blood plasma.The biological composition that contains blood plasma with this device processes makes the biological activity of blood plasma obtain basically keeping.This adsorbing medium comprises by the fixed absorbent particles of inert base.Preferred granule is a lot of holes and has greater than about 750m 2The surface area of/g.
Particularly preferred granule is Norit A Supra, can derive from Norit Americas, and Inc. (Atlanta, GA).Norit A Supra is a kind of little active carbon of USP that is formed by the steam activation of coconut husk.This active carbon has very high total surface area (2000m 2/ g) and be very micro porous.
In addition, these granules can be selected from any following granule, granule wherein preferably has the diameter of the about 200 μ m of about 1 μ m-, through grinding directly synthetic or obtaining with some alternate manners, they are active carbons, as Picactif Medicinal (Pica USA, Columbus, OH), synthetic carbonaceous adsorbent is as Ambersorb 572 (Rohm and Haas, Philadelphia, PA), hydrophobic resin is as Amberlite  adsorbent (for example, Amberlite  XAD-2, XAD-4 and XAD-16), can be from Rohm﹠amp; (Philadelphia PA) obtains Haas; Can be from Toso Haas (TosoHass, Montgomeryville, PA) the Amberchrom  adsorbent of Huo Deing; Diaion  //Sepabeads  adsorbent (for example Diaion  HP20), can be from Mitsubishi Chemical America, (White Plains NY) obtains Inc.; Can be from Purolite (Bala Cynwyd, PA) the Hypersol-Macronet  absorbent resin of Huo Deing (for example Hypersol-Macronet  absorbent resin MN-150 and MN-400) and can be from Dow Chemical Company (Midland, MI) the Dowex  adsorbent of Huo Deing (for example Dowex  XUS-40323, XUS-43493 and XUS-40285).
Inert base can be made up of synthetic or natural polymer fibre or granule.In preferred embodiments, this substrate is the sintered particles of fibrous cellulose or ultra-high molecular weight polyethylene.
Illustration chemical compound by these equipment of the present invention, material and method reduction or control is psoralen, psoralen derivant, isopsoralen, psoralen photoproducts, acridine, acridine derivatives, methylene blue, plasticity extractable, biological respinse modifier, quencher and polyamine derivatives.
When this equipment was used to contain the compositions of blood plasma, this equipment kept the blood coagulation activity of proper level.The measurement of blood coagulation activity comprises prothrombin time (PT), activated partial tissue thromboplastin time (aPTT), and factor I, II, V, VII, VIII, IX, X, the functional measurement value of XI and XII.The appropriate functional measured value of coagulation factor activity about 80% greater than by level before this equipment, or for setting time remains on the normal range that the laboratory that carries out this test is set up.Preferred blood coagulation activity measured value comprises PT and aPTT, because they are measuring of clotting of plasma total capacity, also comprises factor I, II, and V, VII, X, XI and XII are because these factors are substituted by recombinant protein usually.Preferably the blood coagulation activity of these factors is about 90% with respect to being kept above by the level before this equipment, and the variation of PT and aPTT is less than about 1.5 seconds.
In one embodiment, this equipment can comprise adsorbing medium and container.This container should promote the smooth flow of blood plasma to be beneficial to the good utilization of medium and when when perfusion, make blood plasma can promote the air of its front, thereby the elimination bubble because bubble can make blood plasma and adsorbing medium contact area before reduce, reduces the utilization of medium thus.This container can be flat or have certain degree of depth to hold adsorbing medium or granule maintenance medium that this medium is not flat, for example columniform adsorbing medium.In preferred embodiments, this container is flat.This container can have the entrance and exit of various orientations, for example top inlet/top exit or bottom inlet/outlet at bottom.In preferred embodiments, outlet be in the bottom promoting good discharging, inlet then at the top to promote the utilization of medium.
In another embodiment, the equipment that comprises adsorbing medium and container can comprise that also granule keeps medium.In preferred embodiments, this equipment comprises that granule keeps medium, and this medium is arranged in the adsorbing medium downstream to keep keeping high flow rate of liquid and high protein recovery simultaneously from the effusive granule of adsorbing medium.It can be film that granule keeps medium, the fibre substrate of Yu Facheng net or wet-laying, agglomerating polymeric matrix, weaven goods, non-woven fabric (non-woven polyester), or its combination.
Granule in this equipment container keeps medium to be positioned at the downstream of adsorbing medium with the orientation of almost parallel.(United States Patent (USP) 5,660,731 is incorporated herein by reference, and discloses the example of fiber containers).
This container can not produced significant negative effect by the biological activity to liquid anyly has suitable hardness, an impermeable material structure.Preferably this container is constructed by synthetic polymer.The limiting examples of this polymer comprises polyacrylic acid, polyethylene, polypropylene, polystyrene and polycarbonate plastic.
The adsorbing medium that contains by this equipment of inert base immobilization particle should not have big pressure drop with the smooth flow that promotes biofluid for 3-30mm is thick.Preferably this medium should be thick for 3-15mm.More preferably, this medium should be thick for 5-8mm.
For this equipment, gravity flow is preferred.More preferably, this equipment is that to be configured to make differential pressure be that the water flow velocity of 12-72 inch is 0.1-10ml/cm 2The gravity flow equipment of/min.More preferably, to make differential pressure be that the water flow velocity of 24-48 inch is 0.2-5ml/cm to this equipment 2/ min.
Use
The present invention attempts reducing the concentration of low molecular weight compound in the biological composition.The molecular weight of these chemical compounds is the about 30000g/mol of about 100g/mol-.Such chemical compound comprises, for example, and as psoralen inactivation reagent, aminacrine, organic dyestuff and the phenothiazine of photoactivation product.The psoralen inactivation reagent of illustration comprises the furan coumarin, for example psoralen and acridine.Then as described in US5459030 and 5559250 (being incorporated herein by reference), use psoralen deactivation compounds processing blood goods, can contact the concentration that reduces psoralen deactivation compounds in the blood products with equipment of the present invention by the blood products that will handle.
In one embodiment, the present invention attempts the method for psoralen in a kind of inactivation solution, and wherein this method comprises: ⅰ a) is provided successively) cycle compound, the ⅱ) suspension that pollutes with described psoralen, and ⅲ) Fibrized resin; B) handle described solution with described cycle compound, so that produce the solution product of the processing of wherein said psoralen inactivation; With c) solution product of described processing is contacted with described Fibrized resin, and comprise that further the concentration that is used to reduce the medium and small organic compound of blood products has kept the required bioactive equipment of blood products simultaneously basically, this equipment comprises very porous absorbent particles, and wherein these absorbent particles are fixed by inert base.
Except the psoralen deactivation compounds, for example before blood transfusion, can from the material of for example blood products, reduce its reaction catabolite.
Material and facility disclosed herein can be used for separation property blood transfusion method.Whole blood can be divided into two or more specific components (for example, erythrocyte, blood plasma and platelet).Term " separation property blood transfusion " broadly is meant and blood is taken out from donor and is divided into different component, collects and keeps interested component and other component is returned to the process of donor.This donor acceptance replacement liquid remedies because component is removed the volume and the pressure loss that causes with help in blood transfusion process again.The separation property blood transfusion system has description in the open WO96/40857 of PCT, this paper is incorporated herein by reference.
Low molecular weight compound
Equipment of the present invention reduces the concentration of low molecular weight compound in the celliferous compositions.Term " low molecular weight compound " is meant the organic or biomolecule of molecular weight at the about 30000g/mol of about 100g/mol-.Low molecular weight compound includes, but not limited to following chemical compound: little organic compound such as psoralen, acridine or dyestuff; Quencher as glutathion; Plasticity extractable as plasticizer; As the biological instrumentality of complement activation, it has the molecular weight of the about 30000g/mol of about 100g/mol-; And polyamine derivatives.
Little organic compound
Little organic compound on the same group can be not adsorbed by equipment of the present invention.These molecules can be ring-type or acyclic family.In one embodiment, these chemical compounds are preferably for example cyclic compound of psoralen, acridine or dyestuff.In another embodiment, these chemical compounds are mercaptan.
The non-limitative example of cyclic compound comprises D actinomycin D, anthracene nucleus ketone, mitomycin, antramycin and organic dyestuff and photoreaction chemical compound such as benzodipyrane ketone, fluorenes, Fluorenone, furan coumarin, porphyrin, protoporphyrin, alizarinopurpurin, phthalocyanine dye, hypericin, Monostral FastBlue, Norphillin A, phenanthridines, phenazathionium salt, azophenlyene, phenothiazine, triazobenzene, quinoline and thiaxanthone.Preferred these chemical compounds are the furan coumarin.
The non-limitative example of furan coumarin comprises psoralen and psoralen derivant.What pay special attention to is 4 '-aminomethyl-4,5 ', and the psoralen that 8-trimethylpsoralen, 8-methoxypsoralen, halo psoralen, isopsoralen link to each other with quaternary ammonium, sugar or other nucleic acid conjugated group.Be also noted that following psoralen: 5 '-bromomethyl-4,4 ', the 8-trimethylpsoralen, 4 '-bromomethyl-4,5 ', the 8-trimethylpsoralen, 4 '-(4-amino-2-azepine) butyl-4,5 ', the 8-trimethylpsoralen, 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen, 4 '-(2-aminoethyl)-4,5 ', the 8-trimethylpsoralen, 4 '-(5-amino-2-oxa-) amyl group-4,5 ', the 8-trimethylpsoralen, 4 '-(5-amino-2-azepine) amyl group-4,5 ', the 8-trimethylpsoralen, 4 '-(6-amino-2-azepine) hexyl-4,5 ', the 8-trimethylpsoralen, 4 '-(7-amino-2, the 5-oxa-) heptyl-4,5 ', the 8-trimethylpsoralen, 4 '-(12-amino-8-azepine-2,5-two oxa-s) dodecyl-4,5 ', the 8-trimethylpsoralen, 4 '-(13-amino-2-azepine-6,11-two oxa-s) tridecyl-4,5 ', the 8-trimethylpsoralen, 4 '-(7-amino-2-azepine) heptyl-4,5 ', the 8-trimethylpsoralen, 4 '-(7-amino-2-azepine-5-oxa-) heptyl-4,5 ', the 8-trimethylpsoralen, 4 '-(9-amino-2, the 6-diaza) nonyl-4,5 ', the 8-trimethylpsoralen, 4 '-(8-amino-5-azepine-2-oxa-) octyl group-4,5 ', the 8-trimethylpsoralen, 4 '-(9-amino-5-azepine-2-oxa-) nonyl-4,5 ', the 8-trimethylpsoralen, 4 '-(14-amino-2,6,11-three azepines) myristyl-4,5 ', the 8-trimethylpsoralen, 5 '-(4-amino-2-azepine) butyl-4,4 ', the 8-trimethylpsoralen, 5 '-(6-amino-2-azepine) hexyl-4,4 ', 8-trimethylpsoralen and 5 '-(4-amino-2-oxa-) butyl-4,4 ', the 8-trimethylpsoralen.Preferred this psoralen is 4 '-(4-amino-2-oxa-) butyl-4,5 ', and the 8-trimethylpsoralen.
Acridine
The non-limitative example of acridine comprises acridine orange, acriflavinium chloride, quinacrine, N1, N1-two (2-ethoxy)-N4-(6-chloro-2-methoxyl group-9-acridinyl)-1,4-pentanediamine, 9-(3-hydroxypropyl) aminacrine, N-(9-acridinyl) glycine, S-(9-acridinyl)-glutathion.This acridine is N-(9-acridinyl)-Beta-alanine in a preferred embodiment, perhaps is called 5-[(β-carboxyethyl) amino] acridine.
Dyestuff
The non-limitative example of dyestuff comprises for example phenothiazine of methylene blue, dimethyl diaminophenazine chloride, toluidine blue, crystal violet and azure A; Phenthiazone as methylene-violet Bernthsen; As 1,8,15,22-four phenoxy groups-29H, the phthalocyanine dye of 31H-phthalocyanine aluminum chloride and Silicon stone analog; And hypericin.Preferred this dyestuff is methylene blue or toluidine blue.More preferably this dyestuff is a methylene blue.
Term " thiazine dye " is included in the dyestuff that contains sulphur atom in one or more rings.Modal thiazine dye is methylene blue [chlorination 3,7-two (dimethylamino)-phenothiazine-5-].Other thiazine dye includes, but not limited to azure A, aC and Lauth's violet, as described in the US5571666 of Schinazi.
Term " xanthene dye " is meant the dyestuff into chemical compound xanthene derivant.These xanthene dye branches can be gone into one of three main classification: ⅰ) fluorenes or amino xanthene, ⅱ) paramethylaminophenol or hydroxy amino xanthene and ⅲ) Fluorenone hydroxyl xanthene.The example that trial is used for xanthene dye of the present invention comprises rose-red and eosin W or W S; As described in the US5571666 of Schinazi, these dyestuffs can be from many sources (for example, Sigma Chemical Co., St.Louis, MI) commercially available, this paper is incorporated herein by reference.
Quencher
Can reduce the concentration of all cpds.Other illustration chemical compound comprises quenching compound.Method for quenching does not wish to comprise the side reaction of the psoralen deactivation compounds that contains the functional group that maybe can form, electrophilic group, total U.S. Patent application " Methods for Quenching PathogenInactivators in Biological Systems " as the summary of on January 6th, 1998 application numbers 28217300600 is incorporated herein its disclosed content.In the method, handle as the material of blood products with psoralen deactivation compounds and quencher, wherein this quencher comprises the nucleophilic functional group of can be covalently reacting with electrophilic group.In one embodiment, this psoralen deactivation compounds comprises linking ligand and for example nucleic acid of the functional group of Semen Sinapis group, and it can form electrophilic group by situ reaction.The example of quencher includes, but not limited to contain the chemical compound of nucleophilic group.The nucleophilic group of illustration comprises mercaptan, thionic acid, two sulfur carbonic acid, thiocarbamate, dithiocarbamate, amine, phosphate ester and D2EHDTPA ester group.This quencher can be or contain, for example the azacyclo-of pyridine.This quencher can be to contain for example phosphate ester of the chemical compound of G-6-P ester.This quencher also can be the mercaptan that contains following chemical compound (but being not limited to): glutathion, cysteine, N-acetylcystein, mercaptoethanol, dimercaptopropanol, BAL, mercaptan, sulfhydryl ethylsulfonic acid and its salt, for example, MESNA, homocysteine, aminoethyl mercaptan, dimethylaminoethyl mercaptan, dithiothreitol, DTT and other contain the chemical compound of mercaptan.The aromatic mercaptans chemical compound of illustration comprises 2-mercaptobenzimidazole sulfonic acid, 2-sulfydryl nicotinic acid, naphthalene alkene mercaptan, quinoline mercaptan, 4-nitro-phenylmercaptan. and phenylmercaptan..Other quencher comprises nitrobenzylpyridine and inorganic nucleopilic reagent such as selenides salt or organic selenides, thiosulfate, sulphite, sulfide, thiophosphate, pyrophosphate, sulfhydrate and dithio nitrite.This quencher can be the peptide compounds that contains nucleophilic group.For example, this quencher can be the chemical compound that contains cysteine, for example, and as the dipeptides of GlyCys or as the tripeptides of glutathion.
Can comprise mercaptan such as TGA methyl ester, thiolactic acid, phenylmercaptan., 2-mercaptopyridine, 3-sulfydryl-2-butanols, 2-mercaptobenzothiazole, thiosalicylic acid and thioctic acid by the chemical compound that equipment of the present invention is removed.
The plasticity extractable
Concentration from one group of low molecular weight compound of the extractable of plastics storage container that is used for adorning biological composition and pipe also can use equipment of the present invention to reduce from biological composition.The example of extractable includes, but not limited to plasticizer, residual monomer, low-molecular-weight oligomer, antioxidant and lubricant.Referring to for example R.Carmen, TransfusionMedicine Reviews 7 (1): 1-10 (1993).The sterilization of plastic component by steam, gamma-rays or electron beam can produce oxidation reaction and/or polymer splits, and causes forming the extractable of other type.
Plasticizer often is used to improve performance such as the machinability and the breathability of plastics.The most common plasticizer of finding in the blood storage container is phthalic acid two (the 2-ethyl the is own) ester that is used for the PVC goods.DEHP has been confirmed as potential carcinogen.Develop other plasticizer, included, but not limited to following chemical compound: 1,2,4-benzenetricarboxylic acid three (the 2-ethyl is own) ester (TEHTM), the just own ester of acetyl tributyl citrate three (ATHC), butyryl citric acid tri-n-hexyl ester (BTHC) and phthalate ester decanoate.
Equipment of the present invention can be used for reducing or control the concentration of the plasticity extractable in the biological composition of various environment.These environment include, but not limited to following: blood treatment; The blood storage; And for example external application of hemodialysis and external film oxidation.
Biological respinse modifier (BRMs)
One group of concentration that broadly is referred to as the low molecular weight compound of biological respinse modifier (BRMs) also can use equipment of the present invention to reduce from biological composition.BRMs is meant " changing immunoreactive spectroscopic molecular ".Illustrated?Dictionary?of?Immunology，J.M.Cruse?and?R.E.Lewis。General BRMs group includes, but are not limited to: the micromolecule of histamine and serotonin for example; For example thromboxan, prostaglandin, leukotriene and arachidonic lipid; The little peptide of Kallidin I for example; The bigger polypeptide that contains other group, comprise the complement activation fragment (C3a, C5a); The cytokine of IL-1, IL-6 and IL-8 for example; And the chemotactic factor of RANTES and MIP for example.
May there be side effect gathering of BRMs to the required biological activity of biological composition in the blood products in storage.For example confirmed under standard blood bank condition, in the hematoblastic process of storage complement activation to take place.Complement activation be accompanied by and be referred to as " platelet storage infringement " platelet function and vigor forfeiture.Referring to for example V.D.Mietic and O.Popovic, Transfusion 32 (2): 150-154 (1993).May there be side effect gathering also of BRMs to the patient who for example accepts this blood products in the blood products of being preserved: being collected at of BRMs accepts to be attended by among the hematoblastic patient non-hemolytic heating transfusion reaction in platelet concentrate in storage.Referring to for example N.M.Heddle, Current Opinions inHematology 2 (6): 478-483 (1995).
Polyamine derivatives
One group of concentration that is known as the low molecular weight compound of polyamine derivatives for example also can use equipment of the present invention to reduce from biological composition.Polyamine derivatives is for containing the chemical compound of a plurality of nitrogen-atoms in carbon backbone chain.
Polyethylene Glycol
Other illustration chemical compound comprises activated polyethylene glycol (aPEG), and the surface that can use it for change cell or material is so that provide immune masking performance respectively or the stabilize proteins combination.This equipment can be used to reduce the unreacted derivant of excessive activated polyethylene glycol or PEG, thereby make activated PEG and water or for example phosphate, phosphate ester or as the little nucleopilic reagent reaction of the mercaptan of glutathion.Other chemical compound that can be removed comprises the impurity in the activated PEG goods, and it can influence the function of blood products or make them be not suitable for blood transfusion (for example toxic compounds).At last, also the micromolecule of the N-hydroxy-succinamide that discharges in for example aPEG and the cell surface nucleopilic reagent course of reaction can be reduced.
The example of the chemical compound that can remove by equipment of the present invention comprises linearity or the branched chair polymacrogol that sticks on the bioactive molecule, and these bioactive molecules comprise cyanuric chloride, succinimido ester, oxidation phosphinylidyne imdazole derivatives, carbonic acid Nitrobenzol ester derivant, glycidyl ether derivatives and aldehyde.
Embodiment
The following examples are used to illustrate some preferred embodiment of the present invention and feature, but do not constitute the restriction to its scope.
In following description of test, use following abbreviation: eq (equivalent); M (M); μ M (volume micromolar); N (equivalent); Mol (mole); Mmol (mM); μ mol (micromole); Nmol (nanomole); G (gram); Mg (milligram); μ g (microgram); Kg (kilogram); L (liter); ML (milliliter); μ L (microlitre); Cm (centimetre); Mm (millimeter); μ m (micron); Nm (nanometer); Min. (minute); S and sec. (second); J (joule, or watt. second); ℃ (degree centigrade); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); PHEMA and p (HEMA) (poly-[methacrylic acid 2-hydroxyl ethyl ester]); PC (s) (platelet concentrate); PT (prothrombin time); APTT (activated partial prothrombin time); TT (thrombin time); HSR (hypotonic shock response); FDA (U.S. food and drug administration); GMP (good production practices); DMF (EDMF); SPE (solid phase extractions); Aldrich (Milwaukee, WI); Asahi (Asahi Medical Co., Ltd., Tokyo, Japan); Baker (J.T.Baker, Inc., Phillipsburg, NJ); Barnstead (Barnstead/Thermolyne Corp., Dubuque, IA); BectonDickinson (Becton Dickinson Microbiology Systems; Cockeysville, MD); Bio-Rad (Bio-Rad Laboratories, Hercules, CA); Cerus (Cerus Corporation; Concord, CA); Chrono-log (Chrono-Log Corp.; Havertown, PA); Ciba-Corning (Ciba-CorningDiagnostics Corp.; Oberlin, OH); Consolidated Plastics (Consolidated Plastics Co., Twinsburg, OH); Dow (Dow ChemicalCo.; Midland, MI); Eppendorf (Eppendorf North America Inc., Madison, WI); Gelman (Gelman Sciences, Ann Arbor, MI); GraceDayison (W.R.Grace﹠amp; Co., Baltimore, MD); Helmer (Helmer Labs, Noblesville, IN); Hoechst Celanese (Hoechst Celanese Corp., Charlotte, NC); International Processing Corp. (Winchester, KY); Millipore (Milford, MA); NIS (Nicolet, a Thermo SpectraCo., San Diego, CA); Poretics (Livermore, CA); Purolite (BalaCynwyd, PA); Rohm and Haas (Chauny, France); Quidel (San Diego, CA); Saati (Stamford, CT); Scientific Polymer Products (Ontario, NY); Sigma (Sigma Chemical Company, St.Louis, MO); Spectrum (Spectrum Chemical Mfg.Corp., Gardenia, CA); Sterigenics (Corona, CA); Tetko, and Inc. (Depew, NY); TosoHaas (TosoHass, Montgomeryville, PA); Wallac (Wallac Inc., Gaithersburg, MD); West Vaco (Luke, W.Va); YMC (YMC Inc., Wilmington, NC); DVB (divinylbenzene); LAL (Limulus Amoebocyte Lystate); USP (American Pharmacopeia); EAA (ethyl acetoacetate); EtOH (ethanol); HOAc (acetic acid); W (watt); MW (milliwatt); NMR (nuclear magnetic resonance, NMR; The spectrum that on Varian Gemini 200MHz Fourier TransformSpectrometer, obtains at room temperature); Ft3/min (per minute cubic inch); M.p. (fusing point); G/min and gpm (gallons per minute); UV (ultraviolet); THF (oxolane); The DMEM Eagles culture medium of s improvement (Dulbecco '); FBS (hyclone); LB (LuriaBroth); EDTA (ethylenediaminetetraacetic acid); Phorbol Myristate Acetate (PMA); Phosphate buffered saline (PBS); AAMI (the pharmacy instrument improves association); ISO (International Standards Organization); EU (endotoxin unit); LVI (injected material in a large number); GC (gas chromatogram); M (million); KGy (1000 Grays=0.1 Megarad); M Ω (megohm); PAS III (platelet make-up solution III); DH 2O (distilled water); IAD (fixedly adsorption plant); SCD (aseptic connection device).
One of following examples are mentioned the HEPES buffer.This buffer contains the 1mM MgCl of 2.7mM KCl, 0.203g of 137mMNaCl, the 0.2g of 8.0g 2(6H 2O), the 20mM HEPES (can be from Sigma, St.Louis, MO acquisition) of the 1mg/ml bovine serum albumin of the 5.6mM glucose of 1.0g, 1.0g (can be from Sigma, St.Louis, MO acquisition) and 4.8g.
Embodiment 1
The preparation of Fibrized resin
Preparation Fibrized resin and adsorbent pearl
Obtain the immobilization adsorbent medium that contains Amberlite  XAD-16 (Rohm and Haas) of clean and hydration status by AQF.The fiber of these Hoechst Celanese networks of fibers is made up of polyethylene terephthalate core and nylon sheath, and the melting temperature of this sheath is lower than this core.Being prepared as follows of this Fibrized resin: at first these adsorbent pearls are evenly distributed in the network of fibers.Next, this network of fibers Fast Heating made the polymer sheath fusion of fiber and adhere to the adsorbent pearl and other fiber on, thereby form crosslinked network of fibers.It is 130g/m that formed Fibrized resin contains load 2The Amberlite  XAD-16 of (that is, every square metre of fiber contains 130g adsorbent pearl).
This Fibrized resin is cut into square, and (14cm * 14cm), the gained fragment contains the dried Amberlite  XAD-16 of about 2.5g.Then by this Fibrized resin being immersed in 30% ethanol about 10 minutes with the pre-moistening of this Amberlite  XAD-16 pearl.Other method of moistening Amberlite  XAD-16 and other adsorbent also are effectively and by the present invention to comprise.It should be noted that the Fibrized resin (for example, through bridge joint or super crosslinked resin such as Dowex  XUS-43493) that contains other type pearl does not need to be used for effectively removing the moistening step of psoralen.
Also can directly obtain Amberlite  XAD-16HP (high-purity) pearl of clean and hydration status from Rohm and Haas.Before adding mesh bag, loose (promptly without fixed) Amberlite  XAD-16HP pearl is not needed pre-moistening; But, the moisture (2.5g do agent=6.8g have 62.8% moisture) of amount to calculate pearl of proofreading and correct adsorbent.Obtain Dowex  XUS-43493 pearl from Dow, this drying pearl does not need moistening and does not need water to proofread and correct the quality of this pearl.Then with polyester mesh bag (7cm * 7cm square; 30 μ m openings) fill with loose Amberlite  XAD-16HP or the Dowex  XUS-43493 pearl of 2.5g (dry weight).
The bag of fibre-bearing resin and adsorbent " wets " to circulate under 121 ℃ by autoclaving and sterilized in 45 minutes.Afterwards, the bag with fibre-bearing resin and adsorbent inserts independent sterilization, 1-rises in the PL2410 plastic containers (Baxter).After the insertion, in the laminar flow fume hood, use sterile scissors, hemostat and impulse sealing device that the PL2410 plastic containers are sealed.
Embodiment 2
The adsorbent pearl and the Fibrized resin of preparation pHEMA bag quilt
The Dowex  XUS-43493 (the commercial Optipore of being referred to as  L493) that contains about 50wt% water obtains from Dow, and the polymerization HEMA with viscosity-average molecular weight of 300kD obtains from Scientific Polymer Products.Before the bag quilt, these adsorbent pearls are dried to moisture＜5%.By with this polymer dissolution in 95% denatured alcohol/5% water so that pHEMA concentration reaches 50mg/ml, thereby the preparation pHEMA stock solution.
Is that the 9-inch Wurster fluid bed bag of about 4kg (doing) adsorbent carries out this bag by process in by device by International Processing Corp. having load.This bag is related to the pHEMA flow velocity of 60-70g/min, 50 ℃ inlet temperature and about 200ft by process 3The air velocity of/min.The bag that shifts out 50g in wrapping by process is adsorbed the agent sample, so that the bag of acquisition 3-18% (w/w) pHEMA is by level; Will with 3.7%, 7.3% and the adsorbent pearl of 10.9%pHEMA (w/w) bag quilt be used for following research.
Contain without fixed do (through bag quilt) Dowex  XUS-43493 (2.5g) and be by the adsorbent of required quality being put into square 30 μ m polyester mesh bag (7cm * 7cm) make with the equipment of the Dowex  XUS-43493 (3.0g or 5.0g) of pHEMA bag quilt.The 1-that the bag of filling adsorbent is inserted sterilization separately rises in the PL2410 plastic containers (Baxter), and seals with the impulse sealing device.Afterwards, the PL-2410 plastic containers that contain the bag of filling adsorbent are sterilized to 2.5MRad by electron beam or gamma-rays (SteriGenics); As mentioned above, preferred electron bundle sterilization usually.
According to the method described in the embodiment 1, Hoechst Celanese preparation contains the Fibrized resin of Amberlite  XAD-16.This Fibrized resin is cut into square, and (14cm * 14cm), the gained fragment contains the dried Amberlite  XAD-16 of about 2.5g.With the Amberlite  XAD-16 of this Fibrized resin by moistening simultaneously and bag quilt in the solution that is immersed in 95% ethanol/5% distilled water that contains 50mg/mL pHEMA.Flushing is removed residual ethanol twice in normal saline in 10 minutes.This process obtains the bag quilt of about 6% (w/w) pHEMA.Then this Fibrized resin " is wet " to circulate under 121 ℃ by autoclaving and sterilized in 45 minutes.Afterwards, the independent sterilization of this Fibrized resin insertion, 1-are risen in the PL2410 plastic containers (Baxter), and in the laminar flow fume hood, use sterile scissors, hemostat and the heat-sealing of impulse sealing device.
Embodiment 3
Glycerol and Polyethylene Glycol are to the influence of adsorbent power
This embodiment test glycerol and Polyethylene Glycol as stabilizing agent to from blood plasma, removing the adsorbent power and the effect of kinetics of the psoralen that deaminizes.In the test of this embodiment, use free (promptly without fibrosis) Amberlite  XAD-16 and Dowex  XUS-43493 adsorbent pearl.
Method
((Supelco, Bellefonte PA) are dried to moisture＜5% for Rohm and Haas (Philadelphia, PA)) and Dowex  XUS-43493 with Amberlite  XAD-16HP in 80 ℃ baking oven.The adsorbent of known quantity is immersed in the alcoholic solution that contains 0-50% glycerol, 50%PEG-200 or 50%PEG-400 (glycerol, PEG-200 and PEG-400 are from Sigma).Then at room temperature cultivated 15 minutes, remove excessive solvent and these samples are descended dry a whole nights at 80 ℃; Avoid dry this adsorbent under＞120 ℃ temperature, this is to change because preferentially observe performance of the adsorbent (for example, hole fusion) under higher temperature.After the drying, the sample of sorbent of weighing is to determine the amount of stabilizing agent in the unit mass adsorbent.
Carry out several independent researchs.In research as described below, comprise the control sample of " without moistening " adsorbent and the adsorbent of " through best moistening ".Sample of sorbent without moistening is not stand any pretreated dry adsorbent, and is by with 30% ethanol/70%dH through the sample of sorbent of best moistening 2O moistening adsorbent is made.Will be through the adsorbent dH of best moistening 2The O flushing is to remove residual ethanol.In order to ensure drying not taking place, this adsorbent of preparation before absorption research.
Use contains 150 μ M admixtures 3H-4 '-(4-amino-2-oxa-) butyl-4, and 5 ', 4 ' of 8-trimethylpsoralen-(4-amino-2-oxa-) butyl-4,5 ', 100% human plasma of 8-trimethylpsoralen carries out every kind of absorption research.Blood plasma (6.0mL) is added in the bottle that contains the adsorbent that useful different stabilizers handled.The amount of proofreading and correct adsorbent is so that glycerol or PEG content provide 0.2g adsorbent.Be placed on these bottles in the rotary apparatus and stirring at room temperature.Shift out plasma sample and measure remaining at different time 3H-4 '-(4-amino-2-oxa-) butyl-4,5 ', the level of 8-trimethylpsoralen.Sample (200mL) is diluted among the OptiphaseHiSafe Liquid Scintillation Cocktail (Wallac) of 5.0mL and counting in Wallac1409 Liquid Scintillation Counter (Wallac).
Amberlite  XAD-16 that crosses with glycerin treatment and the absorbability of Dowex  XUS-43493
Fig. 7 has compared with the alcoholic solution that contains varying level glycerol the pretreatment of Amberlite  XAD-16 and Dowex  XUS-43493 relevant 4 '-(4-amino-2-oxa-) butyl-4 in 100% blood plasma, 5 ', the influence of 8-trimethylpsoralen absorbability.80 ℃ down before dry 48 hours with sample of sorbent moistening 15 minutes in ethanol/glycerite.After 4 hours contact, carry out the single mensuration of absorbability.With reference to Fig. 7, the glycerol content shown on the X-axle is the weight/volume percentage rate of glycerol in ethanol.Absorbability shown on the Y-axle is relatively through the percentage rate of the absorbability of the sample of sorbent of best moistening.The absorbability of XUS-43493 represents that with square XAD-16 represents with circle.
Shown in data among Fig. 7, the ability of XAD-16 from drying sample about 30% be increased in the sample of moistening in 205 glycerites more than 90%.These presentation of results dry after in order to keep the very low-level glycerol of high absorption capacity needs.Before drying at 50% ethanol/50%dH 2The control sample of moistening demonstrates and the identical absorbability of the exsiccant undressed sample of process among the O (no glycerol).On the contrary, these XUS-43493 samples do not demonstrate any influence of glycerol to absorbability; Absorbability is near 100% under the glycerol of all levels.Although test of the present invention is not had decisive role, this discovery supports that glycerol plays the hypothesis that prevents in the dry run that the adsorbent hole from subsiding; Because XUS-43493 has highly cross-linked structure, it is subsided by or not the hole when carrying out drying.
Sample with glycerin treatment demonstrates drying highly stable.Sample is preserved the variation (data not shown) that did not observe absorbability in 7 days in the laminar flow fume hood.
Amberlite  XAD-16 that handled with glycerol or PEG and the absorbability of Dowex  XUS-43493
Carry out other research with low molecular poly PEG-200 and PEG-400, non-volatile and hypotoxicity reagent that can be dissolved in the second alcohol and water.In 50% PEG-400, PEG-200 in ethanol or the glycerite sample of sorbent was handled 15 minutes.Fig. 8 compared stabilizing agent to dry adsorbent A mberlite  XAD-16 (following) and Dowex  XUS-43493 (top) 4 '-(4-amino-2-oxa-) butyl-4 in 100% blood plasma, 5 ', the influence of 8-trimethylpsoralen absorbability; Sample without moistening is designated as " No Tx ".Absorbability is to report with the relative percentage rate through the ability of the adsorbent of best moistening.
As shown in the data and with its " macroreticular " structure being basic forecast among Fig. 8, the ability of Dowex  XUS-43493 is not subjected to drying (" No Tx " sample) influence.On the contrary, dry back Amberlite  XAD-16 is about 35% of maximum capacity.Handle the ability that XAD-16 has improved dry adsorbent with glycerol, PEG-200 and PEG-400; Each adsorbent power is all greater than 90%, wherein glycerol＞PEG-200＞PEG-400.Although in order to realize that the present invention does not need to understand its accurate mechanism of action, the difference of the ability between glycerol and the two kinds of PEG solution may be that the infiltration of stabilizing agent reduces with the increase of molecular weight and causes.That is to say that in 15 minutes application process, glycerol (MW=92.1) may can be penetrated in the adsorbent hole more completely than therefore spreading slower PEG-200 (MW=190-210) or PEG-400 (MW=380-420) owing to its size is big.
The adsorption dynamics adsorption kinetics of the Amberlite  XAD-16 that handled with glycerol or PEG
Study equally to determine whether the hole of filling adsorbent with glycerol or PEG causes opposite kinetics to reduce.Fig. 9 compared the Amberlite  XAD-16 that uses in several different solutions from 100% blood plasma through 3 hours 4 '-(4-amino-2-oxa-) butyl-4,5 ', the absorption of 8-trimethylpsoralen.Specifically, data represented XAD-16 ⅰ among Fig. 9) dry preceding with 50% glycerite moistening (open squares that solid line connects), ⅱ) cross (the black circle that dotted line connects) with 50% PEG-400 solution-wet before the drying, ⅲ) pre-moistening, promptly before beginning one's study with 50% ethanol/50%dH 2O moistening (dotted line connect black triangle) is with ⅳ) do not pass through (the black square that solid line is connected of any processing; " No Tx ").Data acknowledgement among Fig. 9 in 50% glycerol/50% ethanol or 50%PEG-400/50% alcoholic solution the adsorption dynamics adsorption kinetics of the Amberlite  XAD-16 sample of moistening very approaching with adsorption dynamics adsorption kinetics in ethanol through the sample (promptly using the sample of alcohol pre-treatment) of best moistening.Drying but undressed XAD-16 sample (No Tx) are by only realizing about 30% remove in 3 hours.
Data declaration shown in the present embodiment handle Amberlite  XAD-16 with the stabilizing agent of the solution form that contains 50% ethanol and 50% glycerol, PEG-200 or PEG-400 and can prevent forfeiture with the dry absorbability that accompanies.The result who obtains with these stabilizing agents hints that the representative of low-molecular-weight wetting agent is used to strengthen the spendable method of adsorbant function.
Embodiment 4
From FFP, remove methylene blue
Present embodiment relates to various different polymeric adsorbant materials and freezes the ability of removing methylene blue the blood plasma from aquatic foods.
The test evaluation of present embodiment " freedom " absorbent resin (that is, not adding the equipment that contains without fixed adsorbent) and Fibrized resin.The free absorbent resin of these that tested is Amberlite  XAD-16 HP (Rohm and Haas), MN-200 (Purolite) and Dowex  XUS-43493 (Dow Chemical Co.).This XAD-16HP comes in hydration status so that do not need pretreatment (that is, nonwetting), and this MN-200 also provides with the state of complete hydration; This XUS-43493 is what do.
The Fibrized resin that contains XAD-16 is normally with preparation described in the embodiment 1.Briefly, will contain 130g/m 22cm * 7cm of XAD-16 (is 14cm 2) the at first moistening in 70% ethanol of Fibrized resin bar, use the distilled water cleaning down then.
Methylene blue (10mM) stock solution is made by U.S.P. methylene blue (Spectrum) is dissolved in the distilled water.Add this methylene blue stock solution to obtain 10 μ M in 100% plasma sample ultimate density." freedom " absorbent resin sample (that is, XAD-16HP, MN-200 and XUS-43493) is weighed into is used for absorption research in the 50mL polypropylene tube.Lose the moisture of determining every kind of adsorbent by dry quality measurement.Proofread and correct the quality of every kind of adsorbent so that every kind is equivalent to use the dried adsorbent of 0.25g with moisture.
In each bottle, add 100% plasma sample that 30mL contains 10 μ M methylene blue.At room temperature these bottles are placed on the rotary apparatus.From each bottle, to remove sample (200mL) at interval in 15 minutes and to identify the residue methylene blue by HPLC.With diluents (ultimate density=35% methanol, 25mM KH 2PO 4, pH=3.5) with 5 times of every kind of plasma sample dilutions.By under 4 ℃, protein and other macromole being precipitated these sample culturing.With the sample centrifugalize and with supernatant filtration (0.2 μ m) and at C-18 reversed-phase column (YMC ODS-AM, 4.6mm * 250mm) go up by in 20 minutes, flowing out from 65% solvent orange 2 A (25mM KH 2PO 4, pH=3.5), 35%B (methanol) to the linear gradient of 80%B by analysis.The detection limit of HPLC test is about 0.5 μ M methylene blue.
Figure 10 has compared the kinetics of adsorbing methylene blue in 2 hours from 100% blood plasma.With reference to Figure 10, the XAD-16HP data are by shown in the open diamonds of dotted line connection, shown in the black triangle that the MN-200 data are connected by solid line, shown in the empty circles that the XUS-43493 data are connected by dotted line, and shown in the black square that connects by solid line of the Fibrized resin that contains XAD-16.Shown in these data, this XAD-16HP and MN-200 provide the fastest adsorption dynamics adsorption kinetics, then are XUS-43493.Use during as XUS-43493 with its drying regime, its kinetics may be a bit slightly slowly since the slow institute of its moistening extremely.At last, the Fibrized resin that contains XAD-16 has the slowest adsorption dynamics adsorption kinetics.This may be in batch incubation, because 14cm 2The part of Fibrized resin bar in whole absorption research, be not fully immersed in the blood plasma, therefore reduced the effective contact area between adsorbent and the blood plasma, cause between Fibrized resin and the blood plasma contact relatively poor.
These data declarations can use in the present invention and to attempt the resin that uses and Fibrized resin and from blood products, remove psoralen deactivation compounds as the non-psoralen of phenothiazine dyestuff.
Embodiment 5
Present embodiment has compared and uses dissimilar powdery carbons as the active component in the medium and illustrated that how essential the careful selection of active component with the concentration that reduces little organic compound and the biological function of liquid hold-up.5 kinds of active carbons of explanation make psoralen in the blood plasma with roughly the same amount among the embodiment 5,4 '-(4-amino-2-oxa-) butyl-4, and 5 ', the concentration of 8-trimethylpsoralen reduces.Yet, when using " A Supra " as absorbent particles, its to the maintenance of thrombin significantly better than other adsorbent.
With 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen joins in the blood plasma with the concentration of 150 μ m, and this blood plasma is with the batch 3.0J/cm of 325ml 2The UVA irradiation is with inactivating pathogens.4 '-(4-amino-2-oxa-) butyl-4,5 ', the residual concentration of 8-trimethylpsoralen in the gained blood plasma storehouse is about 90 μ m.The blood plasma that 325ml shone is crossed 5 kinds of dissimilar 90mm Cuno Zetaplus charcoal pads with the 20mL/min pump.Before plasma flow is crossed these charcoal pads and measure its thrombin level, setting time and 4 '-(4-amino-2-oxa-) butyl-4,5 ', 8-trimethylpsoralen concentration afterwards.
The Cuno grade 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (S) The % yield The % yield The % yield
???R11S ??????????????99.3 ????4.8 ???91 ???89 ???80
???R12S ??????????????99.4 ????4.9 ???93 ???89 ???48
???R13S ??????????????99.4 ????6.4 ???88 ???90 ???42
???R14S ??????????????99.3 ????3.4 ???96 ???85 ???50
?A?Supra ??????????????99.4 ????1.6 ???96 ???81 ???82
The active carbon specification
Active carbon Active carbon Content of ashes Activation Special handling
???R11S Mineral ???14％ Steam Do not have
???R12S Brown coal Do not survey Steam Do not have
???R13S Mix charcoal ????8％ Steam Pickling
???R14S Mix charcoal ????8％ Acid (H 2SO 4) Do not have
?A?Supra Coconut husk ????3％ Steam Do not have
The water flow velocity of R10S medium is 2 gallons waters/min/ foot 2, differential pressure is 1.5p.s.i.
Present embodiment has shown that the selection of used active carbon can have powerful effect for IAD to bioactive influence.
Annotate: the specification that A Supra grade is made with R1 * S series is identical; Just charcoal changes.The increase of aPTT has shown the removal of thrombin.I, VIII and IX are meant specific thrombin.All numerical value all are for after the photochemical treatment.4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is measured by HPLC, and thrombin and setting time are with solidifying analysis-e/or determining automatically.
Embodiment 6
Granular size is removed and bioactive influence low molecular weight compound.The size that present embodiment has illustrated the absorbent particles that is used for IAD has significant effects to the removal degree and the bioactive measurement of low molecular weight compound.
The blood plasma of photochemical treatment is according to the similar approach preparation of embodiment 5.Dowex OptiporeL493 be with Estro Model 480 grinders ground and with the screening of the screen cloth of about 100 μ m and 50 μ m to produce two class granules, a class granule is 50 μ m-100 μ m, another kind of granule is less than 50 μ m.Contain any ZetaPlus spline filter device of this two classes granule according to Cuno R1 * S specification preparation.The blood plasma (325ml) of photochemical treatment is crossed every kind of filter bed with the 20mL/min pump.As analysis 4 '-(4-amino-2-oxa-) butyl-4 as described in the embodiment 5,5 ', 8-trimethylpsoralen and thrombin.
Granular size (μ m) 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (s) The % yield The % yield The % yield
?100＞＞ ????????????96.1 ????0.9 ???97 ???94 ???86
????50
???＜50 ????????????99.2 ????2.2 ???83 ???91 ???76
With this specific adsorbent, its granularity is more little, and removal effect is good more, but records bioactive influence bigger by blood coagulation activity.This has illustrated balance common when the particulate granularity of selected adsorbent.
Embodiment 7
The adsorbent loading is removed and bioactive influence low molecular weight compound.Present embodiment has compared the mass fraction that changes active component to the concentration that reduces little organic compound and to the influence of the balance of the biological function of liquid.
The blood plasma of photochemical treatment is according to the similar approach preparation of embodiment 5.The Supra pad is preparing than low loading with the standard R1 of about 60% charcoal * S loading and 30%.About 230ml blood plasma pump is crossed the disk of each 90mm.As analysis 4 '-(4-amino-2-oxa-) butyl-4 as described in the embodiment 5,5 ', 8-trimethylpsoralen and thrombin.
A Supra loading (%) 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (S) The % yield The % yield The % yield
????61.5 ?????????????99.4 ????1.3 ???93 ???93 ???77
????30.8 ?????????????99.4 ????0.9 ???99 ???90 ???91
This has shown beyond thought result,, by reducing the loading of absorbent particles, may reduce IAD sometimes to bioactive influence that is, and the concentration of low molecular weight compound is reduced.The total capacity of IAD can reduce, but as long as IAD to be starkly lower than the theoretical capacity running of low molecular weight compound, just is out of question.
Embodiment 8
Use the influence of blood compatibility bag quilt.Present embodiment has illustrated in some cases, can be of value to biological function with the hydrophilic polymer treatment media.
The blood plasma of photochemical treatment is according to the similar approach preparation of embodiment 5.A 90mmR14S pad spends the night with the 95% alcoholic solution flushing of 50mg/ml poly-hydroxyethyl methacrylate (pHEMA), and is dry up to no extra weight change in 70 ℃ of baking ovens.Same second pad is also dry with 95% alcohol flushing that does not contain pHEMA.About 325ml blood plasma is crossed disk with the 5mL/min pump.As analysis 4 '-(4-amino-2-oxa-) butyl-4 as described in the embodiment 5,5 ', 8-trimethylpsoralen and thrombin.
The bag quilt 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (S) The % yield
Do not have ??????????????99.6 ????4.1 ??98
?pHEMA ??????????????99.1 ????2.5 ??103
Though bag is shown the biological activity to biological composition, be the benefit of the blood coagulation activity of blood plasma in this example, but bag is reduced the low molecular weight compound that is used for present embodiment to IAD, 4 '-(4-amino-2-oxa-) butyl-4,5 ', the ability of the concentration of 8-trimethylpsoralen has adverse effect.This has illustrated balance common when selecting bag quilt or surface treatment.
Embodiment 9
Flow velocity is removed and bioactive influence low molecular weight compound.Present embodiment has illustrated that flow velocity is influential to the reduction meeting of little organic compound substrate concentration.
The blood plasma of photochemical treatment is according to the similar approach preparation of embodiment 5.The Supra pad is to prepare with the standard R1 of about 60% charcoal * S loading.The blood plasma that 325ml was handled is crossed the disk of the disk of each 47mm diameter with three kinds of different flow pump.As analysis 4 '-(4-amino-2-oxa-) butyl-4 as described in the embodiment 5,5 ', 8-trimethylpsoralen and thrombin.
Flow velocity (mL/min) 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (S) The % yield The % yield The % yield
???10 ????????????99.0 ???1.3 ???98 ???83 ???80
???15 ????????????98.8 ???1.5 ???99 ???85 ???86
???20 ????????????98.7 ???1.4 ???97 ???89 ???86
Demonstrate the slightly reduction that low molecular weight compound is removed degree though improve flow velocity,, as what seen by the factor VIII of higher yields and factor IX blood coagulation activity, it has bigger benefit to biological activity.This has shown that regulating the flux of biological composition by IAD can make the selectivity that low molecular weight compound is reduced surpass bioactive influence.
Embodiment 10
Liquid volume is removed and bioactive influence low molecular weight compound.Present embodiment has illustrated that liquid volume also has significant effects for selectivity to low molecular weight compound is surpassed to bioactive influence.
The blood plasma of photochemical treatment is according to the similar approach preparation of embodiment 5.ZetaPlus spline filter device is to prepare according to Cuno R1 * S specification with the ground Dowex Optipore L493 replacement powdered activated carbon of granule less than 50 μ m.Blood plasma is crossed this filter and is gathered 180mL and the sample of 325mL with the 20mL/min pump.As analysis 4 '-(4-amino-2-oxa-) butyl-4 as described in the embodiment 5,5 ', 8-trimethylpsoralen and thrombin.
Blood plasma volume (mL) 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (S) The % yield The % yield The % yield
???180 ???????????99.3 ???4.1 ???74 ???89 ???66
???325 ???????????99.2 ???2.2 ???83 ???91 ???76
Therefore, by increasing the volume of pending liquid, can make low molecular weight compound removed
Additional selectivity surpasses bioactive reduction.Certainly be conditional to this, when near IAD
During to the capacity of low molecular weight compound, selectivity will reduce once more.
Embodiment 11
The use of sintered medium.Make 90mm diameter, 1/4 with Porex " thick disk.These
Disk contains the in small, broken bits Dowex of granularity between 20 μ m and 100 μ m of Different Weight part
Optipore L493, and the granule of ultra-high molecular weight polyethylene (UF220 grade) are then with they sintering together.The blood plasma of photochemical treatment is crossed each disk with 200mL blood plasma with the 16-18mL/min pump according to the similar approach preparation of embodiment 5.As analysis 4 '-(4-amino-2-oxa-) butyl-4 as described in the embodiment 5,5 ', 8-trimethylpsoralen and thrombin.
Adsorbent weight percentage ratio 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (S) The % yield The % yield The % yield
?????25 ?????????????97.8 ???0.5 ???93 ???95 ???78
?????35 ?????????????99.0 ???1.2 ???90 ???94 ???74
?????50 ?????????????99.3 ???1.2 ???91 ???80 ???76
As what see with the fibrous matrix of the active carbon with embodiment 7, it is also all influential to low molecular weight compound removal and biological activity when using sintering substrate to change the umber of adsorbent in IAD.In this case, 25% preparation can not make 4 '-(4-amino-2-oxa-) butyl-4, and 5 ', the removal of 8-trimethylpsoralen is good as 35% and 50% preparation.50% preparation is compared with other preparation and is made the active forfeiture of factor VIII bigger.In these three kinds of media, 35% preparation surpasses bioactive reduction to the high selectivity of low molecular weight compound.
Embodiment 12
Present embodiment has been described the influence that increases the quality of adsorbent under the constant situation of thickness by the diameter that increases filter.
The blood plasma of photochemical treatment is according to the similarity method preparation of embodiment 5.The treated blood plasma of about 325mL crosses 90 and 47mm diameter RO3S grade disk with the 5mL/min pump.As analysis 4 '-(4-amino-2-oxa-) butyl-4 as described in the embodiment 5,5 ', 8-trimethylpsoralen and thrombin.
Disk diameter (mm) 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen is removed % APTT increases (S) The % yield
????47 ????????????????99.4 ?????2.1 ???96
????90 ????????????????99.6 ?????3.5 ???77
The diameter that increases sorbent material keeps identical thickness and flow velocity same-action such as to have the circulation of minimizing and reduce that the handled volume of per unit filter cross-sectional area has simultaneously.Though these two kinds of effects tend to increase the absorption of low molecular weight compound, they usually increase the absorption of biological activity amboceptor more.We see with larger-diameter sorbent material and have adsorbed more slightly S-59 in the present embodiment, but more in fact factor I loss of activity.
Embodiment 13
Use the mobile research of the activated carbon media of several forms.Studied the use flow device by experimentizing to 5-[(β-carboxyethyl among the PRBCs)-amino] removal of acridine and GSH.PRBCs (Erythrosol, glucose is 63%HCT) with the degradable 5-[(β-carboxyethyl of 300 μ m) amino] acridine derivatives and 3mMGSH feed intake, placing 20 hours under room temperature, not stirring situation before the equipment of flowing through.The medium of flow-type chemical compound adsorption plant is made up of various forms of active carbons, is composite carbon/cellulose discs or carbon fiber felt.This medium be sealed to the 90mm diameter polycarbonate container (Cuno, Meridien, CT) in.The PRBCs that batches inhales with the flow pump of 5mL/min that (Gilson Minipuls, Middleton WI) by medium, and are collected in the PL146 plastic containers (Baxter Healthcare).The results are shown in the table 1 of this research.
Table 1 uses the mobile result of study of various activated carbon media
Medium Describe Remaining acridine *(μM) Remaining GSH *(mM) Haemolysis %
????CUNO A Supra/ cellulose discs (30% loading) ????26.04 ?????0.94 ???4.83
??CUNO95-1 A Supra/ cellulose discs (70% loading) ????25.08 ?????0.68 ???7.56
??CUNO95-2 A Supra/ cellulose discs (70% loading) ????19.22 ?????0.11 ???5.15
??Cellulo A Supra/ cellulose discs (60% loading) ????23.62 ?????0.79 ???5.19
????FPI A Supra/ cellulose discs (70% loading) ????20.78 ?????0.20 ???5.27
???Ertel A Supra/ cellulose discs (60% loading) ????25.13 ?????0.14 ???7.17
??Actitex Activated carbon felt-1 layer-162g/m 2 ????51.36 ?????6.14 ???1.27
???Lantor Activated carbon felt ????30.90 ?????4.27 ???1.78
??Ultrasorb Activated carbon felt (200g/m 2) ????77.79 ?????5.13 ???1.06
???Actitex Activated carbon felt-3 layer (162g/m 2) ????28.75 ?????5.58 ???1.37
???Lydall Activated carbon felt ????39.69 ?????5.04 ???1.18
???MN-200 MN-200/ cellulose discs (70% loading) ????87.87 ?????6.44 ???1.11
Embodiment 14
Liquidation compound adsorption plant (CUNO medium) and the intermittently comparison of chemical compound adsorption plant (AQF medium).Study, compared flow with chemical compound adsorption plant intermittently in 5-[(β-carboxyethyl)-amino] the removing of acridine and GSH.Mobile units is by the cellulose/Norit A Supra (Norit Americas, Inc. (Atlanta, GA) the carbon disk formation that are encapsulated in the 90mm shell.The equipment at intermittence that two platform independent are arranged: one by Fibrotic Pica G277 active carbon (AQF 500g/m 2) constitute; Another is by Fibrotic Purolite MN-200 (AQF312g/m 2) constitute.With the degradable 5-[(β-carboxyethyl of 300 μ m)-amino] after acridine derivatives and the 3mM GSH batching, PRBC is passed through cellulose/carbon medium with the flow velocity pump pressure of 2mL/min, after this, 5-[(β-carboxyethyl)-and amino] acridine and the level of GSH in the PRBC supernatant descended 75 and 88% respectively, reaches 24 μ m and 0.71mM.To transfer to 6gMN-200 then through the PRBC that mobile units is handled intermittently in the equipment, through 24 hours with 5-[(β-carboxyethyl)-amino] acridine and GSH level reduced by 5 and 1% again, reaches 20 μ m and 0.67mM.PRBC through 7g Pica G277 intermittently device processes itself make 5-[(β-carboxyethyl)-amino] acridine and GSH level reduced by 92 and 54% concentration that reaches 8 μ m and 3mM.Therefore, removing on the GSH, the path by mobile units is than intermittently device processes 24 hours is more effective with carbon.Yet, removing 5-[(β-carboxyethyl)-amino] on the acridine, intermittently equipment itself is more effective with MN-200 equipment than flowing of associating.As if PRBC ATP concentration is not produced harmful effect by flowing of equipment.When intermittently device processes was compared with 24 hours carbon, the K+ level among the PRBC after mobile units is handled was lower.
Embodiment 15
Present embodiment has been described typical case's performance of the immobilization adsorbent equipment of flow pattern on the blood plasma that uses adsorbent medium, this adsorbent medium is by 30%Norit A Supra carbon (NoritAmericas, Atlanta, GA) constitute, (Meriden CT) makes by the Cuno that has described in advance among the embodiment of front.
The R1OSP medium that floods with the placed in-line 90mm Cuno 30%Norit of polysulfone membrane (hole with 5 μ m) the A Supra with the coating of 90mm diameter Memtec hydroxypropyl cellulose assembles IAD.
In order to finish disposable manufacturing, the ILPL2410 bag is connected to 1/8 " on the OD pipe, then, pipe is linked to each other with the IAD outlet, so that the distance from the IAD center line to bag is 40cm.Onesize pipe is connected on the SRD inlet, so that when the irradiation bag was connected with it, the distance from the center line to the bag was 30cm.
With 4 '-(4-amino-2-oxa-) butyl-4,5 ', the 8-trimethylpsoralen joins in the 500mL blood plasma, is about 150 μ m to ultimate density, uses 6.3J/cm 2The UVA irradiation of plasma is so that the pathogen inactivation.Irradiation back 4 '-(4-amino-2-oxa-) butyl-4,5 ', 8-trimethylpsoralen concentration is about 82 μ M.
Table 2 expression is used with respect to the front later coagulation factor activity and 4 ' of IAD processing-(4-amino-2-oxa-) butyl-4 by the value of IAD, 5 ', the measurement result of 8-trimethylpsoralen level.The triplicate experiment.Record meansigma methods and standard deviation.Processing time average out to 14 minutes.Obviously, in fact factor I, II, V, VII, X or gathering blood coagulation activity, prothrombin time (PT) and the measurement result of activated partial Thrombokinase time (aPTT) do not change, and factor XI and XII have very little variation.Factor VIII and IX show big slightly variation, but these are acceptables, especially consider since their shortage to the regulation of recombinant protein.The selectivity that is noted that this equipment exactly is that in fact it kept whole blood coagulation activities, makes only 0.9% 4 '-(4-amino-2-oxa-) butyl-4 simultaneously, 5 ', and the 8-trimethylpsoralen is passed through.
Table 2
PT(s) aPTT(s) Ⅰ(％) Ⅱ(％) Ⅴ(％) Ⅶ(％) Ⅷ(％) ????0.0±0.1 ????0.7±0.1 ?????98±2 ?????99±1 ????101±2 ?????99±2 ?????86±1
Ⅸ(％) Ⅹ(％) Ⅺ(％) Ⅻ(％) S-59(％) ?????82±3 ?????03±4 ?????94±4 ?????95±5 ????0.9±0.1
Embodiment 16
Adsorbent medium is to the minimizing of active complement.Originally studies have shown that the cellulose media that is impregnated with active carbon has been removed biological respinse modifier with the aerated plastics medium that is impregnated with polystyrene/divinylbenzene adsorbent in small, broken bits.
With zymosan (Sigma chemical company; St.Louis, MO), the powerful activator of complement cascade is added in the blood plasma, and making concentration is 10mg/mL.Shake down in gentleness, blood plasma was cultivated 1 hour at 37 ℃.Then that blood plasma is centrifugal, keep the supernatant to remove the yeast solid polysaccharide.Add this supernatant of about 20mL in each to two 600mL blood plasma is unitary, get from each unit then that a sample is used for C3a and SC5b-9 analyzes.With one in these unit cellulose media (Cat.# 2640ASP, Cellulo, Inc. that floods by carbon with the 40mL/min pump pressure; Fresno, 90mm disk CA).Another unit with same speed pump pressure by as the sintered medium (Porex.Technologies for preparing among the embodiment 11; Fairburn, GA).Be used for C3a and SC56-9 analysis from each unitary filtrate sampling.
Measure test kit with Quidel and carried out complement mensuration.
??[C3a](ng/mL) ???[SC5b-9](ng/mL)
Pre-filtering ?????1597 ????????5210
Filter with charcoal/cellulose media ??????521 ????????1747
Filter with sintered medium ??????68 ????????1592
Shown in preceding table, from biological composition, also can remove biological respinse modifier.
Embodiment 17
The comparison of carbon fiber medium and carbon impregnation of fibers element.Present embodiment has compared and has been disclosed in USP5, the carbon fiber medium in 660,731 and the application of medium disclosed herein.
The blood plasma that has prepared photochemical treatment in mode similar to Example 5.The blood plasma that about 175mL was handled passes through every kind of medium with the speed pump pressure of about 11mL/min.As among the embodiment 5, S-59 and thrombin have been analyzed.
Medium Gross thickness (inch) The number of plies S-59 reduces (%)
Kynol?CAN-211-20 0.203 5 74.9
Kuractive?FT300-20?Felt 0.234 7 37.2
Actitex?FC1201 0.328 7 44.7
Cuno?A?Supra 0.250 1 99.1
Medium source: Kynol (American Kynol, Inc.; Pleasantville, NY); Kuractive (Kuraray Chemical Co.; Bizen City, Japan); Actitex (PicaUSA; Columbus, OH); Cuno A Supra (Cuno, Inc.; Meridien, CT).
As above shown in the table, compare, from biological composition, remove the concentration that low molecular weight compound (as USP#5,660,731 in disclosed) usually is not enough to reduce low molecular weight compound in the biological composition with the carbon fiber medium with adsorbent medium disclosed herein.
Embodiment 18
The adsorbent pore-size distribution is to bioactive influence.Present embodiment proves that the aperture of the adsorbent that contains among the IAD is announced and kept bioactive ability can have material impact to IAD.
By Porex Technologies (Fairburn GA) has made 90 mm dias, 1/4 " the aerated plastics disk of thickness.These disks are the ultra-high molecular weight polyethylene particle of the about 25 μ m diameters of about 50% (weight) and 50% Purolite (Bala Cynwyd, PA) sintered mixture of non-functionalized Hypersol-Macronet adsorbent, described adsorbent is levigate by Porex, is 60-160 μ m so that surpass the diameter of 90% particle (by weight).By adding S-59 solution in each to make S-59 concentration be about 150 μ m to three about 600mL blood plasma being unitary, then as previously mentioned, use 6.3J/cm 2Each unit of UVA illumination, thus prepared the blood plasma of photochemical treatment.Merge the unit of handling, about 600mL mixture pump pressure is passed through each disk with the speed of about 40mL/min.As among the embodiment 5, analyze 3S-59 and thrombin.(Micromeritics, Norcross GA) have analyzed surface area to invade porosimetry forever with equilibrium step.
Adsorbent Accumulation schedule area (the m relevant with the hole of diameter＞3nm 2/g) Accumulation schedule area (the m relevant with the hole of diameter＞20nm 2/g) Accumulation schedule area (the m relevant with the hole of diameter＞40nm 2/g)
???MN-200 ???????188 ????????55 ????????42
???MN-250 ???????172 ????????28 ????????7
???MN-270 ???????165 ????????14 ????????3
Adsorbent S-59 removes (%) APTT increases (S) Factor IX activity (keeping %) Factor XI activity (keeping %)
?MN-200 ?????99.5 ?????5.8 ?????85 ?????55
?MN-250 ?????99.5 ?????2.0 ?????82 ?????77
?MN-270 ?????99.4 ?????0.5 ?????100 ?????91
The selection that is used for these three kinds of particular adsorbent of IAD has strong influence to biological activity (measuring by aPPT), factor IX activity and factor XI activity, but to the not strong influence of reduction degree of the low molecular weight compound S-59 that uses in the present embodiment.
Because be used for three kinds of adsorbents of IAD in the present embodiment, the main distinction of MN200, MN250 and MN270 is that the aperture is (on the aperture, each begin to have can be rated as important surface area) and do not lie in their surface chemistry basically, so the conclusion consistent with top result is, the surface area that low molecular weight compound reaches is similarly in three kinds of adsorbents, thus the reduction that each IAD has been produced the similar degree of S-59.In addition, following situation is possible, promptly contain the biological activity preferably that IAD showed with the adsorbent of the small surface area that interrelates than macropore, be owing to make tested bioactive some amboceptor (these amboceptors have the trend that is adsorbed onto adsorbent surface) than macropore, be factor IX and the factor XI in the present embodiment, absorption or inactivation on than the surface of macropore, and than aperture from these amboceptors of its exclusion.
Embodiment 19
Present embodiment proves, (active complement-C3a) is effective to remove low molecular weight compound such as virally inactivated dose (psoralen) or biological respinse modifier with IAD from whole blood.To cause complement activation, when using cellulose acetate membrane, this can observe in hemodialysis whole blood with the cellulose acetate membrane pretreatment.Carry out hemoperfusion removing the deactivation complement, return mixing pit to whole blood, the psoralen (seeing Figure 13) that simulation adds by making effluent from hemoperfusion equipment.
(Sacramento CA) has obtained two the paired whole blood of ABO-unit from Sacramento Blood Center.After blood supply, this unit is kept at room temperature.With these two unit transfer to comprise four Millipore RA type films (47mm, Millipore, Marlborough, two PL2410 plastics hold-up vessels MA) (Baxter Healthcare, Deerfield, IL) in.Whole blood was at room temperature cultivated 24 hours, and (Millipore RA) brings out complement activation with cellulose acetate membrane.Before the beginning hemoperfusion, in each whole blood unit, add psoralen (150 μ M S-59 (4 '-(4-amino-2-oxa-) butyl-4,5 ', 8-trimethylpsoralen)) immediately.
With IAD medium (300g/m 2MN-200 AQF) is cut into the disk that diameter is 47mm.(CunoInc., Meridien CT) seal sheet with the Merlon protecting cover of the 47mm diameter that has rustless steel supporting screen.To manage (3mm ID PharMed pipe) is connected with protecting cover.Pipe is loaded in the peristaltic pump (Masterflex), and calibration system is to transmit the flow velocity of 75mL/min then.The entrance and exit of pipe links to each other with 600mL beaker (Nalgene) on placing agitating plate.In whole research, the stirring rod that applies with Teflon-stirs the whole blood that is contained in the 500mL beaker gentlely, with the mixing that will take place in the simulation subject body.
Clean whole assembly with the heparin that contains 174USP unit (sodium salt, 1-A level, 174USP unit/mg, Sigma chemical company)/brinish solution of mL.Before importing whole blood, saline is discharged from the IAD assembly.In beaker, add whole blood unit (500mL).Gradually improve and stir, mix apparent until blood.Cause flowing of whole blood.As shown in Figure 13, whole blood upwards flows from the IAD bottom.Got whole blood sample from beaker at interval with 15 minutes.Carry out cell counting immediately with Baker cell counter (maker).Sample microcentrifuge (10,000rpm, centrifugal in 5min), remove the supernatant, and freezingly immediately be used for later analysis.
Supernatant sample is thawed, and analyze the residual level of psoralen with reversed-phase HPLC.In addition, (Quidel, San Diego CA) have measured the level of active complement fragment C3a with ELISA.At last, measured hemolysis levels as previously mentioned.
Summed up the result that cell counting, haemolysis measurement, psoralen measurement and C3a measure in the table 3.In general, proved removing of psoralen and C3a.In addition, in whole research process, leukocyte (WBC) and erythrocyte (RBC) counting keep constant basically.Under study for action, platelet count shows downward trend really, and haemolysis slightly increases.Need further study with fresh whole blood to prove whether hematoblastic minimizing can be owing to the incubated at room temperature of at the beginning whole blood being carried out.
Comprise with the advantage of using the immobilization adsorbent in the hemoperfusion equipment: 1) can independently control adsorbent particle diameter and pressure drop-under high flow rate or to the granule adsorbent, be even more important; 2) thus can reduce physics to greatest extent by the immobilization absorbent particles interacts and controls granule and grind; 3) can reduce small particles of pollution thing and slave unit outflow to greatest extent by the immobilization absorbent particles; 4) can keep even, stable adsorbent bed.
Table 3. whole blood hemoperfusion result of study
Time (min) Lencocyte count (x10 3/μL) Red-cell count (x10 6/μL) Platelet count (x10 3/μL) Haemolysis (%) Remaining psoralen (μ M) Remaining C3a (ng/mL)
????0 ????4.5 ?????3.72 ?????228 ???0.22 ????150.0 ??????959
????18 ????4.3 ?????3.63 ?????224 ???0.29 ????105.8 ??????707
????30 ????4.4 ?????3.79 ?????217 ???0.32 ????92.1 ??????716
???46.5 ????4.2 ?????3.69 ?????204 ???0.32 ????77.7 ??????573
????60 ????3.9 ?????3.79 ?????203 ???0.38 ????68.8 ??????537
????75 ????4.1 ?????3.73 ?????181 ???0.39 ????58.2 ??????477
????90 ????4.1 ?????3.70 ?????186 ???0.42 ????53.1 ??????547

Claims (10)

1. method that reduces the concentration of biological respinse modifier in the biological composition, wherein this method has kept the required biological activity of biological composition basically, comprise with this biological composition of a kind of device processes, wherein this equipment comprises the inert base that contains high absorbent particles, and wherein the diameter range of absorbent particles is at the about 200 μ m of about 1 μ m-, and wherein this equipment is used for flow-type processing.
2. according to the process of claim 1 wherein that this biological respinse modifier is a complement activation.
3. according to the process of claim 1 wherein that this biological composition is a blood plasma.
4. according to the process of claim 1 wherein that the length of this sorbent material is less than three times of width.
5. according to the process of claim 1 wherein that this absorbent particles comprises super crosslinked polystyrene network.
6. according to the process of claim 1 wherein that this absorbent particles is an activated carbon granule, and wherein the surface area of activated carbon granule greater than 1200m 2/ g.
7. according to the method for claim 6, wherein this activated carbon granule is that steam activation by coconut husk forms.
8. according to the process of claim 1 wherein that the inert base of this equipment is the network of fibers of being made up of cellulose.
9. according to the process of claim 1 wherein that this inert base is the particle network that forms with super crosslinked polystyrene particle sintering by the ultra-high molecular weight polyethylene granule.
10. according to the process of claim 1 wherein that this method also reduces psoralen derivant in the biological composition, acridine derivatives, the concentration of dyestuff or quencher.
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CN113670692A (en) * 2021-08-19 2021-11-19 北京大学人民医院 Kit for removing rivaroxaban in blood plasma in vitro

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