WO1999034915A1 - Dispositifs d'ecoulement permettant de reduire la concentration de composes dans des compositions biologiques et procedes associes - Google Patents

Dispositifs d'ecoulement permettant de reduire la concentration de composes dans des compositions biologiques et procedes associes Download PDF

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Publication number
WO1999034915A1
WO1999034915A1 PCT/US1998/014211 US9814211W WO9934915A1 WO 1999034915 A1 WO1999034915 A1 WO 1999034915A1 US 9814211 W US9814211 W US 9814211W WO 9934915 A1 WO9934915 A1 WO 9934915A1
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WO
WIPO (PCT)
Prior art keywords
adsorbent
particles
compounds
biological
plasma
Prior art date
Application number
PCT/US1998/014211
Other languages
English (en)
Inventor
Derek Joseph Hei
Michael S. Clarke
Original Assignee
Cerus Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US1998/000531 external-priority patent/WO1998030327A1/fr
Application filed by Cerus Corporation filed Critical Cerus Corporation
Priority to CA002317430A priority Critical patent/CA2317430A1/fr
Priority to JP2000527350A priority patent/JP2003527230A/ja
Priority to EP98933275A priority patent/EP1051249A1/fr
Priority to AU82956/98A priority patent/AU759541B2/en
Publication of WO1999034915A1 publication Critical patent/WO1999034915A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • 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
    • B01J20/28—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
    • A01N1/0236—Mechanical aspects
    • A01N1/0242—Apparatuses, i.e. devices used in the process of preservation of living parts, such as pumps, refrigeration devices or any other devices featuring moving parts and/or temperature controlling components
    • 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
    • A01N1/0278—Physical preservation processes
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • 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
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—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 physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • 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
    • B01J20/28—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
    • B01J20/28016—Particle form
    • B01J20/28019—Spherical, ellipsoidal or cylindrical
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • 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
    • B01J20/28—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
    • 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
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • 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
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—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
    • B01J20/28078—Pore diameter
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D219/10—Nitrogen atoms attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/64—Acridine or hydrogenated acridine ring systems
    • A—HUMAN NECESSITIES
    • 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
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption

Definitions

  • the present invention relates to methods and devices for the reduction of compounds from biological compositions.
  • the compounds have a molecular weight ranging from about 100 g/mol to about 30,000 g/mol.
  • dialysis means are able to remove low molecular weight compounds from plasma and whole blood.
  • dialysis can successfully remove low molecular weight toxins and pharmaceutical compounds.
  • dialysis might be used to remove, for example, psoralens and psoralen photoproducts from blood products.
  • current dialysis procedures involve very complicated and expensive devices. As such, the use of dialysis machines would not be practical for the decontamination of a large volume of blood products.
  • leukocytes and viral inactivation agents e.g., psoralens, hypericin, and dyes such as methylene blue, toluidine blue, and crystal violet
  • leukocytes and viral inactivation agents e.g., psoralens, hypericin, and dyes such as methylene blue, toluidine blue, and crystal violet
  • WO 95/18665 describes a filter comprising a laid textile web which includes a mechanically stable polymeric substrate.
  • the web itself comprises interlocked textile fibers forming a matrix with spaces and fibrillated particles disposed within the spaces.
  • this device causes a significant decrease in the Factor XI activity.
  • DISCLOSURE OF THE INVENTION Devices are provided for reduction of concentration of compounds from biological compositions.
  • the compounds have molecular weights ranging from about 100 g/mol to about 30,000 g/mol.
  • the device is a flow device.
  • An example of a flow device is shown in Figure 12.
  • Flow devices are known in the literature and are described, for example, in PCT publication WO 96/40857, incorporated by reference herein. Flow devices permit reduction of concentration of low molecular weight compounds from materials such as blood products by perfusing the blood product through the flow device.
  • Exemplary compounds include pathogen inactivating compounds, dyes, thiols, plasticizers and activated complement.
  • Devices comprise a three dimensional network of adsorbent particles immobilized by an inert matrix. This immobilization reduces the risk of leakage of loose adsorbent particles into the blood product. Furthermore, immobilization of the adsorbent particles by an inert matrix simplifies manufacturing by reducing problems associated with handling loose adsorbent particles.
  • the present invention provides a method of reducing the concentration of a biological response modifier in a biological composition, wherein the method substantially maintains a desired biological activity of the biological composition.
  • the method comprises treating the biological composition with a device.
  • the device comprises an inert matrix containing highly adsorbent particles, wherein the adsorbent particles range from about 1 ⁇ m to about 200 ⁇ m in diameter, and wherein the device is for use in a flow process.
  • the biological response modifier is activated complement.
  • the biological composition is plasma.
  • the adsorbent material has a length less than three times the width.
  • the adsorbent particles comprise a hypercrosslinked polystyrene network.
  • the adsorbent particles are activated carbon particles, wherein the activated carbon particles have a surface area greater than about 1200 m 2 /g.
  • the activated carbon particles are formed by steam activation of coconut shells.
  • the inert matrix of the device is a fiber network composed of cellulose.
  • the inert matrix is a particulate network formed by sintering together particles of ultra-high molecular weight polyethylene with particles of hypercrosslinked polystyrene networks.
  • the method further reduces the concentration of a psoralen derivative, an acridine derivative, a dye or a quencher in the biological composition.
  • FIG. 1 diagrammatically depicts a perspective view of one embodiment of a fiber, indicating its inner core and outer sheath, that forms the fiber networks of the fiberized resin.
  • FIG. 2 schematically represents a portion of one embodiment of the fiberized resin of the present invention.
  • FIG. 3 diagrammatically represents a cross-sectional view of one embodiment of fiberized resin in which the adsorbent beads are secured to fibers that make up the fiberized resin.
  • FIG. 4 diagrammatically represents a cross-sectional view of one embodiment of fiberized resin in which the adsorbent beads are immobilized within the fibers of the fiberized resin and the heat seals that encompass samples of fiberized resin.
  • FIG. 5 is a graph showing a comparison of adsorption kinetics for removal of aminopsoralens from platelets with Dowex ® XUS-43493 and Amberlite ® XAD-16 HP loose adsorbent beads and fiberized resin containing Amberlite XAD-16.
  • FIG. 6 is a graph showing a comparison of the adsorption kinetics for removal of aminopsoralens from platelets with p(HEMA)-coated and uncoated Dowex ® XUS-43493 beads.
  • FIG. 7 is a graph showing a comparison of the effect of pre-treatment solution glycerol content on relative aminopsoralens adsorption capacity for Amberlite ® XAD-16 and Dowex ® XUS-43493.
  • FIG. 8 is a graph showing a comparison of the effect of wetting solution on 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen adsorption capacities for dried adsorbent in 100% plasma for Amberlite ® XAD-16 (bottom) and Dowex ® XUS-43493 (top); the samples that were not wet in an ethanol solution are labeled "No Tx". Adsorbent capacities are reported as percentages relative to the capacity of optimally wet adsorbent.
  • FIG. 9 is a graph showing a comparison of adsorption of aminopsoralens over a 3-hour period from plasma using Amberlite ® XAD-16 wet in several different solutions.
  • FIG. 10 is a graph showing a comparison of the kinetics of adsorption of methylene blue over a 2-hour period from plasma.
  • FIG. 11 depicts the chemical structures of acridine, acridine orange, 9- amino acridine, and 5-[( ⁇ -carboxyethyl)amino]acridine.
  • FIG. 12 is an illustration of a flow configuration for the immobilized adsorption device (IAD).
  • IAD immobilized adsorption device
  • FIG. 13 is an illustration of an experimental set-up for a whole blood perfusion study.
  • FIG. 14 shows an exploded view of a disk configuration assembly made according to the invention.
  • FIG. 15 shows an exploded view of a drip chamber assembly made according to the invention.
  • BEST MODE FOR CARRYING OUT THE INVENTION Devices are provided for reduction of concentration of compounds from biological compositions.
  • the compounds have molecular weights ranging from about 100 g/mol to about 30,000 g/mol.
  • the device is a flow device.
  • An example of a flow device is shown in Figure 12.
  • Flow devices are known in the literature and are -described, for example, in PCT publication WO 96/40857, incorporated by reference herein. Flow devices permit reduction of concentration of low molecular weight compounds from materials such as blood products by perfusing the blood product through the flow device.
  • Exemplary compounds include pathogen inactivating compounds, dyes, thiols, plasticizers and activated complement.
  • Devices are provided that comprise a three dimensional network of adsorbent particles immobilized by an inert matrix. This immobilization reduces the risk of leakage of loose adsorbent particles into the blood product. Furthermore, immobilization of the adsorbent particles by an inert matrix simplifies manufacturing by reducing problems associated with handling loose adsorbent particles.
  • acridine derivatives refer to a chemical compound containing the tricyclic structure of acridine (dibenzo[b,e]pyridine; 10-azanthracene). The compounds have an affinity for (and can bind) to nucleic acids non-covalently through intercalation.
  • aminoacridine refers to those acridine compounds with one or more nitrogen-containing functional groups. Examples of aminoacridines include 9-amino acridine and acridine orange (depicted in Figure 11).
  • adsorbent particle broadly refers to any natural or synthetic material which is capable of interacting with molecules in a liquid thus allowing the molecule to be removed from the liquid.
  • adsorbents include but are not limited to activated carbon, silica, diatomaceous earth, and cellulose.
  • synthetic adsorbents include but are not limited to polystyrene, polyacrylics, and carbonaceous adsorbents.
  • Adsorbent particles are often porous, often possess high surface areas, and may be modified with a variety of functional groups (e.g. ionic, hydrophobic, acidic, basic) which can effect how the adsorbent interacts with molecules.
  • aromatic refer broadly to compounds with rings of atoms having delocalized electrons.
  • the monocyclic compound benzene (C 6 H ) is a common aromatic compound. However, electron delocalization can occur over more than one adjacent ring (e.g., naphthalene (two rings) and anthracene (three rings)).
  • aromatic compounds include, but are not limited to, aromatic halides (aryl halides), aromatic heterocyclic compounds, aromatic hydrocarbons (arenes), and aromatic nitro compounds (aryl nitro compounds).
  • biocompatible coating refers broadly to the covering of a surface (e.g., the surface of a polystyrene bead) with a hydrophilic polymer that when in contact with a blood product does not result in an injurious, toxic, or immunological response and renders the surface more biocompatible by decreasing cell adhesion, protein adsorption or improves cell function.
  • Suitable coatings are biocompatible if they have minimal, if any, effect on the biological material to be exposed to them. By “minimal” effect it is meant that no significant biological difference is seen compared to the control.
  • biocompatible coatings improve the surface hemocompatibility of polymeric structures. For example, poly(2-hydroxyethyl methacrylate) (pHEMA) is frequently used for the coating of materials used in medical devices (e.g., blood filters).
  • pHEMA poly(2-hydroxyethyl methacrylate)
  • biocompatible housing refers broadly to filter housings, containers, bags, vessels, receptacles, and the like that are suitable for containing a biological material, such as plasma.
  • Suitable containers are biocompatible if they have minimal, if any, effect on the biological material to be contained therein.
  • minimal effect it is meant that no significant biological difference is seen in blood product function compared to the control as described herein, for example, for plasma.
  • biological compositions may be stored in biocompatible housings prior to transfusion to a recipient.
  • biological fluids include human or non-human whole blood, plasma, platelets, red blood cells, leukocytes, serum, lymph, saliva, milk, urine, or products derived from or containing any of the above, alone or in mixture, with or without a chemical additive solution.
  • the fluid is blood or a blood product with or without a chemical additive solution, most preferably plasma.
  • blood bag refers to a blood product container.
  • blood product refers to the fluid and/or associated cellular elements and the like (such as erythrocytes, leukocytes, platelets, etc.) that pass through the body's circulatory system; blood products include, but are not limited to, blood cells, platelet mixtures, serum, and plasma.
  • platelet mixture refers to one type of blood product wherein the cellular element is primarily or only platelets.
  • a platelet concentrate (PC) is one type of platelet mixture where the platelets are associated with a smaller than normal portion of plasma.
  • synthetic media may make up that volume normally occupied by plasma; for example, a platelet concentrate may entail platelets suspended in 35% plasma/65% synthetic media. Frequently, the synthetic media comprises phosphate.
  • blood separation means refers broadly to a device, machine, or the like that is able to separate blood into blood products (e.g., platelets and plasma).
  • An apheresis system is one type of blood separation means.
  • Apheresis systems generally comprise a blood separation device, an intricate network of tubing and filters, collection bags, an anticoagulant, and a computerized means of controlling all of the components.
  • crosslinked refers broadly to linear molecules that are attached to each other to form a two- or three-dimensional network.
  • divinylbenzene serves as the crosslinking agent in the formation of styrene-divinylbenzene copolymers.
  • the term also encompasses "hypercrosslinking" in which hypercrosslinked networks are produced by crosslinking linear polystyrene chains either in solution or in a swollen state with bifunctional agents.
  • bifunctional agents can be used for cross-linking (for example, see Davankov and Tsyurupa, Reactive Polymers 13:24-42 (1990);
  • cyclic compounds refers to compounds having one (i.e., a monocyclic compounds) or more than one (i.e., polycyclic compounds) ring of atoms.
  • the term is not limited to compounds with rings containing a particular number of atoms. While most cyclic compounds contain rings with five or six atoms, rings with other numbers of atoms (e.g., three or four atoms) are also contemplated by the present invention.
  • the identity of the atoms in the rings is not limited, though the atoms are usually predominantly carbon atoms.
  • the rings of polycyclic compounds are adjacent to one another; however, the term "polycyclic" compound includes those compounds containing multiple rings that are not adjacent to each other.
  • Dyes refers broadly to compounds that impart color.
  • Dyes generally comprise chromophore and auxochrome groups attached to one or more cyclic compounds. The color is due to the chromophore, while the dying affinities are due to the auxochrome.
  • Dyes have been grouped into many categories, including the azin dyes (e.g., neutral red, safranin, and azocarmine B); the azo dyes; the azocarmine dyes; the dephenymethane dyes; the fluorescein dyes; the ketonimine dyes; the rosanilin dyes; the triphenylmethane dyes; the phthalocyanines; and, hypericin. It is contemplated that the methods and devices of the present invention may be practiced in conjunction with any dye that is a cyclic compound.
  • fiberized resin generally refers to immobilization of adsorbent material, including for example, resins, in, on or entrapped to a fiber network.
  • the fiber network is comprised of polymer fibers.
  • the fibers consist of a polymer core (e.g., polyethylene terephthalates [PET]) with a high melting point surrounded by a polymer sheath
  • Fiberized resin may be produced by heating the fiber network, under conditions that do not adversely affect the adsorbent capacity of the resin to a significant degree. Where the resin comprises beads, heating is performed such that the adsorbent beads become attached to the outer polymer sheath to create "fiberized beads".
  • fiberized resin containing a known amount of adsorbent beads per defined area, samples of fiberized resin for use in the removal of cyclic compounds (e.g., psoralens, and, in particular, aminopsoralens) and other products can be obtained by cutting a defined area of the fiberized resin, rather than weighing the adsorbent beads.
  • cyclic compounds e.g., psoralens, and, in particular, aminopsoralens
  • filter refers broadly to devices, materials, and the like that are able to allow certain components of a mixture to pass through while retaining other components.
  • a filter may comprise a mesh with pores sized to allow a blood product (e.g. , plasma) to pass through, while retaining other components such as resin particles.
  • a blood product e.g. , plasma
  • filter is not limited to the means by which certain components are retained.
  • flow adapter refers to a device that is capable of controlling the flow of a particular substance like a blood product.
  • the flow adapter may perform additional functions, such as preventing the passage of pieces of adsorbent resin material.
  • heterocyclic compounds refers broadly to cyclic compounds wherein one or more of the rings contains more than one type of atom.
  • carbon represents the predominant atom, while the other atoms include, for example, nitrogen, sulfur, and oxygen.
  • heterocyclic compounds include furan, pyrrole, thiophene, and pyridine.
  • high temperature activation process refers to a high temperature process that typically results in changes in surface area, porosity and surface chemistry of the treated material due to pyrolysis and/or oxidation of the starting material.
  • immobilized adsorption device refers to immobilized adsorbent material in, on or entrapped to an inert matrix.
  • IAD immobilized adsorption device
  • inert matrix is a fiber network
  • IAD can be used interchangeably with the term fiberized resin.
  • inert matrix refers to any synthetic or naturally occurring fiber or fibrous material which can be used to immobilize adsorbent particles without substantially effecting the desired biological activity of the blood product.
  • the matrix may contribute to the reduction in concentration of small organic compounds although typically it does not contribute substantially to the adsorption or removal process.
  • the inert matrix may interact with cellular or protein components resulting in cell removal (e.g. leukodepletion) or removal of protein or other molecules.
  • the matrix may undergo a surface treatment or coating to enhance functionality.
  • the matrix may get a hydrophobic coating or glow discharge treatment to increase biocompatibility, increase wettability, and/or facilitate priming.
  • in-line column refers to a container, usually cylindrically shaped, having an input end and an output end and containing a substance disposed therein to reduce the concentration of small organic compounds from a blood product.
  • isolated refers to separating a substance out of a mixture containing more than one component.
  • platelets may be separated from whole blood.
  • the product that is isolated does not necessarily refer to the complete separation of that product from other components.
  • macropores generally means that the diameter of the pores is greater than about 500 A.
  • micropores refers to pores with diameters less than about 20 A.
  • mesopores refers to pores with diameters greater than about 20 A. and less than about 500 A.
  • porous is used to describe a porous structure having a substantial number of pores with diameters greater than about 500 A.
  • macroreticular is a relative term that means that the structure has a high physical porosity (/. e. , a large number of pores are present) a porous adsorbent structure possessing both macropores and micropores.
  • the term "mesh enclosure,” “mesh pouch” and the like refer to an enclosure, pouch, bag or the like manufactured to contain multiple openings.
  • the present invention contemplates a pouch, containing the immobilized adsorbent particle, with pores of a size that allow a blood product to contact the immobilized adsorbent particle, but retain the immobilized adsorbent particle within the pouch.
  • photoproduct refers to products that result from the photochemical reaction that a psoralen or other dye (e.g., methylene blue, phthalocyanines) undergoes upon exposure to ultraviolet radiation.
  • a psoralen or other dye e.g., methylene blue, phthalocyanines
  • polyaromatic compounds refers to polymeric compounds containing aromatic groups in the backbone, such as polyethylene terphalate, or as pendant groups, such as polystyrene, or both.
  • psoralen removal means refers to a substance or device that is able to remove greater than about 80% of the psoralen from, e.g. , a blood product; preferably, greater than about 90%; most preferably greater than about 99%.
  • a psoralen removal means may also remove other components of the blood product, such as psoralen photoproducts.
  • reducing the concentration refers to the removal of some portion of low molecular weight compounds from a biological composition.
  • While reduction in concentration is preferably on the order of greater than about 70%, more preferably on the order of about 90%, and most preferably on the order of about 99%.
  • removing substantially all of said portion of a compound e.g. a psoralen, psoralen derivative, isopsoralen, acridine, acridine derivative, or dye
  • a compound e.g. a psoralen, psoralen derivative, isopsoralen, acridine, acridine derivative, or dye
  • the phrase "removing substantially all of said portion of a compound (e.g. a psoralen, psoralen derivative, isopsoralen, acridine, acridine derivative, or dye) free in solution” refers preferably to the removal of more than about 80% of the compound free in solution, more preferably to the removal of more than about 85%, even more preferably of more than about 90%, and most preferably to the removal of more than about 99%.
  • the term "resin” refers to a solid support (such as particles or beads etc.) capable of interacting and attaching to various small organic compounds, including p
  • a psoralen may be removed by hydrophobic or ionic interaction (i.e., affinity interaction).
  • affinity interaction i.e., affinity interaction
  • adsorbent resin refers broadly to both natural organic substances and synthetic substances and to mixtures thereof.
  • the term "sintered medium” refers to a structure which is formed by applying heat and pressure to a powder or mixture of powders, thereby partially fusing the powder or powder mixture, such that a path for a flowing fluid exists through the structure.
  • the porous structure can be prepared by mixing powders of relatively low melting polymers and heating them so the plastic particles partially fuse but still allow a path for fluids to penetrate the porous mass.
  • Sintered adsorbent media can be prepared similarly by incorporating carbon or other high or non-melting adsorbent particle with that of the low melting powder and heating. Methods of producing porous plastic materials are described in U.S.
  • the process causes fusing of the powder particles resulting in the formation of a porous solid structure.
  • the sintered medium can be formed into a variety of shapes by placing the polymeric powder in a forming tool during the sintering process.
  • Adsorbent particles can be introduced into the sintered medium by mixing adsorbent particles with the powdered thermoplastic polymer before subjecting to the sintering process.
  • stabilizing agent refers to a compound or composition capable of optimizing the adsorption capacity of certain resins.
  • acceptable stabilizing agents should be soluble in water and ethanol (or other wetting agents), nonvolatile relative to water and ethanol, and safe for transfusion in small amounts.
  • stabilizing agents include, but are not limited to, glycerol and low molecular weight PEGs.
  • a "wetting agent” is distinguishable from a “stabilizing agent” in that the former is believed to reopen adsorbent pores of those resins that are not hypercrosslinked (i.e. , non-macronet resins). Wetting agents generally will not prevent pores from collapsing under drying conditions, whereas stabilizing agents will.
  • a general discussion of wetting and wetting agents is set forth in U.S. Patent No. 5,501,795 to Pall et al., hereby incorporated by reference.
  • substantially maintaining a desired biological activity of the biological composition refers to substantially maintaining properties of a biological composition which are believed to be indicative of the potential performance of the composition in a therapeutic setting.
  • in vivo activity is not destroyed or significantly lowered if the level of clotting factors, such as Factors I, II, V, VII, VIII, IX, X, XI, or the change in PT and PTT time are substantially maintained in plasma when treated by the methods described herein.
  • the change in level of clotting factors, such as Factors I, II, V, VII, VIII, IX, X, XI of the treated plasma can be less than about 20%; preferably less than about 10%.
  • the change in PT and PTT time for the treated plasma can be, for example, less than about 3 seconds and greater than 1 second; preferably 1.5 seconds. It is further contemplated that the phrase substantially maintained for each of the properties associated with a described biological composition may also include values acceptable to those of ordinary skill in the art as described in the literature, including for example in Klein H.G. , ed. Standards for Blood Banks and Transfusion Services, 17 th Ed., Bethesda, MD: American Association of Blood Banks, 1996, incorporated by reference herein.
  • an “equivalent thereto” when used in reference to a device of the present invention refers to a device that functions equivalently with respect to the maintenance of biological activity of a biological composition.
  • an “equivalent” device or matrix containing adsorbent particles is one that similarly maintains a suitable coagulation factor level.
  • low molecular weight compound refers to an organic or biological molecule having a molecular weight ranging from about 100 g/mol to about 30,000 g/mol.
  • Low molecular weight compounds include, without limitation, the following compounds: small organic compounds such as psoralens, acridines or dyes; quenchers, such as glutathione; plastic extractables, such as plasticizers; biological modifiers, such as activated complement, that possess a molecular weight between about 100 g/mol and about 30,000 g/mol; and, polyamine derivatives.
  • biological composition that is suitable for infusion refers to a biological composition that maintains its essential biological properties (e.g. clotting function in plasma) while having sufficiently low levels of any undesired compounds (e.g. inactivation compounds, response modifiers) such that infusion provides intended function without detrimental side effects.
  • essential biological properties e.g. clotting function in plasma
  • undesired compounds e.g. inactivation compounds, response modifiers
  • control refers to an experiment performed to study the relative effects of different conditions.
  • untreated control would refer to the biological compostion in the absence of treatment with the device. It may also refer to a comparison between two different types of devices.
  • non-fibrous adsorbent material refers to an adsorbent material composed substantially of particles that have a length, or longest dimension, less than five times their width, or narrowest dimension.
  • adsorbent particles which are useful in a device for reducing the concentration of compounds in a biological composition while substantially maintaining a desired biological activity of the biological composition.
  • the compounds that are reduced in the biological composition have molecular weights ranging from about 100 g/mol to about 30,000 g/mol.
  • the adsorbent particles can be of any regular or irregular shape that lends itself to incorporation into the inert matrix but are preferably roughly spherical.
  • the particles are greater than about 1 ⁇ m in diameter; preferably, the particles are greater than about 10 ⁇ m in diameter when using a sintered medium as the matrix for the adsorbent, more preferably, the particles are between about 50 ⁇ m and about 150 ⁇ m in diameter when using a sintered medium as the matrix.
  • the particles are between about 1 ⁇ m and about 200 ⁇ m in diameter when using a wet laid fibrous medium as the matrix, more preferably between about 1 ⁇ m and about 50 ⁇ m when using a wet laid fibrous medium as the matrix for the adsorbent.
  • the adsorbent particles are activated carbons derived either from natural or synthetic sources.
  • activated carbons include; Picatiff Medicinal, which is available from PICA USA Inc. (Columbus, OH), Norit ROX 0.8, which is available from Norit Americas,
  • Preferred activated carbons are those that are specially cleaned and/or meet United States Pharmacopoeia Standards. Moreover, activated carbons with surface areas greater than 950 m2/g are preferred and those with surface areas greater than 1200 m2/g are more preferred, as activated carbons with more surface area available to the low molecular weight compound generally show better adsorption. Activated carbons formed by steam activation tend to have more hydrophobic surfaces, so for more hydrophobic low molecular weight compounds, these steam activated carbons often have better binding capacity and these carbons are preferred.
  • activated carbons with less macroporosity for example activated carbons prepared from coconut shell are also preferred.
  • the particles are Norit A Supra, which is available from Norit Americas, Inc. (Atlanta, GA).
  • Norit A Supra is a USP-grade activated carbon that is formed by steam activation of coconut shell. This activated carbon has a very high total surface area (2000 m 2 /g) and is very microporous in nature.
  • the particles can be hydrophobic resins.
  • Nonlimiting examples of hydrophobic resins include the following polyaromatic adsorbents: Amberlite adsorbents (e.g., Amberlite XAD-2, XAD-4, and XAD- 16), available from Rohm and Haas (Philadelphia, PA); Amberchrom ® adsorbents available from Toso Haas (TosoHass, Montgomeryville, PA); Diaion®//Sepabeads ® Adsorbents (e.g., Diaion ® HP20), available from Mitsubishi Chemical America, Inc. (White Plains, NY); Hypersol-Macronet ®
  • Amberlite adsorbents e.g., Amberlite XAD-2, XAD-4, and XAD- 16
  • Amberchrom ® adsorbents available from Toso Haas (TosoHass, Montgomeryville, PA)
  • Diaion®//Sepabeads ® Adsorbents
  • Sorbent Resins e.g., Hypersol-Macronet ® Sorbent Resins MN-200, MN-150 and MN-400
  • Purolite Bala Cynwyd, PA
  • Dowex ® Adsorbents e.g., Dowex ® XUS-40323, XUS-43493, and XUS-40285), available from Dow Chemical Company (Midland, MI).
  • Preferred particles are hydrophobic resins which are polyaromatic adsorbents comprising a hypercrosslinked polystyrene network, such as Dowex ® XUS-43493 (known commercially as Optipore ® L493 or V493) and Purolite MN- 200.
  • Hypercrosslinked polystyrene networks such as Dowex ® XUS-43493 and Purolite MN-200 are non-ionic macroporous and macroreticular resins.
  • the non- ionic macroreticular and macroporous Dowex XUS-43493 has a high affinity for psoralens, including for example, 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen, and it possesses superior wetting properties.
  • the phrase "superior wetting properties” means that dry (i.e. essentially anhydrous) adsorbent does not need to be wet with a wetting agent (e.g. , ethanol) prior to being contacted with the blood product in order for the adsorbent to effectively reduce the concentration of small organic compounds from the blood product.
  • a wetting agent e.g. ethanol
  • Hypercrosslinked polystyrene networks such as Dowex ® XUS-43493 and Purolite MN-200 are preferably in the form of spherical particles with a diameter range of about 10 ⁇ m to about 200 ⁇ m.
  • Adsorbent particles including for example, Dowex ® XUS-43493, preferably have extremely high internal surface areas and relatively small pores (e.g. 46 A).
  • the internal surface area of the particle can be from about 300 to about 1100 m 2 /g; preferably 1100 m 2 /g.
  • the pores size of the particle can be greater than 25 A and less than 80 ⁇ A; preferably from about 25A to about 15 ⁇ A; most preferably from about 25A to about 5 ⁇ A.
  • hydrophobic interaction is believed to be the primary mechanism of adsorption. Its porous nature confers selectively on the adsorption process by allowing small molecules to access a greater proportion of the surface area relative to large molecules (i.e., proteins) and cells.
  • Purolite ® has many similar characteristics to Dowex ® XUS-43493, such as high affinity for psoralens and superior wetting properties, and is also a preferred adsorbent particle.
  • Polystyrene particles can be classified, based on their mechanism of synthesis and physical and functional characteristics, as i) conventional networks and ii) hypercrosslinked networks.
  • Preferred adsorbents have a high surface area, have pores that do not collapse, and do not require wetting.
  • preferred adsorbents have low levels of extractable residual monomer, crosslinkers and other organic extractables.
  • the conventional networks are primarily styrene-divinylbenzene copolymers in which divinylbenzene (DVB) serves as the crosslinking agent (i.e., the agent that links linear polystyrene chains together).
  • These polymeric networks include the "gel-type" polymers.
  • the gel-type polymers are homogeneous, non- porous styrene-DVB copolymers obtained by copolymerization of monomers.
  • the macroporous adsorbents represent a second class of conventional networks. They are obtained by copolymerization of monomers in the presence of diluents that precipitate the growing polystyrene chains.
  • the polystyrene network formed by this procedure possess a relatively large internal surface area (up to hundreds of square meters per gram of polymer); Amberlite ® XAD-4 is produced by such a procedure.
  • the preferred adsorbents of the present invention e.g., Dowex ® XUS-43493
  • These networks are produced by crosslinking linear polystyrene chains either in solution or in a swollen state with bifunctional agents; the preferred bifunctional agents produce conformationally-restricted crosslinking bridges, that are believed to prevent the pores from collapsing when the adsorbent is in an essentially anhydrous (i.e., "dry") state.
  • the hypercrosslinked networks are believed to possess three primary characteristics that distinguish them from the conventional networks.
  • Third, the hypercrosslinked polymers are "strained" when in the dry state; that is, the rigidity of the network in the dry state prevents chain-to-chain attractions. However, the strains relax when the adsorbent is wetted, which increases the network's ability to swell in liquid media. Davankov and Tsyurupa, Reactive
  • the bridges are formed between polystyrene chains by reacting one of these cross-linking agents with the styrene phenyl rings by means of a Friedel- Crafts reaction.
  • the resulting bridges link styrene phenol rings present on two different polystyrene chains. See, e.g., U.S. Patent No. 3,729,457, hereby incorporated by reference.
  • the bridges are especially important because they generally eliminate the need for a "wetting" agent. That is, the bridges prevent the pores from collapsing when the adsorbent is in an essentially anhydrous (/ ' . e. , "dry") state, and thus they do not have to be "reopened” with a wetting agent prior to the adsorbent being contacted with a blood product.
  • conformationally-restricted bridges should be formed.
  • Some bifunctional agents like DPB do not result in generally limited conformation; for example, DPB contains four successive methylene units that are susceptible to conformation rearrangements. Thus, DPB is not a preferred bifunctional agent for use with the present invention.
  • the adsorbent particles may be further processed to remove fine particles, salts, potential extractables, and endotoxin.
  • the removal of these extractable components is typically performed by treatment with either organic solvents, steam, or supercritical fluids.
  • the particles are sterilized.
  • adsorbent particles e.g. resins
  • these companies test the adsorbents, and the final adsorbent is certified sterile (USP XXI), pyrogen-free (LAL), and free of detectable extractables (DVB and total organics).
  • Thermal processing is an effective method for processing adsorbent particles.
  • Supelco, Inc. (Bellefonte, PA) uses a non-solvent, thermal proprietary process to clean the Dowex ® XUS-43493 and Amberlite adsorbents.
  • the main advantage of using steam is that it does not add any potential extractables to the adsorbent.
  • One big disadvantage, however, is that this process can strip water from the pores of the resin beads; effective performance of some adsorbents requires that the beads be re-wet prior to contacting the illuminated blood product.
  • the Use of Wetting Agents and Stabilizing Agents with Adsorbent Resins Methods may be used for preventing drying and loss of adsorption capacity of particles, such as Amberlite which lose some of their adsorption capacity under certain conditions (e.g., drying).
  • particles, materials or devices may be manufactured in a wet state which is sealed and not capable of drying. This method is associated with several important drawbacks.
  • the shelf-life of the products could be reduced since levels of extractables from the materials could increase over time.
  • Sterilization may be limited to a steam process because ⁇ -irradiation of wet polymers is typically not performed.
  • a second method for preventing loss of adsorption capacity involves the use of an adsorbent which is not adversely affected by drying.
  • macroreticular adsorbents possessing highly crosslinked porous structures e.g., Dowex ® XUS-43493 and Purolite ® MN-200
  • Amberlite ® XAD-16 these macroreticular adsorbents retain a very high proportion of their initial activity when they are dried.
  • loss of adsorption capacity upon drying may be prevented by hydrating Amberlite ® XAD-16 and related adsorbents (e.g., Amberlite ® XAD-4) in the presence of a non- volatile wetting agent.
  • Amberlite ® XAD-16 as the adsorbent, the adsorbent beads may partially dry prior to use during handling, sterilization, and storage.
  • a rapid loss in adsorption capacity occurs (probably due to "collapse" of the pores); thus, for optimum effectiveness, the pores have to be "reopened” with a wetting agent prior to use.
  • Stabilizing agents are effective in maintaining adsorption capacity near its maximum when certain adsorbent resins are subjected to drying conditions. It is believed that the use of stabilizing agents serves to prevent the adsorbent pores from collapsing.
  • An acceptable stabilizing agent should be soluble in water and ethanol, nonvolatile relative to ethanol and water, and safe for transfusion in small amounts.
  • Glycerol and low molecular weight polyethylene glycol e.g., PEG-200 and PEG-400 are examples of stabilizing agents possessing these characteristics.
  • Glycerol has a positive hemocompatibility history. It is frequently added to blood as a cryo-preservative agent in the frozen storage of red blood cell preparations. See, e.g., Chaplin et al, Transfusion 26:341-45 (1986); Valeri et al, Am. J. Vet. Res. 42(9)1590-94 (1981).
  • glycerol solutions containing up to 1% glycerol are routinely transfused, and glycerol solutions are commercially available (e.g., Glyerolite 57 Solution, Fenwal Laboratories, Deerfield, IL). Adsorbent beads like Amberlite ® XAD-16 may be stabilized in ethanol and glycerol.
  • PEGs are liquid and solid polymers of the general chemical formula H(OCH 2 CH 2 ) consultOH, where n is greater than or equal to 4.
  • PEG formulations are usually followed by a number that corresponds to its average molecular weight; for example, PEG-200 has a molecular weight of 200 and a molecular weight range of 190-210.
  • PEGs are commercially available in a number of formulations (e.g., Carbowax, Poly-G, and Solbase).
  • the adsorbent particles are immobilized by an inert matrix.
  • the inert matrix can be made of fibrous or particulate, synthetic or natural polymer.
  • the inert matrix can be sintered polymers.
  • the inert matrix, as with the other components of the device, preferably is biocompatible and does not substantially adversely affect the biological activity of a material upon contact.
  • the synthetic fibers are polyester fibers (Air Quality Filtration (AQF), a division of Hoechst Celanese (Charlotte, N.C.)).
  • Other preferred examples of synthetic fibers are polyethylene or polyamide fibers.
  • Other exemplary synthetic fibers include polyolefin, polyvinyl alcohol and polysulfone fibers.
  • the synthetic polymer fiber includes a first polymer core with a high melting point surrounded by a sheath with a lower melting temperature.
  • the polymer core can be a poly ester(poly ethylene terephthalate).
  • the sheath can be a nylon, or a modified polyester.
  • Fibers are commercially available from Unitika (Osaka, Japan) and Hoechst Trevira GmbH & Co. (Augsberg, Germany).
  • the most preferred embodiment uses cellulose fibers. These cellulose fibers can be derived from a variety of sources, such as jute, kozu, kraft and manila hemp. Networks of synthetic or natural polymer fibers have been used to make filters as described in U.S. Patent Nos. 4,559,145 and 5,639,376, which are herein incorporated by reference.
  • a sintered matrix is also a preferred embodiment.
  • Synthetic polymers suitable for the construction of such sintered particles are high density polyethylene, ultra high molecular weight polyethylene, polypropylene, polyvinyl fluoride, polytetrafluoroethylene, nylon 6. More preferably the sintered particles are polyolefins, such as polyethylene.
  • Polymeric fibers such as those described above may be adsorbent resins without the attachment of adsorbent particles. Such fibers may be formed into a fiber network or may be immobilized on a fiber network of a less adsorbent fiber. Such fibers are contemplated by the present invention; such fibers preferably contain a large, porous, adsorptive surface area or other adsorptive means to facilitate reduction in the concentration of low molecular weight compounds.
  • the adsorbent particles are immobilized by an inert matrix to produce an adsorption medium for reducing the concentration of small organic compounds in a material.
  • the inert matrix can be a three dimensional network including a synthetic or natural polymer fiber network with adsorbent particles immobilized therein.
  • the adsorption medium comprises small porous adsorbent particles with highly porous structures and very high internal surface areas, as described above, immobilized by the inert matrix.
  • the adsorption medium does not substantially adversely affect the biological activity or other properties of the material.
  • the polymer fibers 600 of the fiber network consist of a polymer core 602 (e.g., polyethylene terephthalates (PET)) with a high melting point surrounded by a polymer sheath 604 (e.g., nylon) with a relatively low melting temperature.
  • PET polyethylene terephthalates
  • the fiberized resin is prepared by first evenly distributing the adsorbent beads in the fiber network.
  • the network is rapidly heated (e.g., 180°C x 1 min.) causing the polymer sheath of the fibers 600 to melt and bond to the adsorbent beads 606 and other fibers, forming a cross-linked fiber network, represented in Figure 2.
  • the fiber networks contain three layers; two outer layers 607 that are densely packed with fibers 600 and a less dense inner layer 609 that contains the adsorbent beads 606 and fewer fibers 600.
  • the edges of the fiberized resin may be sealed with polyurethane or other polymers.
  • heat seals 608 may be made in the resulting fiberized resin at predetermined intervals; for example, heat seals can be made in the fiberized resin in a pattern of squares. Thereafter, the fiberized resin can be cut through the heat seals to form samples of resin containing a desired mass (e.g., preferably less than 5.0 g and more preferably less than 3.0 g) of adsorbent beads and of a size suitable for placement within a blood product container.
  • the heat seals serve to prevent the cut fiberized resin from fraying and help to immobilize the adsorbent beads.
  • the use of such heat seals is not required in order to practice the present invention.
  • the adsorbent beads 606 are not secured to the fibers themselves, but rather are immobilized between the denser outer layers 607 of fibers and with the heat seals 608; this embodiment may also result in samples of fiberized media containing a defined amount of adsorbent after being cut through the heat seals.
  • the present invention also contemplates the use of an adhesive (e.g., a bonding agent) to secure the adsorbent resin to the fibers.
  • an adhesive e.g., a bonding agent
  • the beads may also be physically trapped within the fiber network; this might be accomplished, for example, by surrounding the beads with enough fibers so as to hold the beads in position.
  • the particles can be immobilized using a dry-laid process, as described in U.S. Pat. Nos. 5,605,746 and 5,486,410 (AQF patents), which are herein incorporated by reference.
  • the particles can be immobilized using a wet-laid process, as described in U.S. Pat. Nos. 4,559,145 and 4,309,247, which are herein incorporated by reference.
  • the particles can be immobilized using a melt-blown process, as described in U.S. Pat. No. 5,616,254, which is herein incorporated by reference.
  • the inert matrix preferably includes a binding agent to bond the adsorbent particles to the fibers.
  • binding agents include melamine, polyamines and polyamides.
  • the matrix typically contains 1% or less of such binding agents.
  • the adsorbent particles are immobilized in a fiber matrix that is formed by thermal bonding of a biocomponent fiber network.
  • An alternative embodiment involves immobilizing adsorbent particles in non- biocomponent fibers and using a wet strength resin system, adhesives or additional fusible fibers to form bonds between the fibers and adsorbent particles.
  • useful fibers include polyester, nylon and polyolefin.
  • the resulting adsorption medium comprises known amounts of adsorbent per area.
  • the adsorbent per area is from about 300 g/m 2 to about 1100 g/m , preferably from about 500 g/m to about 700 g/m .
  • the appropriate amount of adsorbent contemplated for a specific purpose can be measured simply by cutting a predetermined area of the fiberized resin (i.e., there is no weighing of the fiberized resin).
  • the adsorption medium preferably is biocompatible (i.e., not producing a toxic, injurious, or immunologic response); has a minimal impact on the properties of the material such as biological composition (e.g., plasma); and is not associated with toxic extractables.
  • the immobilized adsorbent particles of the adsorption medium preferably have high mechanical stability (i.e., no fine particle generation).
  • the adsorption medium contains about 20-70% adsorbent by weight, preferably 30-50% by weight. Preferably the adsorption medium contains about 30% by weight of the adsorbent particle where a fibrous matrix is used. Where a sintered particulate matrix is used with a ground polymeric adsorbent particle, the adsorption medium preferably contains about 50% by weight of the adsorbent particle.
  • hydrophilic polymers include poly(2-hydroxyethyl methacrylate) (pHEMA), which may be obtained from, e.g., Scientific Polymer Products, Inc.
  • cellulose-based polymers e.g., ethyl cellulose, which may be obtained from Dow Chemical (Midland, MI). See, e.g., Andrade et al., Trans. Amer. Soc. Artif Int. Organs XNIL222-28 (1971).
  • coatings include polyethylene glycol and polyethylene oxide, also available from Scientific Polymer Products, Inc.. The polymer coating can increase hemocompatibility and reduce the risk of small particle generation due to mechanical breakdown.
  • the adsorbent surface may also be modified with immobilized heparin.
  • strong anion exchange polystyrene divinylbenzene adsorbents may be modified via heparin adsorption. Heparin, a polyanion, will adsorb very strongly to the surfaces of adsorbents which have strong anion exchange characteristics.
  • a variety of quaternary amine-modified polystyrene divinyl benzene adsorbents are commercially available.
  • the coating can be applied in a number of different methods, including radio frequency glow discharge polymerization, as described in U.S. Patent number 5,455,040, which is hereby incorporated by reference and the Wurster coating process (performed by International Processing Corp. (Winchester, KY).
  • the Wurster coating process can be applied by suspending the adsorbent particles (generally via air pressure) in a chamber such that the hydrophilic polymer, such as pHEM A, can be sprayed evenly onto all surfaces of the adsorbent particle.
  • the hydrophilic polymer such as pHEM A
  • the coating can be applied by soaking the immobilized adsorption medium in the hydrophilic polymer (see Example 2). This process is simpler and less expensive than spraying the adsorbent particles with the hydrophilic polymer.
  • the process is not limited to a process that applies the coating of the adsorption medium at any particular time.
  • the pHEMA coating is applied after production of the adsorption medium, but prior to heat sealing the adsorption medium.
  • the adsorption medium is first heat sealed, and then the pHEMA coating is applied.
  • the rinsing process associated with pHEMA application serves to remove loose particles and fibers.
  • the optimum level of pHEMA coating is the minimum coating at which a protective effect on plasma function is observed.
  • the coatings may be sensitive to sterilization. For example, gamma sterilization may result in cross-linking and/or scission of the coating. Therefore, the type (E-beam vs. gamma irradiation) and dose of sterilization may influence the properties of the coated adsorbent. Generally, E-beam sterilization is preferred.
  • Devices are provided for reduction of concentration of compounds from biological compositions.
  • the compounds have molecular weights ranging from about 100 g/mol to about 30,000 g/mol.
  • the device is a flow device.
  • An example of a flow device is shown in Figure 12.
  • Flow devices are known in the literature and are described, for example, in PCT publication WO 96/40857, incorporated by reference herein. Flow devices permit reduction of concentration of low molecular weight compounds from materials such as blood products by perfusing the blood product through the flow device.
  • the adsorption medium of the flow device is preferably about 3 to 30 mm thick to promote an even flow of biological fluid without a substantial pressure drop.
  • the medium is about 3 to 15 mm thick. More preferably, the medium is about 5 to 8 mm thick.
  • the device is a disk configuration flow device.
  • a disk configuration flow device is shown in reference to Figure 14, which is an exploded view of the device embodiment.
  • a biological composition to be treated with the device flows through the tubing connector for housing inlet (1).
  • the biological composition then flows through the IAD (Immobilized Adsorption)
  • the biological composition then may flow through a pre-filter (4), which is optional. It then flows through a membrane (5) that removes particulate matter from the composition. Finally the treated biological composition exits the device through the IAD housing outlet (6).
  • the device is a drip chamber configuration (Porex IAD).
  • a drip chamber configuration flow device is shown in reference to Figure 15, which is an exploded view.
  • the biological composition to be treated with the device flows through the IAD (Immobilized Adsorption Device) housing inlet (60).
  • the biological composition then flows into the IAD housing (drip chamber) (50) and further into the IAD media (40), which reduces the concentration of a low molecular weight compound in the biological composition.
  • the biological composition then may flow through a pre-filter (30), which is optional. It then flows through a membrane (20) that removes particulate matter from the composition.
  • the treated biological composition exits the device through the IAD housing outlet (10).
  • the present invention provides devices for reducing the concentration of compounds in a biological composition.
  • the devices include an adsorption medium and are of a flow configuration.
  • the compounds have a molecular weight ranging from about 100 g/mol to about 30,000 g/mol.
  • the biological activity of the biological composition is substantially maintained after contact with such devices.
  • Biological response modifiers like the anaphalatoxin C3a and the terminal membrane attack complex SC5b-9 have been shown to be produced by the processing, (e.g., leukofiltration, pheresis, recovery of shed blood, etc.) and storage of whole blood and its components. These biological response modifiers have been implicated in adverse events in surgery and transfusion.
  • the device of the present invention reduces the concentration of activated complement in biological compositions.
  • the concentration of activated complement in the composition is reduced when it is treated with the device, as opposed to a composition that has not been treated with the device.
  • exposure to the device results in at least about a 30% reduction in C3a complement fragment and SC5b-9 terminal component over control.
  • exposure to the device results in at least about a 50% reduction in C3a complement fragment and SC5b-9 terminal component over control.
  • exposure to the device results in at least about a 90% reduction in C3a complement fragment over control.
  • the invention provides a device for reducing the concentration of compounds in a biological composition comprising plasma. Treatment of the biological composition comprising plasma with the device substantially maintains the biological activity of the plasma.
  • the adsorption medium comprises adsorbent particles immobilized by an inert matrix. Preferred particles are highly porous and have a surface area greater than about 750 m 2 /g.
  • Norit A Supra which is available from Norit Americas, Inc. (Atlanta, GA).
  • Norit A Supra is a USP-grade activated carbon that is formed by steam activation of coconut shells. This activated carbon has a very high total surface area (2000 m Ig) and is very microporous in nature.
  • the particles may be selected from any of the following particles wherein the particles preferably possess a size range of about 1 ⁇ m to about 200 ⁇ m in diameter, either by grinding direct synthesis, or some other means, and are activated carbons, such as Picactif Medicinal (Pica USA, Columbus, OH), synthetic carbonaceous adsorbents, such as Ambersorb 572
  • Amberlite adsorbents e.g., Amberlite ® XAD-2, XAD-4, and XAD-16
  • Rohm and Haas Philadelphia, PA
  • Amberchrom ® adsorbents available from Toso Haas (TosoHass, Montgomeryville, PA)
  • Diaion®//Sepabeads ® Adsorbents e.g., Diaion ® HP20), available from Mitsubishi Chemical America, Inc. (White
  • Hypersol-Macronet ® Sorbent Resins e.g., Hypersol-Macronet ® Sorbent Resins MN-150 and MN-400
  • Purolite Bala Cynwyd, PA
  • Dowex ® Adsorbents e.g., Dowex ® XUS-40323, XUS-43493, and XUS- 40285), available from Dow Chemical Company (Midland, MI).
  • the inert matrix may be composed of synthetic or natural polymeric fibers or particles. In preferred embodiments the matrix is fibrous cellulose or sintered particles of ultra high molecular weight polyethylene.
  • Exemplary compounds that are reduced or controlled by the devices, materials and methods of the present invention are psoralens, psoralen derivatives, isopsoralens, psoralen photoproducts, methylene blue, phenothiazine, acridine, plastic extractables, biological response modifiers, quenchers and polyamine derivatives.
  • the device maintains adequate levels of clotting activity.
  • Measures of clotting activity include prothrombin time (PT), activated partial thromboplastin time (aPTT), and functional measures of clotting factors I, II, V, VII, VIII, IX, X, XI, and XII.
  • An adequate functional measure of clotting factor activity is greater than about 80% of the level prior to passing through the device, or in the case of clotting times, one that remains in the normal range established for each laboratory that does this type of testing.
  • Preferred measures of clotting activity include PT and aPTT, as they are measures of the overall ability of the plasma to clot, and factors I, II, V, VII, X, XI, and XII, as these factors are not commonly replaced by recombinant proteins. It is preferred to retain more than about 90% of the clotting activity of these factors relative to the level prior to passing through the device and have changes in PT and aPTT of less than about 1.5 seconds.
  • the device may comprise an adsorption medium and a housing.
  • the housing should promote even flow of the plasma to promote good media utilization and as it primes, allow the plasma to push air ahead of it, thereby eliminating bubbles that would reduce the contact area between the plasma and the adsorption media, thereby reducing the media's utilization.
  • the housing can be flat or have substantial depth to accommodate adsorption media or particle retention media that is not flat, for example cylindrically shaped adsorption media.
  • the housing is flat.
  • the housing can have inlets and outlets in various orientations, for example inlet top/outlet top or inlet bottom/outlet bottom. In a preferred embodiment, the outlet is at the bottom to promote good drainage and the inlet is at the top to promote media utilization.
  • the device comprising an adsorption medium and a housing may also include a particle retention medium.
  • the device includes a particle retention medium downstream of the adsorption medium to retain particles that are shed from the adsorption medium while maintaining a high fluid flow rate and high recovery of proteins.
  • the particle retention medium can be a membrane, a dry or wet laid matrix of fibers, a sintered polymer matrix, a woven material, a nonwoven material (polyester nonwoven), or a combination thereof.
  • the device housing holds the particle retention medium in an approximately parallel orientation downstream of the adsorption medium.
  • U.S. Patent No. 5,660,731 which is herein incorporated by reference, discloses examples of filter housings.
  • the housing can be constructed from any suitably rigid, impervious, material that does not substantially adversely affect the biological activity of a fluid.
  • the housing is constructed from a synthetic polymer.
  • Nonlimiting examples of such polymers include polyacrylic, polyethylene, polypropylene, polystyrene and polycarbonate plastics.
  • the adsorption medium of the device containing particles immobilized by an inert matrix should be between 3 and 30 mm thick to promote an even flow of biological fluid without a substantial pressure drop.
  • the medium should be between 3 and 15 mm thick. More preferably, the medium should be between 5 and 8 mm thick.
  • the device is a gravity flow device that is constructed to permit flow rates of 0.1 - 10 mL/cm 2 /min with differential pressures of 12-72 inches water. More preferably the device permits flowrates of 0.2-5 mL/cm 2 /min with differential pressures of 24-48 inches of water.
  • the present invention contemplates reducing the concentration of low molecular weight compounds in biological compositions.
  • the compounds have a molecular weight ranging from about 100 g/mol to about 30,000 g/mol.
  • Such compounds include, for example, pathogen-inactivating agents such as photoactivation products, aminoacridines, organic dyes and phenothiazines.
  • pathogen inactivating agents include furocoumarins, such as psoralens and acridines.
  • the concentration of pathogen inactivating compounds in the blood product can be reduced by contacting the treated blood product with a device of the invention.
  • the present invention contemplates a method of inactivating pathogens in solution, wherein the method comprises: a) providing, in any order: i) a cyclic compound, ii) a solution suspected of being contaminated with said pathogens, and iii) fiberized resin; b) treating said solution with said cyclic compound so as to create a treated solution product wherein said pathogens are inactivated; and c) contacting said treated solution product with said fiberized resin, and further comprising a device for reducing the concentration of small organic compounds in a blood product while substantially maintaining a desired biological activity of the blood product, the device comprising highly porous adsorbent particles, wherein the adsorbent particles are immobilized by an inert matrix.
  • reactive degradation products thereof can be reduced from the material such as a blood product, for example prior to transfusion.
  • a device of the present invention reduces the concentration of low molecular weight compounds in a biological composition.
  • low molecular weight compound refers to an organic or biological molecule having a molecular weight ranging from about 100 g/mol to about 30,000 g/mol.
  • Low molecular weight compounds include, without limitation, the following compounds: small organic compounds such as psoralens, acridines or dyes; quenchers, such as glutathione; plastic extractables, such as plasticizers; biological modifiers, such as activated complement, that possess a molecular weight between about 100 g/mol and about 30,000 g/mol; and, polyamine derivatives.
  • Small Organic Compounds A diverse set of small organic compounds can be adsorbed by the device of the present invention.
  • the molecules can be cyclic or acyclic.
  • the compounds are preferably, cyclic compounds such as psoralens, acridines or dyes.
  • the compounds are thiols.
  • Nonlimiting examples of cyclic compounds include actinomycins, anthracyclinones, mitomyacin, anthramycin, and organic dyes and photoreactive compounds such as benzodipyrones, fluorenes, fluorenones, furocoumarins, porphyrins, protoporphyrins, purpurins, phthalocyanines, hypericin, Monostral Fast Blue, Norphillin A, phenanthridines, phenazathionium salts, phenazines, phenothiazines, phenylazides, quinolines and thiaxanthenones.
  • the compounds are furocoumarins or organic dyes. More preferably the compounds are furocoumarins.
  • Nonlimiting examples of furocoumarins include psoralens and psoralen derivatives. Specifically contemplated are 4'-aminomethyl-4,5',8- trimethylpsoralen, 8-methoxypsoralen, halogenated psoralens, isopsoralens and psoralens linked to quaternary amines, sugars, or other nucleic acid binding groups.
  • psoralens 5'-bromomethyl-4,4',8- trimethylpsoralen, 4' -bromomethy 1-4,5 ' ,8-trimethylpsoralen, 4' -(4-amino-2- aza)butyl-4,5 ',8-trimethylpsoralen, 4' -(4-amino-2-oxa)butyl-4,5 ' ,8- trimethylpsoralen, 4' -(2-aminoethyl)-4,5 ',8-trimethylpsoralen, 4'-(5-amino-2- oxa)pentyl-4,5 ',8-trimethylpsoralen, 4'-(5-amino-2-aza)pentyl-4,5',8- trimethylpsoralen, 4'-(6-amino-2-aza)hexyl-4,5',8-trimethylpsoralen, 4'-(7- amino-2
  • Nonlimiting examples of acridines include acridine orange, acriflavine, quinacrine, Nl, Nl-bis (2 -hydroxy ethyl)-N4-(6-chloro-2-methoxy-9-acridinyl)- 1 ,4-pentanediamine, 9-(3-hydroxypropyl)aminoacridine, N-(9-acridinyl)glycine, S-(9-acridinyl)-glutathione.
  • the acridine is N-(9- acridinyl)- ⁇ -alanine, alternatively, named 5-[( ⁇ -carboxyethyl)amino]acridine.
  • Nonlimiting examples of dyes include phenothiazines such as methylene blue, neutral red, toluidine blue, crystal violet and azure A, phenothiazones such as methylene violet Bernthsen, phthalocyanines such as aluminum 1,8,15,22- tetraphenoxy-29H,31H-phthalocyanine chloride and silica analogues, and hypericin.
  • the dye is methylene blue or toluidine blue. More preferably, the dye is methylene blue.
  • thiazine dyes includes dyes that contain a sulfur atom in one or more rings.
  • the most common thiazine dye is methylene blue [3,7-
  • thiazine dyes include, but are not limited to, azure A, azure C and thionine, as described e.g. in U.S. Patent No. 5,571,666 to Schinazi.
  • xanthene dyes refers to dyes that are derivatives of the compound xanthene.
  • the xanthene dyes may be placed into one of three major categories: i) fluorenes or amino xanthenes, ii) the rhodols or aminohydroxyxanthenes, and iii) the fluorones or hydroxyxantheses.
  • Examples of xanthene dyes contemplated for use with the present invention include rose bengal and eosin Y; these dyes may be commercially obtained from a number of sources (e.g., Sigma Chemical Co., St. Louis, MI), and as described e.g. in U.S. Patent No. 5,571,666 to Schinazi, hereby incorporated by reference.
  • the concentration of a variety of compounds may be reduced.
  • Other exemplary compounds include quenching compounds. Methods for quenching undesired side reactions of pathogen inactivating compounds that include a functional group which is, or which is capable of forming, an electrophilic group, are described in the co-filed U.S. Patent Application, "Methods for Quenching Pathogen Inactivators in Biological Systems", Docket Number 282173000600, filed January 6, 1998, the disclosure of which is incorporated herein.
  • a material such as a blood product, is treated with the pathogen inactivating compound and a quencher, wherein the quencher comprises a nucleophilic functional group that is capable of covalently reacting with the electrophilic group.
  • the pathogen inactivating compound includes a nucleic acid binding ligand and a functional group, such as a mustard group, which is capable of reacting in situ to form the electrophilic group.
  • quenchers include, but are not limited to, compounds including nucleophilic groups. Exemplary nucleophilic groups include thiol, thioacid, dithoic acid, thiocarbamate, dithiocarbamate, amine, phosphate, and thiophosphate groups.
  • the quencher may be, or contain, a nitrogen heterocycle such as pyridine.
  • the quencher can be a phosphate containing compound such as glucose-6-phosphate.
  • the quencher also can be a thiol containing compound, including, but not limited to, glutathione, cysteine, N-acetylcysteine, mercaptoethanol, dimercaprol, mercaptan, mercaptoethanesulfonic acid and salts thereof, e.g., MESNA, homocysteine, aminoethane thiol, dimethylaminoethane thiol, dithiothreitol, and other thiol containing compounds.
  • glutathione glutathione, cysteine, N-acetylcysteine, mercaptoethanol, dimercaprol, mercaptan, mercaptoethanesulfonic acid and salts thereof, e.g., MESNA, homocysteine, aminoethane thiol, dimethylaminoethane thiol, dithiothreitol, and other thiol containing compounds.
  • Exemplary aromatic thiol compounds include 2-mercaptobenzimidazolesulfonic acid, 2-mercapto- nicotinic acid, napthalenethiol, quinoline thiol, 4-nitro-thiophenol, and thiophenol.
  • quenchers include nitrobenzylpyridine and inorganic nucleophiles such as selenide salts or organoselenides, thiosulfate, sulfite, sulfide, thiophosphate, pyrophosphate, hydrosulfide, and dithionitrite.
  • the quencher can be a peptide compound containing a nucleophilic group.
  • the quencher may be a cysteine containing compound, for example, a dipeptide, such as GlyCys, or a tripeptide, such as glutathione.
  • Compounds that may be removed by the device of the present invention may include thiols such as methyl thioglycolate, thiolactic acid, thiophenol, 2- mercaptopyridine, 3-mercapto-2-butanol, 2-mercaptobenzothiazole, thiosalicylic acid and thioctic acid.
  • thiols such as methyl thioglycolate, thiolactic acid, thiophenol, 2- mercaptopyridine, 3-mercapto-2-butanol, 2-mercaptobenzothiazole, thiosalicylic acid and thioctic acid.
  • the concentration of a group of low molecular weight compounds that are extractables from plastic storage containers and tubing used to handle biological compositions may also be reduced in a biological composition using a device of the present invention.
  • extractables include, but are not limited to, plasticizers, residual monomer, low molecular weight oligomers, antioxidants and lubricants. See, e.g., R. Carmen, Transfusion Medicine Reviews 7(1):1-10 (1993).
  • the sterilization of plastic components by steam, gamma irradiation or electron beam can produce oxidative reactions and/or polymer scission, resulting in the formation of additional extractable species.
  • Plasticizers are commonly used to enhance properties of plastics such as processability and gas permeability.
  • the most common plasticizer found in blood storage containers is di(2-ethylhexyl) phthalate (DEHP), which is used in PVC formulations.
  • DEHP has been identified as a potential carcinogen.
  • Alternative plasticizers have been developed, including, without limitation, the following compounds: tri (2-ethylhexyl) trimellitate (TEHTM), acetyl-tri-n-hexyl citrate (ATHC), butyryl-tri-n-hexyl-citrate (BTHC), and di-n-decyl phthalate.
  • a device of the present invention may be used to reduce or control the concentration of plastic extractables in a biological composition in a variety of settings.
  • Such settings include, but are not limited to, the following: blood treatment; blood storage; and, extracorporeal applications such as hemodialysis and extracorporeal membrane oxygenation.
  • BRMs Biological Response Modifiers
  • BRMs biological response modifiers
  • BRMs include, without limitation, the following types of compounds: small molecules such as histamine and serotonin; lipids such as thromboxanes, prostaglandins, leukotrienes and arachidonic acid; small peptides such as bradykinin; larger polypeptides that contain further groups, including activated complement fragments (C3a, C5a); cytokines such as IL-1, IL-6 and IL-8; and chemokines such as RANTES and MIP.
  • C3a, C5a activated complement fragments
  • cytokines such as IL-1, IL-6 and IL-8
  • chemokines such as RANTES and MIP.
  • the accumulation of BRMs in a blood product during storage can adversely affect the desired biological activity of a biological composition. Complement activation, for example, has been demonstrated to occur during storage of platelets under standard blood bank conditions. Complement activation has been associated with a loss of platelet function and viability termed "platelet storage le
  • BRMs in a stored blood products can also, for example, adversely affect a patient that receives the blood product: the accumulation of BRMs in platelet concentrates during storage has been associated with non-hemolytic febrile transfusion reactions in patients receiving platelets. See, e.g. , N.M. Heddle, Current Opinions in Hematology 2(6):478-483 (1995).
  • Polyamine Derivatives The concentration of a group of low molecular weight compounds known as polyamine derivatives may also, for example, be reduced in a biological composition using a device of the present invention.
  • Polyamine derivatives are compounds that contain multiple nitrogen atoms in a carbon backbone.
  • Polyethylene Glycols are compounds that contain multiple nitrogen atoms in a carbon backbone.
  • exemplary compounds include activated polyethylene glycols (aPEG), which may be used for the modification of the surface of cells or materials in order to provide immunomasking properties or pacification toward protein binding, respectively.
  • the device may be used for the reduction of either the excess activated polyethylene glycol or the unreactive derivative of the PEG resulting from the reaction of the activated PEG with water or small nucleophiles such as phosphate, phosphate esters or thiols, such as glutathione.
  • Other compounds that may be removed include impurities in the activated PEG preparation, which may affect the function of the blood products or make them unsuitable for transfusion (eg. toxic compounds).
  • Examples of compounds that may be removed by the device of the present invention include linear or branched polyethylene glycols attached to activating moeities which may include cyanuryl chloride, succinimidyl esters, oxycarbonyl imidazole derivatives, nitrophenyl carbonate derivatives, glycidyl ether derivatives, and aldehydes.
  • NIS Nicolet, a Thermo Spectra Co., San Diego, CA); Poretics (Livermore, CA); Purolite (Bala Cynwyd, PA); Quidel (San Diego, CA); Rohm and Haas (Chauny, France); 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, Inc. (Depew, NY);
  • TosoHaas TosoHas (TosoHass, Montgomeryville, PA); Wallac (Wallac Inc., Gaithersburg, MD); West Vaco (Luke, W.Va.); YMC (YMC Inc., Wilmington, NC); DVB (divinyl benzene); LAL (Limulus Amoebocyte Lystate); USP (United States Pharmacopeia); EAA (ethyl-acetoacetate); EtOH (ethanol); HOAc (acetic acid); W (watts); mW (milliwatts); NMR (Nuclear Magnetic Resonance; spectra obtained at room temperature on a Varian Gemini 200 MHz Fourier Transform Spectrometer); f Vmin (cubic feet per minute); m.p.
  • HEPES buffer contains 8.0 g of 137 mM NaCl, 0.2 g of 2.7 mM KCI, 0.203 g of 1 mM MgCl 2 (6H 2 0), 1.0 g of 5.6 mM glucose, 1.0 g of 1 mg/ml Bovine Serum Albumin (BSA) (available from Sigma, St. Louis, MO), and 4.8 g of 20 mM HEPES (available from Sigma, St. Louis, MO).
  • BSA Bovine Serum Albumin
  • Immobilized adsorbent media containing Amberlite ® XAD-16 in a cleaned and hydrated state was obtained from AQF.
  • the fibers of Hoechst Celanese's fiber network consisted of a polyethylene terephthalate core and a nylon sheath, the sheath having a lower melting temperature than the core.
  • the fiberized resin was prepared by first evenly distributing the adsorbent beads in the fiber network. Next, the fiber network was rapidly heated causing the polymer sheath of the fibers to melt and bond to the adsorbent beads and other fibers, forming a cross-linked fiber network.
  • the fiberized resin formed contained the Amberlite ® XAD-16 at a loading of 130 g/m 2 (i.e., each square meter of fiber contained 130 g of adsorbent beads).
  • the fiberized resin was cut into squares (14 cm x 14 cm), and the resulting sections contained approximately 2.5 g of dry Amberlite ® XAD-16.
  • the Amberlite ® XAD-16 beads were then pre- wet by soaking the fiberized resin in 30% ethanol for approximately 10 minutes. The residual ethanol was then removed by rinsing twice in saline for 10 minutes.
  • Alternative methods of wetting the Amberlite ® XAD-16 and other adsorbents are also effective and are contemplated by the present invention.
  • fiberized resin containing other types of beads do not require a wetting step for effective psoralen removal.
  • the Dowex ® XUS-43493 beads were obtained from Dow, and the dry beads did not require wetting nor did the mass of the beads require correction for water.
  • Polyester mesh pouches (7 cm x 7 cm square; 30 ⁇ m openings) were then filled with 2.5 g (dry weight) of either the loose Amberlite ® XAD-16 HP or Dowex ® XUS-43493 beads.
  • the fiberized resin and adsorbent-containing pouches were sterilized by autoclaving on "wet" cycle for 45 minutes at 121 °C. Thereafter, the fiberized resin and the adsorbent-containing pouches were inserted into separate, sterile, 1 - liter PL 2410 Plastic containers (Baxter). Following insertion, the PL 2410 Plastic containers were heat sealed in a laminar flow hood, using sterile scissors, hemostats, and an impulse sealer.
  • pHEMA-Coated Adsorbent Beads And Fiberized Resin Dowex ® XUS-43493 (commercially known as Optipore ® L493) containing approximately 50% water by weight was obtained from Dow, and polymerized HEMA with a viscosity average molecular weight of 300 kD was obtained from Scientific Polymer Products. Prior to coating, the adsorbent beads were dried to a water content of ⁇ 5%. A stock solution of pHEMA was prepared by dissolving the polymer in 95% denatured ethanol/5% water to achieve a pHEMA concentration of 50 mg/ml.
  • the coating process was performed by International Processing Corp. in a 9-inch Wurster fluidized bed coater with a charge of approximately 4 kg (dry) of adsorbent.
  • the coating process involved a pHEMA flow rate of 60-70 g/min, an inlet temperature of 50°C, and an air flow rate of approximately 200 ft 3 /min.
  • Samples (50 g) of coated adsorbent were removed during the coating process so that coating levels ranging from 3-18% (w/w) pHEMA were obtained; adsorbent beads coated with 3.7%, 7.3%, and 10.9% pHEMA (w/w) were used in the studies described below.
  • a device containing non-immobilized dry (uncoated) Dowex ® XUS-43493 (2.5 g) and pHEMA-coated Dowex ® XUS-43493 (3.0 g or 5.0 g) were prepared by placing the desired mass of adsorbent into a square 30 ⁇ m polyester mesh pouch (7 cm x 7 cm). The adsorbent-filled pouches were inserted into separate sterile, 1 -liter PL 2410 Plastic containers (Baxter) and heat sealed with an impulse sealer. Thereafter, the adsorbent-filled pouches containing PL-2410 Plastic containers were sterilized by either E-beam (NIS) or gamma irradiation
  • EXAMPLE 3 Effect Of Glycerol And Polyethylene Glycol On Adsorbent Capacity This example examines the effect of glycerol and polyethylene glycol as stabilizing agents on adsorbent capacity and kinetics of removal of aminopsoralens from plasma. Free (i. e., not fiberized) Amberlite ® XAD-16 and
  • Plasma 6.0 mL was added to vials containing adsorbent treated with different stabilizing agents. Masses of adsorbent were corrected for glycerol or PEG content to give 0.2 g of adsorbent. The vials were placed on a rotator and agitated at room temperature.
  • Plasma samples were removed at various times and levels of residual 3 H-4'-(4- amino-2-oxa)butyl-4,5',8-trimethyl psoralen were determined.
  • Samples 200 ⁇ L were diluted in 5.0 mL of Optiphase HiSafe Liquid Scintillation Cocktail (Wallac) and were counted on a Wallac 1409 Liquid Scintillation Counter (Wallac).
  • Wallac Optiphase HiSafe Liquid Scintillation Cocktail
  • FIG. 7 compares the effect of pre-treatment with ethanol solutions containing various levels of glycerol on relative 4' -(4-amino-2-oxa)butyl-4,5 ' ,8- trimethyl psoralen adsorption capacity in 100% plasma for Amberlite ® XAD-16 and Dowex ® XUS-43493.
  • Adsorbent samples were wet in the ethanol/glycerol solutions for 15 minutes prior to drying for 48 hours at 80°C. Single measurements of adsorption capacity were made after 4 hours of contact.
  • glycerol content shown on the x-axis is weight/volume percent of glycerol in ethanol.
  • Adsorption capacities shown on the y-axis are percentages relative to the adsorption capacity of the optimally wet adsorbent sample.
  • the adsorption capacity of XUS-43493 is represented by the squares, while that of XAD-16 is represented by the circles.
  • the capacity of XAD-16 increased from about 30% in the dry sample to over 90% in the sample wet in a 20% glycerol solution.
  • FIG. 8 compares the effect of the stabilizing agents on 4' -(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen adso ⁇ tion capacities with dried adsorbent in 100% plasma for Amberlite ® XAD-16 (bottom) and Dowex ® XUS-43493 (top); the samples that were not wet are labeled "No Tx".
  • Adsorbent capacities are reported as percentages relative to the capacity of optimally wet adsorbent. As indicated by the data in FIG. 8 and predictable based on the its
  • FIG. 9 compares adso ⁇ tion of 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen over a 3 -hour period from 100% plasma using Amberlite ® XAD-16 wet in several different solutions. Specifically, the data in FIG.
  • stabilizing agents in the form of solutions containing 50% ethanol and 50% glycerol, PEG-200, or PEG-400 can prevent loss of adso ⁇ tion capacity associated with drying.
  • the results obtained with these stabilizing agents suggest that low molecular weight wetting agents represent viable methods for enhancing adsorbent function.
  • EXAMPLE 4 Removal Of Methylene Blue From FFP This example is directed at the ability of a variety of different polymeric adsorbent materials to remove methylene blue from fresh frozen plasma.
  • the experiments of this example evaluated "free" adsorbent resin (i.e., not inco ⁇ orated into device containing non-immobilized adsorbents) and fiberized resin.
  • the free adsorbent resins tested were Amberlite XAD-16 HP (Rohm and Haas), MN-200 (Purolite), and Dowex ® XUS-43493 (Dow Chemical Co.).
  • the XAD-16 HP came in a hydrated state so that no pre-treatment (i.e., no wetting) was necessary, and the MN-200 was also supplied in a fully hydrated state; the XUS-43493 was dry.
  • Fiberized resin containing XAD-16 was prepared as generally described in Example 1. Briefly, a 2 cm x 7 cm (i.e., 14 cm ) strip of fiberized resin containing 130 g/m 2 XAD-16 was first wet in 70% ethanol and then rinsed exhaustively in distilled water. A stock solution of methylene blue (10 mM) was prepared by dissolving
  • FIG. 10 compares the kinetics of adso ⁇ tion of methylene blue over a 2- hour period from 100% plasma.
  • XAD-16 HP data is represented by open diamonds connected by dashed lines
  • MN-200 data is represented by shaded triangles connected by solid lines
  • XUS-43493 data is represented by open circles connected by dashed lines
  • the fiberized resin containing XAD-16 is represented by shaded squares connected by solid lines.
  • the XAD-16 HP and MN-200 gave the fastest adso ⁇ tion kinetics, followed by XUS-43493.
  • the slightly slower kinetics of the XUS-43493 may be a result of slower wetting, as it was used in the dry state.
  • the fiberized resin containing XAD-16 had the slowest adso ⁇ tion kinetics.
  • non-psoralen pathogen-inactivating compounds like the phenothiazine dyes can be removed from blood products using the resins and fiberized resin contemplated for use with the present invention.
  • EXAMPLE 5 This example compares the use of different types of powdered carbon as the active component in the media and demonstrates how careful choice of the active constituent is necessary to reduce the concentration of a small organic compound and preserve the fluid's biological function.
  • the five activated carbons illustrated in Example 5 reduce the concentration of the psoralen, 4'-(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen, in plasma by approximately the same amount.
  • a Supra is used as the adsorbent particle, however, there is substantially better retention of clotting factors relative to the other adsorbents.
  • 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen was added to plasma at a concentration of 150 ⁇ M, and the plasma was illuminated in 325 mL batches with 3.0 J/cm2 UVA to inactivate pathogens.
  • the residual 4'-(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen concentration was approximately 90 ⁇ M in the resulting plasma pool.
  • 325 mL of illuminated plasma was pumped at 20 mL/min through 5 different types of 90 mm Cuno ZetaPlus carbon pads. Plasma clotting factor levels, clotting times, and 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen concentration were assayed before and after flow through the carbon pads.
  • the water flow rate for R10S media is 2 gallons water/min/square foot with a differential pressure of 1.5 p.s.i. This example shows that the choice of activated carbon used can have a strong effect on the IAD's impact on biological activity.
  • the A Supra grade was prepared to the same specifications as the RlxS series; only the carbon was changed.
  • An increase in aPTT indicates removal of clotting factors.
  • I, VIII, and IX refer to particular clotting factors. All values are relative to post-photochemical treatment. 4'-(4-amino-2-oxa)butyl- 4,5',8-trimethyl psoralen was assayed by HPLC and clotting factors and times were assayed by an automated coagulation analyzer.
  • Dowex Optipore L493 was ground with a Estro Model 480 grinder and sieved with approximately 100 ⁇ m and 50 ⁇ m sieves to generate two classes of particles, those between 50 ⁇ m and 100 ⁇ m and those less than 50 ⁇ m.
  • ZetaPlus-like filters were prepared containing either of these two classes of particles according to Cuno RlxS specifications. Photochemically treated plasma (325 mL) was pumped through each pad at 20 mL/min. 4'-(4-amino-2-oxa)butyl-4,5',8-trimethylpsoralen and clotting factors were analyzed as in Example 5.
  • the smaller particle size resulted in substantially better removal but had a larger impact or biological activity, as measured by clotting activity. This illustrates the trade-off that is often seen with selecting a particle size for the adsorbent particle.
  • EXAMPLE 7 Effect of Adsorbent Loading on Low Molecular Weight Compound Removal and Biological Activity. This example compares the effect of changing the mass fraction of the active component on reducing the concentration of a small organic compound and the tradeoff with the fluid's biological function.
  • Photochemically treated plasma was similarly prepared as in Example 5.
  • One 90 mm R14S pad was flushed overnight with a 50 mg/mL solution of polyhydroxyethymethacrylate (pHEMA) in 95% ethanol dried in a 70°C oven until there was no additional weight change.
  • the second pad was similarly flushed with 95% ethanol without pHEMA and dried.
  • Approximately 325 mL plasma was pumped through the discs at 5 mL/min. 4'-(4-amino-2-oxa)butyl- 4,5',8-trimethyl psoralen and clotting factors were analyzed as in Example 5.
  • Photochemically treated plasma was similarly prepared as in Example 5.
  • a Supra pads were prepared with the standard RlxS loading of approximately 60% carbon and 325 mL of the treated plasma was pumped through each of the 47 mm diameter discs at three different flowrates.
  • 4'-(4-amino-2-oxa)butyl-4,5',8- trimethyl psoralen and clotting factors were analyzed as in Example 5.
  • Fluid volume can also have an important effect on conferring selectivity for low molecular weight compounds over mediators of biological activit
  • Photochemically treated plasma was similarly prepared as in Example 5.
  • ZetaPlus-like filters were prepared with ground Dowex Optipore L493 with particles less than 50 ⁇ m instead of powdered activated carbon according to the Cuno RlxS specifications.
  • Plasma was pumped through the filter at 20 mL/min and samples were taken at 180 mL and 325 mL.
  • 4'-(4-amino-2-oxa)butyl-4,5',8- trimethyl psoralen and clotting factors were analyzed as in Example 5.
  • EXAMPLE 11 Use of Sintered Media.
  • Ninety millimeter diameter by 1/4" thick discs were fabricated by Porex.
  • the discs contained various weight fractions of finely ground Dowex Optipore L493 with particle sizes between 20 ⁇ m and 100 ⁇ m, and small particles of ultra high molecular weight polyethylene (grade UF220), which were then sintered together.
  • Photochemically treated plasma was similarly prepared as in Example 5 and 200 mL of plasma was pumped through each disc at 16-18 mL/min. 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen and clotting factors were analyzed as in Example 5.
  • This example describes the effect of increasing the mass of adsorbent by increasing the diameter of the filter at constant thickness.
  • Photochemically treated plasma was similarly prepared as in Example 5. Approximately 325 mL of treated plasma was pumped through 90 and 47 mm diameter R03S grade discs at 5 mL/minute. 4'-(4-amino-2-oxa)butyl-4,5',8- trimethyl psoralen and clotting factors were analyzed as in Example 5.
  • the media were sealed into a 90 mm diameter polycarbonate housing (Cuno, Meridien, CT).
  • the dosed PRBCs were pumped (Gilson Minipuls, Middleton, WI) through the media at a flow rate of 5 mL/min, and collected in a PL 146 plastic container (Baxter Healthcare). The results of this study are shown in Table 1.
  • EXAMPLE 14 Flow Compound Adsorption Devices (CUNO media) vs. Batch Compound Adsorption Devices (AQF media). Studies were performed which compared 5- [( ⁇ -carboxyethyl)amino]acridine and GSH removal in flow versus batch compound adso ⁇ tion devices.
  • the flow device consisted of a cellulose/Norit A Supra (Norit Americas, Inc. (Atlanta, GA)) carbon disk enclosed in a 90 mm housing. There were two separate batch devices: one consisted of fiberized Pica G277 activated carbon (AQF 500 g/m 2 ); the other consisted of fiberized Purolite MN-200 (AQF 312 g/m 2 ).
  • PRBCs were then transferred to the 6 g MN-200 batch device, which decreased 5- [( ⁇ -carboxyethyl)-amino]acridine and GSH levels by an additional 5 and 1%, reaching 20 ⁇ m and 0.67 mM over 24 hours.
  • Exposure of PRBCs to a 7 g Pica G277 batch device alone resulted in a drop in 5 -[( ⁇ -carboxyethyl)-amino] acridine and GSH levels by 92 and 54% to concentrations of 8 ⁇ M and 3 mM. Therefore, one pass through the flow device was more effective in removing GSH than exposure to the carbon batch device for 24 hours.
  • the batch device alone was more effective in removing 5-[( ⁇ -carboxyethyl)-amino]acridine than the flow and MN-200 devices combined.
  • Flow through the device did not seem to have an adverse effect on PRBC ATP concentration.
  • K+ levels in PRBCs were lower after exposure to the flow device as compared to a 24 hour carbon batch device exposure.
  • This example describes the typical performance of an immobilized adsorbent device in a flow mode on plasma using adsorbent media composed of 30% Norit A Supra carbon (Norit Americas, Atlanta, GA) and manufactured by Cuno (Meriden, CT) previously described in an earlier example.
  • IADs were assembled using 90 mm Cuno 30% Norit A Supra impregnated R10SP media in series with 90 mm diameter Memtec hydroxypropylcellulose coated polysulfone membrane with 5 ⁇ m pores.
  • tubing 1/8" OD tubing and the tubing was then attached to the outlet of the IAD such that the distance from the midline of the IAD to the bag was 40cm.
  • the same sized tubing was attached to the inlet of the SRD such that when the illumination bag is docked to it, the distance from the midline to the bag would be 30 cm.
  • 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen was added to 500 mL of plasma to a final concentration of approximately 150 ⁇ M, and the plasma was illuminated to 6.3 J/cm2 UVA to inactivate pathogens.
  • the post-illumination 4'- (4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen concentration was approximately 82 ⁇ M.
  • Table 2 shows measures of clotting factor activity and 4'-(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen levels after having been treated by the IAD relative to values beforebeing passed through the IAD. The experiment was repeated three times. Means and standard deviations are reported. Treatment time averaged 14 minutes. It is apparent that there is virtually no change in factors I, II, V, VII, X or measures of aggregate clotting activity, the prothrombin time (PT) and activated partial thromboplastin time (aPTT) and very small changes in factors XI and XII. Factors VIII and IX show somewhat larger changes but these are acceptable, especially in light of the prescription of recombinant proteins for their deficiency.
  • PT prothrombin time
  • aPTT activated partial thromboplastin time
  • the very selective nature of the device should be noted in that it retains virtually all the clotting activity while allowing only 0.9% of the 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen to pass through.
  • EXAMPLE 16 Reduction of Activated Complement by Adsorbent Medias. This study demonstrates the removal of biological response modifiers by cellulose media impregnated with activated carbon and porous plastic media impregnated with ground polystyrene/divinylbenzene adsorbent.
  • Zymosan (Sigma Chemical Company; St. Louis, MO), a potent activator of the complement cascade, was added to plasma at a concentration of 10 mg/mL.
  • the plasma was incubated with mild shaking at 37 °C for 1 hour.
  • the plasma was then centrifuged and the supernatant saved to get rid of the solid zymosan.
  • Approximately 20 mL of this supernatant was added to each of two 600 mL units of plasma and a sample from each unit was taken for C3a and SC5b-9 analysis.
  • One of these units was pumped at 40 mL/min through a 90 mm disc of carbon impregnated cellulose media (Cat. #2640ASP, Cellulo, Inc.; Fresno, CA).
  • the other unit was pumped at the same rate through sintered media prepared as in Example 11 (Porex Technologies; Fairburn, GA).
  • the filtrate from each unit was sampled for C3a and SC5b-9 analysis.
  • Biological response modifiers can also be removed from biological compositions, as the previous table indicates.
  • Photochemically treated plasma was similarly prepared as in Example 5. Approximately 175 mL of the treated plasma was pumped through each of the medias at about 11 mL/min. S-59 and clotting factors were analyzed as in Example 5.
  • Kynol American Kynol, Inc.; Pleasantville, NY
  • Kuractive Kerray Chemical Co.; Bizen City, Japan
  • Actitex Pica USA; Columbus, OH
  • Photochemically treated plasma was prepared by adding a solution of S-59 to each of three approximately 600 mL units of plasma for an S-59 concentration of about 150 ⁇ M, and illuminating each unit with 6.3 J/cm2 UVA as previously described.
  • the treated units were pooled and approximately 600 mL of the pool was pumped through each of the discs at about 40 mL/min.
  • S-59 and clotting factors were analyzed as in Example 5. Surface area was analyzed by equilibrated-step mercury intrusion porosimetry (Micromeritics, Norcross, GA).
  • This example demonstrates the utility of using IADs for removing low molecular weight compounds such as viral inactivating agents (psoralen) or biological response modifiers (activated complement-C3a) from whole blood.
  • low molecular weight compounds such as viral inactivating agents (psoralen) or biological response modifiers (activated complement-C3a) from whole blood.
  • Two units of ABO-matched whole blood were obtained from the Sacramento Blood Center (Sacramento, CA). The units were maintained at room temperature following donation. The two units were transferred to two PL2410 plastic storage containers (Baxter Healthcare, Deerfield, IL) containing 4 pieces of Millipore RA type membrane (47 mm, Millipore, Marlborough, MA). The whole blood was incubated for 24 hours at room temperature with the cellulose acetate membranes (Millipore RA) to induce complement activation. Psoralen (150 ⁇ M S-59 (4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen)) was added to each whole blood unit immediately before hemoperfusion was initiated.
  • Psoralen 150 ⁇ M S-59 (4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen
  • the IAD media (300 g/m 2 MN-200, AQF) was cut into circular disks with a diameter of 47 mm. Disks were sealed in a 47 mm diameter polycarbonate housing with a stainless steel support screen (Cuno Inc., Meridien, CT). Tubing (3 mm ID PharMed tubing) was attached to the housing. The tubing was loaded in a peristaltic pump (Masterflex) and the system was calibrated to deliver a flow rate of 75 mL/min. The tubing inlet and outlet were attached to a 600 mL beaker (Nalgene) which was placed on a stir plate (see Figure 13). The whole blood which was contained in the 500 mL beaker was gently agitated with a Teflon- coated stir bar throughout the study to simulate the mixing that would occur in the subject's body.
  • the entire assembly was rinsed with a solution containing 174 USP units heparin (sodium salt, grade 1-A, 174 USP units/mg, Sigma Chemical Co.) per mL of saline.
  • heparin sodium salt, grade 1-A, 174 USP units/mg, Sigma Chemical Co.
  • the saline was purged from the IAD assembly before introducing the whole blood.
  • the unit of whole blood 500 mL was added to the beaker.
  • WBC red blood cell
  • RBC red blood cell
  • the advantages of using immobilized adsorbents in hemoperfusion devices include: 1) the ability to independently control adsorbent particle size and pressure drop-especially important at high flow rates or for small particle adsorbents; 2) the ability to control particle attrition by immobilizing the adsorbent particles thereby minimizing physical interactions; 3) the ability to minimize small particle contamination and shedding from the device by immobilizing adsorbent particles; 4) the ability to maintain a uniform and stable adsorbent bed.

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Abstract

L'invention concerne des procédés et des dispositifs permettant de réduire la concentration de composés à faible masse moléculaire dans une composition biologique, tout en maintenant sensiblement une activité biologique désirée de la composition biologique. Le dispositif comprend des particules adsorbantes très poreuses, lesquelles sont immobilisées par une matrice inerte.
PCT/US1998/014211 1998-01-06 1998-07-08 Dispositifs d'ecoulement permettant de reduire la concentration de composes dans des compositions biologiques et procedes associes WO1999034915A1 (fr)

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CA002317430A CA2317430A1 (fr) 1998-01-06 1998-07-08 Dispositifs d'ecoulement permettant de reduire la concentration de composes dans des compositions biologiques et procedes associes
JP2000527350A JP2003527230A (ja) 1998-01-06 1998-07-08 生物学的組成物からの化合物の減少のためのフローデバイスおよびその使用方法
EP98933275A EP1051249A1 (fr) 1998-01-06 1998-07-08 Dispositifs d'ecoulement permettant de reduire la concentration de composes dans des compositions biologiques et procedes associes
AU82956/98A AU759541B2 (en) 1998-01-06 1998-07-08 Flow devices for the reduction of compounds from biological compositions and methods of use

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PCT/US1998/000531 WO1998030327A1 (fr) 1997-01-06 1998-01-06 Procedes et dispositifs permettant de reduire de petits composes organiques presents dans des produits sanguins

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* Cited by examiner, † Cited by third party
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US9259525B2 (en) 1998-01-06 2016-02-16 Cerus Corporation Adsorbing pathogen-inactivating compounds with porous particles immobilized in a matrix
WO2016070957A1 (fr) * 2014-11-06 2016-05-12 Merck Patent Gmbh Charbon actif pour l'élimination de substances lixiviables et/ou extractibles
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US9717755B2 (en) 2010-04-01 2017-08-01 Cytosorbents Corporation Method of treating inflammation
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2721511A1 (de) * 1976-05-12 1977-11-24 Honshu Paper Co Ltd Adsorbierender, nichtgewebter stoff und verfahren zu dessen herstellung
WO1983000023A1 (fr) * 1981-06-24 1983-01-06 Amf Inc Procede de preparation d'un serum a standard zero
EP0230247A2 (fr) * 1986-01-14 1987-07-29 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Adsorbant pour enlever un composant complément
US5147722A (en) * 1989-02-23 1992-09-15 Koslow Technologies Corporation Process for the production of materials and materials produced by the process
WO1996039818A1 (fr) * 1995-06-07 1996-12-19 Cerus Corporation Traitement de solutions de globules rouges par des agents antiviraux
WO1997037536A1 (fr) * 1996-04-09 1997-10-16 Therakos, Inc. Procede d'elimination de psoralenes dans des fluides biologiques
WO1998030327A1 (fr) * 1997-01-06 1998-07-16 Cerus Corporation Procedes et dispositifs permettant de reduire de petits composes organiques presents dans des produits sanguins

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2818693B2 (ja) * 1992-11-18 1998-10-30 ヘキスト・セラニーズ・コーポレーション 固定された粒子物質を含有する繊維状構造物およびその製造方法
DE19544297A1 (de) * 1995-11-28 1997-06-05 Behringwerke Ag Verfahren zur Entfernung von aromatischen Verbindungen aus produkthaltigen Lösungen

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2721511A1 (de) * 1976-05-12 1977-11-24 Honshu Paper Co Ltd Adsorbierender, nichtgewebter stoff und verfahren zu dessen herstellung
WO1983000023A1 (fr) * 1981-06-24 1983-01-06 Amf Inc Procede de preparation d'un serum a standard zero
EP0230247A2 (fr) * 1986-01-14 1987-07-29 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Adsorbant pour enlever un composant complément
US5147722A (en) * 1989-02-23 1992-09-15 Koslow Technologies Corporation Process for the production of materials and materials produced by the process
WO1996039818A1 (fr) * 1995-06-07 1996-12-19 Cerus Corporation Traitement de solutions de globules rouges par des agents antiviraux
WO1997037536A1 (fr) * 1996-04-09 1997-10-16 Therakos, Inc. Procede d'elimination de psoralenes dans des fluides biologiques
WO1998030327A1 (fr) * 1997-01-06 1998-07-16 Cerus Corporation Procedes et dispositifs permettant de reduire de petits composes organiques presents dans des produits sanguins

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US10946040B2 (en) 2010-04-01 2021-03-16 Cytosorbents Corporation Method of treating inflammation
US11058715B2 (en) 2010-04-01 2021-07-13 Cytosorbents Corporation Method of treating inflammation
US9717755B2 (en) 2010-04-01 2017-08-01 Cytosorbents Corporation Method of treating inflammation
US10034894B2 (en) 2010-04-01 2018-07-31 Cytosorbents Corporation Method of treating inflammation
US10967001B2 (en) 2010-04-01 2021-04-06 Cytosorbents Corporation Method of treating inflammation
WO2016070957A1 (fr) * 2014-11-06 2016-05-12 Merck Patent Gmbh Charbon actif pour l'élimination de substances lixiviables et/ou extractibles
US10793592B2 (en) 2014-11-06 2020-10-06 Merck Patent Gmbh Activated carbon for the removal of leachables and/or extractables
US11096963B2 (en) 2015-06-26 2021-08-24 Cerus Corporation Cryoprecipitate compositions and methods of preparation thereof
WO2016210374A1 (fr) 2015-06-26 2016-12-29 Cerus Corporation Compositions de cryoprécipités et leurs procédés de préparation
EP4410318A2 (fr) 2015-06-26 2024-08-07 Cerus Corporation Compositions de cryoprécipités et leurs procédés de préparation
US10799533B2 (en) 2015-10-23 2020-10-13 Cerus Corporation Plasma compositions and methods of use thereof
WO2017070619A1 (fr) 2015-10-23 2017-04-27 Cerus Corporation Compositions de plasma et leurs procédés d'utilisation
US11235090B2 (en) 2017-03-03 2022-02-01 Cerus Corporation Kits and methods for preparing pathogen-inactivated platelet compositions
US12064537B2 (en) 2017-03-03 2024-08-20 Cerus Corporation Kits and methods for preparing pathogen-inactivated platelet compositions
WO2019060610A1 (fr) 2017-09-20 2019-03-28 Cerus Corporation Compositions et méthodes d'inactivation de pathogènes de plaquettes
US11554185B2 (en) 2017-12-29 2023-01-17 Cerus Corporation Systems and methods for treating biological fluids
US12011510B2 (en) 2019-06-22 2024-06-18 Cerus Corporation Biological fluid treatment systems
US11883544B2 (en) 2019-06-28 2024-01-30 Cerus Corporation System and methods for implementing a biological fluid treatment device

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AU8294998A (en) 1999-07-26
EP1044066A1 (fr) 2000-10-18
JP2003527230A (ja) 2003-09-16
CN1136042C (zh) 2004-01-28
EP1051249A1 (fr) 2000-11-15
AU759966B2 (en) 2003-05-01
CA2317430A1 (fr) 1999-07-15
AU759541B2 (en) 2003-04-17
AU8295698A (en) 1999-07-26

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