WO2018170320A1 - Compositions and methods for the treatment of metabolic disorders - Google Patents
Compositions and methods for the treatment of metabolic disorders Download PDFInfo
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- WO2018170320A1 WO2018170320A1 PCT/US2018/022738 US2018022738W WO2018170320A1 WO 2018170320 A1 WO2018170320 A1 WO 2018170320A1 US 2018022738 W US2018022738 W US 2018022738W WO 2018170320 A1 WO2018170320 A1 WO 2018170320A1
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Classifications
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Definitions
- compositions, systems, and methods for the selective removal of biological molecules from bodily fluids More particularly disclosed herein are compositions methods and systems for the treatment of one or more metabolic disorders.
- liver dysfunction refers to the inability of the liver to carry out its normal physiological function.
- hepatic encephalopathy which is a devastating complication and the most common consequence of cirrhosis, impacts from 3 to 4 million Americans every year.
- Hepatic encephalopathy refers to a disturbance of the central nervous system function due to hepatic insufficiency. The most distinctive presentation is an acute episode characterized by the sudden onset of confusion that can evolve into coma. The onset of neurological disorders stemming from liver dysfunction is attributable to the presence of elevated amounts of ammonia and bilirubin.
- ELAD is an investigational extracorporeal, human cell-based liver support system designed with the intent to supplement hepatic function has had marginal clinical results.
- IMPACT is an adsorbent device containing (i) activated charcoal, (ii) the chromatographic resins AMBERLITE and (iii) AMBERCHROME, which although well studied, has some biocompatibility problems and can be only used for cleansing of plasma, which significantly increases the therapy time.
- MARS is another extracorporeal system based on the selective removal of albumin-bound toxins from the blood and enables detoxification of the liver and kidney.
- the MARS system has not yet found clinical acceptance due to its poor performance.
- liver dysfunctions such as hepatic encephalopathy it is imperative to seek new modalities to treat these highly morbid conditions.
- an extracorporeal method of treating a metabolic disorder comprising contacting a bodily fluid with (a) a hollow fiber membrane comprising a synthetic polymeric hemobiocompatible material; (b) a hollow fiber composite membrane comprising a carbonaceous material and a membrane-forming material; (c) a hollow fiber composite membrane comprising a carbonaceous material, an ion-exchange resin and a membrane-forming material; or (d) combinations thereof.
- a hollow fiber composite membrane comprising a micronized carbonaceous material and a membrane-forming material.
- FIGS. 1 A and IB are illustrations of an apparatus containing activated carbon blended with ion exchange resin and polysulfone/polyvinyl alcohol (PVS/PVA)-based membranes for use in the treatment of liver dysfunction such as hepatic encephalopathy and other metabolic disorders.
- PVS/PVA polysulfone/polyvinyl alcohol
- FIG. 2 is a graphical representation of the clearance of bilirubin by activated carbon supplemented with ion exchange resin.
- FIG. 3 is a graphical representation of the clearance of cytokines by activated carbon supplemented with ion exchange resin.
- FIG. 4 is a graphical representation of the clearance of endotoxin by activated carbon supplemented with ion exchange resin.
- FIG. 5 is a graphical representation of the clearance of reactive oxygen species by activated carbon supplemented with ion exchange resin.
- compositions and methodologies useful in treatment of a pathophysiology associated with a metabolic disorder comprises any and all mammals and includes the term "patient.”
- a subject to be treated according to the methods described herein may be one who has been diagnosed by a medical practitioner as suffering from a medical condition. Diagnosis may be performed by any suitable means.
- a subject to be treated according to the present disclosure may have been subjected to standard tests to diagnose the medical conditions.
- the clinical features of medical conditions of the type disclosed herein vary according to the pathomechanisms.
- the medical condition is a liver dysfunction such as cirrhosis or a complication resulting from the presence of a liver dysfunction such as hepatic encephalopathy.
- treating refers to utilizing the disclosed methodologies and compositions for therapeutic purposes.
- Therapeutic treatment may be administered, for example, to a subject suffering from the medical condition in order to improve or stabilize the subject's condition.
- treating refers to a subject undergoing for therapeutic purposes, the methodologies disclosed herein.
- treatment may ameliorate the medical condition or one or more symptoms thereof.
- amelioration of the medical condition or symptoms thereof by undergoing the methodologies disclosed herein refers to any lessening, whether lasting or transient, which can be attributed to or associated with undergoing the methodologies disclosed herein. Confirmation of the effect of treatment can be assessed by detecting an improvement in or the absence of symptoms, or by the inability to detect the presence of the medical condition in the treated subject.
- a method of the present disclosure comprises (i) contacting the bodily fluid of a subject with an apparatus for removal of one or more components present in the bodily fluid to produce a decontaminated bodily fluid; and (ii) returning at least a portion of the decontaminated bodily fluid to the subject.
- the term "bodily fluid,” includes without limitation inter alia plasma without blood cellular components and plasma with blood cellular components (i.e., whole blood).
- blood cellular components refers to components such as red corpuscles (erythrocytes), platelets (thrombocytes), and five types of white corpuscles (leukocytes).
- the bodily fluid comprises whole blood or plasma.
- a method of the present disclosure comprises contacting at least a portion of the bodily fluid of a subject suffering from a medical condition, with a composition and/or device component of the type disclosed herein.
- the method may further comprise recovering at least a portion of the subject's bodily fluid to obtain a decontaminated bodily fluid.
- the method may further comprise administering at least a portion of the decontaminated bodily fluid to the subject in order to treat the medical condition.
- a method of the present disclosure comprises identifying a subject suffering from a medical condition.
- the method may further comprise performing extracorporeal cleansing of at least a portion of the subject's bodily fluid utilizing the devices and compositions disclosed herein to generate a decontaminated bodily fluid.
- the method may further comprise administering at least a portion of the decontaminated bodily fluid to the subject.
- a method of the present disclosure comprises contacting a bodily fluid (e.g., whole blood or plasma) with (a) a hollow fiber membrane comprising a membrane-forming synthetic polymeric hemobiocompatible material (hereinafter designated MFM); (b) a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein and a MFM; (c) a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein, an ion-exchange resin and a MFM; or (d) combinations thereof.
- MFM membrane-forming synthetic polymeric hemobiocompatible material
- the hollow fiber membrane is prepared from any MFM compatible with the other materials of this disclosure.
- MFMs examples include without limitation polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or combinations thereof such as PS/PVP.
- PS polysulfone
- PVP polyvinylpyrrolodone
- PMA polymethacrylate
- PES polyethersulfome
- PVA polyvinylalcohol
- Membranes of the present disclosure may be prepared using any suitable methodology.
- hollow fiber membranes may be prepared by casting an MFM (e.g., PS/PVP) into a film while hollow fiber composite membranes may be prepared by casting an MFM (e.g., PS/PVP) into a film in the presence of one or more carbonaceous materials of the type disclosed herein.
- Hollow fiber membranes or hollow fiber composite membranes may display air gap distance in the range of from about 0 cm to about 20 cm, alternatively from about 2 cm to about 18 cm, alternatively from about 4 cm to about 16 cm, alternatively from about 6 cm to about 14 cm, alternatively from about 8 cm to about 12 cm, or alternatively form about 5 cm to about 10 cm.
- a hollow fiber membrane or hollow fiber composite membrane of the type disclosed herein may be characterized by an inner diameter ranging from about 100 ⁇ to about 500 ⁇ , alternatively from about 200 ⁇ to about 500 ⁇ or alternatively from about 300 to about 400 ⁇ .
- the hollow fiber membrane or hollow fiber composite membrane has a thickness ranging from about 10 ⁇ to about 300 ⁇ , alternatively from about 20 ⁇ to about 250 ⁇ , alternatively from about 50 ⁇ to about 200 ⁇ .
- a MFM suitable for use in the present disclosure may be characterized by a membrane rating of 0.022 ⁇ (i.e., able to retain biomolecules of approx. 65 kDa).
- the MFM may be characterized by a pore size cutoff ranging from about 0.01 ⁇ to about 4.0 ⁇ , alternatively from about 0.2 to about 3 ⁇ , alternatively from about 0.3 ⁇ to about 2 ⁇ , alternatively from about 0.4 ⁇ to about 1 ⁇ or alternatively from about 0.5 ⁇ to about 1 ⁇ .
- a hollow fiber composite membrane of the present disclosure comprises any MFM of the type disclosed herein and carbonaceous material of the type disclosed herein.
- the carbonaceous material is a micronized multimodal activated carbon (MMAC).
- the MMAC is prepared from a synthetic carbon particle containing micro-, meso- and macropores.
- a synthetic carbon particle of the type disclosed herein may be prepared using any suitable methodology.
- the synthetic carbon particle is prepared using a phenolic resin.
- micropore refers to pores with diameter ⁇ 2 nm, as measured by nitrogen adsorption and mercury porosimetry methods and as defined by IUPAC.
- meopore 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.
- macropores there are two types of macropores. In macroporous beads they are located within beads and formed by pore-formers. Their size is 50-500 nm, typically 70-200 nm. These macropores are very effective in adsorption of cytokines.
- a synthetic carbon particle suitable for use in the present disclosure may have any shape compatible with the compositions and methodologies disclosed herein.
- the shape of the synthetic carbon particle may be that of an irregular granule, a low angularity shape, spherical (e.g., bead), pellet, minilith, monolith, etc.
- the present disclosure may refer to the use of beads of the MMAC however it is to be understood the synthetic carbon particle may be of any suitable shape.
- the synthetic carbon particles may be formed using any suitable methodology to results in a material having the properties disclosed herein.
- a precursor resin formulation is used which comprises a large proportion of pore former, e.g. 250 parts ethylene glycol or other pore former to 100 parts of resin- forming components.
- a mesoporous resin may be formed 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. ethylene glycol), a diol ether, a cyclic ester, a substituted cyclic ester, a substituted linear amide, a substituted cyclic amide, an amino alcohol and a mixture of any of the above with water to form a resin.
- 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
- 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 carbonized 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 20-500 A.
- the mesoporous carbon may have a BET surface area of 250-800 m 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. by heating it in carbon dioxide at above 800 °C, or it may be activated by heating it in air at above 400 °C. It may then have surface areas of up to 2000 m 2 /g and even higher e.g. 1000-2000 m 2 /g. As used herein the term "BET surface area" is determined by the Brunauer, Emmett, and Teller (BET) method according to ASTM D 1993 -91, see also ASTM D6556-04.
- Resins for making carbonaceous material can be prepared from any of the starting materials such that the 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.
- the 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.
- NOVOLAK phenolic NOVOLAK 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 NOVOLAKs 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 NOVOLAK resins are used, they may be solids with melting points in the region of 100 °C. NOVOLAK resins of AMW less than 2000 and preferably less than 1500 form resins which on carbonization tend to produce carbons with desired pore size distributions using lower amounts of pore former.
- AMW average molecular weights
- NOVOLAKs 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. Whilst commercial NOVOLAKs 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: (a) 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.
- 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.
- Nitrogen containing nucleophilic modifying reagents which can be used possess two or more active sites and are more reactive in condensation reactions than phenol or NOVOLAKs. It means that they are first to react with primary cross-linking agents forming secondary cross-linking agents in situ.
- the nucleophilic component may be provided alone or in association with a polymerization catalyst which may be a weak organic acid miscible with the NOVOLAK and/or soluble in the pore former e.g. salicylic acid, oxalic acid or phthalic acid.
- the concentration of NOVOLAK 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 (NOVOLAK+cross-linking agent) is at least 125: 100 by weight.
- the actual ratios of NOVOLAK: pore former and cross-linking agentpore former are set according to convenience in operation by the operational requirements of a bead production plant and are controlled by the viscosity of the NOVOLAK:pore former solution such that it remains pumpable and by the ratio of cross-linking agentpore former such that the cross- 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. NOVOLAK. 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. In aspects requiring a completely cured resin, it is preferably used for cross-linking NOVOLAK resin at a proportion of 10 to 25 pbw e.g. about 15 to 20 pbw hexamine per 100 pbw of NOVOLAK. 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.
- 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, di ethylene glycol, triethylene glycol, ⁇ -butyrolactone, 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 vapor 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 NOVOLAK for the NOVOLAK-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, NOVOLAK), the presence of water within the solvent and concentration of any curing catalyst if present.
- 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, NOVOLAK), the presence of water within the solvent and concentration of any curing catalyst if present.
- 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 NOVOLAK 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. with a D90.D10 of better than 10 and preferably better than 5.
- the bead size distribution that can be achieved in practice in stirred tank reactors is relatively wide, and the more the process is scaled up the worse the homogeneity of the mixing regime and hence the particle size distribution becomes wider.
- Discrete solid beads of polymeric material e.g. phenolic resin having a porous structure
- the process comprises the steps of: (a) combining a stream of a polymerizable liquid precursor e.g. a NOVOLAK 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.
- a polymerizable liquid precursor e.g. a NOVOLAK and hexamine as cross- linking agent dissolved in a first polar organic liquid e.g. ethylene glycol
- 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 in-line static mixer; (c) allowing the droplets to polymerize 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 C.15-C.40 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. in an amount of 5-10% v/v where Danish oil is used which contains a low concentration of the active component to give final concentration of the dispersant in the dispersion medium 0.2-1% v/v. Higher dispersant concentrations would be used in the case of oxidized vegetable oils.
- the resin beads formed as described above may be carbonized and optionally activated.
- carbonization and activation may comprise 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 synthetic carbon particle suitable for use in the present disclosure is characterized by a microporous/macroporous structure.
- the synthetic carbon particle has a macroporous pore size of from about 75 ⁇ to about 1000 ⁇ , alternatively the synthetic carbon particle has a macroporous size of from about 100 ⁇ to about 750 ⁇ , or alternatively from about 100 ⁇ to about 500 ⁇ .
- a synthetic carbon particle suitable for use in the present disclosure may comprise a synthetic carbon particle having at least two pore size distribution such that the synthetic carbon particle is a mixture of carbon beads having at least two distributions of macroporous pore sizes.
- the synthetic carbon particle may comprise a first population having a macroporous pore size denoted x and a second population having a macroporous pore size y where the synthetic carbon particle provides a mixture having a ratio of xly of about 1; alternatively about 5, alternatively about 10, alternatively about 20; alternatively about 50, or alternatively about 100.
- the synthetic carbon particle comprises a mixture of two populations wherein the pore size of the first population is approximately twice the pore size of the second population.
- the synthetic carbon particle comprises a mixture of three populations where the pore size of a first population is approximately twice the pore size of the second population and the pore size of the third population is approximately two and a half times the pore size of the second population.
- the carbonaceous materials disclosed herein may be derived from polymeric materials tailored to have a porosity in the range of from about 10 nm to about 5000 nm.
- the tailored porosity resins are designated TPR and carbonaceous materials derived from these resins are termed tailored porosity carbons TPR-C.
- TPRs of the type disclosed herein are further characterized by pore volumes that remain substantially similar over the range of porosities disclosed.
- a TPR which may be tailored to have a porosity ranging from about 10 nm to about 5000 nm may be further characterized by a concomitant change in pore volume of less than about 50%, alternatively less than about 45%, alternatively less than about 40%), alternatively less than about 35%, alternatively less than about 30%>, alternatively less than about 25%, alternatively less than about 20%, alternatively less than about 15%, or alternatively less than about 10%.
- TPRs of this disclosure represent structured resins that retain their interconnected pore structure thus providing unhindered access to adsorption, catalytic, ion- exchange or chelating sites.
- polycondensation resins have protonogenic (phenolic hydroxyl -groups or carboxylic groups from modifying agents like salicylic acid and the likes) or proton-accepting (amino-groups from modifying agents like aromatic or heteroaromatic amines) groups in their matrix additional ion-exchange and/or chelating sites could be introduced by any suitable methodology. These include but are not restricted to sulphonation, chloromethylation followed by amination, etc.
- Porous polycondensation resins of the present disclosure can be easily converted by any suitable methodology (e.g., carbonization) into porous carbons which inherit their meso/macroporosity from the resin-precursor (i.e., TPR-C).
- suitable methodology e.g., carbonization
- carbonized materials have BET surface area as determined by nitrogen porosimetry method significantly higher than that of the resin precursor (600 - 700 m 2 /g) due to nanopores (pores with diameter below 2 nm) appearing in the course of carbonization.
- a polycondensation process to produce TPRs of the present disclosure may involve the following major components (i) a nucleophilic component (nonlimiting examples of which include - NOVOLAK phenol-formaldehyde linear pre-polymers with or without addition of modifying nucleophilic amines (e.g.
- phenolcarboxylic acids e.g.- salicylic acid, 5-resorcilol carboxylic acid, etc.
- curing agent nonlimiting examples of which include hexamethylenetetramine (hexamine), or formaldehyde
- solvent/pore former nonlimiting examples of which include ethylene glycol, which may or may not contain modifying additives (water, diethylene glycol, etc.
- solubility modifying agent nonlimiting examples of which include - sodium hydroxide or other alkaline agent soluble in the solvent/pore former.
- the linear phenol-formaldehyde pre-polymers NOVOLAKs comprise the major nucleophilic component of the polycondensation reaction composition.
- the major nucleophilic component of the polycondensation reaction composition consists essentially of the linear phenol-formaldehyde pre-polymers NOVOLAKs.
- of the linear phenol-formaldehyde pre-polymers NOVOLAKs are preferred.
- NOVOLAKs There are two types of industrially manufactured phenol-formaldehyde NOVOLAKs. Most common are randomly substituted NOVOLAKs with different average molecular mass. Structures involving substitution into m-position are practically absent. Randomly substituted NOVOLAK with average molecular weight ⁇ 800 D has been used as an example in this disclosure with -24% of ⁇ , ⁇ '-, -49% of o,p- and - 28% of ⁇ , ⁇ '- substitutions as determined by NMR 13 C - studies.
- High ⁇ , ⁇ ' -substituted NOVOLAK with average molecular weight - 700 g/mol has been used as another example in this disclosure with - 1% of ⁇ , ⁇ '-, - 37% of o,p- and -59% of ⁇ , ⁇ '- substitutions.
- High proportion of ⁇ , ⁇ ' -substitutions enables self- assembling of tetramers and higher oligomers into cyclic structures stabilized by hydrogen bonds between uniformly oriented phenolic hydroxy-groups. These ordered structures are believed to survive the curing sol-gel process and provide chelating sites in meso/macroporous polycondensation resins.
- nucleophilic modifying agents capable of polycondensation with formaldehyde or its analogues are employed alongside NOVOLAKs in order to introduce additional ion-exchange groups into porous matrix (aromatic and heteroaromatic amines, hydroxy- substituted aromatic carboxylic, sulphonic, phosphonic, boronic acids), to modify porosity (urea, melamine), to introduce heteroatoms (nitrogen, phosphorus, boron) into the matrix of carbonized derivatives of porous polycondensation resins.
- nitrogen-containing functionalities are introduced into the TPR matrix via cross-linking agents such as hexamethylenetetramine (hexamine) or soluble poly-methylol derivatives of urea and melamine.
- cross-linking agents such as hexamethylenetetramine (hexamine) or soluble poly-methylol derivatives of urea and melamine.
- mechanistically ⁇ 1 mole of formaldehyde was used in preparation of linear NOVOLAK pre-polymer an additional 0.5 moles of formaldehyde should be used for total cross-linking although in common practice excessive quantities of cross- linking agents are used.
- the present disclosure contemplates the use of an excess of crosslinking agent.
- Hexamine for example, could be used in quantities from 10 to 30 weight parts to 100 weight parts of NOVOLAK to produce solid cross-linked porous resin, though theoretical quantity is 14- 16 weight parts depending on NOVOLAK type.
- Such variation in composition could result in alterations of the porous structure of the resulting resins and other parameters like ability to swell.
- the use of an excess of crosslinking agent may also affect the reactivity of carbon matrix of porous carbons derived from corresponding resins.
- Porosity in polycondensation resins of present disclosure develops in the course of steady growing of cross-linked resin domains occurring at elevated temperature (70°C -150°C) that causes at some stage a nano-scale phase separation of resin rich phase (still containing some solvent) and solvent (turned pore former) rich phase that still contains some linear or partially cross-linked polymer and curing agent.
- the liquid polycondensation resin solution turns solid (sol-gel transformation).
- benzoxazine and benzylamine bridging structures when hexamine is a curing agent
- these transformations are followed by evolution of gaseous ammonia and amines and the resin turns from translucent to opaque.
- the porosity of polycondensation resins is tailored by adjusting the solubility of polycondensation resins with the addition of minute quantities (1 to 40 meqv per 100 g of NOVOLAK) of alkaline agents (e.g., sodium hydroxide) to the reaction composition.
- alkaline agents e.g., sodium hydroxide
- alkali and sodium hydroxide in particular are considered as catalysts in polycondensation reactions of phenols due to formation of electron-rich phenolate anions surprisingly catalytic action was not observed in reality when curing process was not affected by increasing the alkali content from 0 to 40 meqv (1.6 gNaOH) per 100 g of NOVOLAK.
- the TPRs of the present disclosure exhibit a significant decrease in the pore size alongside with decreases in the pore volume of polycondensation resins.
- a carbonaceous material of the type disclosed herein e.g., a synthetic carbon particle, a TPR-C
- a TPR-C is micronized to produce any particle size suitable for inclusion in a composite membrane, alternatively micronization is carried out to achieve average particles sizes ranging from about 5 micrometers to about 10 micrometers.
- Micronization of the MMAC to the sizes disclosed herein may be affected with the use of any suitable apparatus or methodology.
- a hollow fiber composite membrane of the type disclosed herein may be prepared using any suitable methodology.
- a membrane comprising a MFM e.g., PS/PVP
- the hollow fiber composite membrane has MMAC particles uniformly dispersed and immobilized inside the fiber walls while maintaining a sufficient level of porosity to allow for the flow of a bodily fluid (e.g., whole blood) through the membrane.
- the hollow fiber composite membrane is comprised of a multilayer wall surrounding the inner tube of the hollow fiber membrane.
- a hollow fiber composite membrane suitable for use in the present disclosure may comprise a three-layer wall having an MMAC disposed between the two outer walls comprising a MFM of the type disclosed herein.
- the resultant multilayer hollow fiber composite membrane may be characterized by large pores (1-3 micrometers) with a sponge-like structure allowing low-resistance to liquid access to the MMAC particles disposed in the interior of the multilayer structure.
- the multilayer structure allows for the support and isolation of the MMAC particles to prevent them from entering the biological fluid being filtered but also may create a restrictive barrier by substantially modifying the permeability of MFM (e.g., 0.2-0.5 micrometers) thus sequestering large debris from cells associated with the bodily fluid.
- the use of a multilayer hollow fiber composite membrane may also facilitate the control of back pressure due to the formation of a filtrate and thereby ensure the effective distribution of materials (e.g., nutrients, oxygen) through the system.
- the hollow fiber membranes disclosed herein may be used in the detoxification of a bodily fluid.
- toxins that may be removed by the present compositions and methodologies include small inorganic compounds such as NO, N0 2 , NO3, and H2O2; billirubin, creatinine, heme; LPS-endotoxin; growth factors such as VEGF,EDF,FGF,NGF,GRO-alpha, I-TAC, SCF, and TGF-beta; cytokines such as CRP, MIP - la, MCP - 1, TNF-alpha, IL-beta; inter chemokines such as IL-1, IL-2, IL-4, IL-6, IL-8, IL-12, and IL-17 and other; cholesterol, HDL,LDL,VLDL, triglycerides; and liver enzymes such as ALT and AST.
- a hollow fiber composite membrane comprises an MMAC blended with one or more ion-exchange resins (IER) and a MFM (e.g., PS/PVP).
- IER ion-exchange resins
- MFM e.g., PS/PVP
- an IER refers to an insoluble matrix fabricated from a substrate and functionalized with a fixed ion and a mobile counterion. The IER retards ions on the surface of the material with the concomitant release of the mobile counterion.
- IERs can also be described as insoluble polymers that contain ionizable groups distributed regularly along the polymer backbone. As a consequence, any counter ion associated with the ion exchange resin is ionically bound to the ion exchange resin and physically separated from the surrounding fluid.
- an IER suitable for use in the present disclosure has a bead size ranging from about 40 ⁇ to about 1000 ⁇ , alternatively from about 40 ⁇ to about 750 ⁇ , or alternatively from about 100 ⁇ to about 500 ⁇ .
- the IER is an anion exchange resin.
- anion exchange resin refers to an ion exchange resin with covalently bound positively charged groups, such as quaternary amino groups and mobile negatively charged groups.
- the term “anion exchange resin” is intended to encompass strong base anion exchange resins (SB A), weak base anion exchange resins (WBA) and related anionic functional resins, of either the gellular or macroporous type containing quaternary ammonium functionality (chloride, hydroxide or carbonate forms), dialkylamino or substituted dialkylamino functionality (free base or acid salt form), and aminoalkylphosphonate or iminodiacetate functionality, respectively.
- SB A strong base anion exchange resins
- WBA weak base anion exchange resins
- related anionic functional resins of either the gellular or macroporous type containing quaternary ammonium functionality (chloride, hydroxide or carbonate forms), dialkylamino or substituted dialkylamino functionality (free base or acid salt form
- the IER is a cation exchange resin.
- the cation exchange resin of the present disclosure may be strongly or weekly acidic and have a variety of functional groups, e.g., weakly acidic type of resin containing carboxylic acid group, or strongly acidic type of resin containing sulfonic functional groups.
- the carboxylic functional groups may be derived from polymers or copolymers of methacrylic acid or polymethacrylic acid and the sulfonic functional groups may generally be derived from polymers or copolymers of styrene and divinylbenzene.
- ion exchange resins e.g., methacrylic, acrylic and phenol formaldehyde.
- cation exchange resins suitable for use in the present disclosure include without limitation AMBERLITE and UNOSPHERE S Media. AMBERLITE is described by the manufacturer as gel- type divinylbenzene sulfonic acid cation exchange resin that swells in water.
- a hollow fiber membrane comprising a MFM
- a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein and a MFM
- a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein, an ion-exchange resin and a MFM, or (d) combinations thereof
- a disorder such hepatic encephalopathies and other metabolic disorders where the nonspecific sorbing potency of a carbonaceous material of the type disclosed herein is determined by the sieving coefficient of the fully hemobiocompatible non flow restricting hollow-fiber membrane.
- the carbonaceous materials disclosed provides for nonspecific removal of various hepatic encephalopathy mediators such as reactive oxygen species, inflammatory molecules and the like while cation exchange resins accelerate the removal of ammonia and anion exchange resin bilirubin.
- various hepatic encephalopathy mediators such as reactive oxygen species, inflammatory molecules and the like
- cation exchange resins accelerate the removal of ammonia and anion exchange resin bilirubin.
- the sieving coefficient of PS/PVA hollow fiber membranes with porosities ranging from 2 nm to 0.45 ⁇ determines the molecular spectrum of the factors being removed from patients' blood.
- hollow fiber membranes suitable for use in the present disclosure may be characterized by sieving coefficients ranging from about 2 nm to about 0.45 ⁇ alternatively from about 10 nm to about 0.25 ⁇ or alternatively from about 50 nm to about 0.1 ⁇ when such membranes comprise a MMAC blended with anion and cation exchange resins. It is contemplated that the therapeutic utility of the methods and compositions disclosed herein will be determined by the severity of the patient's condition and the type of metabolic disorder.
- compositions, systems, and methods for detoxifying a bodily fluid (e.g., blood) from mediators of liver dysfunctions such as hepatic encephalopathy comprise contacting at least a portion of a subject's blood with one or more extracorporeal devices containing a therapeutic formulation of materials designed to reduce the level of circulating mediators of liver dysfunction.
- a therapeutic formulation of materials refers to a composition of materials that are formulated to address the level of circulating mediators of liver dysfunction.
- a therapeutic formulation of materials comprise a carbonaceous material of the type disclosed herein and optionally an IER and/or and AER as disclosed herein.
- hepatic encephalopathy mediators refers to any organic or inorganic compound that when present in a subject's blood above a tolerable threshold mediates hepatic encephalopathy in the subject.
- Representative examples include, but are not limited to ammonia, bilirubin, reactive oxygen species, inflammatory cytokines, anaphylatoxins (i.e., C3a), endotoxin, and the like.
- contacting of at least a portion of the subject's blood with one or more extracorporeal devices comprising the therapeutic formulation of materials results in the removal of at least a portion of the circulating mediators of liver dysfunction.
- the level of circulating mediators of liver dysfunction are reduced to an extent sufficient to ameliorate the subject's disease state.
- a method of treating a subject suffering from a liver dysfunction comprises subjecting at least a portion of the subject's blood to contact with an extracorporeal device comprising the therapeutic formulation of materials.
- the subject's blood may be characterized by an initial level of circulating mediators of a liver dysfunction x. It is to be understood the subject's blood may be further characterized by the presence of desirable blood components present in an amount a. After contact with the extracorporeal device, the subject' s blood may be characterized by a final level of circulating mediators of liver dysfunction y where y is less than x and a level of desirable blood components b where a is about equal to b.
- the compositions, methodologies, and systems disclosed herein result in the selective reduction of the level of circulating mediators of liver dysfunction with a concomitant retention of desirable blood components.
- a method of treating a subject experiencing liver dysfunction comprises incorporation of a carbonaceous material of the type disclosed herein (i.e., MMAC) blended with ion exchange resins filled PS/PVA hollow fiber device into the existing liver support system or any other body detoxification systems intended to treat or prolong life of said subjects.
- a carbonaceous material of the type disclosed herein i.e., MMAC
- ion exchange resins filled PS/PVA hollow fiber device into the existing liver support system or any other body detoxification systems intended to treat or prolong life of said subjects.
- a hollow fiber membrane of the type disclosed herein is utilized in a device to supplement the function of an organ such as a liver.
- a method of further mimicking the environment of the liver comprising assembling a device comprising living liver cells and artificial polymeric particles in the form of smooth surfaced ellipsoids and spheres.
- Such artificial polymeric particles may operate as spacers in-between cell agglomerates making nutrients, and oxygen flow penetrate freely into and through cells environment, delivering food and provide gas exchange through the entire volume of the device (e.g., membrane bioreactor).
- Polymeric spacers suitable for use in such aspects can be bioinert, or be bioactive like ion exchange resin beads, for example.
- ion exchange beads target specific, in advance predetermined toxins, such as bilirubin, blood clotting factors, and other, to adsorb or otherwise neutralize its and remove from permeate flow.
- ion active beads may increase the longevity of any extracorporeal device and/or circuit in which it is utilized in general.
- these polymeric spacers may be applied together with an MMAC to increase the nonselective adsorbent capacity of the liver cell environment in case of heavy load of permeate toxins, toxins emitted by cells mortality, and additional contaminants introducing by extra corporeal circuit components.
- FIG. 1A and IB an aspect of a hollow fiber membrane of the type disclosed herein is depicted in Figures 1A and IB.
- the hollow fibers 118 comprise a hemobiocompatible material (PS/PVA) having activated carbon 114 (e.g., MMAC) and IERs (e.g., anion exchanger 116 and cation exchanger 112) which can affect the removal of hematoencephalopathic mediators such as endotoxins 102, bilirubin 104, reactive oxygen species 106, ammonia 108, and cytokines 110 from blood 100.
- PVA hemobiocompatible material having activated carbon 114 (e.g., MMAC) and IERs (e.g., anion exchanger 116 and cation exchanger 112) which can affect the removal of hematoencephalopathic mediators such as endotoxins 102, bilirubin 104, reactive oxygen species 106, ammonia 108, and cytokines 110 from blood 100.
- MMAC activated carbon
- anion exchangers 116, activated carbons 114, cation exchangers 112, cytokines 110, ammonia 108, reactive oxygen species 106, bilirubin 104, and endotoxins 102 are each represented by differently shaped and/or shaded figures.
- hollow fibers 118 are represented by extended, oblong, unshaded ovals.
- hollow fibers 118 are represented by a series for four parallel, differently dashed lines.
- hollow fibers 118 As is also shown in Figures 1A and IB, certain, representative examples of hollow fibers 118, anion exchangers 116, activated carbons 114, cation exchangers 112, cytokines 110, ammonia 108, reactive oxygen species 106, bilirubin 104, and endotoxins 102 are labeled with their respective numerical identifiers.
- mesoporous/microporous synthetic carbon 125/250 & 250/500
- mesoporous/microporous synthetic carbon beads were used in combination with an ion exchange resin.
- the carbon beads Prior to testing, the carbon beads were treated/coated with a solution containing 1% dextran in 09% NaCl, USP ( DC 0409-7419-03, Hospira, Lake Forest, IL) and 3,000U HMW heparin (Heparin, Sodium Injection, USP, lOOOU/mL, NDC 0641-2440-41 6505-00-153-9740, Elkins-Sinn, Inc., Cherry Hill, NJ), and later in the agitation experiment combined with 15 mL of spiked fresh human blood or in extracorporeal experiment filled with 76 mL of spiked fresh human whole blood, warmed to 37 °C. Before spiking, human whole blood was filtered using 20 ⁇ Pall filter, which was disconnected during testing. In the extracorporeal experiment, the back-pressure determined the flow rate generated by a peristaltic pump. In both experiments, sampling occurred at 0, 1, and 4 hours. Experiments were done in duplicate, human whole blood was spiked with the indicated mediators.
- a first aspect which is an extracorporeal method of treating a metabolic disorder comprising contacting a bodily fluid with (a) a hollow fiber membrane comprising a synthetic polymeric hemobiocompatible material; (b) a hollow fiber composite membrane comprising an carbonaceous material and a membrane-forming material; (c) a hollow fiber composite membrane comprising a carbonaceous material, an ion-exchange resin and a membrane-forming material, or (d) combinations thereof.
- a second aspect which is the method of the first aspect wherein the synthetic polymeric hemobiocompatible material comprises polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or a combination thereof.
- PS polysulfone
- PVP polyvinylpyrrolodone
- PMA polymethacrylate
- PES polyethersulfome
- PVA polyvinylalcohol
- a third aspect which is the method of any of the first through second aspects wherein the synthetic polymeric hemobiocompatible material comprises a combination of polysulfone and polyvinylpyrrolodone, a combination of polyethersulfome and polyvinylpyrrolodone, a combination of polysulfone and polyvinylalcohol or a combination of polyethersulfome and polyvinylalcohol.
- a fourth aspect which is the method of any of the first through third aspects wherein the synthetic polymeric hemobiocompatible material has a pore size cutoff ranging from about 0.01 ⁇ to about 4.0 ⁇ .
- a fifth aspect which is the method of any of the first through fourth aspects wherein the hollow fiber membrane has an air gap distance in the range of from about 0 cm to about 20 cm.
- a sixth aspect which is the method of any of the first through fifth aspects wherein the hollow fiber membrane has an inner diameter ranging from about 100 ⁇ to about 500 ⁇ .
- a seventh aspect which is the method of any of the first through sixth aspects wherein the hollow fiber membrane has a thickness ranging from about 10 ⁇ to about 300 ⁇ .
- An eighth aspect which is the method of any of the first through seventh aspects wherein the hollow fiber membrane has a sieving coefficient ranging from about 2 nm to about 0.45 ⁇
- a ninth aspect which is the method of any of the first through eighth aspects wherein the carbonaceous material is a synthetic carbon particle having a bimodal distribution of pore size.
- a tenth aspect which is the method of the ninth aspect wherein the carbonaceous material is micronized.
- An eleventh aspect which is the method of any of the first through tenth aspects wherein the carbonaceous material is a prepared from a tailored porosity resin.
- a twelfth aspect which is the method of the eleventh aspect wherein the carbonaceous material is micronized.
- a thirteenth aspect which is a hollow fiber composite membrane comprising a micronized carbonaceous material and a membrane-forming material.
- a fourteenth aspect which is the hollow fiber composite membrane of the thirteenth aspect wherein the membrane forming material is a synthetic hemobiocompatible material.
- a fifteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through fourteenth aspects wherein the membrane forming material comprises polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or a combination thereof.
- PS polysulfone
- PVP polyvinylpyrrolodone
- PMA polymethacrylate
- PES polyethersulfome
- PVA polyvinylalcohol
- a sixteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through fifteenth aspects wherein the membrane forming material comprises a combination of polysulfone and polyvinylpyrrolodone, a combination of polyethersulfome and polyvinylpyrrolodone, a combination of polysulfone and polyvinylalcohol or a combination of polyethersulfome and polyvinylalcohol.
- a seventeenth aspect which is the hollow fiber composite membrane of any of the thirteenth through sixteenth aspects wherein the carbonaceous material is a synthetic carbon particle having a bimodal distribution of pore size.
- An eighteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through seventeenth aspects wherein the carbonaceous material is prepared from a tailored porosity resin.
- a nineteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through eighteenth aspects wherein the hollow fiber membrane has a thickness ranging from about 10 ⁇ to about 300 ⁇ .
- a twentieth aspect which is the hollow fiber composite membrane of any of the thirteenth through nineteenth aspects wherein the hollow fiber membrane has a sieving coefficient ranging from about 2 nm to about 0.45 ⁇ .
Abstract
An extracorporeal method of treating a metabolic disorder comprising contacting a bodily fluid with (a) a hollow fiber membrane comprising a synthetic polymeric hemobiocompatible material; (b) a hollow fiber composite membrane comprising a carbonaceous material and a membrane-forming material; (c) a hollow fiber composite membrane comprising a carbonaceous material, an ion-exchange resin and a membrane-forming material, or (d) combinations thereof. A hollow fiber composite membrane comprising a micronized carbonaceous material and a membrane-forming material.
Description
COMPOSITIONS AND METHODS FOR THE TREATMENT OF METABOLIC
DISORDERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of and claims priority to U.S. Provisional Application No. 62/471,824 entitled "Compositions and Methods for the Treatment of Metabolic Disorders," filed March 15, 2017 by Rae et. al., and to U.S. Provisional Application No. 62/472,390 entitled "Compositions and Methods for the Treatment of Metabolic Disorders," filed March 16, 2017 by Rae et. al., which are both incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] Generally disclosed herein are compositions, systems, and methods for the selective removal of biological molecules from bodily fluids. More particularly disclosed herein are compositions methods and systems for the treatment of one or more metabolic disorders.
BACKGROUND
[0003] Liver dysfunction refers to the inability of the liver to carry out its normal physiological function. In particular hepatic encephalopathy, which is a devastating complication and the most common consequence of cirrhosis, impacts from 3 to 4 million Americans every year. Hepatic encephalopathy refers to a disturbance of the central nervous system function due to hepatic insufficiency. The most distinctive presentation is an acute episode characterized by the sudden onset of confusion that can evolve into coma. The onset of neurological disorders stemming from liver dysfunction is attributable to the presence of elevated amounts of ammonia and bilirubin. According to the Global Burden of Disease study of 2010 cirrhosis caused 31 million Disability Adjusted Life Years (DALYs), or 1.2% of global DALYs and one million deaths, or 2% of all deaths worldwide in that year, ranking fourteenth as the leading cause of death in the world.
[0004] Various devices and methodologies have been proposed as therapeutic interventions in the progression of liver diseases. For example, ELAD is an investigational extracorporeal, human cell-based liver support system designed with the intent to supplement hepatic function has had marginal clinical results. Another example is the IMPACT system which is an adsorbent device containing (i) activated charcoal, (ii) the chromatographic resins AMBERLITE and (iii) AMBERCHROME, which although well studied, has some biocompatibility problems and can be only used for cleansing of plasma, which significantly increases the therapy time. Yet another example is MARS which is another extracorporeal system based on the selective removal of
albumin-bound toxins from the blood and enables detoxification of the liver and kidney. However, the MARS system has not yet found clinical acceptance due to its poor performance.
[0005] Taking into consideration that there exist no definitive treatments for liver dysfunctions such as hepatic encephalopathy it is imperative to seek new modalities to treat these highly morbid conditions.
SUMMARY
[0006] Disclosed herein is an extracorporeal method of treating a metabolic disorder comprising contacting a bodily fluid with (a) a hollow fiber membrane comprising a synthetic polymeric hemobiocompatible material; (b) a hollow fiber composite membrane comprising a carbonaceous material and a membrane-forming material; (c) a hollow fiber composite membrane comprising a carbonaceous material, an ion-exchange resin and a membrane-forming material; or (d) combinations thereof.
[0007] Also disclosed herein is a hollow fiber composite membrane comprising a micronized carbonaceous material and a membrane-forming material.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIGS. 1 A and IB are illustrations of an apparatus containing activated carbon blended with ion exchange resin and polysulfone/polyvinyl alcohol (PVS/PVA)-based membranes for use in the treatment of liver dysfunction such as hepatic encephalopathy and other metabolic disorders.
[0009] FIG. 2 is a graphical representation of the clearance of bilirubin by activated carbon supplemented with ion exchange resin.
[0010] FIG. 3 is a graphical representation of the clearance of cytokines by activated carbon supplemented with ion exchange resin.
[0011] FIG. 4 is a graphical representation of the clearance of endotoxin by activated carbon supplemented with ion exchange resin.
[0012] FIG. 5 is a graphical representation of the clearance of reactive oxygen species by activated carbon supplemented with ion exchange resin.
DETAILED DESCRIPTION
[0013] Disclosed herein are compositions and methodologies useful in treatment of a pathophysiology associated with a metabolic disorder. The term "subject," as used herein, comprises any and all mammals and includes the term "patient." A subject to be treated according
to the methods described herein may be one who has been diagnosed by a medical practitioner as suffering from a medical condition. Diagnosis may be performed by any suitable means. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests to diagnose the medical conditions. As known to the ordinarily skilled artisan, the clinical features of medical conditions of the type disclosed herein vary according to the pathomechanisms. In an aspect, the medical condition is a liver dysfunction such as cirrhosis or a complication resulting from the presence of a liver dysfunction such as hepatic encephalopathy.
[0014] Herein "treating" refers to utilizing the disclosed methodologies and compositions for therapeutic purposes. Therapeutic treatment may be administered, for example, to a subject suffering from the medical condition in order to improve or stabilize the subject's condition. Thus, in the claims and aspects described herein, treating refers to a subject undergoing for therapeutic purposes, the methodologies disclosed herein.
[0015] In some instances, as compared with an equivalent untreated control, treatment may ameliorate the medical condition or one or more symptoms thereof. As used herein, amelioration of the medical condition or symptoms thereof by undergoing the methodologies disclosed herein refers to any lessening, whether lasting or transient, which can be attributed to or associated with undergoing the methodologies disclosed herein. Confirmation of the effect of treatment can be assessed by detecting an improvement in or the absence of symptoms, or by the inability to detect the presence of the medical condition in the treated subject.
[0016] In an aspect, a method of the present disclosure comprises (i) contacting the bodily fluid of a subject with an apparatus for removal of one or more components present in the bodily fluid to produce a decontaminated bodily fluid; and (ii) returning at least a portion of the decontaminated bodily fluid to the subject. As used herein the term "bodily fluid," includes without limitation inter alia plasma without blood cellular components and plasma with blood cellular components (i.e., whole blood). Herein the term "blood cellular components" refers to components such as red corpuscles (erythrocytes), platelets (thrombocytes), and five types of white corpuscles (leukocytes). In an aspect, the bodily fluid comprises whole blood or plasma.
[0017] In an alternative aspect, a method of the present disclosure comprises contacting at least a portion of the bodily fluid of a subject suffering from a medical condition, with a composition and/or device component of the type disclosed herein. The method may further comprise
recovering at least a portion of the subject's bodily fluid to obtain a decontaminated bodily fluid. The method may further comprise administering at least a portion of the decontaminated bodily fluid to the subject in order to treat the medical condition.
[0018] In an alternative aspect, a method of the present disclosure comprises identifying a subject suffering from a medical condition. The method may further comprise performing extracorporeal cleansing of at least a portion of the subject's bodily fluid utilizing the devices and compositions disclosed herein to generate a decontaminated bodily fluid. The method may further comprise administering at least a portion of the decontaminated bodily fluid to the subject.
[0019] A method of the present disclosure comprises contacting a bodily fluid (e.g., whole blood or plasma) with (a) a hollow fiber membrane comprising a membrane-forming synthetic polymeric hemobiocompatible material (hereinafter designated MFM); (b) a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein and a MFM; (c) a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein, an ion-exchange resin and a MFM; or (d) combinations thereof. In an aspect, the hollow fiber membrane is prepared from any MFM compatible with the other materials of this disclosure. Examples of such MFMs include without limitation polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or combinations thereof such as PS/PVP. PES/PVP, PS/PVA, or PES/PVA.
[0020] Membranes of the present disclosure may be prepared using any suitable methodology. For example, hollow fiber membranes may be prepared by casting an MFM (e.g., PS/PVP) into a film while hollow fiber composite membranes may be prepared by casting an MFM (e.g., PS/PVP) into a film in the presence of one or more carbonaceous materials of the type disclosed herein. Hollow fiber membranes or hollow fiber composite membranes may display air gap distance in the range of from about 0 cm to about 20 cm, alternatively from about 2 cm to about 18 cm, alternatively from about 4 cm to about 16 cm, alternatively from about 6 cm to about 14 cm, alternatively from about 8 cm to about 12 cm, or alternatively form about 5 cm to about 10 cm. The air gap distance affects the stress strength of hollow fiber membranes. In an aspect, a hollow fiber membrane or hollow fiber composite membrane of the type disclosed herein may be characterized by an inner diameter ranging from about 100 μπι to about 500 μπι, alternatively from about 200 μπι to about 500 μπι or alternatively from about 300 to about 400 μπι. In an aspect, the hollow fiber membrane
or hollow fiber composite membrane has a thickness ranging from about 10 μπι to about 300 μπι, alternatively from about 20 μπι to about 250 μπι, alternatively from about 50 μπι to about 200 μπι.
[0021] In an aspect, a MFM suitable for use in the present disclosure may be characterized by a membrane rating of 0.022 μπι (i.e., able to retain biomolecules of approx. 65 kDa). Alternatively, the MFM may be characterized by a pore size cutoff ranging from about 0.01 μπι to about 4.0 μπι, alternatively from about 0.2 to about 3 μπι, alternatively from about 0.3 μπι to about 2 μπι, alternatively from about 0.4 μπι to about 1 μπι or alternatively from about 0.5 μπι to about 1 μπι.
[0022] In an aspect, a hollow fiber composite membrane of the present disclosure comprises any MFM of the type disclosed herein and carbonaceous material of the type disclosed herein. In an aspect the carbonaceous material is a micronized multimodal activated carbon (MMAC).
[0023] In an aspect, the MMAC is prepared from a synthetic carbon particle containing micro-, meso- and macropores. A synthetic carbon particle of the type disclosed herein may be prepared using any suitable methodology. Alternatively, the synthetic carbon particle is prepared using a phenolic resin. As used herein, the term "micropore" refers to pores with diameter <2 nm, as measured by nitrogen adsorption and mercury porosimetry methods and as defined by IUPAC. As used herein, the term "mesopore" 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. As used herein, the term "macropore" refers to pores with diameters larger than 50 nm, as measured by nitrogen adsorption and mercury porosimetry methods and as defined by IUPAC. In relation to this disclosure there are two types of macropores. In macroporous beads they are located within beads and formed by pore-formers. Their size is 50-500 nm, typically 70-200 nm. These macropores are very effective in adsorption of cytokines.
[0024] A synthetic carbon particle suitable for use in the present disclosure may have any shape compatible with the compositions and methodologies disclosed herein. For example the shape of the synthetic carbon particle may be that of an irregular granule, a low angularity shape, spherical (e.g., bead), pellet, minilith, monolith, etc. For simplicity, the present disclosure may refer to the use of beads of the MMAC however it is to be understood the synthetic carbon particle may be of any suitable shape. The synthetic carbon particles may be formed using any suitable methodology to results in a material having the properties disclosed herein. In an exemplary method for the formation of an synthetic carbon particle, a precursor resin formulation is used which comprises a large
proportion of pore former, e.g. 250 parts ethylene glycol or other pore former to 100 parts of resin- forming components.
[0025] Herein a mesoporous resin may be formed 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. ethylene glycol), a diol ether, a cyclic ester, a substituted cyclic ester, a substituted linear amide, a substituted cyclic amide, an amino alcohol and a mixture of any of the above with water to form a resin. 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 carbonized 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 20-500 A. The mesoporous carbon may have a BET surface area of 250-800 m2/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. by heating it in carbon dioxide at above 800 °C, or it may be activated by heating it in air at above 400 °C. It may then have surface areas of up to 2000 m2/g and even higher e.g. 1000-2000 m2/g. As used herein the term "BET surface area" is determined by the Brunauer, Emmett, and Teller (BET) method according to ASTM D 1993 -91, see also ASTM D6556-04.
[0026] Resins for making carbonaceous material can be prepared from any of the starting materials such that the 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.
[0027] It is preferred to use as nucleophilic component a phenolic NOVOLAK 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 NOVOLAKs 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 NOVOLAK
resins are used, they may be solids with melting points in the region of 100 °C. NOVOLAK resins of AMW less than 2000 and preferably less than 1500 form resins which on carbonization tend to produce carbons with desired pore size distributions using lower amounts of pore former. NOVOLAKs 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. Whilst commercial NOVOLAKs 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: (a) 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, (b) 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. Like hydroquinone and resorcinol, all the nitrogen containing nucleophilic modifying reagents which can be used possess two or more active sites and are more reactive in condensation reactions than phenol or NOVOLAKs. It means that they are first to react with primary cross-linking agents forming secondary cross-linking agents in situ.
[0028] The nucleophilic component may be provided alone or in association with a polymerization catalyst which may be a weak organic acid miscible with the NOVOLAK and/or soluble in the pore former e.g. salicylic acid, oxalic acid or phthalic acid. The concentration of NOVOLAK 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 (NOVOLAK+cross-linking agent) is at least 125: 100 by weight. The actual ratios of NOVOLAK: pore former and cross-linking agentpore former are set according to convenience in operation by the operational requirements of a bead production plant and are controlled by the viscosity of the NOVOLAK:pore former solution such that it remains pumpable and by the ratio of cross-linking agentpore former such that the cross- linking agent remains in solution throughout the plant.
[0029] 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. NOVOLAK. It may be, for example, an aldehyde e.g. formaldehyde or furfural, it could be hexamethylenetetramine (hexamine), or hydroxymethylated melamine.
[0030] Hexamine is preferably used as cross-linking agent. In aspects requiring a completely cured resin, it is preferably used for cross-linking NOVOLAK resin at a proportion of 10 to 25 pbw e.g. about 15 to 20 pbw hexamine per 100 pbw of NOVOLAK. 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.
[0031] The pore former also acts as solvent. Thus, 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.
[0032] 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, di ethylene glycol, triethylene glycol, γ-butyrolactone, 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 vapor pressure at the temperatures used in the curing process.
[0033] It is thought that the mechanism of meso- and macropore generation is due to a phase separation process that occurs during the cross-linking reaction. In the absence of a pore former, as the linear chains of pre-polymer undergo cross-linking, their molecular weight initially increases. Residual low molecular weight components become insoluble in the higher molecular weight regions causing a phase separation into cross-linked high molecular weight domains within the lower molecular weight continuous phase. Further condensation of light components to the outside of the growing domains occurs until the cross-linked phase becomes essentially continuous with residual lighter pre-polymer trapped between the domains. 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 NOVOLAK for the NOVOLAK-Hexamine-Ethylene Glycol reaction system), whilst the remainder forms a solution with the partially cross-linked polymer between the domains. In the presence of higher levels of pore former, which exceed the capacity of the cross-linked resin, 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. In general, the higher the pore former content, the wider the mesopores, up to macropores, and the higher the pore volume.
[0034] 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, NOVOLAK), the presence of water within the solvent and concentration of any curing catalyst if present.
[0035] 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 μιη 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. In a preparative example, industrial NOVOLAK 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. On completion of 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. with a D90.D10 of better than 10 and preferably better than 5. However, the bead size distribution that can be achieved in practice in stirred tank reactors is relatively wide, and the more the process is scaled up the worse the homogeneity of the mixing regime and hence the particle size distribution becomes wider.
[0036] Discrete solid beads of polymeric material e.g. phenolic resin having a porous structure may be formed, 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 NOVOLAK 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 in-line static mixer; (c) allowing the droplets to polymerize 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.
[0037] For bead production, 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. Both protic and aprotic solvents of different classes of organic compounds match these requirements and can be used as pore formers, both individually and in mixtures. In addition to dissolving the reactive components and any catalyst, 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.
[0038] 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 C.15-C.40 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.
[0039] 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. in an amount of 5-10% v/v where Danish oil is used which contains a low concentration of the active component to give final concentration of the dispersant in the dispersion medium 0.2-1% v/v. Higher dispersant concentrations would be used in the case of oxidized vegetable oils.
[0040] The resin beads formed as described above may be carbonized and optionally activated. For example, carbonization and activation may comprise 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. In an aspect, a synthetic carbon particle suitable for use in the present disclosure is characterized by a microporous/macroporous structure.
[0041] In an aspect, the synthetic carbon particle has a macroporous pore size of from about 75 μπι to about 1000 μπι, alternatively the synthetic carbon particle has a macroporous size of from about 100 μπι to about 750 μπι, or alternatively from about 100 μπι to about 500 μπι. Herein a synthetic carbon particle suitable for use in the present disclosure may comprise a synthetic carbon particle having at least two pore size distribution such that the synthetic carbon particle is a mixture of carbon beads having at least two distributions of macroporous pore sizes. In an aspect, the synthetic carbon particle may comprise a first population having a macroporous pore size denoted x and a second population having a macroporous pore size y where the synthetic carbon particle provides a mixture having a ratio of xly of about 1; alternatively about 5, alternatively about 10, alternatively about 20; alternatively about 50, or alternatively about 100. In some aspects, the synthetic carbon particle comprises a mixture of two populations wherein the pore size of the first population is approximately twice the pore size of the second population. In some aspects, the synthetic carbon particle comprises a mixture of three populations where the pore size of a first
population is approximately twice the pore size of the second population and the pore size of the third population is approximately two and a half times the pore size of the second population.
[0042] In an alternative aspect, the carbonaceous materials disclosed herein may be derived from polymeric materials tailored to have a porosity in the range of from about 10 nm to about 5000 nm. Herein the tailored porosity resins are designated TPR and carbonaceous materials derived from these resins are termed tailored porosity carbons TPR-C. In an aspect, TPRs of the type disclosed herein are further characterized by pore volumes that remain substantially similar over the range of porosities disclosed. In an aspect, a TPR which may be tailored to have a porosity ranging from about 10 nm to about 5000 nm may be further characterized by a concomitant change in pore volume of less than about 50%, alternatively less than about 45%, alternatively less than about 40%), alternatively less than about 35%, alternatively less than about 30%>, alternatively less than about 25%, alternatively less than about 20%, alternatively less than about 15%, or alternatively less than about 10%. TPRs of this disclosure represent structured resins that retain their interconnected pore structure thus providing unhindered access to adsorption, catalytic, ion- exchange or chelating sites. Though polycondensation resins have protonogenic (phenolic hydroxyl -groups or carboxylic groups from modifying agents like salicylic acid and the likes) or proton-accepting (amino-groups from modifying agents like aromatic or heteroaromatic amines) groups in their matrix additional ion-exchange and/or chelating sites could be introduced by any suitable methodology. These include but are not restricted to sulphonation, chloromethylation followed by amination, etc.
[0043] Porous polycondensation resins of the present disclosure (i.e., TPR) can be easily converted by any suitable methodology (e.g., carbonization) into porous carbons which inherit their meso/macroporosity from the resin-precursor (i.e., TPR-C). Typically, carbonized materials have BET surface area as determined by nitrogen porosimetry method significantly higher than that of the resin precursor (600 - 700 m2/g) due to nanopores (pores with diameter below 2 nm) appearing in the course of carbonization.
[0044] A polycondensation process to produce TPRs of the present disclosure may involve the following major components (i) a nucleophilic component (nonlimiting examples of which include - NOVOLAK phenol-formaldehyde linear pre-polymers with or without addition of modifying nucleophilic amines (e.g. - aniline, phenylenediamines, aminophenols, melamine), dihydric phenols, phenolcarboxylic acids (e.g.- salicylic acid, 5-resorcilol carboxylic acid, etc.) and other
compounds with multiple nucleophilic sites; (ii) a cross-linking electrophilic component (curing agent), nonlimiting examples of which include hexamethylenetetramine (hexamine), or formaldehyde; (iii) a solvent/pore former, nonlimiting examples of which include ethylene glycol, which may or may not contain modifying additives (water, diethylene glycol, etc.); and (iv) solubility modifying agent, nonlimiting examples of which include - sodium hydroxide or other alkaline agent soluble in the solvent/pore former.
[0045] In an aspect, the linear phenol-formaldehyde pre-polymers NOVOLAKs comprise the major nucleophilic component of the polycondensation reaction composition. In an alternative aspect, the major nucleophilic component of the polycondensation reaction composition consists essentially of the linear phenol-formaldehyde pre-polymers NOVOLAKs. In an alternative aspect, of the linear phenol-formaldehyde pre-polymers NOVOLAKs.
[0046] There are two types of industrially manufactured phenol-formaldehyde NOVOLAKs. Most common are randomly substituted NOVOLAKs with different average molecular mass. Structures involving substitution into m-position are practically absent. Randomly substituted NOVOLAK with average molecular weight ~ 800 D has been used as an example in this disclosure with -24% of ρ,ρ'-, -49% of o,p- and - 28% of ο,ο'- substitutions as determined by NMR 13C - studies. High ο,ο' -substituted NOVOLAK with average molecular weight - 700 g/mol has been used as another example in this disclosure with - 1% of ρ,ρ'-, - 37% of o,p- and -59% of ο,ο'- substitutions. High proportion of ο,ο' -substitutions enables self- assembling of tetramers and higher oligomers into cyclic structures stabilized by hydrogen bonds between uniformly oriented phenolic hydroxy-groups. These ordered structures are believed to survive the curing sol-gel process and provide chelating sites in meso/macroporous polycondensation resins.
[0047] In some aspects of the present disclosure, other nucleophilic modifying agents capable of polycondensation with formaldehyde or its analogues are employed alongside NOVOLAKs in order to introduce additional ion-exchange groups into porous matrix (aromatic and heteroaromatic amines, hydroxy- substituted aromatic carboxylic, sulphonic, phosphonic, boronic acids), to modify porosity (urea, melamine), to introduce heteroatoms (nitrogen, phosphorus, boron) into the matrix of carbonized derivatives of porous polycondensation resins.
[0048] In some aspects, nitrogen-containing functionalities are introduced into the TPR matrix via cross-linking agents such as hexamethylenetetramine (hexamine) or soluble poly-methylol derivatives of urea and melamine. As will be understood by the ordinarily skilled artisan, the
stoichiometric quantity of formaldehyde required for substitution of all three reactive positions in phenolic molecule to form a cross-linked phenol-formaldehyde network is 1.5 moles per 1 mole of phenol. Without wishing to be limited by theory, mechanistically ~1 mole of formaldehyde was used in preparation of linear NOVOLAK pre-polymer an additional 0.5 moles of formaldehyde should be used for total cross-linking although in common practice excessive quantities of cross- linking agents are used. The present disclosure contemplates the use of an excess of crosslinking agent. Hexamine, for example, could be used in quantities from 10 to 30 weight parts to 100 weight parts of NOVOLAK to produce solid cross-linked porous resin, though theoretical quantity is 14- 16 weight parts depending on NOVOLAK type. Such variation in composition could result in alterations of the porous structure of the resulting resins and other parameters like ability to swell. The use of an excess of crosslinking agent may also affect the reactivity of carbon matrix of porous carbons derived from corresponding resins.
[0049] Porosity in polycondensation resins of present disclosure develops in the course of steady growing of cross-linked resin domains occurring at elevated temperature (70°C -150°C) that causes at some stage a nano-scale phase separation of resin rich phase (still containing some solvent) and solvent (turned pore former) rich phase that still contains some linear or partially cross-linked polymer and curing agent. Typically, at this point the liquid polycondensation resin solution turns solid (sol-gel transformation). On further heating different transformations of initially formed benzoxazine and benzylamine bridging structures (when hexamine is a curing agent) take place alongside further growth of resin domains at the expense of partially cured polymer from the solution rich phase. These transformations are followed by evolution of gaseous ammonia and amines and the resin turns from translucent to opaque.
[0050] Alternatively, the porosity of polycondensation resins is tailored by adjusting the solubility of polycondensation resins with the addition of minute quantities (1 to 40 meqv per 100 g of NOVOLAK) of alkaline agents (e.g., sodium hydroxide) to the reaction composition. Though alkali and sodium hydroxide in particular are considered as catalysts in polycondensation reactions of phenols due to formation of electron-rich phenolate anions surprisingly catalytic action was not observed in reality when curing process was not affected by increasing the alkali content from 0 to 40 meqv (1.6 gNaOH) per 100 g of NOVOLAK. In an aspect, the TPRs of the present disclosure exhibit a significant decrease in the pore size alongside with decreases in the pore volume of polycondensation resins.
[0051] In an aspect, a carbonaceous material of the type disclosed herein (e.g., a synthetic carbon particle, a TPR-C) is micronized to produce any particle size suitable for inclusion in a composite membrane, alternatively micronization is carried out to achieve average particles sizes ranging from about 5 micrometers to about 10 micrometers. Micronization of the MMAC to the sizes disclosed herein may be affected with the use of any suitable apparatus or methodology.
[0052] In an aspect, a hollow fiber composite membrane of the type disclosed herein may be prepared using any suitable methodology. For example, a membrane comprising a MFM (e.g., PS/PVP) may be formed in the presence of a MMAC. In an aspect, the hollow fiber composite membrane has MMAC particles uniformly dispersed and immobilized inside the fiber walls while maintaining a sufficient level of porosity to allow for the flow of a bodily fluid (e.g., whole blood) through the membrane. In some aspects, the hollow fiber composite membrane is comprised of a multilayer wall surrounding the inner tube of the hollow fiber membrane. For example, a hollow fiber composite membrane suitable for use in the present disclosure may comprise a three-layer wall having an MMAC disposed between the two outer walls comprising a MFM of the type disclosed herein.
[0053] The resultant multilayer hollow fiber composite membrane may be characterized by large pores (1-3 micrometers) with a sponge-like structure allowing low-resistance to liquid access to the MMAC particles disposed in the interior of the multilayer structure. The multilayer structure allows for the support and isolation of the MMAC particles to prevent them from entering the biological fluid being filtered but also may create a restrictive barrier by substantially modifying the permeability of MFM (e.g., 0.2-0.5 micrometers) thus sequestering large debris from cells associated with the bodily fluid. Without wishing to be limited by theory, the use of a multilayer hollow fiber composite membrane may also facilitate the control of back pressure due to the formation of a filtrate and thereby ensure the effective distribution of materials (e.g., nutrients, oxygen) through the system.
[0054] In an aspect, the hollow fiber membranes disclosed herein may be used in the detoxification of a bodily fluid. Nonlimiting examples of toxins that may be removed by the present compositions and methodologies include small inorganic compounds such as NO, N02, NO3, and H2O2; billirubin, creatinine, heme; LPS-endotoxin; growth factors such as VEGF,EDF,FGF,NGF,GRO-alpha, I-TAC, SCF, and TGF-beta; cytokines such as CRP, MIP - la, MCP - 1, TNF-alpha, IL-beta; inter chemokines such as IL-1, IL-2, IL-4, IL-6, IL-8, IL-12,
and IL-17 and other; cholesterol, HDL,LDL,VLDL, triglycerides; and liver enzymes such as ALT and AST.
[0055] In another aspect, a hollow fiber composite membrane comprises an MMAC blended with one or more ion-exchange resins (IER) and a MFM (e.g., PS/PVP). Herein an IER refers to an insoluble matrix fabricated from a substrate and functionalized with a fixed ion and a mobile counterion. The IER retards ions on the surface of the material with the concomitant release of the mobile counterion. IERs can also be described as insoluble polymers that contain ionizable groups distributed regularly along the polymer backbone. As a consequence, any counter ion associated with the ion exchange resin is ionically bound to the ion exchange resin and physically separated from the surrounding fluid.
[0056] In an aspect, an IER suitable for use in the present disclosure has a bead size ranging from about 40 μιη to about 1000 μιτι, alternatively from about 40 μιη to about 750 μιτι, or alternatively from about 100 μιη to about 500 μιη.
[0057] In an aspect, the IER is an anion exchange resin. Herein "anion exchange resin" refers to an ion exchange resin with covalently bound positively charged groups, such as quaternary amino groups and mobile negatively charged groups. The term "anion exchange resin" is intended to encompass strong base anion exchange resins (SB A), weak base anion exchange resins (WBA) and related anionic functional resins, of either the gellular or macroporous type containing quaternary ammonium functionality (chloride, hydroxide or carbonate forms), dialkylamino or substituted dialkylamino functionality (free base or acid salt form), and aminoalkylphosphonate or iminodiacetate functionality, respectively. Examples of commercially available anion exchange resins suitable for use in the present disclosure include without limitation those sold under the tradename of DEAE, QAE, and UNOSPHERE. In an aspect, the anion exchange resin comprises UNOSPHERE Q Media.
[0058] In an aspect, the IER is a cation exchange resin. The cation exchange resin of the present disclosure may be strongly or weekly acidic and have a variety of functional groups, e.g., weakly acidic type of resin containing carboxylic acid group, or strongly acidic type of resin containing sulfonic functional groups. Generally, the carboxylic functional groups may be derived from polymers or copolymers of methacrylic acid or polymethacrylic acid and the sulfonic functional groups may generally be derived from polymers or copolymers of styrene and divinylbenzene. Other polymeric matrices, organic ion exchange matrices or inorganic ion exchange matrices may be used
as suitable ion exchange resins, e.g., methacrylic, acrylic and phenol formaldehyde. For example, cation exchange resins suitable for use in the present disclosure include without limitation AMBERLITE and UNOSPHERE S Media. AMBERLITE is described by the manufacturer as gel- type divinylbenzene sulfonic acid cation exchange resin that swells in water.
[0059] In an aspect, (a) a hollow fiber membrane comprising a MFM; (b) a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein and a MFM; (c) a hollow fiber composite membrane comprising a carbonaceous material of the type disclosed herein, an ion-exchange resin and a MFM, or (d) combinations thereof may be used in the treatment of a disorder such hepatic encephalopathies and other metabolic disorders where the nonspecific sorbing potency of a carbonaceous material of the type disclosed herein is determined by the sieving coefficient of the fully hemobiocompatible non flow restricting hollow-fiber membrane.
[0060] For hollow fiber composite membranes of the type disclosed herein the carbonaceous materials disclosed provides for nonspecific removal of various hepatic encephalopathy mediators such as reactive oxygen species, inflammatory molecules and the like while cation exchange resins accelerate the removal of ammonia and anion exchange resin bilirubin. For example, the sieving coefficient of PS/PVA hollow fiber membranes with porosities ranging from 2 nm to 0.45 μπι determines the molecular spectrum of the factors being removed from patients' blood.
[0061] In an aspect, hollow fiber membranes suitable for use in the present disclosure may be characterized by sieving coefficients ranging from about 2 nm to about 0.45 μπι alternatively from about 10 nm to about 0.25 μπι or alternatively from about 50 nm to about 0.1 μπι when such membranes comprise a MMAC blended with anion and cation exchange resins. It is contemplated that the therapeutic utility of the methods and compositions disclosed herein will be determined by the severity of the patient's condition and the type of metabolic disorder.
[0062] Disclosed herein are compositions, systems, and methods for detoxifying a bodily fluid (e.g., blood) from mediators of liver dysfunctions such as hepatic encephalopathy. In an aspect, the methods disclosed herein comprise contacting at least a portion of a subject's blood with one or more extracorporeal devices containing a therapeutic formulation of materials designed to reduce the level of circulating mediators of liver dysfunction. Herein the "therapeutic formulation of materials" refers to a composition of materials that are formulated to address the level of circulating mediators of liver dysfunction. In an aspect, a therapeutic formulation of materials comprise a carbonaceous material of the type disclosed herein and optionally an IER and/or and AER as disclosed herein. As used
herein "hepatic encephalopathy mediators" refers to any organic or inorganic compound that when present in a subject's blood above a tolerable threshold mediates hepatic encephalopathy in the subject. Representative examples include, but are not limited to ammonia, bilirubin, reactive oxygen species, inflammatory cytokines, anaphylatoxins (i.e., C3a), endotoxin, and the like.
[0063] In some aspects, contacting of at least a portion of the subject's blood with one or more extracorporeal devices comprising the therapeutic formulation of materials (for example in the form of a hollow fiber membrane of the type disclosed herein) results in the removal of at least a portion of the circulating mediators of liver dysfunction. Alternatively, the level of circulating mediators of liver dysfunction are reduced to an extent sufficient to ameliorate the subject's disease state.
[0064] In an aspect, a method of treating a subject suffering from a liver dysfunction such as hepatic encephalopathy comprises subjecting at least a portion of the subject's blood to contact with an extracorporeal device comprising the therapeutic formulation of materials. The subject's blood may be characterized by an initial level of circulating mediators of a liver dysfunction x. It is to be understood the subject's blood may be further characterized by the presence of desirable blood components present in an amount a. After contact with the extracorporeal device, the subject' s blood may be characterized by a final level of circulating mediators of liver dysfunction y where y is less than x and a level of desirable blood components b where a is about equal to b. In an aspect, the compositions, methodologies, and systems disclosed herein result in the selective reduction of the level of circulating mediators of liver dysfunction with a concomitant retention of desirable blood components.
[0065] In an aspect, a method of treating a subject experiencing liver dysfunction comprises incorporation of a carbonaceous material of the type disclosed herein (i.e., MMAC) blended with ion exchange resins filled PS/PVA hollow fiber device into the existing liver support system or any other body detoxification systems intended to treat or prolong life of said subjects.
[0066] In an aspect, a hollow fiber membrane of the type disclosed herein is utilized in a device to supplement the function of an organ such as a liver. In such aspects, a method of further mimicking the environment of the liver comprising assembling a device comprising living liver cells and artificial polymeric particles in the form of smooth surfaced ellipsoids and spheres. Such artificial polymeric particles may operate as spacers in-between cell agglomerates making nutrients, and oxygen flow penetrate freely into and through cells environment, delivering food and provide gas exchange through the entire volume of the device (e.g., membrane bioreactor). Polymeric spacers
suitable for use in such aspects can be bioinert, or be bioactive like ion exchange resin beads, for example. These ion exchange beads target specific, in advance predetermined toxins, such as bilirubin, blood clotting factors, and other, to adsorb or otherwise neutralize its and remove from permeate flow. These ion active beads may increase the longevity of any extracorporeal device and/or circuit in which it is utilized in general. In such aspects, these polymeric spacers may be applied together with an MMAC to increase the nonselective adsorbent capacity of the liver cell environment in case of heavy load of permeate toxins, toxins emitted by cells mortality, and additional contaminants introducing by extra corporeal circuit components.
[0067] In an aspect, an aspect of a hollow fiber membrane of the type disclosed herein is depicted in Figures 1A and IB. As shown in Figures 1A and IB, the hollow fibers 118 comprise a hemobiocompatible material (PS/PVA) having activated carbon 114 (e.g., MMAC) and IERs (e.g., anion exchanger 116 and cation exchanger 112) which can affect the removal of hematoencephalopathic mediators such as endotoxins 102, bilirubin 104, reactive oxygen species 106, ammonia 108, and cytokines 110 from blood 100. As shown in Figures 1A and IB, anion exchangers 116, activated carbons 114, cation exchangers 112, cytokines 110, ammonia 108, reactive oxygen species 106, bilirubin 104, and endotoxins 102 are each represented by differently shaped and/or shaded figures. As shown in Figure 1A, hollow fibers 118 are represented by extended, oblong, unshaded ovals. As shown in Figure IB, hollow fibers 118 are represented by a series for four parallel, differently dashed lines. As is also shown in Figures 1A and IB, certain, representative examples of hollow fibers 118, anion exchangers 116, activated carbons 114, cation exchangers 112, cytokines 110, ammonia 108, reactive oxygen species 106, bilirubin 104, and endotoxins 102 are labeled with their respective numerical identifiers.
EXAMPLES
[0068] Hepatoencephalopatic Mediators by Mesorporous/Microporous Synthetic Carbon Beads from Human Whole Blood.
[0069] Two formulations of mesoporous/microporous synthetic carbon (125/250 & 250/500) were brought to pharmaceutical grade using validated sanitization and fine particulates removal methods. Then mesoporous/microporous synthetic carbon beads were used in combination with an ion exchange resin. Prior to testing, the carbon beads were treated/coated with a solution containing 1% dextran in 09% NaCl, USP ( DC 0409-7419-03, Hospira, Lake Forest, IL) and 3,000U HMW heparin (Heparin, Sodium Injection, USP, lOOOU/mL, NDC 0641-2440-41 6505-00-153-9740,
Elkins-Sinn, Inc., Cherry Hill, NJ), and later in the agitation experiment combined with 15 mL of spiked fresh human blood or in extracorporeal experiment filled with 76 mL of spiked fresh human whole blood, warmed to 37 °C. Before spiking, human whole blood was filtered using 20 μπι Pall filter, which was disconnected during testing. In the extracorporeal experiment, the back-pressure determined the flow rate generated by a peristaltic pump. In both experiments, sampling occurred at 0, 1, and 4 hours. Experiments were done in duplicate, human whole blood was spiked with the indicated mediators.
[0070] These results are presented in: Figure 2, clearance of bilirubin; Figure 3, clearance of cytokines; Figure 4, endotoxin clearance; and Figure 5, reactive oxygen species clearance. The results demonstrate that mesoporous/microporous synthetic carbon beads were effective in removal of EVD mediators responsible for SIRS, immune system suppression, hypotension and MOF. Synthetic carbon beads in experimental conditions investigated, extracorporeal and agitation, showed similar cleansing effectiveness toward EVD mediators.
[0071] In Figure 2, the least squares regression line equation for (Bilirubin) was y = 2.0700 - 2.3625x + 0.47250xA2 and RA2= 1.000 where RA2 is the square of the correlation.
[0072] In Figure 3, the following are the least squares regression line equation for the indicated cytokine along with the square of the correlation: (TNF-alpha) y = 365.96 * xA-0.41797 and RA2= 0.950; (TL-1 beta) y = 275.77 * xA-0.27748 and RA2= 0.949; (TL-6) y = 182.55 * xA-0.29597 and RA2= 0.889; (TL-8) y = 5.5374 * xA-1.0650 and RA2= 0.555; (MXP - la) y = 0.29337 * xA-1.3731 and RA2= 0.951; and (MCP - 1) y = 140.55 * xA-0.20709 and RA2= 0.946.
[0073] In Figure 4, least squares regression line equation for (Endotoxin) was y = 9.5290e-2 * xA0.23713 and RA2= 0.886.
[0074] In Figure 5, the least squares regression line equation values where 100% H2O2 = 7.76 ± 0.90 nM)) was y = 100.00 - 125.00x + 25.000xA2 with RA2 = 1.000.
ADDITIONAL ASPECTS
[0075] The following enumerated aspects are provided as non-limiting examples:
[0076] A first aspect which is an extracorporeal method of treating a metabolic disorder comprising contacting a bodily fluid with (a) a hollow fiber membrane comprising a synthetic polymeric hemobiocompatible material; (b) a hollow fiber composite membrane comprising an carbonaceous material and a membrane-forming material; (c) a hollow fiber composite membrane
comprising a carbonaceous material, an ion-exchange resin and a membrane-forming material, or (d) combinations thereof.
[0077] A second aspect which is the method of the first aspect wherein the synthetic polymeric hemobiocompatible material comprises polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or a combination thereof.
[0078] A third aspect which is the method of any of the first through second aspects wherein the synthetic polymeric hemobiocompatible material comprises a combination of polysulfone and polyvinylpyrrolodone, a combination of polyethersulfome and polyvinylpyrrolodone, a combination of polysulfone and polyvinylalcohol or a combination of polyethersulfome and polyvinylalcohol.
[0079] A fourth aspect which is the method of any of the first through third aspects wherein the synthetic polymeric hemobiocompatible material has a pore size cutoff ranging from about 0.01 μπι to about 4.0 μπι.
[0080] A fifth aspect which is the method of any of the first through fourth aspects wherein the hollow fiber membrane has an air gap distance in the range of from about 0 cm to about 20 cm.
[0081] A sixth aspect which is the method of any of the first through fifth aspects wherein the hollow fiber membrane has an inner diameter ranging from about 100 μπι to about 500 μπι.
[0082] A seventh aspect which is the method of any of the first through sixth aspects wherein the hollow fiber membrane has a thickness ranging from about 10 μπι to about 300 μπι.
[0083] An eighth aspect which is the method of any of the first through seventh aspects wherein the hollow fiber membrane has a sieving coefficient ranging from about 2 nm to about 0.45 μπι
[0084] A ninth aspect which is the method of any of the first through eighth aspects wherein the carbonaceous material is a synthetic carbon particle having a bimodal distribution of pore size.
[0085] A tenth aspect which is the method of the ninth aspect wherein the carbonaceous material is micronized.
[0086] An eleventh aspect which is the method of any of the first through tenth aspects wherein the carbonaceous material is a prepared from a tailored porosity resin.
[0087] A twelfth aspect which is the method of the eleventh aspect wherein the carbonaceous material is micronized.
[0088] A thirteenth aspect which is a hollow fiber composite membrane comprising a micronized carbonaceous material and a membrane-forming material.
[0089] A fourteenth aspect which is the hollow fiber composite membrane of the thirteenth aspect wherein the membrane forming material is a synthetic hemobiocompatible material.
[0090] A fifteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through fourteenth aspects wherein the membrane forming material comprises polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or a combination thereof.
[0091] A sixteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through fifteenth aspects wherein the membrane forming material comprises a combination of polysulfone and polyvinylpyrrolodone, a combination of polyethersulfome and polyvinylpyrrolodone, a combination of polysulfone and polyvinylalcohol or a combination of polyethersulfome and polyvinylalcohol.
[0092] A seventeenth aspect which is the hollow fiber composite membrane of any of the thirteenth through sixteenth aspects wherein the carbonaceous material is a synthetic carbon particle having a bimodal distribution of pore size.
[0093] An eighteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through seventeenth aspects wherein the carbonaceous material is prepared from a tailored porosity resin.
[0094] A nineteenth aspect which is the hollow fiber composite membrane of any of the thirteenth through eighteenth aspects wherein the hollow fiber membrane has a thickness ranging from about 10 μπι to about 300 μπι.
[0095] A twentieth aspect which is the hollow fiber composite membrane of any of the thirteenth through nineteenth aspects wherein the hollow fiber membrane has a sieving coefficient ranging from about 2 nm to about 0.45 μπι.
[0096] While various aspects of the presently disclosed have been shown and described, modifications thereof can be made by one skilled in the art without departing from the spirit and teachings herein. The aspects described herein are exemplary only and are not intended to be limiting. Many variations and modifications of the subject matter disclosed herein are possible and are within the scope of the present disclosure Where numerical ranges or limitations are expressly stated, such express ranges or limitations should be understood to include iterative ranges or limitations of like magnitude falling within the expressly stated ranges or limitations (e.g., from about 1 to about 10 includes, 2, 3, 4, etc.; greater than 0.10 includes 0.11, 0.12, 0.13, etc.). Use of
the term "optionally" with respect to any element of a claim is intended to mean that the subject element is required, or alternatively, is not required. Both alternatives are intended to be within the scope of the claim. Use of broader terms such as comprises, includes, having, etc. should be understood to provide support for narrower terms such as consisting of, consisting essentially of, comprised substantially of, etc.
[0097] Accordingly, the scope of protection is not limited by the description set out above but is only limited by the claims which follow, that scope including all equivalents of the subject matter of the claims. The claims are a further description and are an addition to the aspects of the present invention. The claims of all patents, patent applications, and publications cited herein are hereby incorporated by reference, to the extent that they provide exemplary, procedural, or other details supplementary to those set forth herein.
Claims
1. An extracorporeal method of treating a metabolic disorder comprising contacting a bodily fluid with (a) a hollow fiber membrane comprising a synthetic polymeric hemobiocompatible material; (b) a hollow fiber composite membrane comprising a carbonaceous material and a membrane-forming material; (c) a hollow fiber composite membrane comprising a carbonaceous material, an ion-exchange resin and a membrane-forming material, or (d) combinations thereof.
2. The method of claim 1 wherein the synthetic polymeric hemobiocompatible material comprises polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or a combination thereof.
3. The method of claim 1 wherein the synthetic polymeric hemobiocompatible material comprises a combination of polysulfone and polyvinylpyrrolodone, a combination of polyethersulfome and polyvinylpyrrolodone, a combination of polysulfone and polyvinylalcohol or a combination of polyethersulfome and polyvinylalcohol.
4. The method of claim 1 wherein the synthetic polymeric hemobiocompatible material has a pore size cutoff ranging from about 0.01 μπι to about 4.0 μπι.
5. The method of claim 1 wherein the hollow fiber membrane has an air gap distance in the range of from about 0 cm to about 20 cm.
6. The method of claim 1 wherein the hollow fiber membrane has an inner diameter ranging from about 100 μπι to about 500 μπι.
7. The method of claim 1 wherein the hollow fiber membrane has a thickness ranging from about 10 μπι to about 300 μπι.
8. The method of claim 1 wherein the hollow fiber membrane has a sieving coefficient ranging from about 2 nm to about 0.45 μπι
9. The method of claim 1 wherein the carbonaceous material is a synthetic carbon particle having a bimodal distribution of pore size.
10. The method of claim 9 wherein the carbonaceous material is micronized.
11. The method of claim 1 wherein the carbonaceous material is a prepared from a tailored porosity resin.
12. The method of claim 11 wherein the carbonaceous material is micronized.
13. A hollow fiber composite membrane comprising a micronized carbonaceous material and a membrane-forming material.
14. The hollow fiber composite membrane of claim 13 wherein the membrane forming material is a synthetic hemobiocompatible material.
15. The hollow fiber composite membrane of claim 13 wherein the membrane forming material comprises polysulfone (PS), polyvinylpyrrolodone (PVP), polymethacrylate (PMA), polyethersulfome (PES), polyvinylalcohol (PVA) or a combination thereof.
16. The hollow fiber composite membrane of claim 13 wherein the membrane forming material comprises a combination of polysulfone and polyvinylpyrrolodone, a combination of polyethersulfome and polyvinylpyrrolodone, a combination of polysulfone and polyvinylalcohol or a combination of polyethersulfome and polyvinylalcohol.
17. The hollow fiber composite membrane of claim 13 wherein the carbonaceous material is a synthetic carbon particle having a bimodal distribution of pore sizes.
18. The hollow fiber composite membrane of claim 13 wherein the carbonaceous material is a prepared from a tailored porosity resin.
19. The hollow fiber composite membrane of claim 13 wherein the hollow fiber membrane has a thickness ranging from about 10 μπι to about 300 μπι.
20. The hollow fiber composite membrane of claim 13 wherein the hollow fiber membrane has a sieving coefficient ranging from about 2 nm to about 0.45 μπι.
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US201762472390P | 2017-03-16 | 2017-03-16 | |
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Cited By (2)
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CN114471199A (en) * | 2022-03-31 | 2022-05-13 | 天津工业大学 | Polyether sulfone membrane with dual functions of separation and adsorption and preparation method thereof |
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