WO2011070363A1 - Le charbon et son utilisation dans des applications de nettoyage du sang - Google Patents

Le charbon et son utilisation dans des applications de nettoyage du sang Download PDF

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Publication number
WO2011070363A1
WO2011070363A1 PCT/GB2010/052056 GB2010052056W WO2011070363A1 WO 2011070363 A1 WO2011070363 A1 WO 2011070363A1 GB 2010052056 W GB2010052056 W GB 2010052056W WO 2011070363 A1 WO2011070363 A1 WO 2011070363A1
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Prior art keywords
carbon
resin
blood
size
contrary
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PCT/GB2010/052056
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English (en)
Inventor
Stephen Robert Tennison
Oleksandr Prokopovyeh Kozynchenko
Anthony Paul Rawlinson
Gary James Phillips
Carol Angela Howell
Susan Rachel Sandeman
Sergey Victorovich Mikhalovsky
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Mast Carbon International Ltd
University Of Brighton
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Priority to EP15186129.1A priority Critical patent/EP2985046B1/fr
Priority to EP10801449A priority patent/EP2531231A1/fr
Priority to US13/513,340 priority patent/US9278170B2/en
Publication of WO2011070363A1 publication Critical patent/WO2011070363A1/fr
Priority to US15/061,656 priority patent/US9700561B2/en

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    • 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
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • 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
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3496—Plasmapheresis; Leucopheresis; Lymphopheresis
    • 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
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • 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
    • A61M1/362—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits changing physical properties of target cells by binding them to added particles to facilitate their subsequent separation from other cells, e.g. immunoaffinity
    • 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/0057—Special media to be introduced, removed or treated retained by adsorption
    • 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0405—Lymph
    • A61M2202/0407—Lymphocytes
    • 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/07—Proteins
    • 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/08—Lipoids
    • 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/20—Pathogenic agents
    • A61M2202/203—Bacteria

Definitions

  • This invention relates to microporous/mesoporous or microporous/macroporous carbon and its use for the removal from blood of substances contrary to health.
  • These include externally introduced toxins such as bacterially derived staphylococcus enterotoxins A, B, TSST-1 or autologous, biologically active molecules with harmful, systemic effects when their activity is excessive or unregulated. Examples include the removal of inappropriate amounts of pro- or anti-inflammatory molecules and toxic mediators of systemic inflammatory response syndrome related to sepsis, cardiopulmonary by-pass surgery, ischaemic reperfusion injury; the removal of larger molecular weight and protein bound uremic and liver toxins related to chronic kidney and liver failure respectively, the removal of toxins relevant to biological and chemical warfare.
  • End-stage renal failure is an increasingly prevalent and disproportionately costly condition.
  • the majority of patients receiving renal replacement therapy (R T) undergo haemodialysis (HD) which primarily removes small water soluble molecules.
  • HD haemodialysis
  • ESRF maintains a high morbidity and mortality rate despite improved therapy options.
  • a complex picture is emerging of the pathophysiology associated with CKD progression in which newly identified uremic toxins not removed by HD appear to play a central role.
  • a clinically effective and cost efficient device could transform ESRF patient care.
  • Uremic toxin retention in renal failure is a complex problem that cannot be adequately modelled by measuring simple markers like urea and creatinine.
  • Middle molecules and protein bound molecules are not very efficiently removed by current dialysis therapies and may be very important mediators of pathology associated with chronic kidney disease.
  • the removal of currently "difficult to remove" uremic toxins may diminish complications, extending and greatly improving patient quality of life. No cost-effective and clinically efficient devices exist currently.
  • US-A-4169051 Satoh is concerned with the use of activated carbon as an adsorbent for the purification of blood in dialysis patients. It discusses the use of crushed activated carbon of vegetable origin but mentions problems of carbon dust and platelet adhesion which are not overcome by coating. Furthermore the crushed activated carbon cannot adsorb materials of medium molecular weight e.g. so-called "kidney toxin". Molecular weight in this context is explained in US 5194157 Ghezzi, "medium molecules” being defined as those of molecular weight 300-1500 D. Granular activated carbon was said to have superior properties with regard to dust but is poorly adsorbent.
  • the proposed solution is to use beads of activated carbon derived from pitch and coated with a semi-permeable film-forming material selected from pyroxylin, polypropylene, vinyl chloride- vinylidene chloride copolymer, ethylene glycol polymethacrylate and collagen.
  • beads are formed from pitch softening at 205°C which was melt-dispersed into water using benzene and aqueous polyvinyl alcohol as suspending agent to form beads which were heated in a fluidized bed to remove benzene, carbonised in nitrogen at 1000°C and coated with pyroxylin.
  • the resulting beads were said to be able to remove kidney toxin from blood and to exhibit only slight platelet adhesion, which could be avoided completely by coating with albumen.
  • US-A-5194157 Ghezzi prefers to use vegetable-derived activated carbon in the form of microgranules which have "a multitude of minute channels opening in corresponding pores on its surface", a contact surface area of up to 1000 m 2 /g and adsorption spectrum of 100-20000D, but to use that material only in relation to an ultrafiltrate from which blood corpuscles have been removed.
  • RU-C-2119351 Petrik discloses separation of plasma from blood and treatment of the plasma with expanded graphite and carbon nanotubes to remove uric acid and creatine.
  • US-A-2004/0141932 Umekawa et al. discloses a medical adsorbent comprising activated carbon obtained by carbonising and activating a spherical phenolic resin. However, only microporoisty is indentified and there is no disclosure or suggestion of incorporating mesoporosity into the resin.
  • GB-A-2025385 Murakama et al.
  • spherical active carbon made by suspension polymerization of styrene/divinylbenzene, treatment of the resulting polymer with S0 3 to make it infusible, followed by carbonisation and activation.
  • mesopores or active macropores are stated to be substantially all of size ⁇ 500 A, preferably ⁇ 20 ⁇ so as to substantially avoid adsorption of high molecular weight materials such as blood serum protein.
  • WO 2005/099789 Tennison is concerned with the treatment of sepsis by removal of inappropriate amounts of pro or anti- inflammatory mediators e.g. IL-4, IL,6, IL,8, IL-10, IL-11 , IL-13 and IL-1. It discloses passing blood through a monolithic porous carbon structure. Plasma components are allowed to pass through the walls of the monolith. Two streams are thereby formed: a plasma permeate stream that has passed through the walls of the monolith and a retentate stream containing the majority of the blood cells.
  • the monolithic porous carbon through which the blood plasma passes may have a mean pore size > 500 nm and pores of size 2-500 nm within the carbon matrix for adsorption of middle and high molecular weight molecules.
  • One embodiment of the monolith is tubular and another embodiment has rectangular channels of size 100-2000 ⁇ , wall thickness 100-2000 ⁇ and open area 30-60%.
  • the monolithic porous structure may have a surface area of at least 600 m 2 /g.
  • Preferred products are derived from resin of powder size 20-75 ⁇ which provides for a macropore size of 4-15 ⁇ and a macropore volume of about 40%.
  • WO 2007/070455 Gogotsi explains that even advanced activated carbons exhibit only partial performance in adsorption of large inflammatory proteins, mostly due to a limited surface area accessible to the adsorbate. It discloses a carbon composition produced from a carbon-containing inorganic precursor e.g. a ternary carbide such as Ti 2 AlC or carbonitride which was said to have a large surface area accessible to cytokines e.g. TNF and IL-6.
  • a carbon-containing inorganic precursor e.g. a ternary carbide such as Ti 2 AlC or carbonitride which was said to have a large surface area accessible to cytokines e.g. TNF and IL-6.
  • a novel, finely controlled multi-porous and surface structure activated carbon material can be used for the direct and effective removal of cytokines, uremic toxins, liver toxins and other biologically active molecules such as bacterial endotoxin and exotoxin from blood without prior separation of the blood into cells and plasma. This occurs with no detectable degradation of the blood cells and without any significant blocking of the carbon surface due to platelet adhesion. Other adverse effects including haemolysis, cytotoxicity, activation of white blood cells leading to an inflammatory cascade have not been noted. Treatment of plasma cannot be equated with treatment of whole blood since the possibility of adverse effects on the blood cells cannot be ignored.
  • the carbon may be uncoated so that the range of pores within it are available for adsorption of contrary substances, whereas coated carbons have no or limited capacity to adsorb middle and larger molecular weight proteins.
  • the invention provides a method for extracorporeal treatment of whole blood to remove contrary substances described herein and provide treated blood returnable to the body, which method comprises contacting the blood with microporous/mesoporous or microporous/macroporous carbon.
  • the blood may be from a patient with end-stage renal failure who is receiving hemodialysis (HD), that does not remove protein bound and larger molecular weight uremic toxins which remain in the body, impairing cardiovascular function and contributing to the morbidity and mortality of patients.
  • HD hemodialysis
  • the carbon provides an effective sorbent adjunct to augment HD wherein the incoming stream from the patient is cleaned of remaining uremic toxins with the treated blood for return to the bloodstream of the patient.
  • the blood may alternatively be from a patient with liver failure, where build-up of hepatic toxins can result in conditions such as Hepatic encephalopathy and jaundice caused by increased levels of bilirubin.
  • the carbon provides an effective sorbent to remove the build-up of hepatic toxins in acute or acute-on-chronic liver failure, wherein the incoming stream from the patient is cleansed of hepatic toxins with the treated blood for return to the bloodstream of the patient.
  • the invention uses in some embodiments a highly porous, multi-modal, synthetic pyrolysed carbon for use as an adsorbent blood filtration module to augment HD and for other blood purification applications.
  • Bimodal micro/meso and micro/macro porous carbon materials have been developed for direct contact with blood.
  • the carbons are haemocompatible (Assessing the in vitro biocompatibility of a novel device for the treatment of sepsis, Biomaterials, 23(205) 7124 Sandeman et al) and can remove middle molecular weight inflammatory cytokines and bacterial toxins implicated in the progression of sepsis and other systemic inflammatory conditions and in a size range suggesting suitability additionally for removal of the larger molecular weight and protein bound uremic and liver toxins.
  • the present carbons in bead and monolith form have been shown to remove protein bound uremic toxins from human plasma.
  • the present carbon beads have been shown to remove the protein bound liver toxin bilirubin from human plasma.
  • the tailored porosity of the carbons and superior surface area available for adsorption permits removal of key protein bound and larger uremic toxins not removed by current RRT.
  • a method for the treatment of blood which comprises passing the blood through either a bed of the controlled structure carbon in bead form where the bed can comprise either a packed bed of the beads, or the beads immobilised in a porous polymeric carrier or through an open monolithic structure where the blood passes along the channels of the monolith.
  • the latter channel structure has the benefit of a low pressure drop but is less effective in the adsorption of the macromolecules due to the hydrodynamic characteristics of the channel structure. Nonetheless satisfactory removal can still be achieved by continuous recycle of the blood from the patient, through the device and back to the patient.
  • a haemoperfusion renal assist device may be provided that could run in line with current dialysis membranes, consisting of a haemocompatible medical grade carbon monolith with a pore structure tailored to remove middle molecules and protein bound uremic toxins, or with a similar removal; system based on small carbon beads, and may provide toxin removal and may result in improved patient outcome, an enhanced quality of life, and a reduction in complications associated with CKD.
  • current dialysis membranes consisting of a haemocompatible medical grade carbon monolith with a pore structure tailored to remove middle molecules and protein bound uremic toxins, or with a similar removal; system based on small carbon beads, and may provide toxin removal and may result in improved patient outcome, an enhanced quality of life, and a reduction in complications associated with CKD.
  • the ability to remove both small molecules and larger molecules via the mesoporous or active microporous structure of the carbon may be of assistance.
  • Fig 1 is a trimetric view of a monolith showing a longitudinal channel structure thereof, accompanying detail views showing macroparticles forming the wall structure of the monolith and micro-domains of an individual particle;
  • Fig. 2 shows nitrogen adsorption isotherms (a) and calculated pore size distributions (b) (BJH model) of activated carbons;
  • Fig. 3 is a graph of dV/d(log d) against diameter d for a carbon monolith, the data being obtained by mercury porosimetry;
  • Figs 4-17 are bar charts, graphs and micrographs showing results obtained with carbon monoliths and carbon beads contacting human plasma and whole blood spiked with contrary substances.
  • Whole blood may be treated extracorporeally to remove substances contrary to health using mesoporous/microporous or macroporous/microporous carbon in the form of beads or a channel monolith.
  • the carbon may be the result of carbonising a mesoporous or macroporous phenolic resin.
  • the contrary substances include externally introduced toxins such as bacterially derived staphylococcal enterotoxins A, B, TSST-1 or autologous, biologically active molecules with harmful, systemic effects when their activity is excessive or unregulated.
  • Examples include the removal of inappropriate amounts of pro- or anti-inflammatory molecules and toxic mediators of systemic inflammatory response syndrome related to sepsis, cardio-pulmonary by-pass surgery, ischaemic reperfusion injury; the removal of larger molecular weight and protein bound uremic toxins related to chronic kidney and liver failure; the removal of toxins relevant to biological and chemical warfare.
  • the contrary substances which can be removed from the blood include:
  • free water soluble low mol weight solutes eg creatinine, urea, ADMA (asymmetrical dimethylarginine);
  • protein bound solutes eg leptin peptide, p-cresol sulphate, indoxyl sulphate, AGE (advanced glycation end products);
  • middle MW and large molecules including bacterial endotoxins e.g. Lipopolysaccharide (LPS); exotoxins e.g. Staphylococcal aureus entertotoxin A (SEA), Staphylococcal aureus entertotoxin B (SEB), toxic shock syndrome toxin 1 (TSST-1)); cytokines; circulating pro and anti-inflammatory mediators e.g.IL- ⁇ , IL-4, IL-6, IL-8, IL-10, IL-11, IL-13, and TNF .
  • bacterial endotoxins e.g. Lipopolysaccharide (LPS); exotoxins e.g. Staphylococcal aureus entertotoxin A (SEA), Staphylococcal aureus entertotoxin B (SEB), toxic shock syndrome toxin 1 (TSST-1)
  • cytokines circulating pro and anti-inflammatory mediators e.g.IL- ⁇ , IL-4, IL-6, IL
  • micropore refers to a pores with diameter ⁇ 2 nm, as measured by nitrogen adsorption and mercury porosimetry methods and as defined by IUPAC.
  • pores refers to pores with diameter from ca. 2 nm to ca. 50 nm, as measured by nitrogen adsorption and mercury porosimetry methods and as defined by IUPAC.
  • macropore refers to pores with diameters larger than 50 nm, as measured by nitrogen adsorption and mercury porosimetry methods and as defined by IUPAC.
  • macroporous beads they are located within beads and formed by pore-formers. Their size is 50-500nm, typically 70 - 200 nm. These macropores are very effective in adsorption of cytokines.
  • simple monoliths there are macropores present that are formed due to the voids between sintered particles. Their size is typically 700 - 2000 nm. These macropores do not work for cytokines adsorption and that is why monoliths with more complex pore structures comprising micropores, small macropores and large macropores have had to be created.
  • a precursor resin formulation which comprises a large proportion of pore former, e.g.
  • WO 02/12380 discloses making a mesoporous resin by condensing a nucleophilic component which comprises a phenolic compound or a phenol condensation prepolymer with at least one electrophilic cross-linking agent selected from formaldehyde, paraformaldehyde, furfural and hexamethylene tetramine in the presence of a pore-former selected from the group consisting of a diol (e.g.
  • the pore-former is present in an amount effective to impart meso- or macroporosity to the resin (e.g. at least 120 parts by weight of the pore former being used to dissolve 100 parts by weight of the total resin forming components, i.e. nucleophilic component plus electrophilic component), and it is removed from the porous resin after condensation by cascade washing with water or by vacuum drying.
  • the resulting resin may be carbonised by heating in an inert atmosphere to a temperature of at least 600°C to give a material having a bimodal distribution of pores, the pore structure as estimated by nitrogen adsorption porosimetry comprising micropores and mesopores or macropores.
  • the value for the differential of pore volume with respect to the logarithm of pore radius (dV/dlogR) for the mesopores is greater than 0.2 for at least some values of pore size in the range 20-500A.
  • the mesoporous carbon may have a BET surface area of 250-800m 2 /g without activation. It may be activated by heating it at high temperature in the presence of carbon dioxide, steam or a mixture thereof, e.g.
  • BET surface area is determined by the Brunauer, Emmett, and Teller (BET) method according to ASTM D 1993-91, see also ASTM D6556-04.
  • Phenolic resins - nucleophilic component Resins for making carbonaceous material can be prepared from any of the starting materials disclosed in WO 02/12380.
  • Nucleophilic components may comprise phenol, bisphenol A, alkyl phenols e.g. cresol, diphenols e.g. resorcinol and hydroquinione and aminophenols e.g. m-amino-phenol.
  • nucleophilic component a phenolic novolac or other similar oligomeric starting material which because it is already partly polymerized makes polymerization to the desired resin a less exothermic and hence more controllable reaction.
  • the preferred novo lacs have average molecular weights (AMW) in the range of from 300 to 3000 prior to cross-linking (corresponding to a DP with respect to phenol of about 3-30). Where novolac resins are used, they may be solids with melting points in the region of 100°C.
  • Novolac resins of AMW less than 2000 and preferably less than 1500 form resins which on carbonisation tend to produce carbons with desired pore size distributions using lower amounts of pore former.
  • Novolacs are thermally stable in that they can be heated so that they become molten and cooled so that they solidify repeatedly without structural change. They are cured on addition of cross-linking agents and heating. Fully cured resins are infusible and insoluble.
  • modifying reagents Whilst commercial novolacs are largely produced using phenol and formaldehyde, a variety of modifying reagents can be used at the pre-polymer formation stage to introduce a range of different oxygen and nitrogen functionalities and cross- linking sites. These include but are not limited to: -
  • Dihydric phenols e.g. resorcinol and hydroquinone. Both are more reactive than phenol and can lead to some cross-linking at the pre-polymer production stage. It is also possible to introduce these compounds at the cross-linking stage to provide different cross-linking paths. These also increase the oxygen functionality of the resins.
  • Nitrogen containing compounds that are active in polycondensation reactions such as urea, aromatic (aniline, m-amino phenol) and heteroaromatic (melamine) amines. These allow the introduction of specific types of nitrogen functionality into the initial polymer and final carbon and influence the development of the mesoporous structure of both the resins and the final carbons.
  • urea aromatic (aniline, m-amino phenol) and heteroaromatic (melamine) amines.
  • the nucleophilic component may be provided alone or in association with a polymerization catalyst which may be a weak organic acid miscible with the novolac and/or soluble in the pore former e.g. salicylic acid, oxalic acid or phthalic acid.
  • a polymerization catalyst which may be a weak organic acid miscible with the novolac and/or soluble in the pore former e.g. salicylic acid, oxalic acid or phthalic acid.
  • the concentration of novolac in the pore former may be such that when combined with the solution of cross-linking agent in the same pore former the overall weight ratio of pore former to (novolac + cross-linking agent) is at least 125: 100 by weight.
  • the actual ratios of novolac :pore former and cross-linking agentpore former are set according to convenience in operation e.g. in the case of the process disclosed in WO 2008/043983 (Tennison) by the operational requirements of a bead production plant and are controlled by the viscosity of the novolac:pore former solution such that it remains pumpable and by the ratio of cross-linking agentpore former such that the corss-linking agent remains in solution throughout the plant.
  • the cross-linking agent is normally used in an amount of from 5 to 40 parts by weight (pbw) per 100 parts by weight of the nucleophilic components e.g. novolac,. It may be, for example, an aldehyde e.g. formaldehyde or furfural, it could be hexamethylenetetramine (hexamine), or hydroxymethylated melamine.
  • Hexamine is preferably used as cross-linking agent.
  • it is preferably used for cross-linking novolac resin at a proportion of 10 to 25 pbw e.g. about 15 to 20 pbw hexamine per 100 pbw of novolac. This ensures formation of the solid resin with maximal cross-linking degree and ensures the stability of the mesopore structure during subsequent removal of the pore former.
  • the pore former also acts as solvent.
  • the pore former is preferably used in sufficient quantities to dissolve the components of the resin system, the weight ratio of pore former to the total components of the resin system resin being preferably at least 1.25: 1. Details of suitable pore formers are given in WO 02/12380 (Tennison).
  • the pore former may be, for example, a diol, a diol-ether, a cyclic ester, a substituted cyclic or linear amide or an amino alcohol e.g.
  • ethylene glycol 1,4-butylene glycol, diethylene glycol, triethylene glycol, ⁇ -butyro lactone, propylene carbonate, dimethylformamide, N-methyl-2-pyrrolidinone and monoethanolamine, ethylene glycol being preferred, and where the selection is also limited by the thermal properties of the solvent as it should not boil or have an excessive vapour pressure at the temperatures used in the curing process.
  • the pore former In the presence of a low level of pore former the pore former is compatible with, and remains within, the cross- linked resin domains, (e.g., ⁇ 120 parts/100 parts Novolac for the Novolac-Hexamine- Ethylene Glycol reaction system), whilst the remainder forms a solution with the partially cross-linked polymer between the domains.
  • the pore former adds to the light polymer fraction increasing the volume of material in the voids between the domains that gives rise to the mesoporosity and/or macroporosity.
  • the higher the pore former content the wider the mesopores, up to macropores, and the higher the pore volume.
  • This phase separation mechanism provides a variety of ways of controlling the pore development in the cross-linked resin structures. These include chemical composition and concentration of the pore former; chemical composition and quantity of the cross-linking electrophilic agents, presence, chemical nature and concentration of modifying nucleophilic agents, chemical composition of phenolic nucleophilic components (phenol, novo lac), the presence of water within the solvent and concentration of any curing catalyst if present.
  • Production of the resin in both powder and bead form is disclosed.
  • Production of the bead form may be by pouring a solution of a partially cross-linked pre-polymer into a hot liquid such as mineral oil containing a dispersing agent and stirring the mixture.
  • the pre-polymer solution forms into beads which are initially liquid and then, as curing proceeds, become solid.
  • the average bead particle size is controlled by several process parameters including the stirrer type and speed, the oil temperature and viscosity, the pre-polymer solution viscosity and volume ratio of the solution to the oil and the mean size can be adjusted between 5 and 2000 ⁇ , although in practice the larger bead sizes are difficult to achieve owing to problems with the beads in the stirred dispersion vessel.
  • the beads can then be filtered off from the oil.
  • industrial novolac resin is mixed with ethylene glycol at an elevated temperature, mixed with hexamine and heated to give a viscous solution which is poured into mineral oil containing a drying oil, after which the mixture is further heated to effect curing.
  • the reaction mixture is cooled, after which the resulting porous resin is filtered off, and washed with hot water to remove pore former and a small amount of low molecular weight polymer.
  • the cured beads are carbonized to porous carbon beads which have a pore structure as indicated above, and may be activated as indicated above. It is stated that the beads can be produced with a narrow particle size distribution e.g.
  • WO 2008/043983 describes and claims a process for producing discrete solid beads of polymeric material e.g. phenolic resin having a porous structure, which process may produce resin beads on an industrial scale without aggregates of resin building up speedily and interrupting production.
  • the process comprises the steps of: (a) combining a stream of a polymerizable liquid precursor e.g. a novolac and hexamine as cross-linking agent dissolved in a first polar organic liquid e.g. ethylene glycol with a stream of a liquid suspension medium which is a second non-polar organic liquid with which the liquid precursor is substantially or completely immiscible e.g.
  • transformer oil containing a drying oil (b) mixing the combined stream to disperse the polymerizable liquid precursor as droplets in the suspension medium e.g. using an inline static mixer; (c) allowing the droplets to polymerise in a laminar flow of the suspension medium so as to form discrete solid beads that cannot agglomerate; and (d) recovering the beads from the suspension medium.
  • the pore former comprises a polar organic liquid e.g. ethylene glycol chosen in combination with dispersion medium which is a non-polar organic liquid so as to form a mainly or wholly immiscible combination, the greater the incompatibility between the pore former which forms the dispersed phase and the dispersion medium, the less pore former becomes extracted into the dispersion medium.
  • the pore former desirably has a greater density than the dispersion medium with which it is intended to be used so that droplets of the pore former containing dissolved resin- forming components will pass down a column more rapidly than a descending flow of dispersion medium therein.
  • the pore former should also, in the case of phenolic resins, be compatible with water and/or other minor condensation products (e.g. ammonia) which are formed by elimination as polymerization proceeds, and the pore former is preferably highly miscible with water so that it can be readily removed from the polymerized resin beads by washing.
  • minor condensation products e.g. ammonia
  • the dispersion medium is a liquid which can be heated to the temperature at which curing is carried out e.g. to 160°C without boiling at ambient pressure and without decomposition and which is immiscible with ethylene glycol and with the dissolved components therein.
  • It may be hydrocarbon-based transformer oil which is a refined mineral oil and is a by-product of the distillation of petroleum. It may be composed principally of C15-C40 alkanes and cycloalkanes, have a density of 0.8-0.9 depending upon grade and have a boiling point at ambient pressure of 260-330°C, also depending upon grade.
  • Transformer oil has a viscosity of about 0.5 poise at 150°C which is a typical cure temperature.
  • Transformer oil or other dispersion medium may be used in volumes 3-10 times the volume of the combined streams of nucleophilic precursor and crosslinking agent e.g. about 5 times.
  • Preferred dispersing agents which are dissolved in the dispersion medium before that medium is contacted with the reaction mixture to be dispersed therein to retard droplet coalescence are either sold as drying oils e.g. Danish oil or are produced by partially oxidizing naturally occurring precursors such as tung oil, linseed oil etc.
  • the dispersing agents are consumed as the process proceeds, so that if the dispersion medium is recycled, dispersing agent in the recycled oil stream should be replenished.
  • the dispersing agent is conveniently supplied as a stream in solution in the dispersion medium e.g. transformer oil and e.g.
  • the resin beads formed as described above may be carbonised and optionally activated.
  • WO 2008/043982 (Tennison, the disclosure of which is incorporated herein by reference) there is provided a process for carbonizing and activating carbonaceous material and especially the solid beads of polymeric material resulting from the process of WO 2008/043983, which comprises supplying the material to an externally fired rotary kiln maintained at carbonizing and activating temperatures, the kiln having a downward slope to progress the material as it rotates, the kiln having an atmosphere substantially free of oxygen provided by a counter-current of steam or carbon dioxide, and annular weirs being provided at intervals along the kiln to control progress of the material.
  • a continuous channel structure is defined by a channel dimension, W, and a wall thickness, t, or for an asymmetric monolith by channel length and width or other relevant dimensions as well as wall thickness t. These fix the ratio of open to closed area and therefore the flow velocity along the channels of the monolith.
  • the walls of the monolithic carbon have a macroporous structure providing continuous voids or pores generated by the voids between the resin particles as shown in Fig. 1.
  • the green body is then further fired to pyrolyse the binder and this is then typically further activated in steam, air, carbon dioxide or mixtures of these gases to give the high surface activated carbon product.
  • the drawback to this route is that the binder, which is usually a thermoplastic material, goes through a melting transition prior to pyrolytic decomposition. At this point the material is weak and unable to support a complex form. This, combined with the problems of activating the fired body, limits the size and shape of the products to typically simple extrudates.
  • An alternative route is to take an activated carbon powder and form this directly into the final shape. In this instance a range of polymeric binders have been used that remain in the final product.
  • the main drawback to this route is that high levels of binders are required and these then tend to both fill the pores of the activated carbon powder and encapsulate the powder leading to a marked reduction in adsorption capacity and deterioration in the adsorption kinetics.
  • the presence of the polymeric phase also degrades the physical and chemical stability of the formed material, severely limiting the range of applicability.
  • a further alternative is to take a formed ceramic material, such as a multichannel monolith, and to coat this with a carbon forming precursor such as a phenolic resin; this can then be fired and activated to produce a ceramic-carbon composite.
  • the main limitations of this route are the cost associated with the ceramic substrate and the relatively low volume loading of carbon. At high degrees of activation it is possible to produce a mesoporous carbon although the carbon volumetric loading and the mechanical stability of the carbon is further reduced.
  • carbonised and optionally activated monoliths are now formed from phenolic resin precursors.
  • Monolithic porous carbon can be made by partially curing a phenolic resin to a solid, comminuting the partially cured resin, forming the comminuted particles into a dough by the addition of water and extrusion agents such as MethocellTM , and extruding the dough to form a resin monolith. Provided that the cure of the resin was carried out correctly the resin particles sinter without the application of heat so as to produce a form-stable sintered resin product and then the form- stable sintered product is carbonised andactivated.
  • EP 0 254 551 gives details of methods of production of the porous resins suitable for forming the porous carbon used in the present invention and its contents are included herein by reference.
  • WO 02/072240 (Place et al. the disclosure of which is incorporated herein by reference) gives details of producing monolithic structures using the sintered resin structures of EP-A- 0254551.
  • the resin cure is controlled so that it is sufficient to prevent the resin melting during subsequent carbonisation but low enough that the particles produced during the milling step can sinter during subsequent processing.
  • the temperature and duration of the partial curing step are selected as to give a degree of cure sufficient to give a sinterable product, and such that a sample of the partially cured solid when ground to produce particles in the size range 106-25 ⁇ and tabletted in a tabletting machine gives a pellet with a crush strength which is not less than 1 N/mm.
  • the pellet after carbonisation has a crush strength of not less than 8 N/mm.
  • sintering we mean a step which causes the individual particles of phenolic resin to adhere together without the need for a separately introduced binder, while retaining their individual identity to a substantial extent on heating to carbonisation temperatures.
  • the particles must not melt after forming so as to produce a molten mass of resin, as this would eliminate the internal open porosity of the article.
  • the open porosity (as opposed to the closed cells found in certain types of polymer foams) is believed to be important in enabling formed particles to retain their shape on carbonisation.
  • the comminuted resin particles have a particle size of 1- 250 ⁇ , more preferably 10-70 ⁇ .
  • the resin powder size is 20-50 ⁇ which provides for a macropore size of 4-10 ⁇ with a macropore volume of around 40%.
  • the size of the particles is selected to provide a balance between diffusivity through the interparticle voids and within the particles.
  • the milled powder can then be extruded to produce polymeric monolithic structures with a wide range of cell structures, limited only by the ability to produce the required extrusion die and suitable dies are available commercially.
  • the monolith has a bimodal structure - the visible channel structure with either the central channel in a simple tube or the open cells in a square channel monolith of 100-1000 ⁇ cell dimension and cell walls with thickness 100- ⁇ and the macropore structure within the walls generated by the sintered resin particles.
  • the carbonisation steps take place preferably by heating above 600°C for the requisite time e.g. 1 to 48 hours and takes place under an inert atmosphere or vacuum to prevent oxidation of the carbon.
  • the material loses about 50% weight and shrinks by about 65 % volume but, provided the resin cure stage was correctly carried out, this shrinkage is accommodated with no distortion of the monolith leading to a physical structure identical to that of the resin precursor but with dimensions reduced by ⁇ 30%.
  • the macropore size is also reduced by ⁇ 30%> although the macropore volume (ml/ml) remains unaltered.
  • the microporosity of the porous carbon develops. After carbonisation there may be partial blocking of the micropores by the decomposition products from the carbonisation process. These blockages may be removed by activation to provide rapid access to the internal structure of the carbon that is essential for the operation of the monoliths as adsorption devices.
  • an embodiment of a standard monolith production process comprises the steps of (i) pouring a mixture of novolak, cross-linking agent (hexamine) and pore former (ethylene glycol) into a tray, (ii) partially curing e.g.
  • the partially cured resin should be in a sinterable state, and that requirement limits the amount of cross-linking agent that can be used.
  • the standard process used by the applicants for making micro/macroporous monolithic carbon from phenolic resins uses 5 parts by weight of hexamine as cross- linking agent, but if the same amount is used in the production sequence indicated above the induced mesoporosity collapses during pore former removal. It is therefore desirable to increase the proportion of cross-linking agent to an amount sufficient to stabilise the mesoporous structure but less than an amount that prevents the partially cured resin from sintering.
  • the monoliths of the current invention have been produced with 16 or 20 parts hexamine along with mesoporous resin produced with at least 150 parts ethylene glycol to 100 parts resin in the block cure process described above.
  • the walls of the monolithic carbon have a macroporous structure.
  • macroporous is meant that the carbon has continuous voids or pores. The macropore structure in the walls of a monolith is controlled by the particles used to form the monolith.
  • the macro pore size is typically 20% of the size of the precursor resin particles. This can be varied over a wide range from a maximum particle size of approximately 10% of the wall thickness, t, to a minimum practical particle size of about ⁇ . This gives a macropore size of 2-20 ⁇ within the wall for a 1mm wall thickness. The pore size fixes the diffusivity of the adsorbate molecules within the matrix.
  • the monoliths are square channel monoliths with a cell structure (cells per square cm) where the channel size is between 100 and 2000 ⁇ and the wall thickness is between 100 and 2000 ⁇ and with an open area of between 30 and 60% to give a good carbon packing density per unit volume and acceptable mass transfer characteristics.
  • Activated carbon materials for blood filtration in the present patent application have been prepared by the generic methods described below though they may be prepared also by numerous variations of this method according to WO 02/12380 and WO 2008/043983.
  • mesoporous or macroporous resin-precursors for carbons may be prepared in blocks, then crushed, washed with water or vacuum-dried from ethylene glycol and further processed into monoliths.
  • the following examples illustrate a number of experiments conducted using whole blood and further experiments using plasma.
  • the plasma experiments are used to model the ability of certain carbons to remove materials from whole blood.
  • the resulting clear solution was poured in a stream into 2.5-6 fold volume of stirred hot (150-155°C) low viscosity mineral oil (insulating oil or transformer oil) containing 0.2 - 1% (v/v) of a dispersing agent which was an industrial drying oil (Danish oil), a major component being polyunsaturated (oxidised) vegetable oils.
  • a dispersing agent which was an industrial drying oil (Danish oil), a major component being polyunsaturated (oxidised) vegetable oils.
  • the temperature of the mixture fell to 135-140°C, and the mixture was reheated to 150- 155°C over a period of 15-20 minutes. Typically curing occurred within 1-2 minutes at around 140°C followed by substantial evolution of gas, predominantly ammonia. The further heating to 150-155°C for 15-20 minutes ensured the completion of curing.
  • Water-washed wet, dried or vacuum-dried resin beads were heat treated to produce carbon materials.
  • a typical procedure comprised but is not restricted to carbonisation in a flow of carbon dioxide with temperature ramping from ambient to 800°C at 3°C/min, classification by particle size and further "physical" activation of selected fraction in carbon dioxide flow at 900°C. Many variations of this routine known in the art may also be applied.
  • Pore size distribution in the resulting carbons is pre-determined by the porosity of the resin-precursor, which is controlled by the content of the solvent/pore former (typically but not restricted to ethylene glycol) in the resin composition.
  • Table 1 gives details of three resins compositions that are precursors to micro-, meso- and macro-porous carbons, as illustrated by nitrogen adsorption tests of activated materials used in adsorption studies (up to -40% of activation burn-off in carbon dioxide) (Figs. 2a and 2b).
  • the particle size distribution of resulting resin beads depends on various parameters including but not restricted to the type of stirring tool, stirring rate, viscosity of the resin solution, concentration of the dispersing agent, resin solution to oil ratio and temperature of the dispersion. Though the distribution is typically broad the size of the predominant fraction could effectively be shifted between ⁇ 10 micron and ⁇ 1 mm.
  • Fig. 2 shows nitrogen adsorption isotherms (a) and calculated pore size distributions (BJH model) (b) of activated carbons derived from the resins of examples 1,2 and 3 respectively (compositions from Table 1):
  • a hot solution of 100 parts by weight of Novolac resin in 100 w.p. of ethylene glycol was thoroughly mixed with a hot solution of 16 parts by weight of hexamine in 190 parts by weight of ethylene glycol.
  • the resulting solution was transferred into a stainless steel tray, covered with a lid and placed into flameproof oven. Raising the temperature to 150°C and maintaining it for 1-4 hrs ensured formation of a solid cross- linked resin cake from a resin solution. After crushing the cake into ⁇ 1cm pieces of resin it was either dried in vacuum at 110-130°C or washed repeatedly with hot (90- 95 °C) water to remove ethylene glycol and than dried until water- free, milled and used for the preparation of monoliths.
  • the resin was formed into a stiff dough which was then extruded through a multi-channel die.
  • the dough incorporated several extrusion aids in order to modify its rheological properties and enhance both the ease of extrusion and quality of the extruded monolith.
  • These additives included grades of Methocel (TM), forms of poly-ethylene oxide of different chain length, poly-ethylene glycol, poly-vinyl alcohol, Revacryl (TM) and glycerol.
  • TM Methocel
  • TM Methocel
  • TM poly-ethylene glycol
  • TM poly-vinyl alcohol
  • Revacryl TM
  • glycerol glycerol
  • the water required for the mesoporous dough was 60% of the resin weight compared to approximately 30% for a corresponding non-porous resin.
  • Monoliths were extruded using an Instron Model 4302 universal testing machine fitted with a piston and barrel assembly to act as a ram extruder. Lengths of extruded monolith were dried on a roller table for a minimum of 24 hrs at room temperature before being cut to length and carbonised and activated at 850°C in flowing carbon dioxide. Samples of carbonised monolith were retained for pore size and surface area analyses. Finally the monoliths were shrink-wrapped using clear heat shrink tubing (Tyco Electronics) ready for use.
  • Fig.3 shows mesopores and macropores.
  • the carbon monolith had pores in the mesopore range of 200-500nm in size and also a larger population of macropores in the 10000-20000nm range. Pores above 100,000 nm (100 microns) in size most likely represent channels within the monolith. The importance of the mesopores and macropores within the monolith for removal of inflammatory cytokines is considered in Example 5.
  • Example 5 shows mesopores and macropores.
  • Carbon bead removal of cytokines from human plasma and whole blood An in vitro experiment was performed to test the ability of the carbon beads, with differing pore size distribution and specific surface area (see Table 2), to adsorb inflammatory cytokines from plasma.
  • PBS phosphate buffered saline
  • Fresh human plasma (National Blood service) was spiked with the human recombinant inflammatory cytokines (BD Biosciences), TNF (lOOOpg/ml), IL-6 (lOOOpg/ml) and IL-8 (500 pg/ml). 800 ⁇ 1 of spiked plasma was added to each carbon bead type and incubated on a shaking incubator at 37 °C. At timed intervals (30, 60 and 90 minutes) the samples were removed and centrifuged at 8000rpm and the plasma was removed and frozen at -20°C before analysis. Samples were analysed by enzyme linked immuno-adsorbent assay (ELISA) (BD Biosciences) and the concentrations of cytokines were calculated.
  • ELISA enzyme linked immuno-adsorbent assay
  • the removal of TNF by the carbon beads was restricted to carbons 2 and 3 which contain the meso-macroporous domains,
  • the TNF molecule has a larger molecular weight than IL-8 and IL-6 and its removal is dependent on the presence of the larger meso-macropores.
  • Figure 6 shows the concentration of IL-6 remaining in spiked plasma incubated with the same carbon beads.
  • Carbon 1, with limited mesoporosity reduced the concentration of IL-6 in the plasma by half.
  • Carbons 2 and 3 with larger mesopores removed almost all of the IL6 present. It is believed having regard to the observed absence of haemolysis with the present carbons that the above results may be extrapolated to removal from whole blood.
  • a continuous circuit was set up drawing fluid from a reservoir via a peristaltic pump through silicon tubing to pass through a carbon monolith made as described with reference to Example 4 and having the pore size distribution of Fig 3 and back to the reservoir.
  • Monoliths of Example 4 were pre-equilibrated with phosphate buffered saline (PBS) for 20 minutes at a flow rate of 5 ml/min.
  • PBS phosphate buffered saline
  • Fresh frozen plasma from the NBS was defrosted, or human blood was drawn from volunteers into heparinised vacuette tubes, pooled and then the plasma or blood was spiked with the human recombinant inflammatory cytokines (BD Biosciences) TNF (500pg/ml), IL-6 (lOOOpg/ml) and IL-8 (200 pg/ml).
  • TNF 500pg/ml
  • IL-6 IL-6
  • IL-8 200 pg/ml
  • TNF is a relatively large protein of 51kDa in size, with a unit cell size of 9.4x9.4x11.7nm, (see Reed C, Fu ZQ et al (1997) Protein Eng 10: 1101-1107) and therefore orientation into pores is restricted by its size, Meso-macroporous domains are required for its removal.
  • IL-6 is a 26kDa protein with a unit cell size 4.9x4.9x12.2 nm, (see Somers, W. Stahl, M. Seehra, J.S., EMBO J. vl6 pp.989-997, 1997). It is smaller in size and will orientate into both small macropores and smaller mesopores unlike TNF. This is reflected in the 80 % removal observed after 60 minutes.
  • the smallest cytokine, IL-8 is an 8kDa protein with a unit cell size of 4x4x9 nm (Rajarathnam K, Clark-Lewis I, Sykes BD (1995) Biochem 34: 12983-12990) and shows the greatest removal with complete removal from blood after 30 minutes circulation.
  • Example 7 Granulocyte activation during continuous circulation through carbon monolith channels.
  • HNE Human neutrophil elastase
  • FIG. 8 is an SEM image of the internal surface of a monolith produced according to the method described in Example 4, after passage of unspiked blood, showing erythrocytes and leukocytes adhering to the walls of the monolith.
  • the images show that inflammatory white blood cells while they have adhered to the monolith surface, they have not spread out and become activated.
  • the erythrocytes are also in good conformation and have not been haemolysed by contact with the surface of the monolith.
  • Plasma samples collected after circulation through the monoliths of Example 4 were used to determine haemolysis. Samples were collected at the start and end of blood circulation through the monoliths. 20 ⁇ ⁇ aliquots of cytokine spiked and un-spiked blood were collected, diluted in PBS and centrifuged at lOOOg for 15 minutes. The control, showing full haemolysis, was prepared by diluting a blood sample in water. The absorbance of the supernatant was measured on a spectrophotometer at 405nm, zeroed for PBS. The absorbance values indicate that there is a small degree of haemolysis experienced in the spiked blood that has passed through the monoliths, in comparison to no haemolysis measured for the un-spiked blood.
  • Measurement of hemolysis of blood is a standard practice for extracorporeal devices. There is always a certain degree of hemolysis to blood caused by the collection procedure from a volunteer, but other factors such as surface roughness of the device can cause further hemolysis.
  • the levels of hemolysis that were measured for the monoliths was only slightly increased in the case of the spiked cytokine-containing blood on passage through the monolith.
  • the increased levels of inflammatory cytokines may have influenced the degree of hemolysis, because in the case of the un-spiked blood there was no increase in hemolysis measured after passage through the monolith.
  • the results indicate that the monolith is not causing blood cell hemolysis upon circulation through the monolith and is therefore suitable as a device for extracorporeal applications.
  • Samples were centrifuged at 8000 rpm and the supernatant removed prior to addition of 800 of the spiked plasma and incubation in the shaking incubator at 37 °C. At timed intervals the samples were removed and centrifuged at 8000rpm andfrozen at -20°C before analysis. Samples were analysed by ELISA using a set of paired antibodies (Toxin Technology) and the concentration of SEA or SEB was calculated. The example was repeated exotoxin toxic shock syndrome toxin l(TSST-l) in PBS (data not shown). Fig.
  • SEB was not removed by the purely microporous el carbon but was removed by up to 50% by te9 the meso-macroporous carbon bead.
  • Fig. 12 shows significant removal of the toxin SEA from plasma by meso-macroporous carbon te7 in 3 different activation degrees 00C, 32C and 49C.
  • the Tyrode's buffer was then removed and 5ml of different concentrations of creatinine in Tyrode's buffer were added to each carbon (0.5mM, lmM, 2mM, 4mM, 8mM, 12mM, 16mM).
  • the samples were incubated shaking for 24 hours at 37°C. Samples were measured with a UV-spectrophotometer, and concentrations of creatinine remaining in the solution calculated from the standard curve. All the activated carbons studied possessed the ability to adsorb creatinine from solution (see Fig.
  • Human plasma was spiked with indoxyl sulphate (IS) (125 ⁇ ), p-cresyl sulphate (PCS) (250 ⁇ ) and IL-6 (1000 pg ml "1 ).
  • the carbon monoliths tested were mesoporous monoliths made from TE7-20 cake and a microporous monolith control made from microporous resin only.
  • the monoliths were connected, via tubing, to a multiple channel peristaltic pump and a reservoir containing the spiked plasma.
  • the monoliths were pre-equilibrated with PBS and drained.
  • the spiked plasma was then passed through the monoliths at a flow rate of 5 ml per minute and plasma samples were collected at specific time points.
  • Cytokine removal was measured by ELISA. Indoxyl suphate and p-cresyl sulphate removal was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the mesoporous monoliths removed the uremic toxins indoxyl sulphate and p-cresyl sulphate and the cytokine IL-6 (Figs 14a,14b &15).
  • Monolith filtration reduced IS concentration to one sixth of the original spiked concentration and PCS concentration to one quarter the original spiked concentration over the 60 minute filtration time.
  • Some reduction in PCS and IS levels occurred on filtration through the microporous monolith. It is believed having regard to the observed absence of haemolysis with the present carbons that the above results may be extrapolated to whole blood.
  • Human plasma was spiked with 300 ⁇ bilirubin, 100 ⁇ cholic acid, 100 ⁇ tryptophan and 2 mM phenol. 5.4 mL of spiked plasma was added to each tube of carbon adsorbent. The mixtures were then incubated in a rotating oven at 37 °C for 5 min, 15 min, 30 min and 60 min. One mL of adsorbent/plasma mixture was taken from the tube at each time point. The adsorbent/plasma mixtures were then centrifuged, and the supernatants were transferred into eppendorf tubes with 400 ⁇ , aliquots. The samples were all kept in -20 °C freezer prior to HPLC and Hitachi analysis.
  • FIG. 16a shows removal of liver toxin bilirubin by carbon beads in mg per gram of carbon.

Abstract

Le sang total est traité de manière extracorporelle pour éliminer les substances qui ne sont pas saines en utilisant du charbon mésoporeux/microporeux ou macroporeux/microporeux sous forme de billes ou de structure monolithique à canal unique. Le charbon peut résulter de la carbonisation d'une résine phénolique mésoporeuse ou macroporeuse. Les substances qui ne sont pas saines comprennent des toxines introduites par voie externe telles que des entérotoxines A, B, TSST-1 de staphylococcus dérivées de bactéries ou des autologues, des molécules biologiquement actives dotées d'effets nocifs, systémiques lorsque leur activité est excessive ou non régulée. Des exemples comprennent l'élimination de quantités inappropriées de molécules pro- ou anti-inflammatoires et de médiateurs toxiques du syndrome de réponse inflammatoire systémique lié à la sepsie, une chirurgie de pontage cardio-pulmonaire, une blessure par reperfusion ischémique; l'élimination de toxines urémiques de poids moléculaire plus important, et liées à des protéines, associées aux reins et de toxines hépatiques associées à une insuffisance hépatique et l'élimination de toxines en rapport avec les guerres biologiques et chimiques.
PCT/GB2010/052056 2009-06-16 2010-12-09 Le charbon et son utilisation dans des applications de nettoyage du sang WO2011070363A1 (fr)

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US13/513,340 US9278170B2 (en) 2009-12-09 2010-12-09 Carbon and its use in blood cleansing applications
US15/061,656 US9700561B2 (en) 2009-06-16 2016-03-04 Drug combinations and uses in treating a coughing condition

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Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4169051A (en) 1976-06-22 1979-09-25 Eisai Co., Ltd. Blood purification with coated activated carbon spheres
GB2025385A (en) 1978-07-12 1980-01-23 Sumitomo Chemical Co Activated carbon and apparatus for hemoperfusion
US4358376A (en) 1979-10-29 1982-11-09 Terumo Corporation Apparatus for detoxifying body fluid
EP0254551A1 (fr) 1986-07-22 1988-01-27 The British Petroleum Company P.L.C. Procédé pour la production d'articles conformés poreux
US5194157A (en) 1990-03-09 1993-03-16 Sorin Biomedica Emodialisi Srl Blood purifying equipment particularly for the treatment of patients suffering from renal insufficiency, and a method of producing a reinfusion liquid for haemodiafiltration (HDF)
DE4331507A1 (de) * 1993-07-24 1995-04-06 Bitzer Christa Verfahren zum Entfernen von Harnstoff aus wäßriger Lösung
US5660731A (en) * 1994-11-08 1997-08-26 Pall Corporation Filter for separating photoactive agent
RU2119351C1 (ru) 1994-06-01 1998-09-27 Юхан Корпорейшн Иммуносупрессорная композиция, содержащая циклоспорин, и способ ее получения
WO2002012380A2 (fr) 2000-08-09 2002-02-14 Materials And Separations Technology International Limited Carbones poreux
WO2002072240A2 (fr) 2001-03-13 2002-09-19 Carbon Technologies Nv Procede et equipement permettant d'eliminer des composes volatils de l'air
US20040141932A2 (en) 2001-10-05 2004-07-22 L'oreal S.A. Methods of use and of making a mascara comprising at least one coloring agent and at least one polyamide polymer chosen from ethylenediamine stearyl dimer tallate copolymer
WO2004087612A1 (fr) 2003-03-29 2004-10-14 Mast Carbon International Ltd Materiaux poreux façonnes
WO2005099789A1 (fr) 2004-04-16 2005-10-27 Mast Carbon International Limited Traitement de la sepsie
WO2007070455A2 (fr) 2005-12-09 2007-06-21 Drexel University Carbones mesoporeux
WO2008043983A2 (fr) 2006-10-09 2008-04-17 British American Tobacco (Investments) Limited Production de particules solides discrètes de matière polymère
WO2008043982A2 (fr) 2006-10-09 2008-04-17 British American Tobacco (Investments) Limited Carbonisation et/ou activation de matière carbonée
EP2072117A1 (fr) * 2007-12-19 2009-06-24 Nederlandse Organisatie voor toegepast- natuurwetenschappelijk onderzoek TNO Matériau sorbant
EP2087916A1 (fr) * 2008-02-11 2009-08-12 ICinnovation BV Dispositif d'électrosorption pour la purification du sang et d'autres fluides
WO2010082064A2 (fr) 2009-01-15 2010-07-22 Brightwake Limited Filtration extracorporelle du sang

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9217914D0 (en) 1992-08-22 1992-10-07 British Petroleum Co Phenolic resin & carbon products
RU2199351C1 (ru) 2001-09-04 2003-02-27 Петрик Виктор Иванович Способ очистки плазмы крови от мочевой кислоты и креатинина
ITPD20030076A1 (it) * 2003-04-16 2003-07-15 Federico Nalesso Macchina per plasma purificazione combinata a plasma adsorbimento-perfusione mediante utilizzo di dializzatore tricompartimentale
FR2891747B1 (fr) * 2005-10-10 2007-12-14 Maco Pharma Sa Unite de filtration pour l'elimination selective d'une substance cible

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4169051A (en) 1976-06-22 1979-09-25 Eisai Co., Ltd. Blood purification with coated activated carbon spheres
GB2025385A (en) 1978-07-12 1980-01-23 Sumitomo Chemical Co Activated carbon and apparatus for hemoperfusion
US4358376A (en) 1979-10-29 1982-11-09 Terumo Corporation Apparatus for detoxifying body fluid
EP0254551A1 (fr) 1986-07-22 1988-01-27 The British Petroleum Company P.L.C. Procédé pour la production d'articles conformés poreux
US5194157A (en) 1990-03-09 1993-03-16 Sorin Biomedica Emodialisi Srl Blood purifying equipment particularly for the treatment of patients suffering from renal insufficiency, and a method of producing a reinfusion liquid for haemodiafiltration (HDF)
DE4331507A1 (de) * 1993-07-24 1995-04-06 Bitzer Christa Verfahren zum Entfernen von Harnstoff aus wäßriger Lösung
RU2119351C1 (ru) 1994-06-01 1998-09-27 Юхан Корпорейшн Иммуносупрессорная композиция, содержащая циклоспорин, и способ ее получения
US5660731A (en) * 1994-11-08 1997-08-26 Pall Corporation Filter for separating photoactive agent
WO2002012380A2 (fr) 2000-08-09 2002-02-14 Materials And Separations Technology International Limited Carbones poreux
WO2002072240A2 (fr) 2001-03-13 2002-09-19 Carbon Technologies Nv Procede et equipement permettant d'eliminer des composes volatils de l'air
US20040141932A2 (en) 2001-10-05 2004-07-22 L'oreal S.A. Methods of use and of making a mascara comprising at least one coloring agent and at least one polyamide polymer chosen from ethylenediamine stearyl dimer tallate copolymer
WO2004087612A1 (fr) 2003-03-29 2004-10-14 Mast Carbon International Ltd Materiaux poreux façonnes
WO2005099789A1 (fr) 2004-04-16 2005-10-27 Mast Carbon International Limited Traitement de la sepsie
WO2007070455A2 (fr) 2005-12-09 2007-06-21 Drexel University Carbones mesoporeux
WO2008043983A2 (fr) 2006-10-09 2008-04-17 British American Tobacco (Investments) Limited Production de particules solides discrètes de matière polymère
WO2008043982A2 (fr) 2006-10-09 2008-04-17 British American Tobacco (Investments) Limited Carbonisation et/ou activation de matière carbonée
EP2072117A1 (fr) * 2007-12-19 2009-06-24 Nederlandse Organisatie voor toegepast- natuurwetenschappelijk onderzoek TNO Matériau sorbant
EP2087916A1 (fr) * 2008-02-11 2009-08-12 ICinnovation BV Dispositif d'électrosorption pour la purification du sang et d'autres fluides
WO2010082064A2 (fr) 2009-01-15 2010-07-22 Brightwake Limited Filtration extracorporelle du sang

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HOWELL CA, BIOMATERIALS, vol. 27, no. 30, 2006, pages 5286 - 5291
RAJARATHNAM K; CLARK-LEWIS I; SYKES BD, BIOCHEM, vol. 34, 1995, pages 12983 - 12990
REED C; FU ZQ ET AL., PROTEIN ENG, vol. 10, 1997, pages 1101 - 1107
SANDEMAN, BIOMATERIALS, vol. 23, no. 205, pages 7124
SOMERS, W.; STAHL, M.; SEEHRA, J.S., EMBO J., vol. L6, 1997, pages 989 - 997

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8695811B2 (en) * 2011-11-04 2014-04-15 Samsung Electronics Co., Ltd. Hybrid porous structured material, membrane including the same, and method of preparing hybrid porous structure material
KR101852924B1 (ko) 2011-11-04 2018-04-30 삼성전자주식회사 혼성 다공성 구조체, 이를 포함하는 분리막 및 혼성 다공성 구조체의 제조 방법
US20130112613A1 (en) * 2011-11-04 2013-05-09 Samsung Electronics Co., Ltd. Hybrid porous structured material, membrane including the same, and method of preparing hybrid porous structure material
US9873622B2 (en) 2011-11-04 2018-01-23 Samsung Electronics Co., Ltd. Hybrid porous structured material, membrane including the same, and method of preparing hybrid porous structured material
US9707331B2 (en) 2011-11-07 2017-07-18 Delcath Systems, Inc. Apparatus for removing chemotherapy compounds from blood
US11633528B2 (en) 2011-11-07 2023-04-25 Delcath Systems, Inc. Apparatus for removing chemotherapy compounds from blood
US11241522B2 (en) 2011-11-07 2022-02-08 Delcath Systems, Inc. Apparatus for removing chemotherapy compounds from blood
US10569004B2 (en) 2011-11-07 2020-02-25 Delcath Systems, Inc. Apparatus for removing chemotherapy compounds from blood
US10369264B2 (en) 2011-11-07 2019-08-06 Delcath Systems, Inc. Apparatus for removing chemotherapy compounds from blood
US10098997B2 (en) 2011-11-07 2018-10-16 Delcath Systems, Inc. Apparatus for removing chemotherapy compounds from blood
KR101852925B1 (ko) 2011-11-29 2018-04-30 삼성전자주식회사 혼성 다공성 구조체, 혼성 다공성 구조체의 제조 방법, 혼성 다공성 구조체를 포함하는 분리막, 및 상기 분리막을 포함하는 수처리 장치
JP2015516373A (ja) * 2012-03-16 2015-06-11 ユーシーエル ビジネス ピーエルシー 肝疾患の治療及び予防における使用のための多孔性炭素粒子
EP3650031A1 (fr) * 2012-03-16 2020-05-13 Ucl Business Ltd Particules de carbone poreuses destinées à une utilisation dans le traitement ou la prévention d'une maladie hépatique
US9844568B2 (en) 2012-03-16 2017-12-19 Ucl Business Plc Porous carbon particles for use in the treatment or prevention of liver disease
WO2013136094A1 (fr) * 2012-03-16 2013-09-19 Ucl Business Plc Particules de carbone poreuses destinées à une utilisation dans le traitement ou la prévention d'une maladie hépatique
KR102441934B1 (ko) * 2012-03-16 2022-09-08 유씨엘 비즈니스 리미티드 간질환의 치료 또는 예방용 다공성 탄소 입자
EA038965B1 (ru) * 2012-03-16 2021-11-16 Юсл Бизнес Плк Частицы пористого углерода для применения при лечении или профилактике заболевания печени
JP2018111699A (ja) * 2012-03-16 2018-07-19 ユーシーエル ビジネス ピーエルシー 肝疾患の治療及び予防における使用のための多孔性炭素粒子
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AU2013282320B2 (en) * 2012-06-29 2017-10-19 Cytosorbents Corporation Methods of using polymers
CN104582751A (zh) * 2012-06-29 2015-04-29 西托索尔本茨公司 使用聚合物的方法
WO2014005039A3 (fr) * 2012-06-29 2014-03-13 Cytosorbents Corporation Procédés d'utilisation de polymères
US20150335576A1 (en) * 2012-06-29 2015-11-26 Cytosorbents Corporation Methods of using polymers
US11602585B2 (en) 2012-06-29 2023-03-14 Cytosorbents Corporation Methods for reducing contamination in a biological substance
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US10773011B2 (en) 2014-04-17 2020-09-15 ImMutriX Therapeutics, Inc. Therapeutic compositions for viral-associated disease states and methods of making and using same
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