Abstract:
A crosslinked polymer for binding phosphate anions is provided, the polymer comprises a polyvalent cation attached to the polymer through at least one covalently bound anionic functional group, and wherein the anionic group is selected from a group consisting of sulfonate, carboxylate, phosphonate and mixtures thereof and wherein the cation is selected from a group consisting of aluminum, calcium, magnesium, molybdenum, manganese, titanium, barium, strontium, zirconium, vanadium, scandium, lanthanum, yttrium, cerium, nickel, iron, copper, cobalt, chromium, zinc and mixtures thereof.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     1. Field of the Invention  
         [0002]     The present invention relates to a hemocompatible polymeric resin functionalized to remove phosphate anions from whole blood without appreciably effecting the concentration of the other major anions of chloride and bicarbonate. The polymeric resin is targeted for extracorporal application in conjunction with hemodialysis. The functioning binding agent for the phosphate is a polyvalent cation attached to the polymer via an anionic group.  
         [0003]     2. Description of Related Art  
         [0004]     People with functioning kidneys have normal phosphate levels in their blood of 2.5 to 4.5 mg/dl of blood (measured as phosphorus), so that the phosphate anion concentration calculated as a millimole of HPO 4   2−  anion ranges within 0.081 to 0.145 mmole per dl (deciliter). At the pH of blood ranging from 7.35 to 7.45, the predominant monomeric phosphate anion is the monohydrogenphosphate anion, HPO 4   2− . The phosphate anion level is held in this narrow concentration range for a healthy homeostasis by the normal functioning kidney via a check and balance system that involves hormones and reabsorption of water and electrolyte (ions) in the tubules of the kidney.  
         [0005]     People with End Stage Renal Function or Disease are not able to keep the phosphate level in the blood within the proper normal range when eating a normal protein diet. Phosphate enters the body primarily through ingested protein. The phosphate level rises out of control with such individuals reaching blood levels as high as four times (4×) the normal blood concentration. This condition, known as hyperphosphatemia, if untreated allows calcium to be pulled from the bone mass producing degenerative bone disease.  
         [0006]     For people with End Stage Renal Disease (ESRD), the phosphate concentration in the blood is regulated by either a low protein diet or by ingesting phosphate binders with the food intake. The phosphate anions from the ingested protein are trapped by the binder or sequestrant and are carried out with the feces with only a very small amount of absorption into the blood from the intestinal tract. The phosphate binders initially used were aluminum and calcium compounds, but these were found to have moderately severe to very severe side effects. More recently (1997-2004), phosphate binding agents have been developed that are anion exchange polymers (RenaGel® and a polymer bound guanidinium hydrochloride) and less toxic inorganic compounds such as lanthanum carbonate tetrahydrate (Fosrenal™), ferric salts of citrate and acetate, and a lanthanum based porous ceramic material (RenaZorb™). All of these phosphate-binding agents are ingested with food and are designed to sequester phosphate anions during the digestive process in the intestinal tract. The absorption through the intestinal wall into the blood by the bound or sequestered phosphate is hindered and, consequently, the phosphate is carried out by way of the feces.  
         [0007]     This invention defines polymeric sequestrants for phosphate anions that are not ingested with food at mealtime. They function by binding phosphate anions directly from the blood as part of the hemodialysis system during the treatment sessions for people with End Stage Renal Disease (ESRD). These polymers function as selective sequestrants for the divalent monohydrogenphosphate anion and the anions of polyphosphoric acids without disturbing the concentrations of the other major anions of chloride and bicarbonate. Since bicarbonate is not bound by these sequestrants, the pH of the blood is unaltered during the treatment session.  
       SUMMARY OF THE INVENTION  
       [0008]     The present invention provides for a crosslinked polymer for binding phosphate anions wherein the polymer comprises at least one polyvalent cation wherein the cation functions as the binding site for phosphate anions. In another embodiment, the polymer is selected from a group consisting of divinylbenzene, styrene, ethylvinylbenzene, acrylic acid, methacrylic acid, esters of acrylic acid, esters of methacrylic acid, maleic acid and esters thereof, itaconic acid and esters thereof, trimethylolpropane trimethacrylate, trimethylolpropane triacrylate, and mixtures thereof.  
         [0009]     In still another embodiment, the cation is attached to the polymer through at least one anionic group and the anionic group is selected from a group consisting of sulfonate, carboxylate, phosphonate and mixtures thereof. In yet another embodiment, the cation is selected from a group consisting of aluminum, calcium, magnesium, molybdenum, manganese, titanium, barium, strontium, zirconium, vanadium, scandium, lanthanum, yttrium, cerium, nickel, iron, copper, cobalt, chromium, zinc and mixtures thereof.  
         [0010]     In still yet another embodiment, the polymer is a hemocompatible polymer. For purposes of this invention, the term “hemocompatible” is defined as a condition whereby a material, when placed in contact with whole blood and blood components or physiological fluids, results in clinically acceptable physiological changes. In a further embodiment, the polymer is a biocompatible polymer. For purposes of the invention, the term “biocompatible” is defined as being able to coexist with body fluids—whole blood, blood plasma, and lymph fluid—without initiating an adverse physiologic change within the fluid or at the surface interfacing with the fluid.  
         [0011]     The polymer of the present invention can be porous, non-porous or microporous. The term “porous polymer” is defined as a polymer particle having an internal pore structure with a porosity resulting from voids or holes throughout the polymer matrix. The term “non-porous polymer” is defined as an amorphous, gellular material without pores. The term “microporous polymer” is synonymous with non-porous polymer. In still another embodiment, the polymer is an ion exchange resin or polymer. An ion exchange resin or polymer is a resin or polymer carrying ionogenic groups that are capable of exchanging ions or of sequestering ions. The ion exchange polymers of the present invention are beneficial when used with blood for removing and isolating varying ions and ionogenic molecules.  
         [0012]     In still a further embodiment, the polymer binds to phosphate in a human bodily fluid environment, wherein the human bodily fluid environment is selected from a group consisting of whole blood, lymph fluid, blood plasma and mixtures thereof.  
         [0013]     In yet a further embodiment, the present invention relates to a crosslinked polymer for binding phosphate anions, the polymer comprising a polyvalent cation attached to the polymer through at least one covalently bound anionic functional group. In still yet a further embodiment, the polymer is selected from a group consisting of divinylbenzene, styrene, ethylvinylbenzene, acrylic acid, methacrylic acid, esters of acrylic acid, esters of methacrylic acid, maleic acid and esters thereof, itaconic acid and esters thereof, trimethylolpropane trimethacrylate, trimethylolpropane triacrylate, and mixtures thereof. In another further embodiment, the anionic functional group is selected from a group consisting of sulfonate, carboxylate, phosphonate and mixtures thereof. In still another further embodiment, the cation is selected from a group consisting of aluminum, calcium, magnesium, molybdenum, manganese, titanium, barium, strontium, zirconium, vanadium, scandium, lanthanum, yttrium, cerium, nickel, iron, copper, cobalt, chromium, zinc and mixtures thereof.  
         [0014]     In another embodiment, the present invention provides a polymer for removing phosphate anions from a human bodily fluid environment, the polymer is manufactured by a method comprising: forming a crosslinked polymer, attaching at least one anionic group to the polymer, and binding at least one polyvalent cation onto the anionic group attached to the polymer.  
         [0015]     In a further embodiment, the present invention relates to a method of manufacturing a polymer for binding phosphate anions, the method comprising: forming a crosslinked polymer, attaching at least one anionic group to the polymer, and binding at least one polyvalent cation onto the anionic group attached to the polymer to form a ligand whereby the ligand is design to remove phosphate anions. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0016]     As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in various ways.  
         [0017]     The specific examples below will enable the invention to be better understood. However, they are given merely by way of guidance and do not imply any limitation.  
         [0018]     The polymers are prepared in spherical bead geometry by suspension polymerization of the monomers in a formulated aqueous phase. The aqueous phase is formulated to provide droplet stability by a polymeric dispersant, to quench aqueous phase polymerization by a water-soluble free radical inhibitor and, where needed, a buffer to maintain a pH above nine (9.0) during the conversion of the monomer droplets into a suspension of polymer beads.  
         [0019]     The polymers are prepared from both aromatic monomers and aliphatic monomers with crosslinking provided by divinylbenzene (DVB) and trimethylolpropane trimethacrylate (TMPTMA). The initiator most used is benzoyl peroxide, although the azo-and peroxydicarbonate-initiators may also be used. The polymers in the attached examples are non-porous gel polymers, although porous polymers may also be prepared and used as the anchoring substrate for the functionality, provided the maximum pore diameter is kept under 100 Å so as to exclude protein sorption during direct contact with whole blood.  
         [0020]     With benzoyl peroxide as the initiator, the polymerizations are carried out at 70 to 75° C. for five (5) to eight (8) hours followed by a temperature ramp to 95° C. for an additional two (2) hours to decompose unreacted benzoyl peroxide.  
         [0021]     The active group that sorbs the phosphate anions from the blood is any one of the polyvalent cations (listed in Table 1 below) attached to the polymeric matrix via covalenty bound anionic groups. The anionic groups most used in this invention are sulfonate and carboxylate. The sulfonate group is covalently bound to the crosslinked aromatic polymer by sulfonation at 80 to 100° C. for four hours with 96 to 99% sulfuric acid. The aromatic polymers are terpolymers of styrene, ethylvinylbenzene (EVB) and varying levels of divinylbenzene (DVB). The divinylbenzene is the crosslinking agent that provides the insolubility to the sulfonated aromatic bead polymers.  
         [0022]     The spherical carboxylate polymers are prepared by suspension polymerization of acrylate and methacrylate esters in the presence of 3 to 5 wt. % sodium sulfate with crosslinking provided by either divinylbenzene or trimethylolpropane trimethacrylate. The ester group is transformed into the carboxylate anion by caustic hydrolysis with 5 wt. % sodium hydroxide, with the methyl esters being the easiest to hydrolyze.  
         [0023]     The polyvalent cations are loaded onto the polymer bound anionic groups via an ion exchange procedure. The functionalized bead polymers are loaded into a glass column to give a bead bed aspect ratio (bed height/bed diameter) of 10 to 12. The bead bed is treated downflow with a 3 to 5 wt. % aqueous solution of the nitrate salt of the polyvalent cation at a flow rate of 2 to 4 bed volumes per hour until the effluent exiting the bottom of the column has the composition of the influent entering the top of the column. At this point all the counter ions initially associated with the anionic groups bound to the polymeric matrix have been displace by the polyvalent cation.  
         [0024]     The polyvalent cations that are effective for binding phosphate anions selectively from whole blood are identified in the attached tabulation set forth below in Table 1:  
                                 TABLE 1                           Polyvalent Cations to be anchored to the Polymers            Cation   Available Salt   Solubility   MW               Al 3+     Al(NO 3 ) 3 .9H 2 O   67.3 g/100 ml H 2 O   375.134       Ca 2+     Ca(NO 3 ) 2 .4H 2 O   129 g/100 g H 2 O   236.149       Mg 2+     Mg(NO 3 ) 2 .6H 2 O   Soluble in 0.8 parts H 2 O   256.406       Mn 2+     Mn(NO 3 ) 2 .4H 2 O   Very Soluble in H 2 O   251.010       Ti 4+     TiCl 4     Soluble in cold H 2 O   189.678       Ba 2+     Ba(NO 3 ) 2     9.27 g/100 g H 2 O   261.336       Sr 2+     Sr(NO 3 ) 2     40.7 g/100 g H 2 O   211.629       Zr 4+     Zr(NO 3 ) 4 .5H 2 O   Very Soluble in H 2 O   429.320       V 3+     VCl 3     Decomposes in H 2 O   157.300       Sc 3+     Sc(NO 3 ) 3 .5H 2 O   Very Soluble in H 2 O   321.047       La 3+     La(NO 3 ) 3 .6H 2 O   136 g/100 g H 2 O   433.012       Y 3+     YCL 3     78.8 g/100 g H 2 O   195.264       Y 3+     Y(NO 3 ) 3 .6H 2 O   123 g/100 ml H 2 O   383.012       Y 3+     YCl 3 .6H 2 O   235 g/100 ml H 2 0   303.355       Ce 3+     Ce(NO 3 ) 3 .6H 2 O   Soluble in H 2 O   434.221       Ni 2+     Ni(NO 3 ) 2 .6H 2 O   Soluble in 0.4 parts H 2 O   290.794       Fe 3+     Fe(NO 3 ) 3 .9H 2 O   137.7 g/100 g H 2 O   403.997       Cu 2+     Cu(NO 3 ) 2 .3H 2 O   137.8 g/100 g H 2 O   241.602       Co 3+     Co(NO 3 ) 3     Soluble in H 2 O   244.948       Co 2+     Co(NO 3 ) 2 .6H 2 O   133.8 g/100 ml H 2 O   291.034       Cr 3+     Cr(NO 3 ) 3 .9H 2 O   74% H 2 O   400.148       Zn 2+     Zn(NO 3 ) 2 .6H 2 O   56.1 g/100 g H 2 O   297.491       Cr 3+     CrCl 3 .6H 2 O   Soluble in H 2 O   266.445                  
 
         [0025]     The dispersion mixture for a five (5) liter reactor for preparing the aromatic polymers is set forth below in Table 2:  
                             TABLE 2                       Dispersion Mixture For Five (5) Liter Reactor       For Preparing Aromatic Polymers                                Aq/Org. Vol. Ratio   1.1           Volume of Organic Phase   1900   ml       Volume of Aqueous Phase   2090   ml       Density of Organic Phase   0.905   g/ml       Weight of Organic Phase   1720.0   g       Density of Aqueous Phase   1.005   g/ml       Weight of Aqueous Phase   2100.0   g       Polymerizable Monomers; DVB, EVB, and Styrene   1720.0   g       Total Volume of Organic and Aqueous Phases   3990.0   ml       Total Weight of Organic and Aqueous Phases   3820.0   g                  
 
         [0026]     The aqueous phase composition for preparing the aromatic, crosslinked polymers of the present invention is set forth in Table 3 below:  
                             TABLE 3                       Aqueous Phase Composition For Preparing       Aromatic, Crosslinked Polymers                                    Ultrapure Water, wt. %   98.700           Dispersant 1  (Pure), wt. %   0.500           Sodium Carbonate 2 , wt. %   0.500           Sodium Nitrite 2 , wt. %   0.300                           1 Dispersant may be any of those listed in Dispersant Table 5.                  2 Values are for anhydrous salts.             
 
         [0027]     The aqueous phase charges for preparing aromatic, crosslinked polymers in a five (5) liter reactor is set forth in Table 4 below:  
                             TABLE 4                       Aqueous Phase ChargesFor Preparing       Aromatic, Crosslinked Polymers in a Five (5) Liter Reactor                                    Ultrapure Water, g   2072.7           Dispersant 1  (Pure), g   10.5           Sodium Carbonate 2 , g   10.5           Sodium Nitrite 2 , g   6.3           Total Weight Aqueous Phase, g   2100.0                           1 Dispersant may be any of those listed in Dispersant Table 5.                  2 Values are for anhydrous salts.             
 
         [0028]     The dispersants that can be used in the manufacturing of the polymers and that provide hemocompatibility to the polymeric bead surface are set forth in Table 5 below. In one embodiment, the dispersants provide the hemocompatible and/or biocompatible properties of the polymeric bead surfaces.  
                         TABLE 5                       Dispersant List                                    Poly(N-vinylpyrrolidinone); BASF Luviskol K60           Sodium Polyacrylate           Poly(hydroxyethyl acrylate)           Poly(hydroxypropyl acrylate)           Poly(hydroxyethyl methacrylate)           Poly(hydroxypropyl methacrylate)           Carrageenan; FMC Kappa and Lambda           Guar Gum Derivatives: Stein-Hall           Jaguar HP-11; Hydroxypropyl Guar Gum           Jaguar CMHP; Sodium Salt of Carboxymethyl, hydroxypropyl           Guar Gum                      
 
         [0029]     The organic phase composition for the aromatic, crosslinked gel polymer of the present invention is set forth in Table 6 below:  
                             TABLE 6                       Organic Phase Composition       For an Aromatic, Crosslinked Gel Polymer                                    Styrene, wt. %   91.0           Divinylbenzene (DVB), wt. %   5.0           Ethylvinylbenzene EVB, wt. %   4.0           Total Polymerizable Monomers, wt. %   100.0           Benzoyl Peroxide (Pure), wt. % of   0.5           Polymerizable Monomers                      
 
         [0030]     The organic phase charges for an aromatic, crosslinked gel polymer prepared in a five (5) liter reactor is set forth in Table 7 below:  
                             TABLE 7                       Organic Phase Charges For an       Aromatic. Crosslinked Gel Polymer Prepared in a Five (5) Liter Reactor                                    Styrene, g   1565.2           Divinylbenzene (DVB), g Pure   (86.0)           From Commercial 55% DVB of Composition           55 wt. % DVB, 44 wt. % EVB, and 1 wt. % Inerts           Ethylvinylbenzene (EVB), g   (68.8)           Commercial 55% DVB, g   156.364           Inerts, g   (1.564)           Weights in Parenthesis are Part of Commercial DVB               Total Weight of Organic Phase Excluding BPO, g   1721.564           Benzoyl Peroxide, 75 wt. % active, g   11.467                      
 
         [0031]     The dispersion mixture for a five (5) liter reactor for preparing aliphatic polymers of the present invention is set forth in Table 8 below:  
                                 TABLE 8                       Dispersion Mixture For Five (5) Liter Reactor       For Preparing Aliphatic Polymers                                    Aq/Org. Vol. Ratio   1.1               Volume of Organic Phase   1900.0   ml           Volume of Aqueous Phase   2090.0   ml           Density of organic Phase   0.963194   g/ml           Weight of Organic Phase   1830.07   g           Density of Aqueous Phase   1.005   g/ml           Weight of Aqueous Phase   2153.95   g           Polymerizable Monomers;           Methyl Acrylate (MA) and   1830.07   g           Trimethylolpropane Trimetbacrylate           (TMPTMA)               Total Volume of Organic &amp; Aqueous Phases   3990.0   ml           Total Weight of Organic &amp; Aqueous Phases   3930.52   g                      
 
         [0032]     The aqueous phase composition for preparing the aliphatic, crosslinked gel polymers of the present invention is set forth in Table 9 below:  
                             TABLE 9                       Aqueous Phase Composition For       Preparing Aliphatic, Crosslinked Polymers                                    Ultrapure Water, wt. %   95.7           Dispersant 1  (Pure), wt. %   0.500           Sodium Carbonate 2 , wt. %   0.500           Sodium Nitrite 2 , wt. %   0.300           Sodium Sulfate 2 , wt. %   3.0                           1 Dispersant may be anyone of those listed in Dispersant Table (Table 5).                  2 All the salts are computed on an anhydrous salt basis.             
 
         [0033]     The aqueous phase charges for preparing aliphatic, crosslinked gel polymers of in a five (5) liter reactor is set forth in Table 10 below:  
                             TABLE 10                       Aqueous Phase Charges For       Preparing Aliphatic, Crosslinked Polymers in a Five (5) Liter Reactor                                    Ultrapure Water   2061.33           Dispersant 1  (Pure), g   10.77           Sodium Carbonate 2 , g   10.77           Sodium Nitrite 2 , g   6.46           Sodium Sulfate 2 , g   64.62           Total Weight Aqueous Phase, g   2153.95                           1 Dispersant may be anyone of those listed in Dispersant Table (Table 5).                  2 All the salts are computed on an anhydrous salt basis.             
 
         [0034]     The organic phase composition for an aliphatic, crosslinked gel polymer of the present invention is set forth in Table 11 below:  
                             TABLE 11                       Organic Phase Composition       For An Aliphatic, Crosslinked Gel Polymer                                    Methyl Acrylate (MA), wt. %   90.0           Trimethylolpropane Trimethacrylate (TMPTMA) wt. %   10.0           Total Polymerizable Monomers, wt. %   100.0           Benzoyl Peroxide (Pure), wt. % of   0.5           Polymerizable Monomers                      
 
         [0035]     The organic phase charges for an aliphatic, crosslinked gel polymer of one of the embodiments of the polymers of the present invention is set forth in Table 12 below:  
                             TABLE 12                       Organic Phase Charges For An       Aliphatic, Crosslinked Gel Polymer Prepared in a Five (5) Liter Reactor                                    Methyl Acrylate (MA)   1647.1 g           Trimethylolpropane Trimethacrylate (TMPTMA)    183.0 g           Total Weight of Organic Phase Excluding   1830.1 g           Benzoyl Peroxide (BPO)           Benzoyl Peroxide, 75 wt. % active, g    12.2 g                      
 
         [0036]     Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the attendant claims attached hereto, this invention may be practiced otherwise than as specifically disclosed herein.