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    • 专利摘要:
    SIZE-SELECTIVE POLYMER SYSTEM A size-selective, hemocompatible polymeric system is provided, this polymeric system comprising at least one polymer with a plurality of pores, and the polymer having at least one transport pore with a diameter of about 250 Angstroms at about 2,000 Angstroms, and the polymer having a transport pore volume greater than about 1.8% to about 78% of a pore volume capacity of said polymer.
    公开号:BR112013005793B1
    申请号:R112013005793-9
    申请日:2011-09-07
    公开日:2020-12-08
    发明作者:Wei-Tai Young；Robert Albright；Thomas Golobish；Vincent Copponi；Philip Chan
    申请人:Cytosorbent, Inc.；
    IPC主号:
    专利说明:

    BACKGROUND OF THE INVENTION Field of invention
    The present invention relates to the size selective polymer system and, in particular, to polymer systems having a plurality of pores with transport pores and a negative ionic charge on their surface.
    The size-selective porous polymeric adsorbents of the present invention are biocompatible and hemocompatible and are designed to work in direct contact with body fluids. These adsorbents are useful in conjunction with hemodialysis to extract and control the blood level of β2-microglobulin without significantly disturbing the levels of albumin, immunoglobulins, leukocytes, erythrocytes and platelets. These polymeric adsorbents are also very effective in extracting cytokines associated with the systemic inflammatory response syndrome (SIRS), from blood and / or physiological fluid, in patients with sepsis, burns, trauma, flu, etc. while maintaining the physiologically necessary blood components at clinically acceptable levels. Description of the related technique
    Extracorporeal blood purification techniques are important in many medical treatments, including hemodialysis, hemofiltration, hemoperfusion, plasma perfusion and combinations of these methods. Hemodialysis and hemofiltration involve the passage of whole blood through hollow fibers to remove excess water and small molecular compounds, but are unable to remove toxins from proteins such as beta-2-microglobulin (B2M) and cytokines. Hemoperfusion is the passage of whole blood over an adsorbent to remove contaminants from the blood. Plasma perfusion is the passage of blood plasma through an adsorbent. In hemoperfusion, the treated whole blood returns to the patient's blood circulatory system.
    In addition to common requirements such as hemocompatibility and sterility for medical devices, an ideal adsorbent for hemoperfusion and plasma perfusion must have adequate adsorption and selectivity to absorb toxins to the exclusion of useful components to be beneficial to the patient.
    Conventional adsorption materials include activated carbon, silicates, diatomite and porous synthetic resins. Activated carbon has been reported in extracorporeal adsorption for the treatment of schizophrenia (Kinney, US Patent No. 4,330,551; 1981). Various synthetic polymeric adsorbents have been disclosed to remove toxin 1 from toxic shock syndrome, bradykinin and endotoxins from the blood (Hirai, et al. U.S. Patent 6,315,907; 2001; 6,387,362; 2002 and 6,132,610; 2000) , and to remove poisons and / or drugs from the blood of animals (Kunin, et al., U.S. Patent No. 3,794,584; 1974). The adsorption by the above adsorbents is generally quite non-selective and is therefore limited to short-term treatments.
    Most porous resins are most synthesized by macroreticular synthesis (Meitzner, et al., US Patent 4,224,415; 1980), such as Amberlite XAD-4® and Amberlite XAD-16® from Rohm and Haas Company or by synthesis of hyper-crosslinking [Davankov, et al. J. Polymer Science, Symposium No. 47, 95-101 (1974)], used to make resins
    Hpersol-Macronet® by Purolite Corp. Many conventional polymeric adsorbents have a large pore surface and adsorption capacity, but a lack of selectivity due to the wide distribution of pore sizes. Others are produced to adsorb small organic molecules or are not blood-friendly and therefore are not suitable for selective adsorption of medium-sized proteins directly from body fluids.
    To improve hemocompatibility, many techniques involve coating the hydrophobic adsorbent with hydrophilic materials, such as polyacrylamide and (poly) hydroxyethylmethacrylate (Clark, USA (Clark, U.S. Patent No. 4,048,064; 1977; Nakashima, et al., Patent No. 4,171,283; 1979) A coating of 2-hydroxyethyl methacrylate copolymer with diemylaminoethyl methacrylate is reported by Watanabe, et al. (U.S. Patent No. 5,051,185, 1991). et al. (U.S. Patent 6,114,466; 2000) have disclosed a method of grafting on the outer surface of hydrophilic porous polymeric pearl monomers including 2-hydroxyethyl methacrylate, N-vinylpyrrolidinone, N-vinylcaprolactam and acrylamide. Recently, Albright ( US Patent 6,884,829 B2; 2005) disclosed the use of surfactant dispersants [including polyvinyl alcohol, (poly) dimethylaminoethyl methacrylate, (poly) vinylpyrrolidone and hydroxyethylcellulose] during macroreticular synthesis to produce a hemocompatible surface in porous beads in a one-step synthesis.
    The internal pore structure (distribution of pore diameters, pore volume and pore surface) of the adsorbent is very important for the adsorption selectivity. A cartridge containing an adsorbent bed packaged with effective pore diameters ranging from 2 Â to 60 Â (Angstrom) was disclosed for hemoperfusion by Clark (United States Patent 4,048,064; 1977). This pore size range was first specified for detoxification and to prevent the adsorption of anticoagulants, platelets and blood leukocytes, but is unsuitable for absorbing medium-sized proteins, such as cytochrome c and beta-2-microglobulin. Likewise, inorganic coating adsorbents, such as silicate and diatomite, with a membrane film with pore sizes greater than 20 Â were disclosed by Mota (United States Patent 5,149,425; 1992) for the preparation of hemoperfusion adsorbents. More recently, Giebelhausen (United States Patent 551,700; 2003) disclosed a spherical adsorbent with pronounced microstructure with pore diameters from 0 to 40 Â and a total micropore volume of at least 0.6 cm3 / g for adsorption of agents used in chemical warfare, toxic gases and vapors, and cooling agents. The pore structures above are too small for the adsorption of medium-sized proteins from physiological fluids.
    An adsorbent with a wide distribution of pore sizes (diameter 40 to 9,000 Â) was disclosed for the adsorption of proteins, enzymes, antigens and antibodies by Miyake et al. (United States Patent 4,246,351, 1981). The adsorbent absorbs both toxins as well as beneficial proteins such as blood albumin due to its wide pore size distribution. Immobilizing antibodies and IgG-binding proteins in porous polymeric adsorbents have been described to increase the selectivity of adsorbents with wide pore size distributions to reduce low-density lipoproteins, to treat arteriosclerosis, to adsorb the rheumatoid arthritis factor (Strahilevitz, United States Patent 6,676,622; 2004), and to remove hepatitis C viruses from the blood (Ogino et al. United States Patent 6,600,014; 2003). Antibodies or proteins bind to adsorbents, however, they could significantly increase the side effects for a hemoperfusion or plasma perfusion device and could significantly increase the difficulty in maintaining the sterility of the devices.
    The removal of beta-2-microglobulin by direct hemoperfusion was beneficial for renal patients (Kazama, "Nephrol. Dial. Transplant", 2001, 16: 31-35). An adsorbent with a larger portion of pores in a diameter range between 10 and 100 Â was described by Braverman et al. (United States Patent 5,904,663; 1999) for the removal of beta-2-microglobulin from the blood and by Davankov et al (United States Patent 6,527,735; 2003) for the removal of toxins in the molecular weight range of 300 -30,000 Daltons of a physiological fluid. Strom, et al. (United States Patent 6,338,801; 2002) described a synthetic method for polymeric resins with pore sizes in the range of 20 Å to 500 Å intended to absorb beta-2-microglobulin. The in vitro study by the present inventors shows that the pore structures proposed by Davankov and Strom, however, are unsuitable for selective adsorption of medium-sized proteins, such as beta-2-microglobulin and cytochrome-c, in the presence of albumin of the serum.
    Unlike the previous disclosures, the porous polymeric adsorbents specified in the present invention demonstrate a high selectivity for absorbing small and medium size proteins to the exclusion of large proteins with a molecular weight greater than 50,000 Daltons. More significantly, the present invention discloses adsorbents for hemoperfusion suitable for long-term clinical treatment, since healthy components, such as albumin, erythrocytes, platelets and leukocytes, are maintained at clinically acceptable levels. SUMMARY OF THE INVENTION
    In one embodiment, the present invention provides a polymeric system comprising at least one polymer with a plurality of pores, and the polymer has at least one transport pore with a diameter of about 250 Angstroms to about 2,000 Angstroms, and the polymer it has a transport pore volume greater than about 1.8% to about 78% of a polymer volume capacity pore.
    For the purposes of the present invention, the term "transport pore" is defined as a pore that allows rapid "transport" of molecules to the effective pores, and the term "transport pore volume" means the volume of the pores of "transport" per unit mass of the polymer.
    In another embodiment, the pores have diameters from more than 100 Angstroms to about 2,000 Angstroms. In yet another embodiment, the polymer is able to adsorb protein molecules greater than 20,000 to less than 50,000 Daltons from the blood and exclude the adsorption of blood proteins from more than 50,000 Daltons.
    In yet another embodiment, the polymer has a pore volume of about 0.315 cm3 / g to about 1.516 cm3 / g. In yet another additional embodiment, the polymer has an effective pore volume greater than about 21.97% to about 98.16% of the pore volume capacity. In an additional embodiment, the polymer comprises effective pores, said effective pores having a diameter greater than about 100 Angstroms up to about 250 Angstroms.
    For the purposes of the present invention, the term "total pore volume" is defined as the volume of all pores in a polymer per unit mass and the term "effective pore volume" means any pore that is selective for the adsorption of molecules. The term "pore volume capacity" is defined as the "capacity" volume of all pores per unit mass of polymer, and the term "effective pores" means functional pores designed to adsorb particular molecules. The term "capacity pore" is the sum total of effective pores and transport pores.
    In an additional embodiment, the polymer is biocompatible. In yet another embodiment, the polymer is hemocompatible. In yet another embodiment, the geometry of the polymer is a spherical granule.
    In yet another modality, the polymer is used in direct contact with whole blood to absorb protein molecules selected from a group consisting essentially of cytokines and B2-microglobulin and exclude the adsorption of large blood proteins, and large blood proteins are selected from a group consisting essentially of hemoglobin, albumin, immunoglobulins, fibrinogen, whey proteins and other blood proteins greater than 50,000 Daltons.
    In yet another modality, the polymer has an internal surface selectivity to absorb proteins less than 50,000 Daltons, having little or no selectivity to adsorb vitamins, glucose, electrolytes, fats and other small hydrophilic molecular nutrients carried by the blood.
    In another embodiment, the polymer is made using suspension polymerization. In yet another embodiment, the polymer is constructed from aromatic monomers of styrene and ethyl vinyl benzene with a crosslinking agent selected from the group consisting of divinyl benzene, trivinyl cyclohexane, trivinyl benzene, divinyl naphthalene, 15 divinyl sulfone, trimethylpropane triacrylate and trimethylolane triacrylate. mixtures thereof.
    In another embodiment, the crosslinking agent is DVD in an amount of about 20% to about 90% of the polymer.
    In yet another embodiment, the stabilizing agent for droplet suspension polymerization is selected from a group consisting essentially of hemocompatibilizing polymers, said polymers being (poly) N-vinylpyrrolidinone, (poly) hydroxyethyl acrylate, hydroxyethylcellulose, hydroxypropylcellulose, salts 25 (poly) acrylic acid, (poly) methacrylic acid salts, (poly) dimethylaminoethyl acrylate, (poly) dimethylaminoethyl methacrylate, (poly) diethylaminoethyl acrylate, (poly) diethylaminoethyl methacrylate, (poly) vinyl alcohol and mixtures thereof.
    In yet another additional embodiment, the polymer is made hemocompatible by outer coatings selected from a group consisting essentially of (poly) N-vinylpyrrolidinone, (poly) hydroxyethyl acrylate, (poly) hydroxyethyl methacrylate, hydroxyethylcellulose, hydroxypropylcellulose, salts (poly) acrylic acid, (poly) methacrylic acid salts, (poly) dimethylaminoethyl methacrylate, (poly) dimethylaminoethyl acrylate, (poly) diethylaminoethyl acrylate, 10 (poly) diethylaminoethyl methacrylate, (poly) vinyl alcohol and mixtures thereof.
    In another embodiment, the polymer is made hemocompatible by grafting the hemocompatible outer coatings to the surface concomitantly with the formation of porous polymer beads.
    In another additional embodiment, the polymer is made hemocompatible by grafting the hemocompatible outer coatings onto the preformed porous polymeric beads.
    In yet another additional embodiment, the polymer has an external surface with a negative ionic charge that prevents albumin from entering said pores.
    In yet another additional embodiment, the present invention relates to a selective size polymer that comprises at least one polymer with a plurality of pores, which have diameters greater than more than 100 Angstroms up to about 2,000 Angstroms, and the The polymer has a transport pore volume greater than about 1.8% to about 78% of a pore volume capacity of the polymer.
    In yet another additional embodiment, the present invention provides a selective size polymer comprising a plurality of pores, which have diameters from more than 100 Angstroms to about 2,000 Angstroms, and the polymer has at least one transport pore with a diameter from about 250 Angstroms to about 2,000 Angstrons, and the polymer has an outer surface with a negative ionic charge that prevents albumin from entering said pores at a pH of about 7.2 to about 7.6.
    In one embodiment, the present invention relates to a porous polymer for adsorbing protein molecules of small to medium size and which excludes the adsorption of large blood proteins, the polymer comprising a plurality of pores. The pores adsorb protein molecules of small to medium size equal to or less than 50,000 Daltons. In another embodiment, the polymer is biocompatible and / or hemocompatible.
    In yet another embodiment, the polymer comprises a plurality of pores with diameters from about 75 Angstroms to about 300 Angstroms. In another embodiment, the polymer may have a plurality of pores within the above range. In another additional embodiment, the polymer has its functional pores within the range mentioned above and may also have non-functional pores below the range of 75 Angstroms. In another embodiment, the polymer at most 2.0% by volume of its total pore volume of pores with diameters greater than 300 Angstroms. For the purposes of the present invention, the term "large blood proteins" is defined as any blood protein greater than 50,000 Daltons in size, and the term "blood protein molecules" refers to small to medium-sized blood proteins equal to or less than 50,000 Daltons.
    In yet another additional embodiment, the geometry of the polymer is a spherical pearl. In another embodiment, the polymer has a pore volume greater than 98.0% in pores smaller than the diameter of 300 Angstroms.
    In another additional embodiment, the polymer is used in direct contact with whole blood to adsorb protein molecules, such as b2-microglobulin, but excluding the adsorption of larger blood proteins, said large blood proteins being selected from a group consisting of 10 essentially in hemoglobin, albumin, immunoglobulins, fibrinogen, whey proteins greater than 50,000 Daltons and their mixtures. In yet another additional embodiment, the polymer has an internal surface selectivity to absorb proteins smaller than 50,000 Daltons, having little or no selectivity to adsorb vitamins, glucose, electrolytes, fats and other small hydrophilic molecular nutrients carried by the blood.
    In yet another embodiment, the polymer becomes porous using macroreticular or macro-network synthesis.
    In yet another additional embodiment, the polymer is made using suspension polymerization.
    In another embodiment, the polymer is constructed from aromatic monomers of styrene and ethyl vinyl benzene with the crosslinking provided by divinyl benzene, 25 trivinylcyclohexane, trivinyl benzene, divinyl naphthalene, divinyl sulfone, trimethylolpropane triacrylate and trimethylolpropane triacrylate and trimethacrylate.
    In yet another embodiment, the stabilizing agent for droplet suspension polymerization is selected from a group consisting essentially of hemocompatibilizing polymers, said polymers being (poly) N-vinylpyrrolidinone, (poly) hydroxyethyl acrylate, hydroxyethylcellulose, hydroxypropylcellulose, salts (poly) acrylic acid, (poly) methacrylic acid salts, (poly) dimethylaminoethyl acrylate, (poly) dimethylaminoethyl methacrylate, (poly) diethylaminoethyl acrylate, (poly) diethylaminoethyl methacrylate, (poly) vinyl alcohol and mixtures of the same.
    In yet another embodiment, the polymer is made hemocompatible by outer coatings of (poly) N-vinylpyrrolidinone, (poly) hydroxyethyl acrylate, (poly) hydroxyethyl methacrylate, hydroxyethylcellulose, hydroxypropylcellulose, (poly) acrylic acid salts, acid salts (poly) methacrylic, (poly) dimethylaminoethyl methacrylate, (poly) dimethylaminoethyl acrylate, (poly) diethylaminoethyl acrylate, (poly) diethylaminoethyl methacrylate, (poly) vinyl alcohol and mixtures thereof.
    In yet another embodiment, the polymer is made hemocompatible by grafting the hemocompatible outer coatings to the surface concomitantly with the formation of the porous polymer beads. In yet another additional embodiment, the polymer is made hemocompatible by grafting the hemocompatible outer coatings onto the preformed porous polymeric beads.
    In a further embodiment, the present invention relates to an absorbent polymer for excluding albumin from adsorption. The polymer comprises pores with diameters from about 75 Angstroms to about 300 Angstroms.
    In yet another embodiment, the present invention provides a hemocompatible polymer that comprises a range of functional pores. The functional pore range has pore diameters from about 75 Angstroms to about 300 Angstroms, and the polymer is designed to adsorb blood protein molecules.
    In another embodiment, the present invention relates to a selective size polymer for adsorbing proteins of blood origin from small to medium in size and which excludes the adsorption of proteins of large blood origin; the polymer comprises a plurality of pores, which have diameters from about 75 Angstroms to about 300 Angstroms. The polymer is used in direct contact with whole blood to adsorb cytokines and b2-microglobulin, but excludes the adsorption of large blood proteins and these are selected from a group consisting essentially of hemoglobin, albumin, immunoglobulins, fibrinogen, serum proteins greater than 50,000 Daltons and their mixtures. For the purposes of the present invention, the term "blood proteins" includes enzymes, hormones and regulatory proteins, such as cytokines and chemokines.
    The present invention discloses porous, size-selective, biocompatible and hemocompatible polymeric adsorbents whose pore structures are designed for hemoperfusion efficacy. For hemoperfusion efficacy, adsorbents must selectively adsorb proteins in relation to other small molecular species and the hydrophilic molecules present in the blood. Protein absorption should also be restricted to molecular sizes less than 50,000 Daltons, so that the important proteins needed for health homeostasis - albumin, immunoglobulins, fibrinogen - remain in the blood during the treatment of hemoperfusion.
    The porous polymeric adsorbents of this invention have a hemocompatible outer surface coating and an internal pore system with an aromatic pore surface for protein selectivity and a main pore volume in the pore diameter range of 100 to 300 Â essentially without pores greater than 300 Â in diameter. The pore volume in the pores greater than 300 Å is 2.0% or less of the total pore volume. These porous polymeric adsorbents exclude protein molecules larger than 50,000 Daltons from entering the pore system, but provide good mass transport into the pore system for protein molecules smaller than 35,000 Daltons.
    The porous polymers of this invention are constructed from aromatic monomers of styrene and ethyl vinyl benzene with crosslinking provided by one of divinyl benzene, trivinylcyclohexane, trimethylolpropane thiacrylate and trimethylolpropane trimethacrylate, or mixtures thereof. Other crosslinking agents that can be used to build the porous polymeric adsorbents of this invention are divinylnaphthalene, trivinylbenzene and divinylsulfone, and mixtures thereof.
    In another embodiment, the polymer adsorbent is synthesized by an organic solution in which 25 mol% to 90 mol% of the monomer comprises crosslinking agents such as divinylbenzene and trivinylbenzene, and the resulting polymer adsorbent has sufficient structural strength.
    The porous polymers of this invention are made by suspension polymerization in an aqueous phase formulated with initiation of free radicals in the presence of aqueous phase dispersants that are selected to provide a biocompatible and hemocompatible outer surface with the polymer beads formed. The pearls become porous by macroreticular synthesis with an appropriately selected pore builder (precipitator) and an appropriate time-temperature profile for polymerization in order to develop the appropriate pore structure.
    Porous beads are also made with small pore sizes using the hyper-crosslinking methodology, which is also known as macrorede synthesis or macrorede formation. In this methodology, a lightly crosslinked gel polymer - with crosslinking normally less than two (2)% by weight - is swollen on a good bifunctional swelling schedule for the polymeric matrix. In the swollen state, the polymeric matrix is cross-linked by a catalyzed reaction. The catalyzed reaction is most commonly a Friedel-Crafts reaction, catalyzed by a Lewis acid catalyst. The resulting product is a macroporous polymer which is a crosslinked polymer having a permanent pore structure in a dry, non-swollen state.
    For the purposes of the present invention, the term "biocompatible" is defined as a condition of compatibility with physiological fluids without producing unacceptable clinical changes within the physiological fluids. The term "hemocompatible" is defined as a condition whereby a material, when brought into contact with whole blood or blood plasma, results in clinically acceptable physiological changes.
    The biocompatible and hemocompatible outer surface coatings on the polymer beads are covalently attached to the pearl surface by grafting free radicals. The grafting of free radicals occurs during the transformation of the monomer droplets into polymer beads. The dispersing coating and stabilization of the monomer droplets becomes covalently bonded to the droplet surface as the monomers within the droplets polymerize and are converted to polymer. Biocompatible and hemocompatible outer surface coatings can be covalently grafted onto preformed polymer beads if the dispersant used in suspension polymerization is not the one that confers biocompatibility or hemocompatibility. The grafting of the biocompatible and hemocompatible coatings onto the preformed polymer beads is carried out by activating free radical initiators in the presence of the low molecular weight monomers or oligomers of the polymers that confer biocompatibility or hemocompatibility to the surface coating.
    Biocompatible and hemocompatible outer coatings on polymer beads are provided by a group of polymers consisting of (poly) N-vinylpyrrolidinone, (poly) hydroxyethyl methacrylate, (poly) hydroxyethyl acrylate, hydroxyethylcellulose, hydroxypropylcellulose, (poly) acrylic acid salts , (poly) methacrylic acid salts, (poly) dimethylaminoethyl methacrylate, (poly) dimethylaminoethyl acrylate, (poly) diethylaminoethyl acrylate, (poly) diethylaminoethyl methacrylate and (poly) vinyl alcohol.
    In one embodiment, the outer surface coatings, such as (poly) methacrylate and (poly) acrylate polymers, form anionic ions at pH 7.2 to 7.6, and said outer surface expels albumin that carries a negative ionic charge at pH of normal blood (7.4) and inhibit the entry of albumin into the pores on the outer surface of the absorbent by repulsion. In yet another embodiment, the outer surface of the thin layer of the divinylbenzene copolymer is modified to become an anionic exchanger, so that the outer surface forms negative charges to prevent albumin from entering the internal pores of the adsorbent. Albumin has an isoelectric point at pH 4.6 and has a net negative charge at normal blood pH and other physiological fluids. With the negative charges on the thin layer of the external surface of the adsorbent, the limitation of pore size can be expanded to a larger scale, with said polymer still exhibiting a preference for selectivity of toxin adsorption for albumin.
    Hemoperfusion and perfusion devices consist of a bed of pearls packaged from porous polymer beads selective for size in a passage container fitted with a retaining screen at both the outlet and the inlet end to keep the bed of pearls in the container . Hemoperfusion and perfusion operations are carried out by passing whole blood, blood plasma or physiological fluid through the bed of packaged beads. During perfusion through the bed of pearls, protein molecules smaller than 35,000 Daltons are extracted by adsorption, while the rest of the fluid components pass with essentially unchanged concentration.
    For the purposes of the present invention, the term "perfusion" is defined as the passage of a physiological fluid through a suitable extracorporeal circuit through a device containing the porous polymeric adsorbent to remove toxins and proteins from the fluid. The term "hemoperfusion" is a special case of perfusion where the physiological fluid is blood. The term "dispersant" or "dispersing agent" is defined as a substance that imparts a stabilizing effect by means of a finely divided matrix of immiscible liquid droplets suspended in a fluidization medium. The term "macroreticular synthesis" is defined as a polymerization of monomers into polymer in the presence of an inert precipitant that forces the growing polymer molecules out of the monomer liquid at a given molecular size 15 determined by phase equilibrium to provide nanoparticles of solid microgels of spherical or quasi-spherical symmetry together to produce a pearl with physical pores of an open cell structure [United States Patent 4,297,220, Meitzner and Oline, October 27, 20 1981; R.L.Albright, Reactive Polymers, 4, 155-174 (1986)].
    For the purposes of the present invention, the term "sorption" is defined as "absorption and binding by absorption and adsorption". BRIEF DESCRIPTION OF THE DRAWINGS
    Associated drawings are included to provide a further understanding of the present invention. These drawings are incorporated into and constitute a part of this specification, illustrate one or more embodiments of the present invention and, together with the description, serve to explain the principles of the present invention.
    FIGURE 1 is a graph from Table 2 showing a graph of pore volume versus pore diameter (dV / dD vs. D) for various adsorbents measured by the Nitrogen Desorption Isotherm.
    Among the benefits and improvements that have been disclosed, other objects and advantages of this invention will become evident from the description below, taken in conjunction with the associated drawings. The drawings form a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof. DETAILED DESCRIPTION OF THE INVENTION
    As necessary, the detailed embodiments of the present invention are disclosed in this document; it should be considered that the disclosed modalities are merely exemplary of the invention that can be presented in different ways. Therefore, the specific structural and functional details disclosed in this document are not to be construed as limits, but merely as a basis for teaching a person skilled in the art to employ the present invention. The specific examples below will allow the invention to be better understood. However, they are given for guidance only and do not represent any limitation.
    Five porous polymeric adsorbents are characterized by their porous structures and are evaluated for their competitive adsorption of cytochrome-c (11,685 Daltons in size) in relation to serum albumin (66,462 Daltons in size). The syntheses of adsorbents are described in Example 1; the characterization of the pore structure is given in Example 2; the competitive dynamic adsorption procedure and the results are provided in Example 3; and the competitor's effectiveness in capturing the smaller size cytochrome-c protein is discussed in Example 4. Example 1: Synthesis of adsorbents
    The synthesis process consists of (1) preparing the aqueous phase (2) preparing the organic phase, (3) carrying out suspension polymerization and (4) purifying the resulting porous polymeric adsorbent product. The aqueous phase compositions are the same for all polymerizations. Table 1A lists the percentage composition of the aqueous phase and Table 1B provides the typical material loads for a polymerization process in a five (5) liter reactor. TABLE IA
    TABLE 1B
    Material Loads for a Typical Five (5) Liter Reactor Polymerization Process
    Volume of the Water Phase 1750.00 mL 20 Density of the Water Phase 1.035 g / mL Weight of the Water Phase 1811.25 g Volumetric Ratio, Water Phase / Organic Phase 1.05 Volume of the Organic Phase 1665.0 mL Density of the Organic Phase 0, 84093 g / mL Weight of the organic phase, excluding the Initiator Charge 1400.15 g Total Reaction Volume 3415.0 mL Total Reaction Weight 3211.40 g Initiator, Pure Benzoyl Peroxide (BPO) 8.07606 g Initiator, 97% BPO 8.3258 (Note: the initiator charge is calculated only based on the amount of polymerizable monomers introduced into the reactor). 63% commercial divinylbenzene (DVB) 794,814 [98.65% of polymerizable monomers of DVB and EVB (ethylvinylbenzene); 1.35% inert compounds; 63.17% DVB; 35.48% EVB] Toluene 269,300 g Iso-octane 336,036 g Benzoyl peroxide, 97% 8.3258 g Total, organic load 1408.4758 g By means of the preparation of the aqueous phase and the organic phase, the aqueous phase is poured in the five-liter reactor and heated to 65 ° C, with stirring. The pre-mixed organic phase, including the initiator, is poured into the reactor over the aqueous phase with the agitation speed set at rpm to form the appropriate droplet size. The dispersion of the organic droplets is heated to the temperature selected for the polymerization and is maintained at this temperature for the desired period of time to complete the conversion of the monomers into the cross-linked polymer and, thus, fix the pore structure. The unreacted initiator is destroyed by heating the pearl slurry for two (2) two hours at a temperature where the half-life of the initiator is one hour or less. For the initiator, benzoyl peroxide, the unreacted initiator is destroyed by heating the slurry to 95 ° C for two (2) hours. 5 The slurry is cooled, the mother liquor is pulled by the siphon from the pearls and these are washed five (5) times with ultrapure water. Pearls are released from pore-forming and other organic compounds by a thermal cleaning technique. This process results in a clean and dry porous adsorbent 10, in the form of spherical and porous polymer granules.

    Example 2: Characterization of the pore structure
    The pore structures of the adsorbent polymer beds identified in Table 1C were analyzed using a Micromeritics ASAP 2010 instrument. The results are provided in GRAPH 1, where the pore volume is plotted as a function of the pore diameter. This graph shows the distribution of pore volume across a range of pore sizes. The pore volume is divided into categories within the pore size ranges for each of the five adsorbent polymers, and these values are given in TABLE 2. The pore volume capacity is that pore volume that is accessible to protein sorption and consists of the pore volume in pores larger than 100  in diameter. The effective pore volume is that pore volume that is selectively accessible to proteins less than 35,000 Daltons and that consists of pore diameters in the range of 100 to 250  in diameter. The oversized pore volume is the pore volume accessible to proteins greater than 35,000 Daltons and consists of the pore volume in pores larger than the 250 µm diameter. The undersized pore volume is the pore volume in the pores smaller than the diameter of 100 Šand is not accessible to proteins larger than about 10,000 Daltons. TABLE 2
    Dp = pore diameter in (Angstrom)
    FIGURE 1 shows a graph from Table 2 showing a graph of pore volume vs pore diameter (dV / dD or several 5 adsorbents measured by the nitrogen desorption isotherm. Example 3: Protein Adsorption Selectivity
    The polymeric adsorbent beads produced in Example 1 are wetted with an aqueous solution of 20% by weight of isopropyl alcohol and thoroughly washed with ultrapure water. The beads with diameters from 300 to 850 microns are packaged in a 200 ml hemoperfusion device that is a cylindrical cartridge with an internal diameter of 5.4 cm and a length of 8.7 cm. The beads are retained within the cartridge by screens at each end with a 200 micron orifice size. End caps with a center luer port 10 are threaded at each end to secure the screens and provide fluid distribution and tubing fixation.
    Four liters of a 0.9% aqueous saline solution buffered to a pH of 7.4 are prepared with 50 mg / liter of 15 horse heart cytochrome c and 30 g / liter of serum albumin. These concentrations are chosen to simulate a clinical treatment of a typical renal patient where albumin is abundant and b2-microglobulin is at much lower levels in the blood. Horse heart cytochrome c with a molecular weight of 11,685 daltons has a molecular size very close to B2-microglobulin at 11,845 daltons and is therefore chosen as a substitute for β2-microglobulin. Serum albumin is a much larger molecule than cytochrome c with a molecular weight of 66,462 daltons of cytochrome-c and therefore makes possible the appropriate competitive adsorption studies necessary to select the porous polymer with the ideal pore structure for selective exclusion by size of albumin.
    The protein solution is circulated by a dialysis pump 30 from a reservoir through a passing UV spectrophotometer cell, the bed of beads and then returns to the reservoir. The pumping rate is 400 mL / minute for a duration of four (4) hours. The concentration of both proteins in the reservoir is measured periodically by 5 UV absorbances at 408 nm for cytochrome-c and at 279 nm for albumin. All five adsorbents identified in TABLE 1C were examined for this competitive protein sorption assessment and the measured results are provided in TABLE 10 3. TABLE 3

    Dp = pore diameter in (Angstrom)
    Example 4: Pore volume and pore size range for proper kinetics and size selectivity for cytochrome C over albumin
    TABLE 3 and GRAPHIC 1 summarize the relevant pore structure data and protein perfusion results performed on all five (5) adsorbents. The selectivity to adsorb cytochrome-c in relation to albumin decreased in the following order: Adsorbent 4> Adsorbent 5> Adsorbent 1> 10 Adsorbent 2> Adsorbent 3.
    The amount of cytochrome-c adsorbed during the four-hour infusion decreased in the following order: Absorbent 2> Absorbent 3> Absorbent 5> Absorbent 1> Absorbent 4.
    The adsorbent 4 with the highest selectivity at 57.1 15 had the worst capture kinetics, with only 57.4% of the available cytochrome c during the four-hour infusion. This kinetic result occurs due to the effective pore volume being located at the small end of the pore size range, having its entire effective pore volume in the range of 130 to 100 Â pore size. There is an insignificant pore volume in the pores greater than 130 Å and this small pore size delays the entry of cytochrome-c.
    Adsorbent 5, with its main pore volume between 100 to 200 Ã…, presented the second highest selectivity for cytochrome-c in relation to albumin at 50.6, and had good mass transport into the pores with effective volume capturing up to 90.1% of cytochrome-c during the four-hour infusion. This porous polymer has the best balance of properties with excellent size selectivity for cytochrome c over albumin and a very good capacity for cytochrome c during a four hour infusion.
    Adsorbent 1 showed reasonably good selectivity at 24.05 for cytochrome-c sorption in relation to albumin. It also showed good cytochrome-c sorption capacity during the four-hour infusion, capturing up to 89.0% of the available quantity.
    The adsorbent 2 with the highest cytochrome-c sorption capacity during the four-hour infusion captured up to 96.7% of the available cytochrome-c. This high capacity results from having a large pore volume, 0.986 cm3 / g and the effective pore volume range from 100 Â to 250 Â. However, this porous polymer allowed more albumin to be adsorbed than Adsorbers 1, 4 and 5, as it has a significant pore volume, from 0.250 cm3 / g, in the pore size group from 250 Â to 300 Â .
    Adsorbent 3, with a very wide pore size distribution (see GRAPH 1) showed the poorest selectivity among the poorest group in 7.27. It has a pore volume in the pore size range greater than 250 Å. This porous polymer has a pore volume of 1.15 cm3 / g within the pore size range of 250 Å to 740 Å. Unlike the other four adsorbents, this porous polymer is not size-selective for proteins smaller than about 150,000 Daltons, although it absorbs 95.3% of the available cytochrome-c during perfusion.
    In the rest of the properties of selectively to sorb cytochrome-c in relation to albumin and its ability to capture cytochrome-c during a four-hour infusion, the porous polymeric adsorbent 5 provided the best performance. This porous polymer has the appropriate pore structure to perform hemoperfusion well together with 10 hemodialysis for people with Terminal Kidney Disease.
    Numerous modifications and variations of the present invention are possible in light of the above teachings. It should, therefore, be understood that, within the scope of the claims attached to this, this invention can be practiced in other ways than those specifically disclosed in this document.
    权利要求:
    Claims (16)
    [0001]
    1. Polymeric system, CHARACTERIZED by the fact that it comprises a biocompatible and hemocompatible polymer defined by a porous structure, the porous structure comprises transport pores with diameters from 250 Angstroms to 2,000 Angstroms, said polymer having a transport pore volume greater than 1.8% to 78% of a pore volume capacity of said polymer and an effective pore volume greater than 21.97% less than 98.16 of the pore volume capacity, where the pores of capacity have diameters from more than 100 Angstroms to 2,000 Angstroms and said polymer comprises effective pores, said effective pores having a diameter greater than 100 Angstroms up to 250 Angstroms.
    [0002]
    2. System, according to claim 1, CHARACTERIZED by the fact that said system comprises pores with a diameter greater than 300 Angstroms, said pores with a diameter greater than 300 Angstroms having no more than 2.0% of the total volume pores of said polymer.
    [0003]
    3. System according to claim 1, CHARACTERIZED by the fact that it comprises a polymer selected from the group consisting of divinylbenzene, trivinylcyclohexane, trivinylbenzene, divinylnaphthalene divinylsulfone, trimethylol, triacrylate and trimethylolpropane.
    [0004]
    4. System, according to claim 1, CHARACTERIZED by the fact that said pores are measured using a Micromeretics ASAP 2010 porosimeter.
    [0005]
    5. System, according to claim 1, CHARACTERIZED by the fact that said polymer is able to adsorb protein molecules greater than 20,000 to less than 50,000 Daltons from the blood and exclude the sorption of blood proteins of more than 50,000 Daltons.
    [0006]
    6. System, according to claim 1, CHARACTERIZED by the fact that said polymer has a pore volume of 0.315 cm3 / g to 1.516 cm3 / g.
    [0007]
    7. Polymer, according to claim 1, CHARACTERIZED by the fact that the geometry of said polymer is a spherical pearl.
    [0008]
    8. Polymer, according to claim 1, CHARACTERIZED by the fact that said polymer is used in direct contact with whole blood to absorb protein molecules selected from a group consisting essentially of cytokines and β2-microglobulin and excludes sorption of large blood proteins, said large blood proteins being selected from a group consisting essentially of hemoglobin, albumin, immunoglobulins, fibrinogen, whey proteins and other blood proteins greater than 50,000 Daltons.
    [0009]
    9. Polymer, according to claim 1, CHARACTERIZED by the fact that said polymer has an internal surface selectivity to absorb proteins smaller than 50,000 Daltons, having little or no selectivity to adsorb vitamins, glucose, electrolytes, fats and others small hydrophilic molecular nutrients carried by the blood.
    [0010]
    10. Polymer, according to claim 1, CHARACTERIZED by the fact that said polymer is made using suspension polymerization.
    [0011]
    11. Polymer, according to claim 1, CHARACTERIZED by the fact that said polymer is constructed from aromatic monomers of styrene and ethyl vinyl benzene with a crosslinking agent selected from the group consisting of divinyl benzene, trivinylcyclohexane, trivinylbenzene, divinylilsulfone, divinylilsulfone , trimethylolpropane triacrylate, trimethylolpropane trimethacrylate and mixtures thereof.
    [0012]
    12. Polymer, according to claim 1, CHARACTERIZED by the fact that a stabilizing agent for the polymerization in suspension of droplets is selected from a group consisting essentially of hemocompatibilizing polymers, said polymers being (poly) Nvinylpyrrolidinone, (poly acrylate) ) hydroxyethyl, hydroxyethylcellulose, hydroxypropylcellulose, (poly) acrylic acid salts, (poly) methacrylic acid salts, (poly) dimethylaminoethyl acrylate, (poly) dimethylaminoethyl methacrylate, (poly) diethylaminoethyl acrylate, (poly) methacrylate) , (poly) vinyl alcohol and mixtures thereof.
    [0013]
    13. Polymer, according to claim 1, CHARACTERIZED by the fact that said polymer is made hemocompatible by outer coatings selected from a group consisting essentially of (poly) N-vinylpyrrolidinone, (poly) hydroxyethyl acrylate, methacrylate (poly) hydroxyethyl, hydroxyethylcellulose, hydroxypropylcellulose, (poly) acrylic acid salts, (poly) methacrylic acid salts, (poly) dimethylaminoethyl methacrylate, (poly) dimethylaminoethyl acrylate, (poly) diethylaminoethyl acrylate, polyacrylate (poly) ) diethylaminoethyl, (poly) vinyl alcohol and mixtures thereof.
    [0014]
    14. Polymer, according to claim 13, CHARACTERIZED by the fact that said polymer is made hemocompatible by grafting on the surface of the hemocompatible outer coatings concomitantly with the formation of porous polymer beads.
    [0015]
    15. Polymer according to claim 14, CHARACTERIZED by the fact that said polymer is made hemocompatible by grafting the hemocompatible outer coatings onto the preformed porous polymeric beads.
    [0016]
    16. Polymer, according to claim 1, CHARACTERIZED by the fact that said polymer has an external surface with a negative ionic charge, which prevents albumin from entering said pores.
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    法律状态:
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-05-05| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: B32B 3/26 , C08J 9/00 , B82Y 30/00 Ipc: C08J 9/00 (2006.01), B82Y 30/00 (2011.01), B01J 20 |
    2020-08-18| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
    2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-08| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/09/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US12/807,597|US8211310B2|2006-11-20|2010-09-09|Size-selective polymer system|
    US12/807,597|2010-09-09|
    PCT/US2011/001549|WO2012033522A1|2010-09-09|2011-09-07|Size selective polymer system|
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