WO1999034914A1 - Dispositifs de traitement discontinu permettant de reduire la concentration de composes dans des compositions biologiques contenant des cellules, et procedes associes - Google Patents

Dispositifs de traitement discontinu permettant de reduire la concentration de composes dans des compositions biologiques contenant des cellules, et procedes associes Download PDF

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Publication number
WO1999034914A1
WO1999034914A1 PCT/US1998/014134 US9814134W WO9934914A1 WO 1999034914 A1 WO1999034914 A1 WO 1999034914A1 US 9814134 W US9814134 W US 9814134W WO 9934914 A1 WO9934914 A1 WO 9934914A1
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WO
WIPO (PCT)
Prior art keywords
adsorbent
platelet
particles
amino
compounds
Prior art date
Application number
PCT/US1998/014134
Other languages
English (en)
Inventor
Derek Joseph Hei
Thu Anh Phan
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 EP98933264A priority Critical patent/EP1044066A1/fr
Priority to JP2000527349A priority patent/JP2003523777A/ja
Priority to AU82949/98A priority patent/AU759966C/en
Priority to CA002318508A priority patent/CA2318508C/fr
Publication of WO1999034914A1 publication Critical patent/WO1999034914A1/fr

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Classifications

    • 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

  • 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, which may render the treated product unsuitable for its intended use.
  • the present invention provides devices for reducing the concentration of compounds in biological compositions containing cells.
  • the devices include an adsorption medium comprised of particles immobilized by an inert matrix and are of a batch configuration.
  • the compounds reduced in biological compositions using the device have molecular weights ranging from about 100 g/mol to about 30,000 g/mol.
  • the biological composition containing cells includes, for example, cells suspended in a biological medium, such as plasma or tissue culture media. The biological activity of the biological composition is substantially maintained after contact with such devices.
  • the present invention provides methods for reducing the concentration of a biological response modifier in a biological composition containing cells, wherein the method substantially maintains a desired biological activity of the biological composition.
  • the method involves treating the biological composition with a device.
  • the adsorbent particles of the device are polyaromatic adsorbent particles that possess superior wetting properties.
  • the adsorbent particles of the device are activated carbon particles derived from a synthetic source.
  • the inert matrix of the device is a particulate network, and the particulate network comprises polyethylene particles.
  • the biological composition comprises platelets.
  • the biological composition comprises red blood cells.
  • the method further reduces the concentration of a psoralen derivative or an acridine derivative in the biological composition.
  • the method further reduces the concentration of 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 immobilized adsorbent media.
  • FIG. 2 schematically represents a portion of one embodiment of the immobilized adsorbent media of the present invention.
  • FIG. 3 diagrammatically represents a cross-sectional view of one embodiment of immobilized adsorbent media 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 immobilized adsorbent media in which the adsorbent beads are immobilized within the fibers of the immobilized adsorbent media 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 immobilized adsorbent media containing
  • FIG. 6 is a graph showing a comparison of adsorption kinetics for removal of aminopsoralens from platelets with immobilized adsorbent media containing Amberlite ® XAD- 16 and immobilized adsorbent media with the two different loadings of activated charcoal.
  • Fiberized XAD- 16 data is represented by circles, solid line; fiberized AQF-500-B as squares, short dashes; and, fiberized AQF-375- B as triangle, long dashes.
  • FIG. 7 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. 8 is a graph showing a comparison of the effect of pre-treatment with solutions containing glycerol on the relative adsorption capacity of Amberlite ® XAD- 16 and Dowex ® XUS-43493 for aminopsoralens.
  • FIG. 9 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". Adsorption capacities are reported as percentages relative to the capacity of optimally wet adsorbent.
  • FIG. 10 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. 11 is a graph showing a comparison of the kinetics of adsorption of methylene blue over a 2-hour period from plasma.
  • FIG. 12 depicts the chemical structures of acridine, acridine orange, 9- amino acridine, and 5-[( ⁇ -carboxyethyl)amino]acridine.
  • FIG. 13 is a graph showing plots the data for adenine capacity (y-axis) and 5-[( ⁇ -carboxyethyl)amino]acridine capacity (x-axis) for various resins.
  • FIGS. 14A and 14B is a graph showing a comparison of the adsorption kinetics for removal of 5-[( ⁇ -carboxyethyl)amino]acridine with Dowex ® XUS- 43493 and Purolite ® .MN-200 and Amberlite ® XAD- 16 HP.
  • FIG. 15 is a graph showing a comparison of the adsorption kinetics for removal of 9-amino acridine and acridine orange with Dowex ® XUS-43493.
  • FIG. 16 is an illustration of a batch configuration for the immobilized adsorption device (IAD).
  • FIG. 17 is a graph showing a comparison of the adsorption isotherms for various .Ambersorbs as compared to Purolite MN-200.
  • FIG. 18 is a graph showing a comparison of the levels of 5-[( ⁇ - carboxyethyl)amino] acridine and GSH in the supernatant of 300 mL PRBC units with continued or terminated exposure after 24 hours to a fiberized Pica G277 IAD (500 g/m 2 ) over 4 weeks of storage at 4°C.
  • FIG. 19 is a graph showing the effect of enclosure material on adsorption kinetics for 5-[( ⁇ -carboxyethyl)amino]acridine in PRBCs.
  • FIG. 20 is a graph showing a comparison of percent hemolysis for the adsorbent devices containing non-immobilized and immobilized adsorbent particle Purolite MN-200.
  • FIG. 22 is a graph showing kinetics for removal 4'-(4-amino-2-oxa) butyl- 4,5', 8 trimethylpsoralen from platelet concentrates.
  • FIG. 23 is a graph showing psoralen adsorption kinetics for fiber matrix
  • IAD (AQF, squares) and particulate matrix IAD (Porex, triangles).
  • the present invention provides devices for reducing the concentration of compounds in biological compositions containing cells.
  • the devices include an adsorption medium comprised of particles immobilized by an inert matrix and are of a batch configuration.
  • the compounds reduced in biological compositions using the device have molecular weights ranging from about 100 g/mol to about 30,000 g/mol.
  • the biological composition containing cells includes, for example, cells suspended in a biological medium, such as plasma or tissue culture media. The biological activity of the biological composition is substantially maintained after contact with such devices.
  • 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. Immobilization of the adsorbent particles may also enhance the ability of the adsorbent particles to adsorb compounds in biological compositions containing cells without mechanical damage to the cells.
  • 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 12).
  • adsorbent particle broadly refers to any natural or synthetic particulate material which is capable of interacting with molecules in a liquid thus allowing the molecule to be removed from the liquid.
  • naturally occurring 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 affect how the adsorbent interacts with molecules.
  • aromatic refer broadly to compounds with rings of atoms having delocalized electrons.
  • the monocyclic compound benzene (C 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, decreasing protein adsorption or improving 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 containers, bags, vessels, receptacles, and the like that are suitable for containing a biological material, such as, for example, compositions containing platelets or red blood cells.
  • 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 difference is seen in blood product function compared to the control as described herein, for red blood cells, platelets and plasma.
  • blood products may be stored in biocompatible housings prior to transfusion to a recipient.
  • biocompatible housings are blood bags, including a platelet storage container or red blood cell storage container.
  • blood bag refers to a form of 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.
  • 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 foim a two- or three-dimensional network.
  • divinylbenzene serves as the crosslinking agent in the foirnation 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); Tsyurupa et al., Reactive Polymers 25:69-78 (1995).
  • 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 azocaimine B); the azo dyes; the azocaimine 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 entrapped in or attached to a fiber network.
  • the fiber network is comprised of polymer fibers.
  • the fibers consist of a polymer core (e.g., polyethylene terephthalate [PET]) with a high melting point surrounded by a polymer sheath (e.g., nylon or modified PET) with a relatively low melting temperature.
  • PET polyethylene terephthalate
  • 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 (temperature sufficient to melt the sheath but not the core).
  • 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. red blood cell composition) to pass through, while retaining other components such as resin particles.
  • a blood product e.g. red blood cell composition
  • filter is not limited to the means by which certain components are retained.
  • 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.
  • inert matrix refers to any synthetic or naturally occurring fiber or polymeric material which can be used to immobilize adsorbent particles without substantially affecting 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 term "isolating” refers to separating a substance out of a mixture containing more than one component. For example, 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.
  • the term “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.
  • microreticular is a relative term that means that the structure has a high physical porosity (i.e., a large number of pores are present) a porous adsorbent structure possessing both macropores and micropores.
  • partition refers to any type of device or element that can separate or divide a whole into sections or parts.
  • the present invention contemplates the use of a partition to divide a blood bag, adapted to contain a blood product, into two parts.
  • the blood product occupies one part of the bag prior to and during treatment, while the adsorbent resin occupies the other part.
  • the partition is removed (e.g., the integrity of the partition is altered), thereby allowing the treated blood product to come in contact with the adsorbent resin.
  • the partition may either be positioned in the bag's interior or on its exterior.
  • the term "removed” means that the isolation of the two parts of the blood bag no longer exists; it does not necessarily mean that the partition is no longer associated with the bag in some way.
  • 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.
  • the phrase "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, dye, plasticizer or activated complement
  • a compound e.g. a psoralen, psoralen derivative, isopsoralen, acridine, acridine derivative, dye, plasticizer or activated complement
  • removing substantially all of said portion of a compound e.g. a psoralen, psoralen derivative, isopsoralen, acridine, acridine derivative, dye, plasticizer or activated complement
  • the term "resin” refers to a solid support (such as particles or beads etc.) capable of interacting and adsorbing to various small organic compounds, including psoralens, in a solution or fluid (e.g., a blood product), thereby decreasing the concentration of those elements in solution.
  • the removal process is not limited to any particular mechanism.
  • a psoralen may be removed by hydrophobic or ionic interaction.
  • adsorbent resin refers broadly to both natural organic substances and synthetic substances and to mixtures thereof.
  • agitation means refers to any method by which a biological composition can be mixed. Examples of agitation means include, without limitation, the following mechanical agitators: reciprocating, orbital, 3-D rotator and rotator type agitators.
  • shaker device refers to any type of device capable of thoroughly mixing a blood product like a platelet concentrate.
  • the device may have a timing mechanism to allow mixing to be restricted to a particular duration.
  • the process causes fusing of the low melting particles resulting in the formation of a porous solid structure.
  • the sintered medium can be foimed into a variety of shapes by placing the polymer particles in a forming tool during the sintering process.
  • Adsorbent particles can be introduced into the sintered medium by mixing adsorbent particles with the thermoplastic polymer particles before subjecting to the sintering process.
  • stabilizing agent refers to a compound or composition capable of maintaining the adsorption capacity of certain adsorbents (e.g., Amberlites) under drying conditions.
  • 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 (e.g., .Amberlite XAD-4, Amberlite XAD- 16).
  • 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 (e.g., cellular integrity) of the biological composition.
  • the cellular integrity is reflective of the potential performance of the composition in a therapeutic setting.
  • in vivo activity is not destroyed or significantly lowered if ATP levels, extracellular potassium leakage, % hemolysis are substantially maintained in red blood cells treated by the methods described herein.
  • the change in ATP level of the treated red blood cells should be less than about 10%.
  • the hemolysis level in the treated red blood cells following storage should be less than about 1%, preferably less than about 0.8%.
  • the change in extracellular potassium leakage of the treated red blood cells should be less than about 15%.
  • platelets in vivo activity is not destroyed or significantly lowered if, for example, platelet yield, pH, aggregation response, shape change, GMP-140, mo ⁇ hology or hypotonic shock response are substantially maintained in platelets treated by the methods described herein.
  • platelet loss in a biological composition after storage is preferably less than 15%; more preferably 15% after 5 days storage; even more preferably 10% after 5 days storage.
  • the phrase substantially maintained for each of the properties associated with a described blood products 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, inco ⁇ orated 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 cell viability or 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. platelet mo ⁇ hology) 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. platelet mo ⁇ hology
  • undesired compounds e.g. inactivation compounds, response modifiers
  • N-(9-acridinyl)- ⁇ -alanine is alternatively referred to as "5-[( ⁇ - carboxyethyl)amino] acridine.” It is further alternatively refeired to as “S-300.”
  • XUS-43493 is alternatively referred to as "Optipore 493.”
  • adsorbent particles which are useful in a device for reducing the concentration of compounds in a biological composition containing cells 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
  • the adsorbent particles can be of any regular or irregular shape that lends itself to inco ⁇ oration into the inert matrix but are preferably roughly spherical.
  • the particles are greater than about 100 ⁇ m in diameter and less than about 1500 ⁇ m in diameter; preferably, the particles are between about 200 ⁇ m and about
  • a high surface area is characteristic of the particles.
  • the particles have a surface area between about 750 m /g and about 3000 m g. More preferably, the particles have a surface area between about 1000 m 2 /g and about
  • the adsorbent particles are activated carbons derived either from natural or synthetic sources.
  • the activated carbons are derived from synthetic sources.
  • Nonlimiting examples of activated carbons include; Picatiff Medicinal ® , which is available from PICA USA Inc. (Columbus, OH), Norit ® ROX 0.8, which is available from Norit Americas, Inc. (Atlanta,
  • the particles can be hydrophobic resins.
  • hydrophobic resins include the following polyaromatic adsorbents: iAmberlite ® adsorbents (e.g., Amberlite ® XAD-2, XAD-4, and XAD-
  • Prefeired 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.
  • 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 foim of spherical particles with a diameter range of about 200 ⁇ m to about 1300 ⁇ m.
  • Adsorbent particles including for example, Dowex ® XUS-43493, preferably have extremely high internal surface areas and relatively small pores (e.g. average diameter 46 A).
  • the internal surface area of the particle can be from about 300 to about 1100 m 2 /g; preferably about 900 to about 1100 m 2 /g; most preferably about 1100 m 2 /g.
  • 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 upon drying, do not require wetting for biological compositions comprising red blood cells or platelets, and have extremely low levels of small particles and foreign particles (e.g. dust, fibers, non-adsorbent particles, and unidentified particles).
  • 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) sei ⁇ es 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 foimed 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 are hypercrosslinked networks. 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. , "diy”) 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.
  • the bridges are foimed 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 inco ⁇ orated 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 (i.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. In order to prevent the pores from collapsing, conformationally-restricted bridges should be foimed. Some bifunctional agents like DPB do not result in generally limited confoimation; 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).
  • One advantage of the cleaned/processed adsorbent is an extremely low level of particles with diameters less than 30 ⁇ m.
  • Preliminary testing on adsorbents (Dowex ® XUS-43493 and Amberlite ® X . AD-16) processed by Supelco was performed to determine particle counts. The results of these tests indicated that foreign particles (e.g., dust, fibers, non-adsorbent particles, and unidentified particles) were absent and that fine particles ( ⁇ 30 ⁇ m) were essentially absent.
  • Wetting Agents and Stabilizing Agents with Adsorbent Resins Methods may be used for preventing drying and loss of adso ⁇ tion capacity of particles, such as Amberlite ® which lose some of their adso ⁇ tion capacity under certain conditions (e.g., diying).
  • Sterilization may be limited to a steam process because ⁇ -irradiation of wet polymers is typically not perfoimed. Manufacturing a device that requires that a component be maintained in a wet state is, in general, more difficult than manufacturing a dry device; for example, bioburden and endotoxin may become of concern if there is a long lag time between device assembly and terminal sterilization.
  • a second method for preventing loss of adso ⁇ tion capacity involves the use of an adsorbent which is not adversely affected by drying.
  • Amberlite ® XAD- 16 these macroreticular adsorbents retain a very high proportion of their initial activity when they are dried.
  • Stabilizing agents are effective in maintaining adso ⁇ tion 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 hemocompatibihty 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).
  • XAD- 16 may be stabilized in ethanol and glycerol.
  • Low molecular weight polyethylene glycols, commonly used as pharmaceutical bases, may also be used as stabilizing agents.
  • PEGs are liquid and solid polymers of the general chemical formula H(OCH 2 CH ) 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 foimulations (e.g., Carbowax, Poly-G, and Solbase).
  • the adsorbent particles are immobilized by an inert matrix.
  • the inert matrix can be made of a synthetic or natural polymer.
  • the inert matrix can be a synthetic or natural polymer fiber, for example, a fiber network.
  • 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.
  • Exemplary natural polymer fibers include cellulose fibers derived from a variety of sources, such as jute, kozu, l raft 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 inco ⁇ orated by reference.
  • Synthetic polymers suitable for the construction of 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.
  • 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
  • a polymer sheath 604 e.g., nylon
  • 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 diy-laid process, as described in U.S. Pat. Nos. 5,605,746 and 5,486,410 (AQF patents), which are herein inco ⁇ orated 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 inco ⁇ orated 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 inco ⁇ orated 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.
  • the resulting adso ⁇ tion medium comprises .known amounts of adsorbent per area.
  • the adsorbent per area is from about 100 g/m 2 to about 500 g/m 2 , preferably from about 250 g/m to about 350 g/m 2 .
  • the appropriate amount of adsorbent contemplated for a specific pu ⁇ ose can be measured simply by cutting a predetermined area of the fiberized resin (i.e., there is no weighing of the fiberized resin).
  • the surface hemocompatibihty of the particles, matrices or adso ⁇ tion medium can be improved by coating their surfaces with a hydrophilic polymer.
  • exemplary hydrophilic polymers include poly(2 -hydroxy ethyl methacrylate)
  • the polymer coating can increase hemocompatibihty 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 adso ⁇ tion. 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 by soaking the immobilized adso ⁇ tion medium in the hydrophilic polymer (see Example 3). 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 adso ⁇ tion medium at any particular time.
  • the pHEMA coating is applied after production of the adso ⁇ tion medium, but prior to heat sealing the adso ⁇ tion medium.
  • the adso ⁇ tion 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 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.
  • Methods can be used to reduce the presence of adsorbent particles that may come loose from the adsorbent medium.
  • the present invention contemplates a batch device including the immobilized adsorbent medium retained in a container such as a mesh bag/pouch.
  • the mesh/pouch can be constructed of a woven, non- woven or membranous enclosure.
  • the woven mesh pouch can be constructed of medical-grade polyester or nylon.
  • the preferred embodiment is polyester.
  • Commercially-available membranes include, but are not limited to, Supor ® 200, 800, 1200 hydrophilic polyethylene sulfonate (PES) membranes (Gelman Sciences (Ann .Arbor, MI)); Durapore ® hydrophilic modified polyvinylidene difiuoride (PVDF) (Mantee Co ⁇ .
  • the present invention provides devices for reducing the concentration of low molecular weight compounds in biological compositions containing cells.
  • the devices comprise an adso ⁇ tion medium, which is comprised of particles immobilized by an inert matrix.
  • Biological response modifiers like the anaphalatoxin C3a and the teiminal 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 or controls the concentration of activated complement in biological compositions containing cells.
  • the adso ⁇ tion device comprises fiberized Ambersorb IAD, for example, as produced by AQF.
  • exposure of biological compositions containing cells to the device results in a reduction in the C3a complement fragment and SC5b-9 terminal component complex over control.
  • exposure to the device for 5 days results in at least about a 10% reduction of C3a complement fragment over control.
  • exposure to the device for 5 days results in at least about a 30% reduction of C3a complement fragment over control.
  • exposure to the device for 5 days results in at least about a 50% reduction of C3a complement fragment over control.
  • Particularly preferred particles for this embodiment are polyaromatic adsorbents comprising a hypercrosslinked polystyrene network, such as Dowex ® XUS-43493 or Purolite MN-200.
  • the preferred inert matrix includes a synthetic or natural polymer fiber.
  • the inert matrix includes a synthetic polymer fiber which 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 polyethylene te ⁇ hthalate core.
  • the sheath can be a nylon sheath or a modified polyester sheath. Staple fibers are commercially available from Unitika (Osaka, Japan) and Hoechst Trevira.
  • Exemplary compounds that are reduced or controlled by the devices, materials and methods of this embodiment are psoralens, psoralen derivatives, isopsoralens, psoralen photoproducts, acridines, acridine derivatives, methylene blue, plastic extractables, biological response modifiers, quenchers and polyamine derivatives.
  • Biological compositions comprising platelets are typically used within 3 days of donation but may be stored for up to 7 days at room temperature, therefore, it would be advantageous to allow the platelet compositions to remain in contact with the adso ⁇ tion medium for the entire storage period. Preferably, the procedure would result in an acceptable platelet yield (e.g., less than 10% loss).
  • One method contemplated by the present invention allows extended storage by improving the hemocompatibihty of the adsorbent surface.
  • an adso ⁇ tion medium comprising adsorbent particles immobilized by an inert matrix permits the concentration of low molecular weight compounds to be reduced without a substantial loss in platelet count.
  • the phrase "without a substantial loss” refers to a platelet preparation that is suitable for its intended pu ⁇ ose, for example, is suitable for infusion into humans, and may refer to, for example, a loss of platelet count or function of less than about 10%, preferably less than about 5% over a period of time, more preferably at least 5 days.
  • the time that the platelets may be contacted with the adso ⁇ tion medium without substantial loss in platelet count is greater than the amount of time that the platelets can be contacted with the adsorbent particles alone.
  • the immobilization of the particles unexpectedly permits both a longer contact time and a reduction in loss of platelet count.
  • the platelets typically cannot be contacted with non-immobilized adsorbent particles for more than about 20 hours without a significant loss of platelet count e.g. about 20% loss.
  • platelets may be contacted with the adso ⁇ tion medium comprising adsorbent particles immobilized by an inert matrix for more than 20 hours, e.g. about 1 to 7 days without a substantial loss in platelet count.
  • platelet function e.g., shape change, GMP-140, pH
  • GMP-140 shape change
  • pH a pH from greater than about 6 to less than about 7.5.
  • the invention provides a device for reducing the concentration of low molecular weight compounds (e.g., small organic compounds) in a biological composition comprising red blood cells while substantially maintaining the biological activity of the red blood cells.
  • the compounds removed by the device have a molecular weight ranging from about 100 g/mol to about 30,000 g/mol.
  • the adso ⁇ tion medium comprises adsorbent particles immobilized by an inert matrix. Preferred particles for this embodiment are highly porous and have a surface area greater than about 750 m 2 /g.
  • a device used for red blood cell compositions is a device that substantially maintains the biological activity of the red blood cells after reduction of the concentration of low molecular weight compounds.
  • the red blood cell device does not substantially adversely affect the biological activity of a fluid upon contact.
  • the device embodiment comprises an adso ⁇ tion medium containing particles immobilized by an inert matrix and optionally a particle retention device.
  • the particles used in devices for red blood cell compositions are activated charcoal.
  • the activated carbons are derived from synthetic sources.
  • Nonlimiting examples of activated carbons include
  • Picactif Medicinal which is available from Pica U.S.A. (Columbus, Ohio); Norit ROX 0.8, which is available from Norit Americas Inc. (Atlanta, GA); and G-277, which is available from Pica U.S.A. (Columbus, OH).
  • the adsorbent is preferably an activated carbon derived from a synthetic source, such as Ambersorb 572.
  • the Ambersorbs are synthetic activated carbonaceous (i.e. rich in carbon) adsorbents that are manufactured by Rohm & Haas (Philadelphia, PA). Ambersorbs are generally large spherical (300-900 ⁇ m) particles that are more durable than typical activated carbons.
  • the .Ambersorbs are synthetically manufactured by treating highly sulfonated porous polystyrene beads with a proprietary high temperature activation process. These adsorbents do not require pre-swelling to achieve optimal adso ⁇ tion activity.
  • the particles used in devices for use with compositions containing red blood cells can be hydrophobic resins.
  • 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 (Toso Haas, Montgomeryville, PA); and Diaion ® //Sepabeads ® Adsorbents (e.g., Diaion ® HP20), available from Mitsubishi Chemical America, Inc. (White Plains, NY).
  • the particles are Hypersol-Macronet ® Sorbent
  • the preferred inert matrix of a red blood cell device includes a synthetic or natural polymer fiber.
  • the inert matrix includes a synthetic polymer fiber which 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 polyethylene terephthalate or polyester core.
  • the sheath can be a nylon sheath or a modified polyester sheath. Fibers are commercially available from Unitika (Osaka, Japan) and Hoechst Trevira (Augsberg, Germany).
  • the adso ⁇ tion medium of a red blood cell device is in an enclosure.
  • the device comprises an adso ⁇ tion medium, and a housing.
  • the device comprising an adso ⁇ tion medium and a housing may also include a particle retention medium.
  • the housing comprises a blood bag of a volume between about 600 ml and about 1 L.
  • the housing comprises a blood bag of a volume between about 800 ml and about 1 L.
  • the particle retention medium may comprise a polyester woven, polyester non-woven, or synthetic membranous enclosure.
  • the device contact the red blood composition at about 4 " C or about 22 °C (room temperature), in the presence of agitation, over a time period of 1 to 35 days.
  • the red blood composition is contacted with the device at about 22 °C for no more than about 36 hours.
  • the red blood cell composition is contacted with the device at about 22 °C for no more than about 24 hours.
  • the red blood composition is contacted with the device at about 22 °C for no more than about 12 hours.
  • the red blood composition is contacted with the device at about 22 °C for no more than 6 hours.
  • the temperature is changed after the red blood composition is brought into contact with the device.
  • the device is contacted with the red blood composition at about 22 °C for a time ranging from about 0.5 to about 24 hours and then stored at about 4 °C for up to about 5 weeks. In another embodiment, the device is contacted with the red blood composition at about 22 °C for a time ranging from about 0.5 to about 12 hours and then stored at about 4 °C for up to about 5 weeks. In another embodiment, the device is contacted with the red blood composition at about 22 °C for a time ranging from about 0.5 to about 6 hours and then stored at about 4 °C for up to about 5 weeks.
  • an adso ⁇ tion medium comprising adsorbent particles immobilized by an inert matrix permits the treatment of the red blood cell composition without a substantial loss in red blood cell function.
  • the phrase "without a substantial loss” refers to a product that would be allowable for transfusion, or its intended pu ⁇ ose, and in some instances may refer to less than about 1% hemolysis; preferably less than about 0.8% hemolysis, greater than about 80% recovery of red blood cells; preferably greater than 90% recovery of red blood cells, less than about 10% difference from no-device control red blood cells in change in ATP concentration, and less than about 15% difference from no-device control red blood cells in change in extracellular potassium concentration. At 35 days, the change in hemolysis is at least 10% lower for the
  • IAD compared to the non-immobilized particles preferably, 20% lower and more preferably 50%. Most preferably, the change is hemolysis is at least 90% lower for the IAD compared to the non-immobilized particles.
  • Red blood cell function can be assayed using standard kits.
  • hemolysis may be determined by measuring the absorbence at 540 nm of a red blood cell supernatant sample in Drabkin's reagent ((Sigma Chemical Company), St. Louis, MO). Potassium leakage can be assayed using a Na+/K+ analyzer. (Ciba-Corning Diagnostics, Medfield, MA). Quantitative enzymatic determination of ATP in total Red Blood Cell samples is possible using a standard kit (Sigma Diagnostics, St. Louis, MO) and measuring absorbance at 340 nm compared to a water background.
  • the device can reduce the concentration of low molecular weight compounds in a red blood cell sample.
  • the device can reduce the concentration of both acridine derivatives and thiols in a red blood cell sample. More preferably, the device can reduce the concentration of both 5-[( ⁇ - carbethyoxyethyl)amino] -acridine and glutathione in a red blood cell sample.
  • Standard HPLC assays can be used to deteimine concentrations of 5-[( ⁇ - carboxyethyl)amino]acridine and glutathione in red blood cells contacted with the device. Assay mobile phases are 10 mM H PO 4 in HPLC water and 10 mM
  • Zorbax SB-CN and YMC ODSAM-303 columns are available from MacMod Analytical, Inc. (Chadds Ford, PA) and YMC, Inc. (Wilmingtion, N.C.).
  • the agitation can be constant or intermittent.
  • the agitation is provided through any suitable means which maintains the functionality of the cells, including mechanical agitators of the following types: reciprocating, orbital, 3-D rotator and rotator type agitators.
  • the agitation is provided by an orbital agitator and is constant.
  • the agitation is provided by an orbital agitator and is intermittent.
  • the agitation is provided by a reciprocating agitator.
  • the present invention contemplates reducing the concentration of low molecular weight compounds from biological compositions containing cells.
  • 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 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.
  • the materials and devices disclosed herein can be used in apheresis methods.
  • Whole blood can be separated into two or more specific components (e.g., red blood cells, plasma and platelets).
  • the term "apheresis” refers broadly to procedures in which blood is removed from a donor and separated into various components, the component(s) of interest being collected and retained and the other components being returned to the donor.
  • the donor receives replacement fluids during the reinfusion process to help compensate for the volume and pressure loss caused by component removal.
  • Apherersis systems are described in PCT publication WO96/40857, hereby inco ⁇ orated by reference. Low Molecular Weight Compounds
  • a device of the present invention reduces the concentration of a low molecular weight compound in a composition containing cells.
  • 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.
  • 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, po ⁇ hyrins, protopo ⁇ hyrins, pu ⁇ urins, phthalocyanines, hypericin, Monostral Fast Blue, No ⁇ hillin 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'-bromomethyl-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-2,5-oxa)heptyl-
  • the psoralen is 4'-(4-amino-2-oxa)butyl-4,5',8-trimethylpsoralen.
  • 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.
  • 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- Bis(dimethylamino)-phenothiazin-5-ium chloride).
  • Other 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.
  • Quenchers 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-owned U.S. Patent Application, "Methods for Quenching Pathogen Inactivators in Biological Systems", Docket Number 282173000600, filed January 6, 1998, the disclosure of which is inco ⁇ orated herein.
  • a material such as a blood product
  • 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 foim the electrophilic group.
  • quenchers include, but are not limited to, compounds including nucleophihc groups.
  • nucleophihc 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.
  • Other 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 nucleophihc 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.
  • Plastic Extractables 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 fo.rmation 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 foimulations.
  • 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, extraco ⁇ oreal applications such as hemodialysis and extraco ⁇ oreal 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-
  • BRMs 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 lesion.” See, e.g., V.D. Montgomeryic and O. Popovic, Transfusion 33(2): 150- 154 (1993).
  • the accumulation of 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.
  • the concentration of a group of low molecular weight compounds 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.
  • 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).
  • small molecules such as N-Hydroxy succinimide which are released during the reaction of the aPEG with cell surface nucleophiles may also be reduced.
  • 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.
  • NC Chinese Network Culture Collection
  • DVB divinyl benzene
  • LAL Limal Amoebocyte Lystate
  • USP United States Pharmacopeia
  • EAA ethyl-acetoacetate
  • EtOH ethanol
  • HO Ac acetic acid
  • W watts
  • mW milliwatts
  • NMR Nuclear Magnetic Resonance; spectra obtained at room temperature on a Varian Gemini 200 MHz Fourier Transfoim Spectrometer); ft 3 /min (cubic feet per minute); m.p.
  • HEPES buffer contains
  • This example compares both the kinetics of removal of aminopsoralens from platelets and platelet function and mo ⁇ hology utilizing fiberized resin and devices containing non-immobilized adsorbent beads . More specifically, fiberized resin comprising immobilized ⁇ Amberlite ® XAD- 16 was compared with devices containing free (i.e., not immobilized) Amberlite ® XAD- 16 HP and Dowex ® XUS-43493.
  • the fiberized resin foimed 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 e.g., bridged or hypercrosslinked resins like Dowex ® XUS-43493 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.
  • PC Platelet Concentrate
  • Platelet concentrate was prepared by combining 2-3 units of single donor apheresis platelets in 35% autologous plasma/65% Platelet Additive Solution (i.e., synthetic media). To this solution was added the aminopsoralen 4'- (4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen (S-59) in an amount to achieve a final concentration of 150 ⁇ M 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen.
  • S-59 aminopsoralen 4'- (4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen
  • the resulting PC solution was divided into 300 mL units, and the units were then placed in PL 2410 Plastic containers (Baxter) and illuminated with 3 J/cm 2 of UVA. Following illumination, the treated PCs were transfeired into the PL 2410 Plastic containers containing either fiberized resin with immobilized Amberlite ® .XAD-16, loose Amberlite ® XAD-16 HP or loose Dowex ® XUS-43493, or into an empty PL 2410 Plastic container as a control. The PL 2410 Plastic containers (Baxter) were then placed on a Helmer platelet incubator at 22°C and agitated at approximately 70 cycles/minute.
  • TMP trimethylpsoralen
  • Platelet yield during a 5-day storage period with the fiberized resin or one of the loose beads was monitored daily by counting platelets on a Baker System 9118 CP (Baker Instrument Co.; Allentown, PA). Blood gases and pH were evaluated using a Ciba-Corning 238 pH/Blood Gas Analyzer. In vitro platelet function following 5 days ofcontact with the fiberized resin or the device containing free adsorbents was evaluated using assays for mo ⁇ hology, shape change, hypotonic shock response, aggregation, and GMP-140 (p-selectin) expression.
  • Shape change, aggregation, and hypotonic shock response were evaluated using a Lumi-Aggregometer (Chrono-Log ), while GMP-140 was determined by flow cytometry using a Becton-Dickinson FACScan Fluorescence Analyzer (Becton Dickinson).
  • FIG. 5 compares the adso ⁇ tion kinetics for removal of 4'-(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen from platelets in 35% plasma/65% synthetic media (PAS III) with XUS-43493, XAD-16 HP, and fiberized resin containing XAD- 16.
  • the data indicated by the circles connected by the solid line represents the device containing the non-immobilized adsorbent XUS-43493 (2.5 g beads; ⁇ 5% moisture); the data indicated by the triangles connected by the dashed line represents the device containing non-immobilized XAD- 16 HP (6.8 g beads; 62.8% moisture); and the data indicated by the squares connected by the dashed line represents the fiberized resin (Hoechst fibers with XAD- 16 beads wet in 30% ethanol; 14 cm x 14 cm).
  • the data indicated by the circles connected by the solid line represents the device containing the non-immobilized adsorbent XUS-43493 (2.5 g beads; ⁇ 5% moisture); the data indicated by the triangles connected by the dashed line represents the device containing non-immobilized XAD- 16 HP (6.8 g beads; 62.8% moisture); and the data indicated by the squares connected by the dashed line represents the fiberized resin (Hoechst fibers with X
  • the fiberized resin gave better yields (9% loss on day 5) and perfoimed better in all in vitro assays when compared to device containing non-immobilized XAD-16 or XUS-43493 adsorbent particles.
  • the higher values are believed to be caused by a slight decrease in the metabolism of the platelets in the presence of the device containing non- immobilized adsorbent.
  • the fiberized media consistently gave day-5 pH and pO values which were more comparable to the control than the XUS-43493 or XAD- 16 beads.
  • the fiberized media also results in better day-5 platelet function as indicated by pH/pO , shape change, aggregation, mo ⁇ hology and GMP-140. While an understanding of the rationale for the enhanced performance of the fiberized media is not required to practice the present invention, several hypotheses can be proposed. First, the fibers which are attached to the surface of the adsorbent beads may hinder interaction between platelets and the surface of the beads. Second, immobilizing the beads may prevent the beads from interacting and eliminate mechanical effects that are detrimental to platelets.
  • immobilizing the beads may enhance fluid shear at the bead surface, thereby decreasing interaction between platelets and the surface of the beads; by comparison, non-immobilized beads are free to flow with the fluid resulting in low flow of fluid relative to the surface of the bead.
  • Fiberized Resin With Activated Charcoal This example compares the kinetics of removal of 4'-(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen from platelets and platelet function and mo ⁇ hology for fiberized resin comprising Amberlite ® XAD- 16 and for fiberized resin comprising immobilized activated charcoal.
  • samples of each PC were removed at 1 -hour intervals during the first 8 hours of storage for analysis of residual 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen by HPLC.
  • FIG. 6 compares the adso ⁇ tion kinetics for removal of 4'-(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen from platelets in 35% plasma/65% synthetic media (PAS III) with fiberized resin containing XAD- 16 and fiberized resin with the two different loadings of activated charcoal.
  • the charcoal-based fiberized resin gave good platelet yields with losses of less than 10%; as in the studies of the preceding example, the fiberized resin containing .XAD- 16 had a slightly higher platelet loss (about 17%).
  • the day 5 values for the charcoal fiberized resin are comparable to the control.
  • the use of USP charcoals which are associated with fewer extractables, may eliminate the observed initial rise in pH.
  • Dowex ® XUS-43493 (commercially known as Optipore ® L493) containing approximately 50% water by weight was obtained from Dow, and polymerized HEM A 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 Co ⁇ . 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.
  • the resulting PC solution was then divided into 300 mL units, and the units were placed in PL 2410 Plastic containers (Baxter) and illuminated with 3 J/cm 2 of UVA. Following illumination, the treated PCs were transfeired into the PL 2410 Plastic containers containing the devices as indicated in the following result sections. Control samples without an adso ⁇ tion device were also prepared. The PL 2410 Plastic containers were then placed on a Helmer platelet incubator at 22°C and agitated at approximately 70 cycles/minute.
  • Platelet yield after a 5 -day storage period with the fiberized resin or the device containing non-immobilized adsorbent was determined by counting platelets on a Baker System 9118 CP. Blood gases and pH were evaluated using a
  • FIG. 7 compares the adso ⁇ tion kinetics for removal of 4'-(4-amino-2- oxa)butyl-4,5',8-trimethyl psoralen from platelets in 35% plasma/65% synthetic media (PAS III) with pHEMA-coated and uncoated Dowex ® XUS-43493 beads.
  • 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. 8 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 adso ⁇ tion 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 adso ⁇ tion capacity were made after 4 hours of contact. Refe ⁇ ing to FIG.
  • glycerol content shown on the x-axis is weight/volume percent of glycerol in ethanol.
  • Adso ⁇ tion capacities shown on the y-axis are percentages relative to the adso ⁇ tion capacity of the optimally wet adsorbent sample.
  • the adso ⁇ tion capacity of XUS-43493 is represented by the squares, while that of XAD- 16 is represented by the circles.
  • adsorbent 2.5 g dry of adsorbent are used for the removal of psoralen and psoralen photoproducts from each unit of platelets. Soaking the adsorbent in 30% glycerol/70% ethanol, followed by drying, results in adsorbent which contains approximately 50% glycerol. A 5.0 g sample of adsorbent would therefore contain 2.5 g dry adsorbent and 2.5 g of glycerol. Thus, a typical 300 mL unit of platelets would contain 0.8% glycerol, a level thought to be acceptable for transfusion. Adso ⁇ tion Capacities Of Amberlite ® XAD- 16
  • the .amberlite ® XAD- 16 had approximately 35% of the maximum capacity when dried. Treating XAD- 16 with glycerol, PEG-200, and PEG-400 all improved the capacity of the dried adsorbent; the adsorbent capacities with each were all greater than 90%, with glycerol>PEG-200>PEG-400. Though an understanding of the precise mechanism of action is not required to practice the present invention, differences in capacity between the glycerol and the two PEG solutions may be caused by decreasing penetration of the stabilizing agent with increasing molecular weight.
  • FIG. 10 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.
  • EXAMPLE 5 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 2 ) 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 U.S.P. methylene blue (Spectrum) in distilled water. The stock solution of methylene blue was added to a sample of 100% plasma to give a final concentration of 10 ⁇ M. Samples of the "free" adsorbent resin ( . e. , XAD- 16 HP,
  • FIG. 11 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. This may have resulted from poor contacting between the fiberized resin and plasma during the batch incubation, as a portion of the 14 cm strip of fiberized resin was not completely submersed in the plasma throughout the adso ⁇ tion study, thereby reducing the effective contact area between the adsorbent and plasma.
  • the data indicate that 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 6 Removal Of Acridine Compounds From Packed Red Blood Cells
  • This example is directed at the ability of a variety of different resin materials to remove acridine compounds from packed red blood cells (PRBCs). More specifically, the experiments of this example evaluate the removal of the acridine compound, 5-[( ⁇ -carboxyethyl)amino]acridine, from PRBCs.
  • the chemical structures of several acridines are depicted in FIG. 12. As indicated in FIG. 12, 9-amino acridine and 5-[( ⁇ -carboxyethyl)amino]acridine are aminoacridines.
  • Resin Selectivity Equilibrium adso ⁇ tion of compound 5-[( ⁇ -carboxyethyl)amino]acridine was studied with several types of resins.
  • the polymeric adsorbent resins evaluated were Amberlite ® XAD-2, XAD-4, XAD-7, and .XAD- 16 HP (Rolim and Haas); Purolite ® 1V1N-150, MN-170, MN-200, MN-300, MN-400, MN-500, and MN-600; and Dowex ® XUS-43493 and XUS-40285 (Dow Chemical Co.).
  • Cellular products such as red blood cells are typically stored in a medium containing a low percentage of plasma (10-35%) with a balance of synthetic media; Adsol ® is one example of a synthetic media that consists of adenine, dextrose, and mannitol in a saline solution.
  • Adsol ® is one example of a synthetic media that consists of adenine, dextrose, and mannitol in a saline solution.
  • concentrations of acridines other than 100 ⁇ M in mixtures of plasma and other synthetic media.
  • the tubes were placed on a tumbling agitator and incubated for 3 hours at room temperature. Following incubation, aliquots of each sample were removed for analysis of residual 5-[( ⁇ -carboxyethyl)amino]acridine and adenine by HPLC.
  • the adsorbents utilized were Amberlite ® .XAD- 16 HP (Rohm and Haas); Purolite ® MN-200, and Dowex ® XUS-43493 (Supelco).
  • the water content of each adsorbent was determined by measuring the mass loss upon drying; the water content was corrected for so that the equivalent of 0.25 g dry of each adsorbent was used.
  • Adsorbents were accurately weighed into 50 mL Falcon tubes. Thirty (30) mL of the 25% plasma/75% Adsol ® solution containing 100 ⁇ M acridine was added to each tube containing adsorbent. The tubes were then placed on a rotator at room temperature, and 500 ⁇ L samples of solution were removed at various times and stored for later analysis.
  • FIG. 14A and FIG. 14B both represent residual 5-[( ⁇ -carboxyethyl)amino]acridine as a function of time, FIG. 14B presenting the data on a logarithmic scale.
  • the XAD- 16 HP data is represented by shaded circles connected by dashed lines
  • the MN-200 data is represented by shaded squares connected by dashed lines
  • the XUS-43493 data is represented by shaded triangles connected by solid lines.
  • the XUS-43493 and MN-200 gave the fastest adso ⁇ tion kinetics and were nearly equivalent.
  • FIG. 15 compares the adso ⁇ tion kinetics for removal of 9-amino acridine and acridine orange from 25% plasma/75% Adsol ® with Dowex ® XUS-43493. Refeixing to FIG. 15, the shaded squares with the dashed lines represent 9-amino acridine, and the shaded circles with the solid lines represent acridine orange. As the data indicate, levels of 9-amino acridine were undetectable beyond 3 hours. By comparison, the capacity of the Dowex ® XUS-43493 for acridine orange was lower, which may be related to the presence of two tertiary amino groups on acridine orange. EXAMPLE 8
  • HPLC Assay for Glutathione in PRBC and PRBC Supernatant The sample was prepared as for the HPLC assay described above.
  • the plasma-Erythrosol solution was spiked with 5-[( ⁇ - carboxyethyl)amino]acridine to a final concentration of 300 ⁇ M.
  • Glutathione 5-[( ⁇ - carboxyethyl)amino]acridine to a final concentration of 300 ⁇ M.
  • Adsorbent Screen Removal of 5- [( ⁇ -carboxyethyl)amino] acridine from 25% Plasma/75% Erythrosol. ("LOD" is limit of detection.)
  • Adsorption Capacities for Adsorbents were carried out to determine the adsorptive capacities ( ⁇ mole 5-[( ⁇ - carboxyethyl)-amino]acridine/g adsorbent) for various types of adsorbents.
  • Figure 17 shows adsorption isotherms obtained for several Ambersorbs as compared to the adsorption isotherm for Purolite MN-200. Adso ⁇ tion studies were performed in 25% plasma/75% Erythrosol solutions containing 0.2-3 mM 5-
  • the concentration of 5-[( ⁇ -carboxyethyl)-amino]acridine was reduced to 5 ⁇ M in initially shaken PRBCs after 35 days of storage in the presence of a removal device (.MN-200). This indicates that 5-[( ⁇ -carboxyethyl)- amino] acridine removal does occur in static storage conditions at 4 °C.
  • PRBC units 300 mL were dosed with 300 ⁇ M of a degradable 5-[( ⁇ - carboxy ethyl)amino] acridine derivative and 3 mM GSH, held at room temperature for 20 hours on a platelet shaker, and then transferred to IADs. Concentration of 5-[( ⁇ -carboxyethyl)-amino]acridine was monitored over 24 hours.
  • Figure 19 shows 5-[( ⁇ -carboxyethyl)-amino]acridine levels in the supernatant of 300 mL PRBC units exposed to IADs consisting of fiberized Pica G277 activated carbon (500 g/m ) and enclosed by a membrane, woven, or non-woven material.
  • PRBCs (Eiytlirosol, glucose, 62% HCT) were dosed with 300 ⁇ M of a degradable 5-[( ⁇ - carboxyethyl)amino]acridine derivative and 3 mM GSH, and agitated on a platelet shaker at room temperature prior to transfer to the IADs. PRBC-containing IADs were agitated at room temperature for 24 hours.
  • Tetko woven enclosure shows the fastest removal kinetics for 5-[( ⁇ -carboxyethyl)-amino]acridine over 24 hours.
  • Final levels achieved for all enclosure materials after 2 weeks were similar, with 5-[( ⁇ - carboxyethyl)-amino]acridine concentrations decreasing to approximately 2 ⁇ M after 1 day, but rising back to 10 ⁇ M near day 8.
  • the rate of increase of K + in PRBCs varied with the type of adsorbent, with final levels achieved of 40 and 45 mmol/Lfor IvIN-200 and PICA G-277 devices, respectively, compared to the no device control at 39 mmol/L.
  • the percentage of red blood cells lysed in device- exposed and no-device control PRBC units has generally been found to be between 0J and 1% after 24 hours.
  • Table 10 shows lysis values obtained for PRBCs exposed to two types of immobilized adsorption devices over 35 days.
  • Table 11 shows lysis values obtained for PRBCs exposed to loose adsorbent particles enclosed in a woven polyester mesh over 42 days.
  • a wrist action shaker was used in dosing all PRBC units for 1 minute, after which the PRBCs were in a static condition for 4 hours at room temperature.
  • the devices were held at room temperature for 24 hours on a platelet shaker, after which they were in a static condition at 4°C for the duration of the study.
  • the immobilization MN-200 showed lower hemolysis levels than immobilized PICA G-277, while the Ambersorb synthetic carbonaceous adsorbent showed one of the lowest hemolysis levels upon comparison of the loose particle adsordents.
  • the MN-200 IAD showed lower hemolysis than the same non-immobilized adsorbent. Similar observations have been observed for other IADs as compared to the same non-immobilized adsorbent.
  • Table 12 shows a comparative study where supernatants from red blood cell samples containing glutathione and 5-[( ⁇ -carboxyethyl)amino]acridine were contacted with a number of different adsorbents.
  • Activated carbon adsorbents were the only type of adsorbent that was capable of substantially reducing the concentrations of both 5-[( ⁇ -carboxyethyl)-amino]acridine and glutathione. Both natural activated carbons (Norit and PICA) and synthetic activated carbons (Ambersorb) proved to be effective at compound reduction.
  • Fiberized media consisting of Dowex Optipore L-493 attached to a nonwoven polyester fiber matrix (Hoechst-L493) has been manufactured by the
  • Standard removal devices containing 2.5 g of Dowex XUS 43493 were prepared by Baxter Healthcare Corporation (Lot FX1032 D96F20042R). Experimental IADs were prepared with Hoechst-L493 media (Hoechst Celanese
  • Samples of the platelet mixture were removed at 1 hour intervals for the first 8 hours of storage. These samples were stored at 4 °C and later analyzed for residual 4'-(4-amino-2- oxa)butyl-4,5 ',8-trimethyl psoralen by HPLC analysis.
  • the assay involves an initial sample preparation which lyses the platelets and solubilizes the 4 '-(4- amino-2-oxa)butyl-4,5 ',8-trimethyl psoralen and free photoproducts.
  • the supernatant from the sample preparation is analyzed on a C- 18 reverse phase column with a gradient of increasing methanol in KH 2 PO 4 buffer.
  • Platelet mixtures were agitated in contact with the removal devices for 7 days.
  • the platelet mixture was contacted with the IAD for 24 hours and transferred to sterile 1 L PL2410 plastic containers using a sterile tubing welder (Terumo SCD 312). Platelets were placed back in the platelet incubator and stored for the remainder of the 7 day storage period.
  • the platelet count and pH were determined for each platelet unit.
  • the pH and pO2/pCO2 was measured using a CIBA-Corning model 238 Blood Gas .Analyzer.
  • the platelet count of each sample was deteimined using a Baker 9118+ Hematology analyzer.
  • the ability of platelets to aggregate in response to ADP/collagen agonist was indicated by change in optical transmission as measured by a Chrono-Log model 500 VS whole blood aggregometer.
  • Platelet activation as indicated by expression of p-selectin was measured.
  • CD62 antibody was used for the test sample
  • mouse control IgGl was used for the negative control
  • CD62 antibody with phorbal myristate acetate (PMA) was used for the positive control.
  • Samples were analyzed on a FACScan (Becton Dickinson). The percent of activation that is reported is relative to the positive control and is the difference between the test value and negative control value.
  • IADs containing 5.0 g and 7.5 g Hoechst-L493 media to that of a standard removal device containing 2.5 g of loose beads.
  • IADs contained either 5.0 g Hoechst-L493 (triangles), 7.5 g of Hoechst-L493 media (squares), or 2.5 g of loose Dowex L493 adsorbent beads (circles).
  • the Hoechst- L493 media contained adsorbent beads at a loading of 450 g/m 2 .
  • the platelet units within each study were derived from a single pool so that the effect of the IAD media format, adsorbent mass, and contact time could be clearly evaluated.
  • the first study evaluated the effect of fiberization (Hoechst media) on yield and function of the platelets following extended contact (5 and 7 days). A total of four platelet units that were derived from a single pool were used in this study.
  • the no-IAD control unit was treated with psoralen + UV A.
  • Two of the platelet units were contacted with 5.0 g Hoechst-L493. One unit was contacted with the IAD for 24 hours before being transferred to an empty PL 2410 storage container. The other unit remained in contact with the IAD for the duration of the study.
  • the Hoechst-L493 IADs were sterilized with steam (120 °C, 20 min).
  • the standard removal device (2.5 g loose Dowex XUS-43493), which was obtained from Baxter, was sterilized by gamma-irradiation. Note that the platelets were not transfeired away from the standard removal device following 8-16 hour contact as is typically the practice with the device that utilizes loose adsorbent particles. Results from platelet counts and in vitro function following 5 and 7 days of storage are summarized in Table 13A and Table 13B respectively.
  • the platelet yields for the Hoechst-L493 IADs were substantially better than the yield for the standard removal device (2.5 g). Losses of ⁇ 10% were achieved for 7 days of storage in continuous contact with the Hoechst-L493 IAD (5.0 g). Both platelet units that were treated with the Hoechst-L493 IADs displayed better performance in the shape change, aggregation, and GMP-140 assays than the no-IAD control. The platelets that remained in contact with the Hoechst-L493 IAD (5.0 g) for the entire 5 days showed comparable in vitro function to the platelets that were transferred after 24 hours of contact.
  • the second study looked at IADs containing 5.0 g and 7.5 g of Hoechst- L493 media to determine if there was a significant decrease in platelet yield or in vitro function with a higher mass of media.
  • the Hoechst-L493 IADs were sterilized by gamma irradiation.
  • a standard removal device 2.5 g Dowex XUS-43493 was included in the study. Platelets remained in contact with the removal devices for the entire duration of the study. Results from platelet counts and in vitro function following 5 and 7 days of storage are summarized in Table 14A and Table 14B respectively.
  • IADs that were prepared with Hoechst-L493 media (5.0, 7.0 g) resulted in superior in vitro function when compared to standard removal devices (2.5 g loose XUS-43493) stored in contact with the platelets for 5 days.
  • platelets that were treated with 150 ⁇ M 4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen + 3.0 J/cm 2 UVA showed improved in vitro function as indicated by shape change, aggregation, and GMP-140 assays when contacted with Hoechst-L493 IADs (5.0 g) for 5 and 7 days.
  • EXAMPLE 17 Comparison of AQF Fiberized Beads vs. Free Beads in PRBCs. This study compared the removal of S-300 (N-(9-acridinyl)- ⁇ -alanine) and glutathione from PRBC using AQF fiberized vs. free beads of Ambersorb 572.
  • PRBCs were prepared by centrifuging whole blood at 2100 ⁇ m for 5 minutes and expressing off the plasma, then adding 84 mL of Erythrosol per unit.
  • Six ABO matched units were pooled into a 3.0 L Clintec Viaflex bag. Approximately 300 mL was transferred back to each original PL 146 bag and dosed with 6.0 mL of 150 mM glutathione for a final concentration of 3.0 mM and 3.0 mL of 30 mM S-300 derivative for a final concentration of 300 ⁇ M. This was mixed manually and allowed to incubate at room temperature for 4 hours.
  • the PRBCs were transfeired to 1 liter PL 1813 bags containing one of two adso ⁇ tion devices consisting of either 4.8 g of Ambersorb beads in AQF fiberized media (400 g/m ) or 4.8 g of loose Ambersorb beads.
  • the fiberized media or loose beads are enclosed in a Tekto woven mesh pouch.
  • Duplicates were run for each adso ⁇ tion device and a unit in a PL 1813 bag without an adso ⁇ tion device was used as a control. These were stored on a platelet shaker at room temperature for 24 hours, then transferred to storage under static conditions at 4 °C. Units were sampled prior to dosing with the S-300 derivative and glutathione, after treatment but prior to transfer to the adso ⁇ tion devices, and at
  • the results of this experiment suggest that the fiberized resin is preferred over the free beads.
  • the fiberized resin shows equivalent removal of S-300 and glutathione with the benefit of improved red cell function as compared to the free beads.
  • Table 15 shows that the removal of S-300 is similar for the two compound adso ⁇ tion devices. The removal kinetics for glutathione appear to be slightly better for the fiberized beads but is at acceptable levels for either device after 24 hours.
  • Table 16 shows that for red cell functional assays the fiberized resin treated samples are comparable to the control unit. Comparing the two devices, the ATP and pH are essentially the same. The % hemolysis and K + levels are much higher after 24 hours for the free beads, indicating substantial loss or red blood cell function.
  • PRBCs were prepared as one pool and treated as per Example 17. After treatment at room temperature for 4 hours, six units were transferred to IADs consisting of 4.8 g of Ambersorb 572 (AQF manufactured, 400 g/m ) enclosed in a Tekto woven mesh pouch. The IADs were contained in 1 liter PL1813 bags. A control unit was transferred to a PL 1813 bag without an IAD. These were then treated as follows:
  • Example 17 Units were sampled similarly to Example 17. The results indicate that some method of agitation is preferable for the removal of S-300 and glutathione. All modes result in equivalent removal while the orbital shaker shows lower levels of hemolysis than the other methods. Table 17 shows the S-300 and glutathione levels. Table 18 shows the red cell function.
  • PS platelet shaker
  • OS orbital shaker
  • PR platelet rotator
  • N Nutator Table 18 % hemolysis
  • PRBCs were prepared as one pool and treated as per Example 17. After treatment at room temperature for 4 hours, units were transferred to 1 liter PL 1813 bags containing the following:
  • the cellulose acetate membrane is .known to cause complement activation and is used as a positive control. All but unit 2 were treated for 24 hours at room temperature prior to storage under static conditions at 4 °C. Unit 2 was stored at 4 °C continuously. Three 1.5 mL samples were taken from each test article prior to IAD treatment, during treatment after 4, 8, and 24 hours, and 5 days. Each sample was centrifuged at 2000 x g for 15 minutes and 450 ⁇ L of each supernatant was mixed with 50 ⁇ L of cold 200 mM EDTA and vortexed. These were frozen rapidly on dry ice and stored at -70 °C.
  • E.nzyme immunoassays were used to detect the foimation of complement fragments C3a and SC5b-9. Presence of these fragments are an indication of activation of the complement system.
  • the assay involves binding of the target fragment by a mouse antibody which is conjugated to Horse Radish Peroxidase (HRP) and detection using a chromogenic substrate of the HRP. Sample absorbance was measured against a standard curve to calculate the fragment concentration in the sample. Samples were also assessed for S-300, glutathione and hemolysis similarly to Example 17.
  • HRP Horse Radish Peroxidase
  • Hemocompatibihty enhancement of adsorbent by an inert particulate matrix This example demonstrates that immobilization of adsorbent particles in an inert particulate matrix enhances the hemocompatibihty of the adsorbent without substantially impacting removal of low molecular weight compounds.
  • this example supports the contention that immobilizing adsorbent particles in an inert matrix (fiber or particulate) is a general method for enhancing the hemocompatibihty of the adsorbent.
  • results for IADs comprised of adsorbent particles immobilized in a fiber matrix and a particulate matrix are presented below.
  • the media that was studied in this example is comprised of Purolite MN-200 adsorbent particles (200-1200 ⁇ m) immobilized in ultra high molecular weight polyethylene (UHMWPE) particulate matrix.
  • Representative media is manufactured by Porex (Fairburn, GA).
  • Disks of immobilized adsorbent media were formed by mixing approximately 50% (w/w) Purolite MN-200 (200-1200 ⁇ m) with 50% (w/w) UHMWPE particles having a similar particle size. The mixture was placed in a cylindrical cavity and heated under pressure at conditions sufficient to cause the UHMWPE particles to fuse and entrap the adsorbent particles. The resulting disks had a diameter of 3.50 in. and were approximately 0.250 in. thick.
  • the disks weighed approximately 24 g corresponding to approximately 12 g MN-200 in each disk.
  • the IAD was prepared by placing the disk of media in a plastic storage container (PL2410, Baxter Healthcare Co ⁇ .) and the entire assembly was sterilized by irradiating with 25-40 kGy of gamma irradiation (Sterigenics, Hay ward, CA).
  • the fiber matrix IAD was comprised of Purolite MN-200 immobilized in a non- woven polyester matrix at loading of 300 g adsorbent/m 2 .
  • Approximately 2.5 g (adsorbent mass) of immobilized Purolite MN-200 was placed in a pouch constructed from 30 ⁇ m woven polyester material (Tetko, DePew, NY).
  • the pouch assembly was placed in a plastic storage container (PL2410, Baxter Healthcare Co ⁇ .) and the entire assembly was sterilized by irradiating with 25-40 kGy of gamma irradiation (Sterigenics, Hayward, CA).
  • Units of ABO-matched platelet concentrates comprised of platelets (3-5 x 10 11 cells) suspended in approximately 300 mL of 35% autologous plasma, 65% platelet additive solution were obtained from Sacramento Blood Bank (Sacramento, CA). The platelet units were pooled and divided before dosing each unit with 3 mL of 15 mM aminated psoralen (4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen). Each unit was subjected to photochemical treatment by illuminating with 3.0 J/cm2 of UVA in a UNA illumination device (Baxter Healthcare Co ⁇ .).
  • the kinetics of psoralen adso ⁇ tion by each of the IAD embodiments was determined. Samples of each platelet unit (ca. 1 mL) were removed at 2 hour intervals during the first 8 hours of storage. These samples were later analyzed for levels of residual psoralen by High Pressure Liquid Chromatography. Following 5 days of storage at room temperature, the platelet counts, pH, and dissolved gases for each of the units was measured. Platelet function was also assessed by performing in vitro tests which included: shape change, aggregation, hypotonic shock response, GMP-140 (p-selectin expression), and mo ⁇ ohology score. The kinetics for psoralen adso ⁇ tion are shown in Figure 23.
  • the platelet counts, pH measurements, and in vitro platelet function assay results are summarized in Table 21.
  • the fiber and particulate matrix IADs both gave greater than 90% recovery of platelets. This observation is particularly impressive for the particulate IAD considering that it contains about 12 g of MN-200. Note that a removal device that contains 2.5 g of non-immobilized adsorbent particles will typically result in a loss of 25- 35% platelets by day 5. A device containing 12 g of non-immobilized particles would therefore by expected to remove > 50% of the platelets. It is obvious that immobilizing the adsorbent in the particulate matrix has drastically reduced platelet loss while the kinetics of psoralen removal are still very rapid.
  • the particulate matrix IAD may be further optimized from the present configuration by changing the geometry of the disk to allow more complete penetration of the media disk with liquid. A thinner disk would probably result in equivalent removal kinetics with a lower mass of adsorbent.
  • wetting of the device and therefore the adso ⁇ tion kinetics could be further enhanced by increasing the wetting of the media.
  • the inherent hydrophobic nature of the UHMWPE matrix make the device wet slowly during the initial phase of removal.
  • Strategies that could be used to enhance wetting include the use of wetting agents (e.g., glycerol, polyethylene oxide, polyethylene glycol, hydrophilic polymers) or treatment with gas plasma glow discharge. Unlike wetting agents, treatment with glow discharge can be used to directly alter the chemistry of the surface of the UHMWPE binder matrix.

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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/US1998/014134 1998-01-06 1998-07-08 Dispositifs de traitement discontinu permettant de reduire la concentration de composes dans des compositions biologiques contenant des cellules, et procedes associes WO1999034914A1 (fr)

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EP98933264A EP1044066A1 (fr) 1998-01-06 1998-07-08 Dispositifs de traitement discontinu permettant de reduire la concentration de composes dans des compositions biologiques contenant des cellules, et procedes associes
JP2000527349A JP2003523777A (ja) 1998-01-06 1998-07-08 細胞を含む生物学的組成物からの化合物の減少のためのバッチデバイスおよびその使用方法
AU82949/98A AU759966C (en) 1998-01-06 1998-07-08 Batch devices for the reduction of compounds from biological compositions containing cells and methods of use
CA002318508A CA2318508C (fr) 1998-01-06 1998-07-08 Dispositifs de traitement discontinu permettant de reduire la concentration de composes dans des compositions biologiques contenant des cellules, et procedes associes

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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0623361D0 (en) * 2006-11-23 2007-01-03 Techna Display Ltd Connector for use in display frames
CN201710674U (zh) * 2010-03-05 2011-01-19 辛绍祺 吸附隔离装置
CN103037869A (zh) 2010-04-01 2013-04-10 西托索尔本茨公司 治疗炎症的方法
MX2013004688A (es) * 2010-10-27 2013-10-30 Nestec Sa Composiciones para el cuidado de malos olores.
AU2012295350B2 (en) * 2011-08-12 2016-09-22 Cytosorbents Corporation Polymeric sorbent for removal of impurities from whole blood and blood products
US20150174312A1 (en) * 2012-06-11 2015-06-25 Asahi Kasei Medical Co., Ltd. Separation membrane for blood treatment and blood treatment device having same membrane incorporated therein
JP6154678B2 (ja) * 2013-06-28 2017-06-28 旭化成メディカル株式会社 薬剤除去フィルター、薬剤除去システム、及び薬剤除去方法
JP6261282B2 (ja) * 2013-10-21 2018-01-17 旭化成メディカル株式会社 薬剤除去フィルター、薬剤除去システム、及び薬剤除去方法
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230247A2 (fr) * 1986-01-14 1987-07-29 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Adsorbant pour enlever un composant complément
WO1994011556A1 (fr) * 1992-11-18 1994-05-26 Hoechst Celanese Corporation Structure fibreuse contenant un materiau particulaire immobilise et procede de production d'une telle structure
WO1996039818A1 (fr) * 1995-06-07 1996-12-19 Cerus Corporation Traitement de solutions de globules rouges par des agents antiviraux
EP0776668A2 (fr) * 1995-11-28 1997-06-04 Behringwerke Ag Procédé pour éliminer les composés aromatiques des solutions
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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5913244B2 (ja) * 1976-05-12 1984-03-28 本州製紙株式会社 吸着性不織布およびその製造方法
WO1983000023A1 (fr) * 1981-06-24 1983-01-06 Amf Inc Procede de preparation d'un serum a standard zero
US5019311A (en) * 1989-02-23 1991-05-28 Koslow Technologies Corporation Process for the production of materials characterized by a continuous web matrix or force point bonding

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230247A2 (fr) * 1986-01-14 1987-07-29 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Adsorbant pour enlever un composant complément
WO1994011556A1 (fr) * 1992-11-18 1994-05-26 Hoechst Celanese Corporation Structure fibreuse contenant un materiau particulaire immobilise et procede de production d'une telle structure
WO1996039818A1 (fr) * 1995-06-07 1996-12-19 Cerus Corporation Traitement de solutions de globules rouges par des agents antiviraux
EP0776668A2 (fr) * 1995-11-28 1997-06-04 Behringwerke Ag Procédé pour éliminer les composés aromatiques des solutions
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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US9259525B2 (en) 1998-01-06 2016-02-16 Cerus Corporation Adsorbing pathogen-inactivating compounds with porous particles immobilized in a matrix
WO2009023268A1 (fr) * 2007-08-16 2009-02-19 Alltech Associates Inc. Assemblages de colonnes de chromatographie
US10064406B2 (en) 2011-01-06 2018-09-04 Cytosorbents Corporation Polymeric sorbent for removal of impurities from whole blood and blood products
WO2016014854A1 (fr) 2014-07-23 2016-01-28 Cerus Corporation Procédés de préparation de produits contenant des plaquettes
US10842818B2 (en) 2014-07-23 2020-11-24 Cerus Corporation Methods for preparing platelet products
WO2016057965A1 (fr) 2014-10-10 2016-04-14 Cerus Corporation Compositions et méthodes de traitement de la fièvre hémorragique virale
WO2016210374A1 (fr) 2015-06-26 2016-12-29 Cerus Corporation Compositions de cryoprécipités et leurs procédés de préparation
US11096963B2 (en) 2015-06-26 2021-08-24 Cerus Corporation Cryoprecipitate compositions and methods of preparation thereof
WO2017070619A1 (fr) 2015-10-23 2017-04-27 Cerus Corporation Compositions de plasma et leurs procédés d'utilisation
US10799533B2 (en) 2015-10-23 2020-10-13 Cerus Corporation Plasma compositions and methods of use thereof
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WO2017120545A2 (fr) 2016-01-07 2017-07-13 Cerus Corporation Systèmes et méthodes pour la préparation de plaquettes
IL260393B2 (en) * 2016-01-07 2024-06-01 Cerus Corp Systems and methods for preparing platelets
WO2018161020A1 (fr) 2017-03-03 2018-09-07 Cerus Corporation Kits et méthodes de préparation de compositions de plaquettes inactivées par des agents pathogènes
US11235090B2 (en) 2017-03-03 2022-02-01 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
WO2019133929A1 (fr) 2017-12-29 2019-07-04 Cerus Corporation Systèmes et procédés pour traiter de fluides biologiques
US11554185B2 (en) 2017-12-29 2023-01-17 Cerus Corporation Systems and methods for treating biological fluids
WO2019154853A1 (fr) 2018-02-06 2019-08-15 Université De Namur Asbl Procédé de diagnostic de troubles de l'hémostase à l'aide de charbon actif
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CA2318508C (fr) 2004-04-20
JP2003527230A (ja) 2003-09-16
CN1284897A (zh) 2001-02-21
EP1051249A1 (fr) 2000-11-15
AU759541B2 (en) 2003-04-17
AU8295698A (en) 1999-07-26
CN1284896A (zh) 2001-02-21
AU759966C (en) 2004-02-12
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EP1044066A1 (fr) 2000-10-18
WO1999034915A1 (fr) 1999-07-15
CA2318508A1 (fr) 1999-07-15
AU8294998A (en) 1999-07-26
CA2317430A1 (fr) 1999-07-15
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