Anion-binding polymers and uses thereof

Patent description Ser. No. 5,338,532 discloses star-conjugated systems containing branched dendrite macromolecules.

Japanese Patent Publication No. 2003 155429 A discloses inkjet compositions comprising an "amine-forming micelles" component.

In the patent description Ser. No. 5,532,092 discloses dendritic macromolecules containing a core and branching branches therefrom, in which the dendritic macromolecules contain amino groups.

BRIEF PRESENTATION OF THE INVENTION [0009] In one embodiment, the inventive idea provides anion-binding polymers. In some embodiments, the inventive idea provides anion-binding polymer, wherein the polymer binds to a target anion (e.g. phosphate or oxalate) and has at least two of the following properties: a) a swelling ratio of less than about 5; b) a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the MW molecular weight of the target anion, occupying less than about 20% of the gel weight; and c) ion binding interference for the target ion of less than about 60% when measured in a medium imitating gastrointestinal tract content relative to the non-interfering buffer. In some embodiments, the swelling ratio is less than about 4, or less than about 3, or less than about

2.8, or less than about 2.7, or less than about 2.6, or less than about 2.5. In certain embodiments, the polymer binds bile acids or citrate with a yield of less than about 2 mmol / g, or less than about 1 mmol / g, or less than about 0.5 mmole / g, or less than about 0.3 mmol / g, or less than about 0.1 mmol / g. In some embodiments, the swelling ratio is measured in isotonic solution and at neutral pH. In some embodiments, the polymer contains amine monomers. In certain embodiments, the amine monomers are selected from the group consisting of allylamine, vinylamine, ethyleneimine, 1,3-diaminopropane and N, N, N ', N'-tetrakis- (3aminopropyl) -1,4-diaminobutane; 1,2,3,4-tetraaminobutane, a compound of formula 1 and a compound of formula 2, wherein formula 1 and formula 2 represent the following structures:

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NH [0010] In some embodiments, the inventive idea provides an anion-binding polymer comprising cross-linked polyamines, wherein the polymer is obtained by inversion of a suspension and wherein the degree of swelling of the polymer is less than 5.

[0011] In certain embodiments, the inventive idea provides a phosphate-binding polymer, wherein the polymer has at least one of the following features: a) a swelling ratio of less than about 5, preferably less than about 2.5; b. a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes with a molecular weight of more than about 200, occupying less than about 20% of the weight of the gel; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating gastrointestinal tract content relative to the non-interfering buffer. In some embodiments, the swelling ratio is less than about

2.8, or less than about 2.7, or less than about 2.6. In some embodiments, the polymer binds bile acids or citrate with a yield of less than about 2 mmol / g, or less than about 1 mmol / g, or less than about 0.5 mmol / g, or less than about 0.3 mmol / g, or less than about 0.1 mmol / g. In some embodiments, the swelling ratio is measured in isotonic solution and at neutral pH.

[0012] In certain embodiments, the inventive idea provides a phosphate-binding polymer, wherein the polymer has a swelling ratio of less than about 5, preferably less than about 2.8, or less than about 2.7, or less than about 2.6 , most preferably less than about 2.5, this degree being measured in isotonic solution and neutral pH. In an embodiment of the invention, the polymer has an average in vivo phosphate binding capacity greater than about 0.5 mole / g. In embodiments of the invention, the polymer is a polyamine polymer and the chloride content of the polymer is less than about 35 mol% relative to the amino group content.

[0013] In certain embodiments, the inventive idea provides anion-binding polymer, wherein the polymer binds to the target anion (e.g. phosphate or oxalate) and the polymer has at least two of the following characteristics: a) a swelling ratio of less than about 5; b. a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the molecular weight of the target anion, occupying less than about 20% of the gel weight; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating the contents of the gastrointestinal tract, relative to the non-interfering buffer, wherein the polymer contains one or more amine monomers and one or more crosslinkers, and where the polymer produces in a process in which the amine is in the solvent prior to crosslinking in an amine: solvent ratio of from about 3: 1 to about 1: 3, and the total amount of crosslinkers added to the reaction mixture is such that the average amount of connections with the amine monomers (NC) is between about 2.05 and about 6, or between about 2.2 and about 4.5. In some embodiments, the polymer is in turn produced by a process in which the target anion is in the reaction medium during the crosslinking reaction, for example by: a) adding the amine monomer as the free base and adding the target anion in its acid form; b) adding a crosslinker; c) performing a crosslinking reaction; id) elution of the target ion.

In some embodiments, the inventive idea provides anion-binding polymer, wherein the polymer binds to the target anion (e.g. phosphate or oxalate) and the polymer has at least two of the following characteristics: a) a swelling ratio of less than about 5; b) a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the MW molecular weight of the target anion, occupying less than about 20% of the gel weight; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating the contents of the gastrointestinal tract, relative to the non-interfering buffer, wherein the polymer contains one or more amine monomers and one or more crosslinking agents, and where the polymer produces in a process involving: a) preparing a soluble prepolymer by adding all of the amino monomer component followed by continuous addition of the crosslinker fraction to form a syrup; b) emulsifying the syrup in oil; and c) adding the remaining amount of crosslinker to form crosslinked beads.

[0015] In certain embodiments, the inventive idea provides anion-binding polymer, wherein the polymer binds to the target anion (e.g. phosphate or oxalate) and the polymer has at least two of the following characteristics: a) a swelling ratio of less than about 5; b. a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the molecular weight of the target anion, occupying less than about 20% of the gel weight; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating the contents of the gastrointestinal tract, relative to the non-interfering buffer, wherein the polymer contains one or more amine monomers and one or more crosslinkers, and where the polymer produces a process comprising: a) conducting a first reaction between the amine monomer and the crosslinker to form a gel; then b) reacting the gel with an aminoalkyl halide, during which the alkylamino groups chemically attach to the gel by substituting the halide for the amine functional groups of the gel.

[0016] In some embodiments, the inventive idea provides a phosphate-binding polymer comprising one or more amine monomers and one or more crosslinkers, wherein the polymer is made in a process in which the total content of crosslinkers added to the reaction mixture is such that the average number of bonds to amine monomers was between 2.2 and 4.5.

[0017] In some of these embodiments, the amino monomer is selected from the group consisting of 1,3-diaminopropane and N, N, N ', N'-tetrakis- (3-aminopropyl) -1,4-diaminobutane and, wherein the crosslinker is selected from the group consisting of 1,3-dichloropropane and epichlorohydrin. In embodiments, the invention provides an ion-binding polymer comprising N, N, N ', N'-tetrakis- (3-aminopropyl) -1,4-diaminobutane cross-linked with epichlorohydrin, wherein the polymer is prepared by a process in which the ratio of the initial concentration of N, The N'tetrakis- (3-aminopropyl-1,4-diaminobutane to water is from about 1: 3 to about 4: 1, or from about 1.5: 1 to about 4: 1.

[0018] In certain embodiments, the inventive idea provides a phosphate-binding polymer comprising N, N, N ', N'-tetrakis- (3-aminopropyl) -1,4-diaminobutane monomers and an epichlorohydrin crosslinker, wherein the polymer produces in a process in which the total amount of crosslinker - epichlorohydrin added to the reaction mixture is from about 200% to about 300 mol%, or from about 230 to about 270 mole% or about 250 mole% of the total amount of N, N, N ', N'-tetrakis- (3-aminopropyl) -1,4-diaminobutane. In some of these embodiments, the polymer is prepared by a process in which the ratio of the amount of monomers to the amount of water in the starting reaction mixture is from about 3: 1 to about 1: 1, or about 1.73. In some embodiments, the polymer is in the form of round beads.

[0019] In some embodiments, the inventive idea provides a phosphate-binding polymer comprising polyallylamine monomers and a crosslinker epichlorohydrin, wherein the polymer is prepared by initially dissolving polyallylamine monomers in water in a monomer: water ratio of from about 3: 1 to about 1: 3 . In some of these embodiments, the total amount of epichlorohydrin crosslinker added to the reaction mixture is about 10 mole% of the total amount of polyallylamine.

[0020] In certain embodiments, the inventive idea provides a phosphate-binding polymer comprising a prepolymer comprising 1,3-diaminopropane and a crosslinker in the form of 1,3-dichloropropane in a 1: 1 molar ratio, wherein the prepolymer is then subjected to a crosslinker reaction crosslinker - epichlorohydrin and in which the total amount of crosslinker - epichlorohydrin added to the reaction mixture is about 200 mole% of the total amount of prepolymer i, wherein the ratio of prepolymer: water in the reaction mixture is from about 1.1: 1 to about 1.7: 1.

[0021] The inventive idea then provides compositions comprising any of the polymers described above, wherein the polymer is in the form of particles that are surrounded by an outer coating.

[0022] In another embodiment, the inventive idea provides pharmaceutical compositions. In one embodiment, the pharmaceutical composition comprises a polymer of the invention and a pharmaceutically acceptable excipient. In some embodiments, the composition is a liquid preparation in which the polymer is dispersed in a liquid carrier in the form of water, and appropriate excipients. In some embodiments, the inventive idea provides a pharmaceutical composition comprising an anion-binding polymer that binds to the target anion, and one or more suitable pharmaceutical excipients, wherein the composition is in the form of a chewable tablet or orodispersible tablet and the polymer has a degree of swelling at passing through the mouth and esophagus of less than about 5, or less than about 2.8, or less than about 2.7, or less than about 2.6, or preferably less than about 2.5. In some embodiments, the chewable tablet contains a polymer whose glass transition temperature is greater than about 50 ° C.

[0023] In some embodiments, the chewable tablet comprises a pharmaceutical excipient selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose, sorbitol and combinations thereof, and is produced by a process in which the polymer is previously mixed with an excipient from forming a solid solution. In some embodiments, the target anion for the polymer is phosphate. In some embodiments, the polymer binds the target ion in vivo with a binding capacity greater than 0.5 mmol / g. In some embodiments, the anion-binding polymer comprises more than about 50% of the weight of the tablet. In some embodiments, the tablet has a cylindrical shape with a diameter of about 22 mm and a height of about 4 mm, wherein the anion-binding polymer comprises more than about 1.6 g of the total weight of the tablet. In certain types of chewable tablets according to the inventive idea, the excipients are selected from the group consisting of sweeteners, binders, lubricants and tablet disintegrants. Optionally, the polymer is present in the form of particles with an average diameter less than about 40 μη. In some of these embodiments, the sweetener is selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose and sorbitol, and combinations thereof.

In a further embodiment, the inventive idea provides a method of measuring the interference of the target ion binding process by an ion binding polymer that binds the target ion, comprising: a) adding an ion binding polymer to a non-interfering buffer containing the target ion and measuring the polymer binding capacity of the target ion ; b) artificial digestion of a normalized meal using digestive enzymes of the mammalian gastrointestinal tract and / or collection of gastrointestinal tract content from the upper gastrointestinal tract of mammals given a normalized meal; wherein the normalized meal contains a target ion; c) adding an ion binding polymer and measuring the binding capacity of the target ion based on a change in the concentration of the target ion before and after its addition; and d) calculating the degree of interference with the binding process in the form of a decrease in the binding capacity of the target ion, in percentage, observed between the measurement of the binding capacity in a non-interfering buffer environment and in a digested meal or in ex-vivo aspirates at the same ion concentration in equilibrium.

[0025] In a still further embodiment, the inventive idea provides a method for selecting an ion binding polymer, wherein the expressed polymer comprises a monomer and a crosslinking agent, wherein said polymer has at least one of the following properties: a) a swelling ratio of less than about 5; b. gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the molecular weight of the target anion, occupying less than about 20% of the gel; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating gastrointestinal tract content, relative to a non-interfering buffer, which includes the steps of: crosslinking composition (monomer + to monomer; factor of reaction medium;

physiological pH and the hydrophilic / hydrophobic change in the following process variables: 1) agent ratio

2) the ratio of the content of the crosslinking system) to the solvent in

3) polymer network charge at tonicity; and / or 4) polymer backbone balance; ii) assessing the swelling ability, porosity and disruption of the ion binding process by the resulting polymer; and iii) selecting a polymer having at least one of the following characteristics. In another aspect, the inventive idea provides a method of improving the therapeutic properties and / or suitability for administration and / or pharmaceutical properties of a polyamine polymer, which comprises at least one of the following steps: a) crosslinking the polymer with a crosslinking agent such that the average number of bonds to the polyamine monomer was from about 2.05 to about 6; and / or b) producing the polymer by a method in which the polyamine is initially present in water in a polyamine: water ratio of from about 3: 1 to about 1: 3.

[0026] According to another embodiment, the inventive idea provides a method for producing an anion-binding polymer that binds to a target anion, comprising combining the amine monomer with a cross-linking agent in a heterogeneous process in which the phosphate-binding polymer has at least two of the following characteristics: swells less than about 5; b) a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the MW molecular weight of the target anion, occupying less than about 20% of the gel weight; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating gastrointestinal tract content relative to the non-interfering buffer. In some embodiments, the amine monomer is polyallylamine. In some embodiments, the crosslinker is epichlorohydrin.

[0027] In another aspect, the inventive idea provides an anion-binding polymer that binds to a target ion, wherein the polymer is made by a process comprising crosslinking polyallylamine in a heterogeneous environment, said polymer having at least two of the following features: a) swelling ratio less than about 5; b. a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the molecular weight of the target anion, occupying less than about 20% of the gel weight; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating GI gastrointestinal tract content relative to the non-interfering buffer. In one embodiment, the polyallylamine cross-linking agent is epichlorohydrin.

[0028] In another aspect, the inventive idea provides a method of removing anion from an animal's body by administering to the animal an effective amount of a polymer according to the invention. In some embodiments, the polymer is an anion-binding polymer that binds to the target anion (e.g. phosphate or oxalate) and which polymer has at least two of the following characteristics: a) a swelling ratio of less than about 5; b) a gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes having a molecular weight greater than about twice the MW molecular weight of the target anion, occupying less than about 20% of the gel weight; and c) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating GI gastrointestinal tract content relative to the non-interfering buffer. In some embodiments, the target anion for the polymer is phosphate;

solutions, phosphate is removed from the intestinal tract; in some embodiments, the method of administration is oral administration. In certain embodiments, the animal is affected by at least one disorder selected from the group consisting of hypocalcaemia, hyperthyroidism, kidney, tetany of renal failure, ectopic soft tissue calcification and end stage renal disease (ESRD). In certain embodiments, the animal is a human. [0029] In some embodiments, the polymer is administered in parallel with at least one substance, such as a proton pump inhibitor, calcimimetic drug, vitamin and analogues thereof, or with a phosphate binder, e.g. an aluminum carbonate phosphate binder calcium acetate, lanthanum carbonate, or sevelamer hydrochloride.

in certain gastritis hyperphosphataemia, reduced synthesis resulting from calcitriol hypocalcemia,

LITERATURE REFERENCES [0030] All publications and patent applications cited herein are incorporated herein by reference in the same manner as if each separate publication or patent application was specifically and individually indicated as the associated material.

BRIEF DESCRIPTION OF THE DRAWINGS [0031] Fig. 1 is a graph illustrating the determination of binding process interference by comparing the target ion binding isotherm of a non-interfering buffer in a target polymer binding interference for a polymer in an environment relative to ion binding in an interfering environment (e.g., a mixture imitating the contents of the wire digestive tract (GI) or system containing the ex-vivo digestive tract content).

[0032] Fig. 2 is a graph illustrating the unavailable gel volume depending on the radius of the dissolved sample substance.

[0033] Fig. 3 is a graph illustrating the determination of phosphate binding polymer (EC 172A).

[0034] Fig. 4 is a graph illustrating binding interference for a phosphate binding polymer (RENAGEL).

[0035] Fig. 5 is a graph of the inaccessible volume versus molecular weight of a non-interfering test substance, illustrating the difference between the phosphate-binding polymer of the invention (EC 172A) and the commercially available phosphate-binding substance (RENAGEL).

[0036] Fig. 6 is a graph of the inaccessible volume versus radius of a test substance molecule for a non-interfering test substance, illustrating the difference between the phosphate-binding polymer of the invention (EC 172A) and the commercially available phosphate-binding substance (RENAGEL).

[0037] Fig. 7 is a graph illustrating the change in binding capacity for chloropropylamine modified FR-005-144; hydrochloride.

[0038] New embodiments of the invention are presented with particular regard to the embodiments of the appended claims. A better understanding of the embodiments and advantages of the inventive idea will be possible by reference to the following detailed description summarizing illustrative embodiments in which the principles of the inventive idea are used, and the accompanying figures in which:

DETAILED DESCRIPTION OF THE INVENTION IDEA

I. Introduction [0039] One embodiment of the invention provides anion-binding polymer materials that have one or more properties, such as low swelling, high ion binding capacity, low interference by interfering ions, and / or specific porosity. Another embodiment of the inventive idea provides pharmaceutical compositions from anion-binding polymers, which pharmaceutical compositions are in the form of chewable tablets or liquid preparations. Another embodiment of the inventive idea provides methods for making or improving anion-binding polymers such that they have one or more properties such as low swelling, high ion binding capacity, low interference by interfering ions, and / or specific porosity. Still a further embodiment of the inventive idea are methods of using anion-binding polymers according to the inventive idea for the treatment of conditions associated with excess ions. In a preferred embodiment, anion binding polymers are used to remove target anions from the gastrointestinal (GI) tract. Examples of target anions that can be removed from the gastrointestinal (GI) tract include, but are not limited to, phosphate and oxalate. In another preferred embodiment, the compositions described herein are used in the treatment of hyperphosphataemia, hypocalcaemia, hyperparathyroidism, reduced renal calcitriol synthesis, tetany resulting from hypocalcemia, renal failure, ectopic soft tissue calcification, chronic renal failure and anabolic metabolism.

II. Polymers [0040] The polymers according to the invention are characterized by their ion binding capacity. Preferably, the polymers of the present invention bind anions, more preferably bind phosphates and / or oxalates, and most preferably bind phosphate ions. For illustration, anion binding polymers, especially phosphate binding polymers will be described;

however, it is understood by the modifications which the field uses that this description, with appropriate ones, will be apparent to those skilled in the art to all ions and solutes as well. Terms as used herein, such as an "ion-binding" polymer, e.g. an anion, or an "ion-binding" polymer (e.g. "phosphate-binding polymer") is used when the polymer binds to the ion, generally not necessarily in a non-covalent way, with a sufficiently strong association strength such that at least a portion of the ion remains bound in vitro or in vivo during use polymer in which the polymer is used for a sufficient time to effectively remove the ion from the solution or from the body. The term "target ion" means the ion to which the polymer binds and usually refers to the main ion bound by the polymer, or an ion whose binding to the polymer is believed to give a therapeutic effect to the polymer. A polymer can bind more than one target ion. "Anion" bond, means more than minimal bond, i.e., at least about 0.01 mmol anion / g polymer, more preferably at least about 0.05 mmol anion / g polymer, even more preferably at least about 0.1 mmol anion / g polymer and most preferably at least about 0.5 mmol anion / g polymer. The polymers according to the invention are polymers characterized by selective anion binding; for example. in some embodiments, the polymers of the invention bind bile acids with a binding capacity of less than about 2 mmol / g, preferably less than about 1 mmol / g, more preferably less than about 0.5 mmol / g, even more preferably less than about 0, 3 mmol / g most preferably less than about 0.1 mmol / g. In some embodiments, the polymers of the invention bind citrate with a binding capacity of less than about 2 mmol / g, preferably less than about 1 mmol / g, more preferably less than about 0.5 mmol / g, even more preferably less than about 0, 3 mmol / g and preferably less than about 0.1 mmol / g.

most

A. Characteristics [0041] The polymers according to the inventive idea have one or more of the following properties: 1) low swelling; 2) small disruption of the binding process in a physiological environment; 3) suitable porosity for binding the target anion, and disabling interfering solutes; 4) the in vivo binding capacity of the target anion sufficient for effective therapeutic use. In some embodiments, the polymer is an anion-binding polymer (e.g. a polymer that binds phosphate and / or oxalate), which polymer has at least two of the following characteristics: 1) a swelling ratio of less than about 5; 2) gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes with a molecular weight greater than about twice the MW molecular weight of the target anion, occupying less than about 20% of the gel weight; and 3) ion binding interference for the target ion of less than about 60% when measured in a medium imitating the content of the GI gastrointestinal tract, relative to the non-interfering buffer. In some embodiments, the polymer is a phosphate-binding polymer having at least one of the following features: 1) a swelling ratio of less than about 5, preferably less than about 2.5; 2) gel pore volume distribution measured in a physiological environment characterized by a fraction of said pore volume available for non-interacting solutes with a molecular weight greater than about 200, occupying less than about 20% of the gel weight; and 3) ion binding interference for the target ion of less than about 60% when measured in a medium imitating the contents of the gastrointestinal tract, relative to the non-interfering buffer. In some embodiments of the invention, the swelling ratio of the phosphate-binding polymer is less than about 2.8, or less than about 2.7, or less than about 2.6. The "physiological environment" is an isotonic environment with a neutral pH. In some embodiments, the inventive idea provides the polymer with a binding degree less than about embodiment, polymers of swollen characterized phosphates, measured in an isotonic environment with a neutral pH less than about 5, preferably less than about 2.5, optionally with an average in vivo ion binding capacity phosphate content above about 0.5 mole / g. In certain embodiments, the phosphate-binding polymer has a swelling ratio of less than about 2.8, or less than about 2.7, or less than about 2.6. In some embodiments, the polymers of the invention bind bile acids with a binding capacity of less than about 2 mmol / g, preferably less than about 1 mmol / g, more preferably less than about 0.5 mmol / g, even more preferably less than about 0.3 mmol / g and most preferably 0.1 mmol / g. In certain embodiments of the invention, they bind citrate with a binding capacity of less than about 2 mmol / g, preferably less than about 1 mmol / g, more preferably less than about 0.5 mmol / g, even more preferably less than about 0.3 mmol / g and most preferably less than about 0.1 mmol / g. Preferably, the polymers consist of amine monomers.

[0042] In general, these features are achieved by changing one or several parameters during polymer production.

[0043] 1) Degree of swelling. The polymers according to the inventive idea are crosslinked materials, which means that they do not dissolve in solvents, and at most swell in solvents.

[0044] The degree of swelling in an isotonic physiological buffer representing the application environment, i.e. the gastrointestinal tract, typically ranges from about 1.2 to about 100, preferably from about 2 to 20. In some embodiments, the polymers of the invention have a swelling ratio of less than 5, or less than about 4, or less than about 3, or less than about

2.8, or less than about 2.7, or less than about 2.6, or less than about 2.5. The term "swelling ratio" as used herein refers to the number of grams of solvent absorbed by one gram of dry crosslinked polymer after reaching equilibrium in an aqueous environment. In the case where more than one swelling measurement was carried out for a given polymer, it is assumed that the swelling ratio is the average of the measurements.

[0045] Swelling rates can be measured using a variety of methods: the gravimetric method in which the dried polymer is weighed and added to excess liquid is most preferred. In some cases, the liquid may be distilled water; preferably the liquid is an aqueous isotonic solution with blood plasma; most preferably the liquid is an aqueous solution isotonic with blood plasma and buffered to a neutral pH. For example, a 0.9% NaCl solution can be used. Phosphate buffered saline (PBS) may also be used. The most preferred physiological medium for swelling measurements is 0.9% NaCl buffered with 30 mM MES / electrolyte fluid to a pH value of about 6.5 to 7.5. The dry polymer (e.g., phosphate-binding polymer) is generally used in a fully protonated form with a counter-ion such as chloride. The polymer is soaked in a liquid until equilibrium is reached. Then, the soaked gel is centrifuged, the clarified liquid is decanted and the wet gel is weighed. Centrifugation should be carried out very carefully to avoid gel collapse. The swelling ratio (SR) is calculated as the weight of the wet gel minus the weight of the dry polymer divided by the weight of the dry polymer.

[0046] Another method is the dye method, in which a very high molecular weight dye that does not interact with the gel is dissolved in water and a dry polymer sample is introduced into the resulting solution. The ratio of solution mass to polymer mass is adjusted to a value close to and slightly higher than the expected swelling ratio. Because the dye has a very high molecular weight (e.g. above 200,000 g / mol), it does not penetrate into the gel, while water penetrates into it, which leads to an increase in the current concentration of dye, on the basis of which the degree of swelling can be determined. An example of a useful dye is Fluorescein Isothiocyanate (FITC) dextran. [0047] The degree of polymer swelling depends on several variables, such as temperature, ionic strength, polymer charge density, polymer-solvent Flory-Huggins coefficient and crosslinking density. Because the ion-binding polymers of the invention are usually charged polymers (e.g., phosphate-binding polyamines occur in protonated form in an environment with a pH value that is present in the digestive system), their swelling behavior is typical of polyelectrolyte gels. Although the degree of swelling and pore size are somewhat related to each other, i.e. a large degree of swelling is usually accompanied by large pore sizes, there is no theoretical basis to accurately determine the exclusion limit of polyelectrolyte gels.

[0048] 2) Disruption of the binding process. In some embodiments, the polymers according to the inventive idea, when measured in the gastrointestinal (GI) mimetic mixture, show a binding disruption of less than about 70%, more preferably less than about 60%, even more preferably less than about 50%, yet more preferably less than about 40%, even more preferably less than about 30% and most preferably less than about 20%. The phosphate binding polymers according to the inventive idea, when measured in a mixture imitating the content of the gastrointestinal tract (GI), show a binding disruption of less than about 70%, more preferably less than about 60%, even more preferably less than about 50%, more preferably less than about 40%, even more preferably less than about 30% and most preferably less than about 20%.

[0049] As used herein, the terms "degree of binding process disruption" or "binding process disruption" means a fractional decrease in target ion binding capacity, expressed as a percentage, observed between binding performance in a non-interfering buffer environment and in a mixture that mimics the content of the gastrointestinal tract ( GI), with the same equilibrium concentration of the target anion. The term "non-interfering buffer" as used herein means a buffer that does not contain one or more dissolved solubilizers interfering with the target ion binding process, and is buffered to the same pH as the gastrointestinal (GI) mimetic mixture. The non-interfering buffer need not necessarily be free of all interfering dissolved substances, for example, the non-interfering buffer may contain one or both of the commonly occurring chloride and bicarbonate ions in the digestive system; which, if present, may be in a concentration such as under physiological conditions. An example of a non-interfering buffer is given in Example 1. As used herein, the term "gastrointestinal (GI) mimetic mixture" means a system designed to mimic the environment of a portion of the gastrointestinal tract after a meal, preferably a portion of the GI tract in which the polymer will bind most of the target ion. The mixture imitating the content of the GI conduit is typically prepared by the method illustrated in Example 1. The target ion should be present in the mixture that mimics the content of the GI tract in the same concentration (s) used in the non-interfering buffer studies. The degree of interference can be easily illustrated by plotting two appropriate binding isotherms, i.e. for a mixture that mimics the content of the GI conduit and for a non-interfering buffer environment, as shown in Figure 1. An example of measuring interference in the binding process using a mixture that mimics the content of the GI wire is given in Example 1.

[0050] It is also possible to measure the binding interference by comparing the binding of the target ion in the collected food content of patients, preferably human patients, with the binding of the target ion in a non-interfering buffer environment. If this type of measurement is carried out, the nutrient samples should be taken from a certain number of individuals and the average measurement result taken as a disturbance of the binding process.

[0051] It has been found that by carefully choosing the degree of swelling and / or setting the limit molecular weight of the particles excluded by the gel, the binding capacity measured by competing methods can be significantly increased (i.e. in vivo or in a mixture that mimics the content of the GI tract) compared to other gels having such same polymer composition but with non-optimized porosity.

[0052] It is striking that polymers with increased crosslinking and / or entanglement have been found to have less swelling than those with less crosslinking and / or entanglement, and also have the same or greater binding capacity for the target ion (e.g., phosphate) than polymers with less crosslinking and / or entanglement. Without wishing to be bound by theory, the hypothesis that the polymers according to the inventive idea exert a sieve effect and binds only solutes of specific dimensions from the solution and excludes other substances with larger particles that could otherwise compete for binding sites inside the polymer. Higher molecular weight substances include, but are not limited to, inorganic and organic anions, oligopeptides, carbohydrates, bilirubins, lipid micelles, and lipid vesicles.

[0053] 3) Porosity. It has been found that it is possible to manipulate the polymer production process so that the polymer has a more optimal porosity suitable for binding the target ion (e.g., anions) for which the polymer is intended to exclude interfering substances.

[0054] The dispersion of the size of polymer pores is obtained using various methods such as mercury porosimetry, nitrogen adsorption, differential scanning calorimetry or solute permeation separation techniques. The latter method, the technique of permeation separation of the solute, is the most advantageous, since the test is carried out on a completely hydrated gel, i.e. in a condition that prevails in identical applications.

medium

The solute permeation technique is an indirect method introduced by Kuga (Kuga SJ, J.

includes measuring known masses suitable. hereby dissolved and referred to herein as of Chromatography, 1986, 206: 449-461) for the dissolution of solutes with a molecular gel. This method consists of three main stages (Kremer et al., Macromolecules, 1994, 27, 2965-73):

1. Solutions of dissolved substances with known concentrations and particle sizes are brought into contact with the swollen gel. The particle sizes of dissolved substances must cover a wide range.

2. Dissolved substances dissolve into the gel. The distribution of individual dissolved substances depends both on their dimensions and on the distribution of gel pore sizes.

3. The gel is separated from the surrounding solution, and then the solute concentrations in the surrounding solution are measured. To calculate the spread of gel pore sizes, the concentration of each solute is reduced from its initial concentration.

[0055] In order to get rid of the exclusion effects caused by molecular attraction / repulsion effects, the dissolved substances are selected from polymers or oligomers that have little or no interaction with the gel polymer; neutral hydrophilic polymers with a narrow molecular weight distribution, such as polyethylene glycol, polyethylene oxide or dextran, which are

Thus, unless indicated in the description, the volumes for excluding particular sizes (also the critical permeation volume ") refer to the volumes measured using solutes that do not interact with the polymer for which the measurements were carried out.

most differently in the substance [0056] According to the experimental protocol and data provided by Kremer et al., Macromolecules, 1994, 27, 296573, the pore size distribution can be represented as shown in Figure 2. In Figure 2, the Y axis means the volume of swollen gel that is not available for solutes of a given particle size. In the example shown in this figure, small particles smaller than 5 angstroms can penetrate the entire gel. On the other hand, polymers with a hydrodynamic radius greater than 1000 angstroms are completely excluded from the gel. In this case, the inaccessible volume and the gel volume in equilibrium are the same.

[0057] The sizes and molecular weight of the polymers are dependent on each other according to the Mark-Houvink equations, which are tabulated for dissolved polymeric substances used as probe molecules. Ex .:

Radius (angstroms) = 0.0.217M^0,498 dextran

Radius (angstroms) = 0.271M^0,517 poly (ethylene glycol)

Radius (angstreams) = 0.166M^0,573 poly (ethylene oxide) [0058] Low molecular weight probe molecules can also be used:

Urea: 2.5 angstrom particle radius

Ethylene glycol: 2.8 angstrom particle radius

Glycerin: 3.1 angstrom particle radius

Glucose: particle radius 4.4 angstrestr. Sucrose: particle radius 5.3 angstrem [0059] Thus, the molecular weight of the solute can be calculated molecular weight and vice versa. [0060] The particle sizes of the solute are not equal to the dimensions of the pores; otherwise, it could mean that all the liquid in the pores larger than the solute's particle size is the available volume: this is incorrect because of the excluded volume effect, also known as the wall effect.

[0061] A direct way to characterize the particle exclusion limit is: (i) quantifying the partitioning of the probe substance, (ii) calculating the available volume (or mass) by the method described above, and (iii) normalizing the data obtained to the total gel volume (or mass) .

[0062] The desired particle exclusion limit is achieved by changing production variables such as entanglement of polymer chains and the concentration of crosslinker (see below). In general, polymers having an molecular exclusion limit are produced with an ion-dependent size (e.g. anion) to be bound and likely interfering substances to be excluded, as well as the allowable amount of polymer swelling, depending on the intended use. In certain embodiments of the inventive idea, the ion-binding polymer is characterized by a dispersion of gel pore volumes (critical permeation volume) as determined above and measured in a physiological environment in which the pore volume available for non-interacting solutes with a molecular weight greater than about twice the MW molecular weight target anion takes less than about 60%, less than about 40%, or less than about 20% by volume of the polymer.

In certain embodiments of the inventive idea, the ion-binding polymer is characterized by a dispersion of gel pore volumes (critical permeation volume) in which the pore volume available for non-interacting solutes with a molecular weight greater than about 1.8 times the molecular weight of the target ion occupies less than about 60%, less than about 40%, or less than about 20% of the polymer volume. In some embodiments of the inventive idea, the ion-binding polymer is characterized by a gel pore volume distribution (critical permeation volume) in which the pore volume available for non-interacting solutes with a molecular weight greater than about 1.6 times the molecular weight MW of the target ion occupies less than about 60%, less than about 40%, or less than about 20% of the polymer volume. In some embodiments of the inventive idea, the ion-binding polymer is characterized by a gel pore volume distribution (critical permeation volume) in which the pore volume available for non-interacting solutes with a MW molecular weight greater than about 1.4 times the molecular weight of the target ion occupies less than about 60%, less than about 40%, or less than about 20% of the polymer volume. In some embodiments of the inventive idea, the ion-binding polymer is characterized by a gel pore volume distribution (critical permeation volume), in which the pore volume available for non-interacting solutes with a MW molecular weight greater than about 1.2 times the molecular weight of the target ion occupies less than about 60%, less than about 40%, or less than about 20% of the polymer volume. In some embodiments, the inventive idea provides a phosphate-binding polymer that is characterized by a gel pore volume distribution (critical permeation volume) as defined above and measured in a physiological environment in which the pore volume is available for non-interacting solutes with a molecular weight greater than about 200, more preferably above about 180, more preferably above about 160, more preferably above about 140 and most preferably above about 120, it occupies less than about 60%, less than about 40%, or less than about 20% by volume of the polymer.

[0063] 4) Binding capacity. The polymers described here exhibit ion binding properties, mainly anion binding properties. In preferred embodiments, the polymers exhibit the phosphate ion binding property. The ion binding capacity (e.g. phosphate) means the amount of a given ion that a binding agent can bind in a given solution. For example, the binding capacity of the ion binding polymer can be measured in vitro, e.g. in water or in saline, or in vivo, e.g. in the urine excreted for an ion (e.g. phosphate), or ex vivo, e.g. using fluids taken from the body, such as nutrients taken from laboratory animals, patients or volunteers. Measurements may be carried out in a solution containing only the target ion, or at least in a solution not containing other competing solutes that compete with the target ions for binding to the polymer. In such cases, a non-interfering buffer may be used. Alternatively, the measurements can be carried out in the presence of other competing solutes, e.g. other ions or metabolites that compete with the target ions for binding to the resin.

[0064] The ion binding capacity of a polymer can be calculated by the expressions V * (C_start-C_eq) / P, expressed in mmol / g, where is the volume of solution used, expressed in l; C_start means initial expressed in mM; C_eq Binding capacity is useful in conditions and the concentration of the target ion in solution is the equilibrium concentration of the target ion in solution expressed in mM, after adding the polymer with a mass of P, in grams, and achieving equilibrium.

[0065] In some embodiments, the polymer binds phosphate. In in vivo use, e.g. in the treatment of hyperphosphataemia, it is desirable that the polymer has a high phosphate ion binding capacity. In vitro measurements do not always reflect in vivo. Thus, define the binding capacity both in vitro and in vivo.

[0066] The in vitro phosphate binding capacity of polymers according to the inventive idea in a non-interfering buffer environment may take values ​​greater than about 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 3,5; 4.0; 5.0; 6.0; 8.0 or 10.0 mmol / g. In certain embodiments, the in vitro phosphate binding capacity of polymers of the invention for a target ion is greater than about 0.5 mmol / g, preferably above about 2.5 mmol / g, even more preferably above about 3 mmol / g , even more preferably above about 4 mmol / g and still more preferably above about 6 mmol / g. In some embodiments, the phosphate binding capacity may range from about 0.5 mmol / g to about 10 mmol / g, preferably from about 2.5 mmol / g to about 8 mmol / g and even more preferably from about 3 mmol / g to about 6 mmol / g. In the art, several techniques are known for determining the phosphate ion binding capacity. The in vitro binding capacity of polymer phosphate ions according to the inventive idea is measured as described in Example 1 to measure the binding capacity in a non-interfering buffer environment.

[0067] In certain embodiments, the ex vivo average phosphate binding capacity of the phosphate binding polymers of the invention, measured in the food content of human patients, was greater than about 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9; 1.0; 1.2; 1.4; 1.6; 1.8; 2.0; 2.5; 3.0; 4.0; 5.0 or 6.0 mmol / g. Ex vivo food was obtained as described in Example 1 from normal individuals and the binding ability measured in a non-interfering buffer. Average values ​​from about 5-15, or about 15-30, or about 30-60 individuals were obtained. In certain embodiments, measurements were performed on 6-12 individuals.

[0068] The term "average phosphate ion binding capacity in vivo" as used herein, unless otherwise specified, refers to the polymer binding capacity measured for normal human subjects, wherein polymer phosphate binding was determined by reducing the amount of excreted phosphates in urine, in combination with the measurement of the amount of phosphate excreted in the faeces in free and polymer-bound form (see below). Average values ​​were obtained from about 5-15, or about 15-30, or about 30-60 individuals. In certain embodiments, measurements were performed on 6-12 individuals. In certain embodiments, the average in vivo binding capacity of polymer phosphate ions according to the invention, preferably measured in human subjects, was

<td>least</td><td>about</td><td> 0,</td><td> 3</td><td>mmol / g</td><td>What</td><td>least</td><td>about</td><td> 0,</td><td> 5</td><td>mmol / g</td><td>What</td>

<td>least</td><td>about</td><td> 0,</td><td> 8</td><td>mmol / g</td><td>What</td><td>least</td><td>about</td><td> 1,</td><td> 0</td><td>mmol / g</td><td>What</td>

<td>least</td><td>about</td><td> 1,</td><td> 5</td><td>mmol / g</td><td>What</td><td>least</td><td>about</td><td> 2,</td><td> 0</td><td>mmol / g</td><td>What</td>

at least about 3.0 mmol / g, at least about 4.0 mmol / g, at least about 5.0 mmol / g, or at least about 6.0 mmol / g.

[0069] The in vivo binding capacity of a polymer can preferably be determined by measuring the balance of the target ion (e.g., phosphate ion) in mammals, preferably in humans: subjects were given a meal with a controlled phosphate content and a binding polymer, and the intake of phosphate ion and its faeces and urine. The study includes a washing period after which the subjects were given a daily dose, preferably three times daily, of a phosphate binder, followed by recovery for several days without treatment. Urine phosphate loss is usually associated with an increase in phosphate in the excreted feces. The difference between the amount of moles of phosphate excreted in the faeces and the amount at baseline divided by the weight of the binding agent administered gives binding capacity in vivo. Unless otherwise indicated, "in vivo" measurements refer to the method described above. Another method involves measuring phosphate ion binding in vivo and in situ according to the protocol described in Example 1, in which mammals are intubated with a double lumen tube to collect food content over a certain section of the small intestine. A meal with a specific phosphate ion content is given together with a known amount of phosphate absorbent and a marker. The tracer may be a non-absorbable dye or polymer (e.g. poly (ethylene glycol)) which is then titrated in the digestive tract to determine the degree of dilution that occurs during the digestion process. Then, the actual binder concentration is calculated based on the initial concentration in the meal and the degree of dilution measured using the marker. The total phosphate content is analyzed in the food sample. "Dissolved" phosphate is measured by centrifuging the sample, decanting the clarified liquid and analyzing the phosphate content. "Linked" Content

phosphate is obtained from the difference between the total phosphate content and the amount of soluble phosphate. Two series of experiments were performed on a group of subjects (6-12) who alternatively took placebo (microcrystalline cellulose) or drug: binding capacity was obtained by measuring the increase in "bound" phosphate content between two series of experiments, ie with and without drug administration, which was then divided by the value of the binding agent concentration. Calculations can be made for one individual or for a group of individuals.

B. Preparation of polymers [0070] Polymers according to the invention have been prepared by methods known to those skilled in the art; for example: ion binding monomers or their precursors can be subjected to a copolymerization reaction in the presence of a crosslinking agent; the pre-obtained ion binding polymer is then crosslinked by chemical reaction or irradiation; or the polymer precursor is first cross-linked and then reacted to form ion-binding functional groups in the polymer particles.

[0071] Polymers are obtained by direct or inverse suspension polymerization reaction, in emulsion, using precipitation techniques, by aerosol polymerization or using block polymerization / crosslinking methods and size reduction processes such as extrusion and milling. Processes can be carried out in stages, semi-continuous and continuous.

[0072] Quantities such as swelling ratio, disruption of the binding process, binding capacity, and limiting molecular weight of the particles excluded by the gel are influenced, among others, by the following variables regarding composition and manufacturing process:

- Densification of chemical cross-links of polymer chains.

- The ratio of the system (monomer + crosslinking agent) to the amount of solvent in the crosslinking reaction.

- Charging of the polymer network (at the physiological pH and tonicity of the environment in which it will be used).

- Hydrophilic / hydrophobic balance of the main polymer chain.

- The presence or absence of a core-shell structure in which the coating component limits the extent of swelling of the core material.

[0073] The following are examples of preferred ranges of variables for compositions and processes for crosslinked polyamine materials with phosphate ion binding properties. It is understood that these are merely exemplary conditions and that the methods described herein can be used to select and prepare polymers that bind a wide range of dissolved substances, as will be apparent to those skilled in the art.

[0074] 1) Thickening of chemical cross-links of polymer chains. Thickening of chemical crosslinking is one important feature that regulates swelling properties and polymer pore size distribution. One convenient way to describe polymers according to the inventive idea is to define repeating amine units and the average number of bonds of these units with the rest of the polymer. "A" means the repeating amino unit and "NC" means the average number of connections originating from A; NC can take values ​​such as 2, 3, 4 and higher. To produce an insoluble gel, the NC value should generally be greater than 2.

[0075] The NC values ​​can then be translated into stoichiometric ratios of the amine to the crosslinking agent by the following equations:

[0076] For low molecular weight monomers, e.g. N, N, N ', N'-tetrakis- (3-aminopropyl) -1,4-diaminobutane or

1,3-diaminopropane, NC = B^.Fb / A, where B is the amount of mole of crosslinker, Fb is the number of B groups reacting with A to form a covalent bond and A is the amount of mole of the amine.

[0077] If the amine is a high molecular weight amine material and is obtained by the polymerization reaction of an amine monomer such as vinylamine, polyethyleneimine, polyvinylamine, or polyallylamine, the expression is altered to take into account 2 linkages binding repeat monomer units within the main chain polymer. The equation then takes the form: NC = (2^.A + B^.Fb) / A.

Conversely, the molar ratio of crosslinker to amine can be calculated by computer from the desired NC value, using the equations as above:

[0079] Low molecular weight amine:

B / A = NC^.Fb [0080] High molecular weight amine:

B / A = (NC-2)^.Fb [0081] The table below shows some examples of transformations between NC values ​​and the actual ratio of crosslinker to amine in which the amine is either a high or low molecular weight substance and the crosslinker is a bifunctional or trifunctional substance.

<td>Amine</td><td>Type amine</td><td>Means cross-linking</td><td>fb</td><td>desirable value NC</td><td>Ratio molar B / A</td><td>applied equation</td>

<td>polyallylamine</td><td>big m.w.</td><td>epichlorohydrin</td><td> 2</td><td> 2,2</td><td> 0, 10</td><td>b</td>

<td>polyvinylamine</td><td>big m.w.</td><td>1,3dichloropropan</td><td> 2</td><td> 2,5</td><td> 0,25</td><td>b</td>

<td>polyethyleneimine</td><td>big m.w.</td><td>N-tris (2-chloroethyl) amine</td><td> 3</td><td> 2,2</td><td> 0, 07</td><td>b</td>

<td>1,3-diaminopropane</td><td>amine about small m.w.</td><td>1,3dichloropropan</td><td> 2</td><td> 2</td><td> 1, 00</td><td>and</td>

<td>N, N, N ', N'tetrakis (3-aminopropyl) 1,4 diaminobutane</td><td>amine about small m.w.</td><td>epichlorohydrin</td><td> 2</td><td> 4</td><td> 2,00</td><td>and</td>

<td>N, N, N ', N'tetrakis (3-aminopropyl) -</td><td>amine about small</td><td>N-tris (2-chloroethyl) amine</td><td> 3</td><td> 4</td><td> 1,33</td><td>and</td>

<td>1,4-diaminobutane</td><td>m.w.</td><td></td><td></td><td></td><td></td><td></td>

(a): B / A = NC / Fb (b): B / A = (NC-2) / Fb [0082] Surprisingly, it has been found that binding selectivity that reflects in vivo efficacy passes through the optimum relative to NC: in in the range of small NC values, the material has a tendency to swell significantly, as a result of which a lot of interference in the binding process was observed in the mixture imitating the GI content. However, in the high range, a significant reduction in binding capacity was observed within the material, which of course negatively affected the overall in vivo effect. The optimal NC values ​​were found to be between 2.05 and 5, depending on the amine / crosslinker systems.

[0083] However, the optimal range giving the desired combination of properties of the final polymer depends on the particular monomer and crosslinker used as well as other conditions used in the production process, such as the initial concentration of monomer in the reaction medium, and is the object of routine experimentation.

[0084] In some embodiments, the ratio of crosslinker to total amount of amino groups of monomers in the polymer is greater than 50 mole%, 60 mole%, 70 mole%, 80 mole% or 90 mole%.

[0085] In certain embodiments of the inventive idea providing a phosphate-binding polymer comprising one or more low molecular weight amine monomers and one or more crosslinkers, NC is greater than about 2, or greater than about 3, or greater than about 4. In some embodiments, the polymers are composed of monomers in the form of N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diamino-butane (low molecular weight monomers) crosslinked with epichlorohydrin (Fb = 2), where B / A is from about 2.0 (mole / mol) to about 3.0 (mole / mol) (i.e., NC is from about 4 to about 6), or from about 2.3 (mole / mol) to about 2 , 7 (mole / mol) (i.e., NC is from about 4.6 to about 5.4), or about 2.5 (mole / mol) (i.e., NC is about 5.0). In some embodiments, the polymers are composed of monomers in the form of N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane_,cross-linked epichlorohydrin, where the initial monomer to water ratio is from about 3: 1 to 1: 3 by weight, or from about 1.5: 1 to about 2: 1 by weight, or about 1: 1, or about 3: 1, and the ratio B / A values ​​range from about 2.0 (mole / mol) to about 3.0 (mole / mol) (i.e. NC is from about 4 to about 6), or from about 2.3 (mole / mol) to about 2.7 (mole / mole) (i.e., NC is from about 4.6 to about 5.4), or about 2.5 (mole / mole) (i.e., NC is about 5.0).

[0086] 2) The ratio of the amount of system (monomer + crosslinker) to the amount of solvent in the crosslinking reaction. High values ​​of the ratio of the amount of system (monomer + crosslinking agent) to the amount of solvent favor materials with denser crosslinking, while maintaining all other conditions unchanged. For example, when a high molecular weight amine is used and if the chain length and polymer concentration are large enough, the chain becomes entangled, which results in the formation of many network nodes in an already chemically crosslinked structure. More generally, for amines with both high and low molecular weight, the high value of the ratio of the amount of system (monomer + crosslinking agent) to the amount of solvent minimizes the number of side reactions that cause a gel defect (e.g. intra-chain crosslinking leading to the formation of cyclic structures, incomplete reaction crosslinking leading to the formation of free polymer ends).

[0087] This condition essentially depends on the concentration in the reaction medium of both the monomer (e.g. amine) and the crosslinker. In certain embodiments of the inventive idea, the concentration of monomer and crosslinker in the reaction medium is above about 20% by weight, preferably above 40% by weight, more preferably above 60% by weight. In some embodiments, the ratio (monomer + crosslinker): solvent (e.g.

for example.

W water) from certain embodiments (monomer + water factor) from about 3: 1 to about 1: 3 (by weight). In some embodiments, a ratio (monomer + crosslinker): solvent of about 3: 1 to about 1: 1 (by weight) embodiment is used, a crosslinker ratio): solvent (e.g., water) of from about 3: 1, or about 2.5: 1, or about 2.0: 1, or about 1.5: 1 or about 1: 1 (by weight). The crosslinking agent can be added at different times, depending on the polymerization reaction procedure. In some embodiments, the initial monomer: solvent ratio (before adding crosslinker) is between about 4: 1 and about 1: 1, or between about 3: 1 and about 1: 1; the crosslinker is then added in an amount between about 100 mol% and about 400 mol% of the initial monomer content, or between about 200 mol% and about 300 mol% of the initial monomer content. In some embodiments, monomers in are used

N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane, the crosslinker is epichlorohydrin, with an initial monomer: water ratio of between about 4: 1 and 1: 1, or from about 3 : 1 to about 1: 1, or about 1.7 or about 1.73; and the crosslinker is added in an amount of from about 200 mol% to about 300 mol% monomer content, or about 230 mol% to about 270 mol% or about 250 mol%.

[0088] In certain embodiments, e.g., in embodiments in which the monomer is polyallylamine, the amount of monomer is much greater than the amount of crosslinker (e.g., ten times the molar content of the crosslinker and even more by weight) and the above ratios can be expressed as monomer ratios : solvent, ignoring crosslinking agent. In some embodiments, the monomer (e.g. polyallylamine) is contained in an amount such that the monomer: solvent ratio is about 3: 1 to about 1: 3. In some embodiments, the monomer is polyallylamine and the crosslinker is epichlorohydrin, wherein the polyallylamine is used in a monomer: water ratio of form a

of about 3: 1 to about 1: 3 and epichlorhydrin is added to the reaction mixture in an amount of up to about 10 mole% of the total amount of polyallylamine.

[0089] Where possible, it is even more advantageous to run the process without solvent: in one embodiment, the amine and crosslinker are mixed quickly, which is then thoroughly dispersed in a continuous phase, e.g. in water. The crosslinking reaction proceeded inside the dispersed droplets and the product was recovered in the form of beads.

[0090] 3) Polymer network charge (at physiological pH and tonicity). The charge of the polymer network is characterized by the number of moles of ionic bonds, their internal charge and the degree of ionization at physiological pH. The charge density is preferably in the range of 3 to 20 mmol / g, preferably from 6 to 15 mmol / g.

[0091] 4) Hydrophilic / hydrophobic balance of the polymer backbone. The hydrophilic / hydrophobic balance of the polymer makes it possible to control chemical crosslinking density and swelling quite independently. The degree of swelling is very sensitive to the polymer-solvent interaction determined by the parameter% ij, as described in Flory-Huggins (Flory PJ "Principles of Polymer Chemistry, Cornell Ithaca Pub. 1953)). Increasing the value of% ij up to 0.4 and above, creates very poor solvent conditions for the polymer, which then tries to minimize the interaction of monomer and solvent (water) and, as a consequence, significantly less swells. This can be achieved by introducing hydrophobic units into the gel, such as long hydrophobic chains, (poly) aromatic substituents or fluorinated groups. When choosing this strategy to regulate the swelling amount and, consequently, the exclusion limit for gels, the content of hydrophobic monomers and crosslinkers should be from about 0.5 mol% to about 50 mol%, preferably from about 20% to 50%.

chemical introduction.

[0092] In preferred methods, absolute hydrophobicity is quantified as the absolute difference in log P values ​​of the monomers. Quantitatively, the hydrophobic / hydrophilic properties of the monomers can be determined on the basis of the log P values ​​of the individual monomers, which are sometimes referred to as the octanol-water partition coefficient. The log P values ​​are well known and are determined according to standard tests that determine the concentration of monomer in the water / 1-octanol separated mixture. In particular, computer programs are available on the market as well as on the internet to estimate log P values ​​for individual monomers. In this application, some log P values ​​have been estimated using data from the website<a href="http://esc.syrres.com/interkow/kowdemo.htm">http://esc.syrres.com/interkow/kowdemo.htm</a>which provides estimated log P values ​​for molecules via a simple CAS registration number or Log P record for hydrophobic monomers typically takes values ​​above zero, while for hydrophilic monomers log P values ​​are typically close to zero or less. In general, the log P values ​​of hydrophobic monomers for the purposes of this invention should be at least about 0.5; more preferably at least about 0.75; even more preferably at least about 1.0; even more preferably at least about 1.5 and most preferably at least about 2. [0093] 5)

The presence of a core-shell structure, whose shell component limits the extent of swelling of the core-forming material. Gel particles with a morphological structure of the core-shell are useful in the context of the present invention: the coating material can limit swelling, and hence the limit of exclusion, by creating mechanical resistance to the pressure caused by swelling from the core material, which without the coating could swell in much more range. The coating material may have the same composition as the core, but with a higher crosslinking density. Designs of core-shell materials and methods for their production can be found in

Ser. North America

chemically related to the description of the patent application

No. 10 / 814.789.

[0094] The coating material may be a core forming material or may physically cover it.

In the first case, the coating may grow on the core using chemical methods, for example, by chemical grafting of the polymer forming the coating onto the core, using polymerization on a living polymer, using active anchor sites on the core polymer; interfacial reaction, i.e. a chemical reaction occurring on the surface of the core particles, such as interphase polycondensation; and using block copolymers as dispersants during the synthesis of core particles.

[0095] When using chemical methods, interfacial reactions and methods using block polymers are preferably used. Interfacial reaction steps typically involve chemical modification of the outer core particles by reacting small molecules or macromolecules on the surface of the core. For example, amine-containing ion-binding core particles are reacted with a polymer containing amino-reactive groups such as epoxy, isocyanate, activated esters or halide groups to form a cross-bonded coating around the core.

[0096] In another embodiment, a coating is first prepared using interfacial polycondensation or coacervation of the solvent to obtain a capsule.

the inside of the capsule is filled with core precursors to form the core inside

Then, forming capsules.

[0097] In some embodiments, the block copolymerization method uses an amphiphilic block copolymer as a dispersant to form core particles in the process of producing particles in a direct or inverse suspension. In a water-in-oil inverted suspension system process, together with the oil precursor, the block copolymer block copolymer contains the first oil-soluble block and the other hydrophilic block contains functional groups that can react with the core forming polymer. When added to the aqueous phase, the core and phase are positioned at the water / oil interface and act as a dispersant. The hydrophilic block reacts with the core forming material or with the core forming precursors. After separating the particles from the oil phase, block copolymers form a thin coating covalently bonded to the core surface. The chemical properties and block length can be varied depending on the desired permeation properties of the coating for the target solutes.

[0098] If the coating material is physically adsorbed onto the core forming material then well known microencapsulation techniques such as solvent coacervation, fluidized bed coating equipment or multi-emulsion processes can be used. A preferred microencapsulation method is fluid bed coating in a Wurster configuration. In yet another embodiment, the coating material acts only temporarily, delaying the swelling of the core particles in the mouth and esophagus, and possibly undergoing degradation in the stomach or duodenum. In this case, a coating is chosen that is intended to inhibit the transport of water to the core particles, by creating a layer with high hydrophobicity and very low water permeability.

[0099] Thus, in one aspect, the inventive idea provides a method for selecting an ion binding polymer, wherein the polymer comprises a monomer and a crosslinker, and wherein the polymer has at least one of the features a) a swelling ratio less than about 5; b. gel pore volume dispersion measured in a physiological environment characterized in that the pore fraction with the volume available for non-interacting solutes having a molecular weight greater than about twice the MC of the target anion occupies less than about 20% of the gel; and c) in measurements in a mixture that mimics the content of the gastrointestinal tract, the disruption of the ion binding process for the target anion is less than about 60%, relative to the non-interfering buffer, which is obtained by;

i) changing the following composition and process variables:

oxalate, cross-linking.

1) the ratio of the amount of crosslinker to the amount of monomer;

2) the ratio of system content (monomer + crosslinker) to the amount of solvent in the reaction medium;

3) polymer network charge at physiological pH and tonicity; and / or

4) hydrophilic / hydrophobic balance of the polymer backbone;

ii) assessment of swelling capacity, porosity and interference with the ion binding process for the resulting polymer; and iii) selecting a polymer that has at least one of the above characteristics.

[0100] In another aspect, the inventive idea provides a method of improving the therapeutic properties and / or suitability for administration and / or pharmaceutical properties of a polyamine polymer, which comprises at least one of the following steps:

a) cross-linking the polymer with a cross-linking agent such that the average number of polyamine monomer binding sites is from about 2.05 to about 6; and / or

b) producing the polymer in a manner in which the polyamine is initially present in water in a polyamine: water ratio of from about 3: 1 to about 1: 3.

C. Monomers [00101] Any suitable monomers and crosslinkers can be used to prepare the polymers of the invention. In the case of phosphate-binding polymers or the polymer typically contains polyamine and the polyamine agent include amine functional monomers such as those set forth in US Patents. Ser. US 5,496,545; 5,667,775; 6,509,013; 6,132,706 and

5,968,499; and in patent applications Ser. Nos. 10 / 806,495 and 10 / 701,385. These patents and patent applications are hereby incorporated in their entirety as related material.

[00102] In some embodiments, the inventive idea provides an ion binding polymer that contains crosslinked amine units. In some of these forms, the polymers have one or more properties such as low swelling, high ion binding capacity in vivo, low interference by interfering ions, and / or specific porosity. Polymers, including homopolymers and copolymers, with repeating crosslinked amine units are referred to herein as crosslinked amine polymers. Amine repeating units in the polymer can be separated by repeating linking (or intermediary) units of the same or varying lengths. In some embodiments, the polymers contain repeating amine units and intermediate units of linking groups. In other embodiments, multiple amino split units are one or more linking unit.

[00103] One monomer useful for preparing the polymers of the invention is the amine of formula I

<img file="PL1682606T3_D0003.tif" />

(I) wherein each n, independently, is equal to or greater than 3; m is equal to or greater than 1; and each R substituent₁is independently H or optionally substituted alkyl or aryl; or is connected to the adjacent R substituent₁to form an optionally substituted alicyclic, aromatic or heterocyclic group. In one embodiment, the inventive idea is a crosslinked amine polymer containing an amine of formula I as described above, wherein the amine is crosslinked using a crosslinker. [00104] Preferred amines of formula I include:

H 2 N

<img file="PL1682606T3_D0004.tif" />

n: 3, 4 or 5

<img file="PL1682606T3_D0005.tif" />

[00105] In one embodiment, the inventive idea provides methods of treating living organisms, including humans, using polymers according to the inventive idea. One embodiment of this aspect is a method of removing phosphate from the gastrointestinal (GI) tract of a living organism by administering an effective amount of a crosslinked amine polymer, wherein the polymer comprises an amine of formula I.

[00106] The second monomer useful for preparing polymers according to the invention is an amine of formula II ^R1 _N1 ^R2

II) in which p is 1, 2, 3 or 4; each R substituent₁is independently H or optionally substituted alkyl or aryl, or is attached to the adjacent R substituent₁ to form an optionally substituted alicyclic or heterocyclic group; R₂ and R₃each represent H or optionally substituted alkyl or aryl, with the proviso that if p = 1 then both R₂ and R₃ do not represent H and if p = 2 or 4, then R₂ and R₃ are H, alkyl or

-C (R₁)₂-R₄-N (R₁)₂, R₄ is a bond or methylene; in addition, in some embodiments, the amines of Formula II include, independently, aromatic amines in which p is greater than 4. In other embodiments, p may be greater than 8, greater than 12, greater than 16, or greater than 20. In other embodiments, p may be less than

25, less than 20, less than 15 or less than 10. In one embodiment, the inventive idea is a crosslinked amine polymer containing the described amine of formula II, wherein the amine is crosslinked using a crosslinker.

[00107] Preferred amines of formula II include:

<img file="PL1682606T3_D0006.tif" />

HH

<td></td><td>NH2</td>

<td>NH2</td><td>^N</td>

NH

NH

NH2 NH2 NH2 NH2

NH2

NH2 NH2 ² NH₂² [00108] One embodiment of the inventive idea is a method for removing phosphate from the gastrointestinal (GI) tract of an animal by administering an effective amount of a crosslinked amine polymer, wherein the polymer comprises an amine of formula II.

[00110] The third monomer useful for making polymers according to the invention is an amine of formula III

H2 R1

CN

R1 4-q (III) wherein q is 0, 1 or 2; and each R substituent₁, is independently H or optionally substituted alkyl or aryl, or is bonded to the adjacent R substituent₁ to form an optionally substituted alicyclic, aromatic or heterocyclic group. In one embodiment, the inventive idea is a crosslinked amine polymer containing an amine of formula III as described above, wherein the amine is crosslinked using a crosslinker.

[00110] Preferred amines of formula III include:

NH

NH

NH

CH

<td></td><td></td>

<td>NH2</td><td>^NNH2</td>

NH [00111] In one embodiment, the inventive idea is a method of removing phosphate from the gastrointestinal tract of an animal by administering an effective amount of a crosslinked amine polymer, wherein the polymer comprises an amine of formula

III.

[00112] A fourth monomer useful for preparing polymers according to the invention is an amine of formula IV

<img file="PL1682606T3_D0007.tif" />

/

J \

R

N

R (IV) in which each n, independently, is equal to or greater than 3; each r, independently, is 0, 1 or 2; and each R substituent₁, is independently H or optionally substituted alkyl or aryl, or is bonded to the adjacent R substituent₁ to form an optionally substituted alicyclic, aromatic or heterocyclic group. In one embodiment, the inventive idea is a crosslinked amine polymer containing an amine of formula IV as described above, wherein the amine is crosslinked using a crosslinker.

[00113] Preferred amines of formula IV are:

NH ^H2

H2N CN

NH [00114] One embodiment of the inventive idea is a method of removing phosphate from the gastrointestinal tract of an animal by administering an effective amount of a crosslinked amine polymer, wherein the polymer comprises an amine of formula

IV.

[00115] The fifth monomer useful for making polymers according to the invention is an amine of formula V

<img file="PL1682606T3_D0008.tif" />

^R1

C

R

R1 R1 R r-2 r-2

NCN

CN (V) in which each n, independently, is equal to or greater than 3; each r is independently 0, 1 or 2; and each R substituent₁, is independently H or optionally substituted alkyl or aryl, or is bonded to the adjacent R substituent₁ to form an optionally substituted alicyclic, aromatic or heterocyclic group. In one embodiment, the inventive idea is a crosslinked amine polymer containing an amine of formula V as described above, wherein the amine is crosslinked using a crosslinker.

[00116] Preferred amines of formula V and according to the present invention are:

H 2 N

NH2

H 2 N

<img file="PL1682606T3_D0009.tif" />

NH

<img file="PL1682606T3_D0010.tif" />

n: 3, 4 or 5 [00117] One embodiment of the inventive idea is a method for removing phosphate from the digestive tract of an animal by administering an effective amount of a crosslinked amine polymer, wherein the polymer comprises an amine of formula V.

[00118] A sixth monomer useful for preparing polymers according to the invention contains an amine of formula VI h₂n ^ And Vnh₂ (VI) wherein each m is, independently, equal to or greater than 3. In one embodiment, the inventive idea is a crosslinked amine polymer containing an amine of formula VI as described above, wherein the amine is crosslinked using a crosslinker.

[00119] One embodiment of the inventive idea is a method for removing phosphate from the digestive tract of an animal by administering an effective amount of a crosslinked amine polymer, wherein the polymer comprises an amine of formula VI. [00120] The amines represented by general formulas I-VI can be synthesized by methods well known in the art. These synthesis techniques include methods such as catalytic alcohol conversion, reductive amination of carbonyl compounds, Michael addition reactions and hydrogenation of nitriles (see, e.g., Karsten Eller et al., Ullmann's

Encyclopedia of Industrial Chemistry 2002 published by WileyVCH Verlag GmbH &amp; Co. KGaA). There are also several small amine monomers and / or amines with intermediate linking groups available on the market.

[00121] In one embodiment, the useful amine according to the inventive idea is the tetramethylene tetramine shown below, which is prepared by catalytic hydrogenation reaction of commercially available diaminomaleonitrile (DAMN):

H 2 N

NH

Catalyst

H2

-►

CN

NH2 NH2 NH2 NH2 [00122] The amines for use in the present invention are not limited to those described, but typically are small molecules that serve as monomers or parts of monomer units for the polymerization reaction. In some embodiments, the monomers are low molecular weight units, i.e. monomers with a molecular weight of less than 200 g / mol.

[00123] In embodiments of the inventive idea, the monomers are non-polymeric substances such as non-polymeric amines. The term "polymer" as used herein includes a relatively high molecular weight molecule comprising substantially repeating units that are actually or conceptually derived from relatively low molecular weight molecules.

[00124] Examples of amines suitable for polymer synthesis according to the inventive concept include, but are not limited to, the amines shown in Table 1.

Table 1

<td>Mark</td><td>Type</td><td>Building</td><td>Mass Molecular (G / mol)</td>

<img file="PL1682606T3_D0011.tif" />

<td>B-SM-29-TA</td><td>triamine</td><td></td><td>V ^^N</td><td> 125,13</td>

<td></td><td></td><td></td><td>NH2</td><td></td>

<td>B-SM-31-DA</td><td>diamine</td><td></td><td>NH2</td><td> 184,07</td>

<td></td><td></td><td>_NN</td><td>2HCl</td><td></td>

<td></td><td></td><td>H</td><td></td><td></td>

<td>B-SM-32-DA</td><td>diamine</td><td></td><td></td><td> 136,2</td>

<td></td><td></td><td></td><td>ak</td><td></td>

<td></td><td></td><td>NH2</td><td>NH2</td><td></td>

[00125] Additional amine monomers that can be used in the polymers of the invention contain adjacent amine groups. The polymer may be a homopolymer comprising repeating units with adjacent amino groups or a copolymer comprising one or more repeating units with adjacent amino groups and other monomers such as acrylates, methacrylates, acrylamides, methacrylamides, vinyl esters, vinyl amides, olefins, styrene monomers, e.t.c. The molecular weight of the polymer may vary, for example from about 500 to about 1,000,000 daltons.

[00126] One amine monomer containing adjacent amine groups useful for making the polymers of the invention is the monomer of formula VII:

R

<img file="PL1682606T3_D0012.tif" />

<img file="PL1682606T3_D0013.tif" />

formula VII in which n is zero, one or above 1, each R substituent independently represents a suitable chemical group that saturates the valence of the nitrogen atom, and each R 'substituent independently represents H, alkyl or amino.

[00127] In another embodiment, the polymer has a repeating unit of formula VII:

R

<img file="PL1682606T3_D0014.tif" />

R formula VIII or is a copolymer thereof in which n is zero, one or more than 1, each R substituent independently represents a suitable chemical group that saturates the valence of the nitrogen atom, each R 'substituent independently represents H, alkyl or amino and X^- means a negatively charged organic or inorganic counterion.

[00128] Preferred polymers of formula VIII include:

<img file="PL1682606T3_D0015.tif" />

<img file="PL1682606T3_D0016.tif" />

<img file="PL1682606T3_D0017.tif" />

[00129] The polymers of the present invention also include polymers having a repeating unit of formula

<img file="PL1682606T3_D0018.tif" />

XR formula IX in which n is zero, one or more than 1, each R substituent independently represents a suitable chemical group that saturates the valence of the nitrogen atom, each R 'substituent independently represents H, alkyl or amino and X^- means a negatively charged organic or inorganic counterion. [00130] In one embodiment, the R groups located on adjacent nitrogen atoms are bonded to form a moiety having the structure represented by the formula X

<img file="PL1682606T3_D0019.tif" />

R

R formula X wherein Q is a bond, alkyl, alkylamino, alkylcarbonyl, alkenyl, aryl or heterocyclyl.

[131] In the polymers described herein, n is zero, one or more than 1. In preferred embodiments, n is 0-5, even more preferably n is zero or 1.

[00132] The value of n 'depends on the desired polymer properties, the potential use of the polymer and the production method used.

[00133] The free nitrogen atom in formulas VII, VIII, IX and X may be bonded to atoms such as C, H, O, S, P and N, such that the side groups are nitroso, nitro, nitric oxide radicals , nitron, nitrene, isocyanate, carbazide, hydrazino group, diazo, imino, amidine, guanidine, sulfamate, phosphoramidate and heterocycle. [00134] Examples of suitable R groups include H, halogen, R ", CO₂H, CO₂R ", COR", C (= NR ") (NR"), CN, CONH₂, CONR "₂, OR ", SO₃R ", Si (R")₃ and P (O) (OR ")₂. Suitable R "groups include H, optionally substituted alkyl, acyl, alkylamino, alkenyl, heterocyclyl and aryl. A preferred R 'group is H, methyl or amino. [00136] R '' substituents may be ionic units containing oxygen, nitrogen, phosphorus or sulfur atoms. Examples of substituents are carboxylate, sulfonate, sulfamate, sulfone group, phosphonate, phosphazene, phosphoramidate group, quaternary ammonium groups or amino groups, e.g. primary and secondary alkylamines or arylamines. Examples of other suitable substituents include, such as hydroxyl, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanadine, urea and carboxylic acid esters.

[00136] Preferred R groups include H and the following groups:

CH3

CH 2 CH

CH₂CH₂NH

<img file="PL1682606T3_D0020.tif" />

H2CH2NH2P54

OO NH oo

ABOUT

O © oh ^ OH

<img file="PL1682606T3_D0021.tif" />

and ^ (alkyl or aryl) N

H2N NH alkyl or aryl) CO ^COH ^ABOUT

<img file="PL1682606T3_D0022.tif" />

alkyl or aryl) ^P

OH

- binding points with R groups [00137] Counterions X^-, negatively charged may be organic ions, inorganic ions or a combination thereof. Inorganic ions suitable for use in the present invention include halide (especially chloride), carbonate, bicarbonate, sulfate, bisulfate, hydroxide, nitrate, peroxodisulfate / peroxodisulfate, and sulfite. Suitable organic ions include acetate, ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate, tartrate, taurocholate, glycocholate and cholate. Preferable X^-is chloride or carbonate.

[00138] In a preferred embodiment, the counterion does not cause harmful side effects and is selected to provide therapeutic or nutritional benefits to the patient.

[00139] Another monomer applicable to the preparation of polymers according to the invention is illustrated by the following formula XI,

<img file="PL1682606T3_D0023.tif" />

amine of selected styrene, substituted styrene, alkyl acrylate, methacrylate

H2C n = 0.1 NR2 in which R '' 'is H or CH₃, and R has the same meaning as described above. Preferred are monomers of formula XI in which R = H, [00140] In one embodiment, the polymer is a copolymer in which one of the repeating units is the monomer described herein.

[00141] The copolymers of the invention may be alternating or random copolymers. Generally, monomers that can be copolymerized with precursors include one or more target monomers from the group consisting of alkyl acrylate, substituted alkyl, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide, N, N -dialkylacrylamide, N, N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinylamide, maleic acid derivatives, vinyl ether, allyl monomers, methylallyl monomers and combinations thereof. The above monomers with additional functional groups can also be used. Specific monomers or comonomers that can be used according to the inventive idea include, but are not limited to, methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, , methacrylonitrile, α-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N, N-dimethylacetyl methacrylate methacrylate (ethylene glycol), itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N, N-dimethylaminoethyl acrylate, N, N-diethylaminoethyl acrylate, tri (ethylene glycol) acrylate, methacrylamide, N-methylacrylamide, N, N-dimethylacrylamide, Nt.-butylmethacrylamide, N-methacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, Nt.-butylacrylamide, Nn.-butylacrylamide, N-methylolacrylamide, N-ethylacrylamide, 4-acryloylmorpholine, vinylbenzoic acid (all isomers), diethylaminostyrene (all isomers) acid α-metylowinylobenzoesowy (all isomers), diethylamino-a-methylstyrene (all isomers), p-vinylbenzenesulfonic acid sodium salt p-winylobenzenosulfonowego methacrylate, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoksysililopropylu methacrylate dimetoksymetylosililopropylu methacrylate dietoksymetylosililopropylu methacrylate dibutoksymetylosililopropylu methacrylate, diisopropoxymethylsilylpropyl, dimethoxysilylpropyl methacrylate, dietoksysililopropylu methacrylate, methacrylate dibutoksysililopropylu methacrylate diizopropoksysililopropylu acrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoksysililopropylu acrylate dimetoksymetylosililopropylu acrylate dietoksymetylosililopropylu acrylate dibutoksymetylosililopropylu acrylate diizopropoksymetylosililopropylu acrylate dimetoksysililopropylu acrylate dietoksysililopropylu acrylate dibutoksysililopropylu acrylate diizopropoksysililopropylu, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, N-vinylformamide, N-vinylacetamide, allylamine, methylallylamine, allyl alcohol, methyl vinyl ether, ethyl vinyl ether, butyl vinyl ether, butadiene, isoprene, chloroprene, and ethylene, and their combination are not limited to them. Preferred monomers or comonomers are acrylamide, dimethylacrylamide, N-vinylformamide, N-vinylacetamide, vinyl acetate, methyl acrylate and butyl acrylate.

[00142] Further monomers that can be used in the polymer of the inventive concept include:

<img file="PL1682606T3_D0024.tif" />

wherein each R is independently H or substituted or unsubstituted alkyl, such as lower alkyl (e.g., containing 1-5 carbon atoms, inclusive), an alkylamino group (e.g., containing 1-5 carbon atoms, inclusive, such as an ethylamino group ) or aryl (e.g. phenyl);

<img file="PL1682606T3_D0025.tif" />

wherein each R is independently H or substituted or unsubstituted alkyl (e.g., containing

1-5 atoms containing ethylamino carbon, inclusive), 1-5 carbon atoms, or aryl (e.g.

an alkylamino group (e.g. inclusive such as a phenyl group) and each X^- means an exchangeable negative charge counterion.

[00143] Another suitable monomer has the structure illustrated by the formula

<img file="PL1682606T3_D0026.tif" />

wherein R is H or substituted or unsubstituted alkyl (e.g. containing 1-5 carbon atoms), alkylamino (e.g. containing 1-5 carbon atoms, such as ethylamino) or aryl (e.g. phenyl ).

[00144] Another suitable monomer has the structure illustrated by the formula

X

<img file="PL1682606T3_D0027.tif" />

wherein each R substituent₁ and R₂, is independently H5 or substituted or unsubstituted alkyl (e.g., having 1-5 carbon atoms, inclusive) and an alkylamino group (e.g., containing 1-5 carbon atoms, such as ethylamino) or an aryl group (e.g., phenyl ) and each Xmeans an exchangeable negative charge counterion. In one embodiment, at least one of the R groups is hydrogen.

[00145] Another suitable monomer has the structure illustrated by the formula

<img file="PL1682606T3_D0028.tif" />

wherein each R substituent₁ and R₂, is independently H, substituted or unsubstituted alkyl, having 1-20 carbon atoms, an alkylamino group (e.g., containing 1-5 carbon atoms, including, such as ethylamino), or an aryl group containing 6-12 atoms (e.g. phenyl).

[00146] Another suitable monomer has the structure illustrated by the formula

X

<img file="PL1682606T3_D0029.tif" />

wherein each R substituent₁ and R₂ and R₃, is independently H, substituted or unsubstituted alkyl having 1-20 carbon atoms, alkylamino (e.g. containing 1-5 atoms e.g. quaternary e.g. primary carbon, including ethylamino), or aryl containing 6-12 atoms (e.g. phenyl) and each Xmeans an exchangeable negative charge counterion.

[00147] For each of these monomers, the R groups may contain one or more substituents. Suitable substituents include therapeutic anions, ammonium groups, or amino groups, and secondary alkylamines or arylamines. Examples of other suitable substituents include hydroxyl, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanidine, urea and carboxylic acid esters as examples.

[00148] Negative charge counterions X^- they can be organic ions, inorganic ions or a combination thereof. Inorganic ions suitable for use in the present invention include a halide (especially chloride), carbonate, bicarbonate, sulfate, bisulfate, hydroxide, nitrate, peroxyde sulfate and sulfite. Suitable organic ions include acetate, ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate, tartrate, taurocholate, glycocholate and cholate.

[00149] Polymers containing guanidine groups are also compositions, processes are characterized by the desired properties and combine with anions such as phosphate and oxalate. Polymers of this type are described in patents of St. Ser. Nos. 6,132,706 and 5,968,499, which are hereby incorporated in their entirety as bound material. Briefly, guanidine groups are attached to the polymer structure. The nature of the polymer backbone is not critical, because guanidine groups are responsible for the binding effect. Preferred polymers in which crosslinking can be controlled and other factors include polymers containing a polyethylene backbone crosslinked with divinylbenzene. Polymers containing an inorganic backbone can also be used, e.g.

useful as using which can be described herein, because of polyphosphazene polymers. Polymers can be copolymers made of two or more different types of monomers. Further examples of useful polymers include carbohydrate polymers such as cellulose and agarose. Guanidine groups are attached to the polymer backbone by chemical bonds through the NH terminal group of the guanidine residue (NH₂-C (= NH) -NH-). The chemical bonding of guanidine groups to the polymer backbone can be direct or via some form of moieties that act as a "spacer" through which the guanidine residue is attached to the backbone of the polymer. Various attachment forms can be used, the preferred types vary depending on the basic type of polymer. For example, alkylene groups having 1-4 carbon atoms, amide groups, ether groups or combinations thereof may be used. The preferred way of attaching guanidine groups to the polymer backbone of course depends on the nature of the backbone, but for simplicity, direct linkage between the backbone atoms and the NH group of the guanidine residue is preferred, if possible.

[00150] Methods for producing polymers containing guanidine residues are obvious to a person skilled in the art but for example, polymers can be prepared following the procedure described in Schnaar's RL and YC Lee, 1975, Biochemistry 14, 1535-1541, incorporated herein in its entirety as a bound material, which describes a method for binding biologically active ligands to a polymer matrix, or polymers can also be conveniently prepared by reaction with a polymer containing amino groups attached to the polymer backbone ( a) 3,5-dimethylpyrazole-1-carboxamidine nitrate, (b) S-methylthiouronium sulfate or (c) O-methylpseudo urea hydrogen sulfate.

[00151] Preferred monomers according to the invention are amines. Most preferred monomers for use in the polymers of the invention include allylamine, vinylamine, ethyleneimine, methylene-1,3-diaminopropane and

N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane;

1,2,3,4-tetraaminobutane, a compound of formula 1 and a compound of formula 2, wherein compound 1 and compound 2 have the following structures:

NH2

NH2 [00152] In some embodiments, the polymers of the inventive idea consist of one or more amine monomers and one or more crosslinkers, wherein the polymer is produced by a process in which the amine is in a solvent prior to the crosslinking amine: solvent from about 3: 1 to about 1: 3 and the total content of crosslinkers added to the reaction mixture is such that the average amount of bond to amine monomers is from about 2.05 to about 6, or from about 2.2 to about 4.5. In some embodiments, the polymers of the invention are phosphate-binding polymers consisting of one or more amine monomers and one or more crosslinkers, wherein the polymer is made in a process in which the total content of crosslinkers added to the reaction mixture is such that the average number of bonds to amine monomers is from 2.2 to 4.5. In preferred embodiments, the amine monomer is selected from the group consisting of 1,3-diaminopropane and N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane, and the crosslinker is selected from the group consisting of from 1,3-dichloropropane and epichlorohydrin. In some embodiments, the polymers of the inventive idea consist of one or more amine monomers and one or more crosslinkers, wherein the amine monomers are not polyallylamine monomers and / or the crosslinker is not epichlorhydrin.

[00153] In some embodiments, e.g., in the case of a phosphate-binding polymer, it is preferred to keep the chloride to amine ratio in the final polymer below a certain level. In some embodiments, the level is from about 0 to about 35 mole%, preferably from about 0 to about 15 mole%. Monomers can be selected according to this criterion.

D. Cross-linking agents [00154] Cross-linking agents include those described in US Patent Nos. Ser. US 5,496,545; 5,667,775; 6,509,013; 6,132,706 and 5,968,499; and in patent applications Ser. North America Nos. 10 / 806,495 and 10 / 701,385.

[00155] Cross-linking agents are typically compounds containing at least two functional groups that are selected from a halide group, carbonyl group, epoxy group, ester group, acid anhydride group, acid halide group, isocyanate group, vinyl group and chloroformate group. The crosslinking agent may be attached to the main chain carbon atom or to the free nitrogen atom from the amino group of the polymer. Examples of crosslinkers suitable for polymer synthesis according to the invention include, but are not limited to, compounds as shown in Table 2.

Table 2

<td>Mark</td><td>Building</td><td>Mass Molecular</td>

<td>X-EP-1</td><td>ABOUT ^ /^cl</td><td> 92,52</td>

<td>X-EP-2</td><td></td><td> 174,19</td>

<td>X-EP-3</td><td></td><td></td>

<td></td><td>AA</td><td></td>

<td>X-EP-4</td><td>ABOUT_ABOUTABOUT ABOUT_ABOUTABOUT^ABOUTABOUT</td><td> 302,37</td>

<td>Mark</td><td>Building</td><td>Mass Molecular</td>

<td>X-EP-5</td><td>^ITABOUT</td><td> 297,27</td>

<td>X-EP-6</td><td></td><td> 277,32</td>

<td>X-EP-7</td><td></td><td> 86,09</td>

<td>X-EP-8</td><td></td><td> 202,25</td>

<td>X-Cl-1</td><td>© 1-1 at</td><td> 184,41</td>

<td>X-Cl-2</td><td>Cl Cl PP</td><td> 175,06</td>

<td>X-Cl-3</td><td></td><td> 112,99</td>

<td>X-Cl-4</td><td>^H2</td><td> 178,49</td>

<td>Mark</td><td>Building</td><td>Mass Molecular</td>

<td>X-Cl-5</td><td>cl Cl H Cl_cl^-</td><td> 240,99</td>

<td>X-Cl-6</td><td></td><td> 127,01</td>

<td>X-AC-1</td><td>ABOUT</td><td> 203,02</td>

<img file="PL1682606T3_D0030.tif" />

<td rowspan="2">X-Mc-1</td><td rowspan="2"></td><td colspan="2">ABOUT</td><td rowspan="2"> 168,2</td>

<td></td><td></td>

<td>X-Mc-2</td><td></td><td>ABOUT</td><td></td><td> 118,16</td>

<td></td><td></td><td>ABOUT</td><td></td><td></td>

<td>X-Mc-3</td><td></td><td>^ABOUT</td><td></td><td> 249,27</td>

<td></td><td></td><td>AND NN</td><td>^ABOUT</td><td></td>

<td></td><td></td><td>^ABOUT</td><td></td><td></td>

<td>X-IC-1</td><td>OCN</td><td></td><td>NCO</td><td> 168,19</td>

<td>Mark</td><td></td><td>Building</td><td></td><td>Mass</td>

<td></td><td></td><td></td><td></td><td>Molecular</td>

<td>X-IC-2</td><td></td><td>NCO H</td><td></td><td> 174,16</td>

<td></td><td></td><td>X NCO</td><td></td><td></td>

<td>X-IC-3</td><td></td><td>NCO</td><td></td><td> 188,18</td>

<td></td><td></td><td>NCO</td><td></td><td></td>

<td>X-IC-4</td><td colspan="3"></td><td> 222,28</td>

<td></td><td>OCN</td><td>NCO X</td><td></td>

<td>X-ME-1</td><td colspan="2"></td><td> 86,09</td>

<td>X-ME-2</td><td>about \</td><td>μ about \</td><td> 158,16</td>

<td>X-ME-3</td><td colspan="2">ABOUT</td><td> 146,14</td>

<td>Mark</td><td colspan="2">Building</td><td>Mass Molecular</td>

<td>X-ME-4</td><td>XX</td><td>© © oo / \</td><td> 194,19</td>

<td rowspan="2">X-ME-5</td><td rowspan="2">about \</td><td colspan="2">HO</td><td rowspan="2">/ about X</td><td rowspan="2"> 234,2</td>

<td>oA</td><td>ABOUT</td>

<td>X-ME-6</td><td></td><td></td><td></td><td></td><td> 252,22</td>

<td></td><td>ABOUT</td><td colspan="2">^ABOUT</td><td></td><td></td>

<td></td><td></td><td>rS</td><td></td><td></td><td></td>

<td></td><td>^ABOUT</td><td></td><td>AND</td><td>^ABOUT</td><td></td>

<td></td><td>F</td><td></td><td></td><td>ABOUT</td><td></td>

<td>X-ME-7</td><td>ABOUT II</td><td></td><td></td><td>ABOUT II</td><td> 194,19</td>

<td></td><td>AND</td><td></td><td></td><td>ABOUT</td><td></td>

<td></td><td></td><td colspan="2"></td><td></td><td></td>

<td>X-ME-8</td><td></td><td>OH</td><td></td><td>ABOUT</td><td> 178,14</td>

<td></td><td>r about \</td><td>X</td><td></td><td>Γ about \</td><td></td>

<td></td><td></td><td>ABOUT</td><td>H</td><td></td><td></td>

<td>X-ME-9</td><td></td><td></td><td colspan="2">n</td><td> 108,53</td>

<td></td><td>cl</td><td> '1</td><td></td><td></td><td></td>

[00156] Examples of suitable crosslinkers are diacrylates and dimethacrylates (e.g. ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, propylene glycol dimethacrylate, butylene glycol dimethacrylate, poly (ethylene glycol dimethacrylate), poly (ethylene glycol diacrylacrylidrylacrylacrylacrylacrylacrylacrylate) divinylbenzene, bisphenol A dimethacrylate, bisphenol A diacrylate, diepoxides, dihalides, diisocyanates, diacyl chlorides, dianhydrides and dimethyl esters.

[00157] Examples of preferred crosslinking agents include epichlorohydrin, 1,4-butanediol di glycidyl ether, 1,2-ethanediol di glycidyl ether; 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethyl succinate, toluene diisocyanate, acryloyl chloride, methyl acrylate, ethylene bisacrylamide and pyromellitic anhydride.

E. Polymerization [00158] Polymerization can be carried out by methods known in the art, examples of which are detailed in the examples disclosed herein. As described above, the polymerization conditions can be changed to produce polymers with the desired properties.

[00159] The crosslinking reaction is carried out either in bulk (i.e. using pure amine and pure crosslinking agent) or in a dispersing medium. The crosslinking reaction leading to gel formation can be carried out using a variety of processes that can be divided into two categories:

[00160] i) homogeneous processes in which the precursor with amine functional groups (small molecule amine or high molecular weight polyamine) is soluble in the continuous phase and in which the gel obtained in the crosslinking reaction is obtained in the form gel in bulk or as a suspension in the above continuous phase. The gel mass production process describes a situation in which all the solvent is trapped in a gel network to form a mass which is then broken up into smaller particles using extrusion, milling and related methods. When using the bulk process, the solvents are selected so that they dissolve the reagents and do not interfere with the crosslinking reaction of the amine. Suitable solvents include: water, low boiling alcohols (methanol, ethanol, butanol), dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone, and the like . The gel suspension is typically obtained in a low viscosity reaction medium and at such a high shear rate that gel particles remain suspended in the form of dispersed particles.

[00161] ii) heterogeneous processes, where the precursor with amine functional groups (small molecule amine or high molecular weight polyamine) does not dissolve in the continuous phase but only takes the form of dispersed droplets or particles, and then undergoes a cross-linking reaction, forming balls or irregularly shaped particles held in suspension in the above continuous phase.

[00162] Homogeneous processes may be impractical for crosslinked materials with limited swelling rates, such as the polymers according to the inventive idea: the level of crosslinking typical of the desired swelling ratio range and the pore size distribution typically induce very short gel time and high local viscosity, which is impractical for large-scale processes.

[00163] A preferred method of synthesizing polymers according to the present invention is the use of heterogeneous processes. These processes are also referred to as polymerization in dispersion media and include inversion suspension, direct suspension, precipitation polymerization, emulsion polymerization and microemulsion polymerization, aerosol reaction, and the like. The continuous phase can be selected from non-polar solvents such as toluene, benzene, hydrocarbon, halogenated solvents, supercritical carbon dioxide, and the like. For direct suspension or emulsion processes, water can be used, although brines are also useful for "desalting" reagents in the form of amines and crosslinkers in a separate droplet phase as indicated in US Pat. Ser. No. 5,414,068. Monomer precursors can be dispersed either in pure form or as a continuous phase solution. It is preferable to introduce the amine and the crosslinking agent in two separate stages in which the amine is initially dispersed into droplets, then the crosslinking agent is added to the reaction mixture which migrates into the dispersed phase. The crosslinking reaction occurs inside the droplet phase, which does not cause a significant increase in the viscosity of the suspension. This is advantageous due to the dissipation of heat generated in the exothermic reaction, while ensuring the homogeneity of the gel inside the beads. A preferred method of synthesis includes the steps of:

i) dissolving the amine monomer or amine polymer in water ii) neutralizing the amine fraction with an acid such as HCl iii) dispersing the aqueous amine solution in a water-immiscible solvent to form an emulsion iv) stepwise adding the crosslinker to the emulsion

v) allowing the cross-linking reaction to complete it vi) removing water by distillation vii) separating the balls by filtration viii) washing and drying [00164] In this process, polymer particles are obtained in the form of spherical balls, preferably with a controlled diameter in the range from 5 to 500 microns, preferably from 25 to 250 microns. In some of these embodiments, spheres with an average diameter of less than 40 microns are obtained.

[00165] Thus, in one aspect, the inventive idea provides a method of producing an anion-binding polymer that binds to a target anion, comprising combining the amine monomer with a cross-linking agent in a heterogeneous process in which the phosphate-binding polymer has at least two of the following features: a) a swelling ratio of less than about 5 or less than about 4.5; or less than about 4, or less than about 3; b) a polymer fraction that is less than about 20% of its mass available for non-interacting solutes with a molecular weight greater than about twice the molecular weight of the target anion, the above percentage being measured in a physiological environment, and c) disruption of the ion binding process for the target anion in measurements in a mixture that mimics the content of the digestive tract less than about 60%, relative to the non-interfering buffer. In some embodiments, the amine monomer is polyallylamine. In some embodiments, the crosslinker is epichlorohydrin.

[00166] In another aspect, the inventive idea provides an anion-binding polymer that binds to a target ion in which the polymer is produced by a process comprising crosslinking polyallylamine in a non-homogeneous process, said polymer having at least two of the following features: a) less swelling than about 5 or less than about 4.5; or less than about 4, or less than about 3; b) a polymer fraction that is less than about 20% of its mass available for non-interacting solutes with a molecular weight greater than about twice the molecular weight of the target anion, the above percentage being measured in a physiological environment, and c) disruption of the ion binding process for the target anion in measurements in a mixture that mimics the content of the digestive tract less than about 60%, relative to the non-interfering buffer. In one embodiment, the polyallylamine is crosslinked with epichlorohydrin.

[00167] As discussed above, the molar ratios of crosslinker to amine regulate the extent of gel material formation as well as its crosslinking density. Too low a ratio can cause incomplete crosslinking and the production of soluble oligomers, while too high a ratio can lead to a very tight network with poor binding properties. The amine component may be one amine or a combination of several amines and the same applies to the crosslinker. For any new combination of amines and cross-linking agents, it may be necessary to optimize the process because their functionality may affect the extent of gel formation and swelling properties. In some embodiments, e.g. in forms in which low molecular weight monomers are crosslinked using crosslinkers with an Fb value of 2, the molar ratios of crosslinker to amine (B / A) are from about 0.2 to about 10, preferably from about 0.5 to about 5 and most preferably from about 0.5 to about 2. These ratios can be set depending on whether the amine monomer has a high molecular weight or a low molecular weight, and / or the Fb values ​​of the crosslinker (see discussion and table above).

[00168] In some cases, the polymers are crosslinked after polymerization. One method of obtaining such crosslinking involves the reaction of the polymer with crosslinkers containing two functional groups, such as epichlorohydrin, succinyl dichloride, bisphenol diglycidyl ether, pyromellitic dianhydride, toluene diisocyanate and ethylenediamine. A typical example is the reaction of poly (ethyleneimine) with epichlorohydrin. In this example, epichlorohydrin (from 1 to 100 parts) is added to the solution containing polyethyleneimine (100 parts) and heated to a favorable reaction temperature. A typical example is the reaction of a polyamine with adjacent amino groups with epichlorohydrin. In this example, epichlorohydrin (1 to 200 parts) is added to a solution containing polyamine with adjacent amine groups (100 parts) and heated to a favorable reaction temperature. Other methods of inducing crosslinking in previously polymerized materials include, but are not limited to, exposure to ionizing radiation, ultraviolet radiation, electron beam bombardment, radical-based operations, and pyrolysis.

[00169] The crosslinking reaction is carried out in a batch or semi-continuous manner. According to the second method, the amine or crosslinking agent is introduced into the reactor as an initial charge, after which another reagent is added in measured portions over a given period of time. In one embodiment, the soluble prepolymer is first prepared by adding the total amount of amine monomer, then a crosslinker fraction is added continuously to form a syrup. The syrup obtained is then emulsified into droplets in the oil continuous phase, after which the remainder of the crosslinker is added to form crosslinked beads. If the crosslinker is an alkyl halide, then a base may be added to the system to neutralize the acid formed in the reaction. Inorganic or organic bases are suitable. The preferred base is NaOH. The base to crosslinker ratio is preferably from about 0.5 to about 2.

[00170] In certain embodiments, already prepared polymers are subjected to an amination reaction (post-reaction with

3-chloropropylamine). In this embodiment, the first reaction between the amine monomer and the cross-linking agent is carried out to form a gel, which is then reacted with an alkylamine halide, wherein the alkylamino groups are chemically bonded to the gel by substituting the halide with gel functional groups. [00171] All polymers described herein can then be crosslinked and labeled with an anion, e.g., phosphate. In one embodiment, the target anion (e.g. phosphate or oxalate) is present during polymerization, after which it is washed away after the crosslinking reaction. This method is referred to as "significance" and aims to increase the chemical affinity of the gel for the anion by creating "shaped" pockets inside the gel that recognize and bind the anion. Examples of phosphate labeled gels have been described, e.g. by Fujiwara et al., in Analytical Sciences, April 2000, vol. 16, 407 and in the series 703symposium ACS, "Molecular and Ionic Recognition with Imprinted Polymers, Bartsch RA and Maeda M. Editors, 1998, Chap, 22, 315. Typically anion it is present in a molar to amine ratio (expressed as nitrogen atoms) of from about 10% to about 100%, more preferably from about 10% to about 60%, most preferably from about 30% to about 50%. Most preferably, the anion is introduced in acid form (e.g.

amine as the ammonium salt of phosphoric acid, oxalic acid) and the free base to form, in situ, the anion. Crosslinking is then carried out as described above using the correct ratio of crosslinker to amine to achieve desired gel characteristics such as swelling ratio, critical permeation volume and disruption of the binding process. Immediately after the cross-linking reaction, the resulting gel is thoroughly washed with strong acid (e.g. pH &lt;2) or strongly alkaline (e.g. pH&gt; 12) solution to remove the marked anion, followed by elution with a neutral solution. If all parameters have the same values ​​(e.g., ratio of amine to crosslinker, ratio of monomers to solvent), the significance method described here typically increases the binding efficiency 1.1; 1.3 or even 1.5 times.

III. Pharmaceutical compositions [00172] In one aspect, the inventive idea provides pharmaceutical compositions. In one embodiment, the pharmaceutical compositions are chewable tablets. In another embodiment, the pharmaceutical compositions are liquid preparations.

[00173] The pharmaceutical compositions of the present invention include compositions that contain the polymers of the invention, e.g., crosslinked amine polymers in an effective amount, i.e., an amount effective to obtain a therapeutic and / or prophylactic benefit. In fact, the particular application will be (e.g. age, body weight) and condition and method of administration. The effective amount determination depends on the patient being treated;

effective amounts will not be difficult for those skilled in the art, especially in light of the present disclosure. [00174] The effective amount for use in humans can be determined from animal models. For example, a human dose may be formulated to obtain an adequate concentration of active substance in the circulatory and / or gastrointestinal tract that has been found to be effective in animals.

The pharmaceutical compositions contain a polymer, e.g. crosslinked amine polymers, one or more pharmaceutically acceptable carriers, diluents or excipients and optionally additional therapeutic agents.

[00176] Pharmaceutical compositions for use according to the invention may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. The correct formulation combination depends on the chosen route of administration. Suitable techniques for preparing pharmaceutical compositions containing amines are well known in the art, e.g. Gennaro AR (ed), Remington's Pharmaceutical Sciences, 20th Edition, Lippincott, Williams and Wilkins, Baltimore MD (2001), the publication of which is herein incorporated by reference in its entirety .

[00177] The present pharmaceutical compositions are generally prepared by known methods using well known and readily available ingredients. In the process of making the composition of the present invention, the ion-binding polymer, e.g. . When the carrier serves as a diluent, it may be in the form of a solid, semi-solid or liquid material that acts as a substrate, excipient, or polymer medium. Thus, the compositions may take the form of tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, syrups, aerosols, (in solid or liquid form), soft or hard gelatin capsules. , sterile packaged powders, and the like. The preferred preparations are chewable tablets and liquid preparations. Examples of carriers, excipients and diluents that can be used in these, as well as other preparations, include: food, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methyl hydroxybenzoates, propyl hydroxybenzoates, propyl hydroxybenzoates and talc.

[00178] In another aspect of the inventive idea, the anion-binding polymer (e.g., phosphate) is converted into the free amine, free of counterions. Short-term and long-term studies have shown that maintenance of hemodialysis in patients treated with Renagel (polyallylamine hydrochloride) significantly reduced plasma bicarbonate levels compared to patients receiving calcium-containing phosphate (i.e., chloride-free) binders. In the publication (Brezina B. et al., Kidney International, vo.66, suppl.90 (2004), 39-45) it has been shown that sevelamer hydrochloride (trade name of the pharmaceutical active ingredient Renagel) induces acid production, which causes acidosis. Acidosis can have serious side effects in this group of patients. In another embodiment, the crosslinked amine polymer is a polyamine polymer in which the chloride content of the polymer is less than about 40 mol% of the amount of amino groups, more preferably less than about 20 mol% of the amount of amino groups, and even more preferably less than about 5% of the amount of amino groups . Most preferably, the polymer is substantially free of chloride ions.

A. Chewable tablets [00179] In some embodiments, the polymers of the invention are provided as pharmaceutical compositions in the form of chewable tablets.

[00180] Patient compliance is now recognized as one of the main factors limiting patients' use of recommendations for the treatment of ionic imbalances, such as blood excess phosphate ions / hyperphosphataemia. For example, in the treatment of hyperphosphataemia using a commonly used phosphate-binding polymer such as RENAGEL, recent studies have shown that patients need to take an average of nine to ten tablets of 800 mg per day, with 25% of patients taking even higher daily doses of twelve up to fifteen tablets. Renagel comes in the form of swallowing tablets that are given with the amount of liquid needed to swallow the tablet, which is an additional burden for ESRD patients who need to limit their fluid intake. Low patient susceptibility due to high daily doses stands out as a factor that clearly affects the intake of this class of drugs.

[00181] A pharmaceutical formulation in a more readily acceptable form would be more desirable. Although a drug delivered in the form of a chewable tablet would in many cases be very beneficial, the use of this form is limited due to the difficulty in achieving satisfactory sensory properties by this type of preparation. The following sensory parameters are important for chewable tablets: roughness, penetration into interdental gaps, chalkiness, mouthfeel and overall taste.

[00182] Current chewable tablets are usually used in cases where significant amounts of active ingredients need to be administered and include over-the-counter agents such as vitamins, antacids, laxatives and painkillers. Prescription chews include vitamins used during pregnancy, and antibiotics and antivirals for oral administration that require high doses. Although they are often large, the geometry should be optimized to facilitate the chewing process and obtain "hardness" suitable for chewing. Tablets with round shapes, with bevelled edges, with height / diameter ratios ranging from about 0.3 to 0.4 are commonly used.

[00183] In addition to the active ingredients, the following types of excipients are commonly used: sweeteners to provide the necessary taste, additional binder if the main agent does not give the tablet a sufficient hardness; a lubricant that minimizes the effects of friction on the matrix walls and facilitates the ejection of tablets; and in some formulations, a small amount of a substance that breaks the tablet to facilitate chewing. In general, the amounts of excipients in currently available chewable tablets are on the order of 3-5 times the active ingredient (s), while the sweeteners make up the volume of inactive ingredients.

[00184] An important element in the design of a chewable tablet containing an ion binding polymer is the degree of swelling of the polymer. Because the polymers of the invention show little swelling, they can be used in chewable preparations without the unpleasant and sometimes dangerous side effects associated with chewable tablets containing more intumescent polymers. One example of a highly swellable material that causes difficulties during oral administration, potentially resulting in throttling and blockage of the esophagus, is psyllium. Psyllium is obtained from crushed seeds of Plantago ovata (plantain), an herb found in parts of Asia, Mediterranean countries in Europe and northern Africa, and is widely used as a laxative in the United States. Psyllium typically swells 35-50 times in volume during swelling and must be taken with plenty of fluids. Insufficient fluid intake during administration may cause fiber swelling, resulting in choking or even rupture of the esophagus. Psyllium is not indicated for patients with dysphagia and / or narrow esophagus.

[00185] The present inventive idea provides chewable tablets that contain the polymer or polymers of the inventive idea, and one or more pharmaceutical excipients, suitable for a chewable tablet formulation. The polymer used in the chewable tablets of the invention, passing through the mouth and esophagus, has a swelling ratio of preferably less than about 5, preferably less than about 4, more preferably less than about 3, more preferably less than 2.5 and most preferably less than about 2. In some embodiments, the polymer is an anion-binding polymer, such as a phosphate or oxalate-binding polymer; in a preferred embodiment, the polymer is a phosphate-binding polymer. A tablet containing a polymer combined with suitable excipients provides acceptable organoleptic properties such as mouthfeel, taste and penetration into interdental crevices, and at the same time does not cause the risk of clogging of the esophagus after chewing and contact with saliva.

[00186] In certain aspects of the inventive idea, the polymer (s) provide such mechanical and thermal properties as would normally be obtained after the introduction of suitable excipients, thereby reducing the amount of excipients in the formulations of the inventive idea. In some embodiments, the active ingredient (e.g. polymer, preferably anion-binding polymer) constitutes more than about 30%, more preferably more than about 40%, even more preferably more than about 50% and most preferably more than about 60% by weight of the weight of the chewable tablet, the remainder being a suitable excipient (s) . In some embodiments, the polymer, e.g., anion-binding polymer, is from about 0.6 g to about 2.0 g of the total weight of the tablet, preferably from about 0.8 g to about 1.6 g. In some embodiments, the polymer, e.g., anion-binding polymer, is more than about 0.8 g tablet, preferably more than about 1.2 g tablet, and most preferably more than about 1.6 g tablet. The polymer is made in such a way that it has the appropriate strength / brittleness and particle size to ensure the same qualities for which excipients have often been used such as, e.g., proper hardness, good mouth feel, compressibility and the like. The particle sizes of the polymers used in the chewable tablets of the invention have an average diameter less than about 80, 70, 60, 50, 40, 30 or 20 microns. In preferred embodiments, the particle diameter is less than about 80, more preferably less than about 60 and most preferably less than about 40 microns.

[00187] Pharmaceutical excipients useful in chewable tablets according to the invention include: a binder such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, polyvinylpyrrolidone and xanthan gum; a flavoring agent such as sucrose, mannitol, xylitol, maltodextrin, fructose or sorbitol; a lubricant such as magnesium stearate, stearic acid, sodium stearyl fumarate and vegetable fatty acids; and optionally, a tablet disintegrant such as croscarmellose sodium, gellan resin, low-substituted cellulose hydroxypropyl ethers, sodium carboxymethyl starch. Other additives may include plasticizers, pigments, talc, etc. Such additives and other suitable ingredients are well known in the art; see, e.g., Gennaro AR (ed), Remington's Pharmaceutical Sciences, 20th Edition.

[00188] In certain embodiments, the inventive idea provides a pharmaceutical composition in the form of a chewable tablet, comprising a phosphate-binding polymer and a suitable excipient. In some embodiments, the inventive idea provides a pharmaceutical composition in the form of a chewable tablet, comprising a phosphate-binding polymer, filler and lubricant. In some embodiments, the inventive idea provides a chewable tablet, phosphate, filler and pharmaceutical composition in a lubricant-binding polymer composition, wherein the filler is selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose and sorbitol, a lubricant is a magnesium salt of a fatty acid such as magnesium stearate.

[00189] The tablet may have any size and shape suitable for chewing and crushing in the mouth, preferably cylindrical, with a diameter of about 10 mm to about 40 mm and a height of about 2 mm to about 10 mm, most preferably with a diameter of about 22 mm and a height of about 6 mm.

[00190] In one embodiment, the polymer transition temperature to glassiness / glass transition temperature is above about 30 ° C, preferably above about 50 ° C.

[00191] In another embodiment, the polymer is pre-mixed with an excipient having a low molecular weight and high Tg / high melting point, such as mannitol, sorbose, sucrose, to form a solid solution in which the polymer and the excipient are thoroughly mixed. Mixing methods such as extrusion, spray drying, low temperature drying, freeze drying or wet granulation are useful. Guidance on the level of mixing is determined by known physical methods such as differential scanning calorimetry or dynamic mechanical analysis.

[00192] Methods for making chewable tablets containing pharmaceutical components, including polymers, are known in the art. See, e.g., European Patent Application No. EP373852A2, US Patent Ser. No. 6475510 and Remington's Pharmaceutical Sciences, which are hereby incorporated in their entirety as a bound material.

B. Liquid preparations [00193] In some embodiments, the polymers of the invention are provided as pharmaceutical compositions in the form of liquid preparations. In certain embodiments, the pharmaceutical composition comprises an ion-binding polymer dispersed in a suitable liquid excipient. Suitable liquid excipients are known in the art; see, e.g., Remington's Pharmaceutical Sciences.

IV. Methods of treatment [00194] In another aspect, the inventive idea provides methods of treating ionic imbalances. The term "ionic imbalance" as used herein refers to conditions in which the ion concentration in the body is abnormal. In one embodiment, the inventive idea provides methods of treating phosphate imbalances. The term "phosphate imbalance" as used herein refers to conditions in which the concentration of phosphate ions present in the body is abnormal. An example of a phosphate imbalance is, among others excess phosphate in the blood / hyperphosphataemia. The term "hyperphosphataemia," as used herein, refers to a condition in which the elemental phosphorus is present in the body in an increased concentration. Typically, a patient is diagnosed with hyperphosphataemia when blood phosphate levels exceed, e.g., about

4.5 milligrams per deciliter of blood and / or glomerular filtration rate decreases, for example by more than about 20%. [00195] Thus, for example, an inventive idea provides methods for removing anions from an animal's body by administering to the animal an effective amount of a polymer according to the inventive idea. In some embodiments, the polymer is an anion-binding polymer, wherein the polymer binds to the target anion (e.g. phosphate or oxalate), wherein the polymer has at least two of the following characteristics: a) a swelling ratio of less than about 5; b. gel pore volume dispersion measured in a physiological environment characterized in that the pore fraction with the volume available for non-interacting solutes having a molecular weight greater than about twice the molecular weight of the target anion occupies less than about 20% of the gel; and c) interfering with the ion binding process for the target anion in measurements in a mixture mimicking the contents of the gastrointestinal tract of less than about 60%, relative to the non-interfering buffer. In some embodiments, the target anion for the polymer is phosphate; in some embodiments, the phosphate is removed from the gastrointestinal tract; in some embodiments, the formulation is administered orally. In some embodiments, the animal suffers from at least one of the following conditions selected from the group consisting of hyperphosphataemia, hypocalcaemia, hyperthyroidism, decreased kidney calcitriol synthesis, tetany associated with hypocalcemia, renal failure, ectopic focal calcification in soft tissues, and endpoint stage of renal failure (ESRD). In certain embodiments, the animal is a human. It has been found that any polymer described herein may be useful in anion binding in animals and / or in the treatment of diseases caused by electrolyte imbalance in animals. In a preferred embodiment, the polymer is a phosphate-binding polymer, wherein the polymer has at least one of the following features: a) a swelling ratio of less than about 5, preferably less than about 2.5; b. a dispersion of gel pore volume measured in a physiological environment characterized in that less than about 20% of the pore volume by weight of the gel is available for non-interacting solutes with a molecular weight greater than about 200; and c) interfering with the phosphate ion binding process in measurements in a mixture mimicking the content of the gastrointestinal tract, less than about 60%, relative to the non-interfering buffer. In some embodiments, the swelling ratio is below about 2.8, or below about 2.7, or below about 2.6.

[00196] Other conditions in which the inventive methods, compositions and kits can be used include hypocalcaemia, hyperparathyroidism, hungry bone syndrome, decreased kidney calcitriol synthesis, tetany caused by hypocalcemia, renal failure and ectopic foci of calcification in soft tissues , including calcifications in the joints, lungs, kidneys, conjunctiva and myocardium. In addition, the present inventive idea can be used to treat end stage renal disease (ESRD) and dialysis patients, including for the prophylaxis of any of the above diseases.

In addition, the polymers described herein can be used as an adjunct in other therapies e.g. those using dietary phosphorus intake control, dialysis of inorganic metal salts and / or other polymeric resins.

acidosis, esophagus, [00198] The compositions of the invention are also useful in removing chlorides, bicarbonates, iron ions, oxalates and bile acids from the gastrointestinal tract. Polymers that remove oxalate ions find use in the treatment of oxalate imbalances, such as calcium oxalate deposition in the body or excessive excretion of oxalic acid in the urine, which increases the risk of kidney stones. Polymers that remove chloride ions find use in the treatment of, for example, heartburn, acid reflux or gastritis.

In embodiments, inventive compositions are used to remove fatty acids, bilirubin, and related compounds. Some embodiments also allow the binding and removal of high molecular weight molecules such as proteins, nucleic acids, vitamins, or debris from broken cells.

[00199] The present inventive idea provides methods, pharmaceutical compositions and kits for treating animals.

stomach up to

In some or animal "with the form of removal

As used herein, the term "animal includes humans as well as other mammals. One embodiment of the invention is a method of phosphate from the gastrointestinal tract of an animal by administering an effective amount of at least one of the crosslinked amine polymers described herein.

[00200] As used herein, the term "treatment" and its grammatical equivalents include achieving therapeutic and / or prophylactic benefits. The therapeutic benefit is understood to mean curing, alleviating, or preventing the underlying disorder in the animal being treated. For example, in a patient with hyperphosphataemia, the therapeutic benefit includes the elimination or reduction of underlying hyperphosphataemia. In addition, the therapeutic benefit is obtained by curing, alleviating or preventing one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient despite the underlying disorder being present. For example, administration of the crosslinked amine polymers described herein to a patient suffering from renal failure and / or hyperphosphataemia provides therapeutic benefit not only when a decrease in the serum phosphate of the patient is obtained, but also when the patient is observed to improve other disorders associated with renal failure and / or hyperphosphataemia such as e.g. ectopic foci of calcification and osteodystrophy from renal causes. For the benefit of prophylactic treatment, crosslinked amine polymers may, for example, be administered to a patient at risk of hyperphosphataemia or to a patient reporting one or more symptoms of hyperphosphataemia, even if no hyperphosphataemia is diagnosed. For example, the polymers of the invention can be administered to a patient with chronic kidney disease without the diagnosis of hyperphosphataemia. [00201] Dosage of the polymer, e.g. cross-linked amine polymers, in animals will depend on the type of treatment being treated and the physical characteristics of the subject being treated. In some embodiments where cross-linked amine polymers are used, the dosage amount of cross-linked amine polymers for therapeutic and / or prophylactic purposes may be from about 1 g / day to about 30 g / day. It is preferred that these polymers be taken with meals. These polymers can be administered once a day, twice a day, or three times a day. A preferred dosage range is from about 2 g / day to about 20 g / day, and an even more preferred dosage range is from about 3 g / day to about 7 g / day. The dose of polymers described herein may be less than about 50 g / day, preferably less than about 40 g / day, even more preferably less than about 30 g / day, even more preferably less than about 20 g / day, and most preferably less than about 10 g / day.

[00202] Preferably, ion binding polymers, eg crosslinked amine polymers, used for therapeutic and / or disease purposes, animals.

prophylactic may be administered alone or in the form of a pharmaceutical composition as described herein. For example, the crosslinked amine polymers of the present invention may be administered together with other active pharmaceutical agents depending on the condition being treated.

Examples of pharmaceutical agents that can be co-administered include, but are not limited to, proton pump inhibitors, calcimimetics (e.g., cinacalcet), vitamin D and its analogs, and phosphate binding agents. Examples of suitable phosphate binder substances include, but are not limited to, aluminum carbonate, calcium carbonate, calcium acetate (PhosLo), lanthanum carbonate (Fosrenol) and Renagel. Such simultaneous administration may consist in the simultaneous administration of both agents in the same dosage form, the simultaneous administration of these agents in separate dosage forms and their administration separately. For example, for the treatment of hyperphosphataemia, crosslinked amine polymers may be administered in conjunction with calcium salts used to treat hypocalcemia resulting from hyperphosphataemia. The calcium salt and the polymer can be combined together in the same dosage form and administered simultaneously. Alternatively, the calcium salt and polymer may be administered simultaneously, with the two agents being present in separate formulations. Still another way, the calcium salt can be administered just after the polymer, or vice versa. In a mode of administration of these compounds separately, the polymer and calcium salt can be administered with an interval of several minutes, several hours, or several days.

[00203] The polymer can be administered in the form of an injection, topically, orally, transdermally, or rectally. Preferably, the polymer or pharmaceutical composition containing the polymer is administered orally. The oral form in which the polymer is administered may include a powder, tablet, capsule, solution, or emulsion. The effective amount of the preparation can be administered in a single dose or in several divided doses at appropriate intervals, e.g. several hours.

[00204] The inventive idea also provides methods for removing anionic impurities from wastewater by providing instructions for methods and packaging, abstracts, contact of wastewater with the anion-binding polymer according to the inventive idea, wherein the anionic impurities, i.e., phosphates, are adsorbed by the polymer.

V. Kits [00205] In yet another aspect, the inventive idea provides kits for treating electrolyte imbalance, e.g., for treating phosphate imbalance. These kits contain the polymer or polymers described herein and the kit uses for the various approaches described herein. Such kits may also contain information, such as references to scientific literature, leaflets for the results of clinical trials and / or their and similar that indicate the action and / or determine the scope of action and / or the advantages of the composition. Such information may be based on the results of various studies, for example studies involving experimental animals on in vivo models and studies based on human clinical studies. The kits described herein may be provided, distributed and / or promoted to healthcare professionals, including physicians, nurses, pharmacy masters, pharmacy workers, and the like. The delivery, distribution and / or promotion of cosmetic kits may be aimed directly at consumers.

[00206] All publications and patent applications cited herein are incorporated herein by reference to the same extent as it would be specifically and individually indicated that each separate publication or patent application should be incorporated by reference.

[00207] It will be obvious to those of ordinary skill in the art that many changes and modifications may be made to the concepts presented without departing from the keynote or scope of the appended claims.

EXAMPLES

Example 1: Protocols for measuring phosphate ion binding measurements [00208] This example describes various protocols for measuring polymer anion (in this case, phosphate) binding performance measurements.

Measurements of phosphate binding capacity in a non-interfering buffer [00209] A dry polymer sample of P (g) was mixed gently in a fixed volume of V (l), the following buffer: 20 mM H₃AFTER₄, 80 mM NaCl, 100 mM sodium MES (morpholinoethanesulfonic acid) and a pH of 6.5. For single binding measurements, a second buffer was used. If measurements were made repeatedly, e.g. when plotting the binding isotherms, different phosphate concentrations in buffer were used. The starting concentration of phosphate ion was designated as P_start (MM). The solution may be referred to as a non-interfering buffer because it does not contain other competing solutes that could compete with phosphate ions for polymer binding. After the resin reached equilibrium, the solution was decanted by centrifugation and the concentration of remaining P phosphate ions was analyzed_eq (mM), in a clarified liquid using ion chromatography. Binding capacity was calculated as V * (P_start-P_eq/ P, given in mmol / g, as indicated in the tables for the respective polymers.

Binding capacity in a medium that mimics the content of the gastrointestinal tract [00210] This study was designed to mimic the conditions of use of phosphate-binding polymer in the gastrointestinal tract, and to measure the polymer-phosphate binding properties (target solute) in the presence of other metabolites (competitive) solutes). The liquid meal was subjected to artificial digestion in the presence of pepsin and pancreatic juice to create a medium that mimics the contents of the gastrointestinal tract. The order of enzyme addition and the pH profile of the mixture were controlled to simulate digestion to the jejunum:

[00211] The following ingredients were added once in the following order: powdered milk 291 g, Beneprotein 72.8 g, dextrose 152 g, polycose 156 g, NaCl

17.6 g to ~ 2.5 liters of double-distilled H₂O until dissolved (stirred vigorously but foaming was avoided). After dissolving NaCl, 240g of corn oil was added. The volume of the mixture was then made up to 4 liters with double-distilled H₂A. The mixture was stirred vigorously for 2 hours. The pH value was then ~ 6.4. Then, 153 ml 3M HCl was gradually added dropwise to reach pH 2.0 (~ 150 ml). The mixture was stirred for 15 minutes after which time the pH increased to ~ 2.1. Then 800 ml pepsin in 10mM HCl solution was added to achieve a final concentration of 1 mg / ml. The mixture was stirred at room temperature for 30 minutes after which the pH was ~ 2.3. Then 5 liters of stock solution of pancreatin and bile salts in 100 mM NaHCO were added₃, at a pH of 8.4 to obtain a final concentration of 0.3 mg / ml pancreatin and 2mg / ml bile salts. The mixture was stirred for 120 minutes at room temperature after which the pH was ~ 6.5. The mimicking mixture was stored at -80 ° C for up to one month before use.

[00212] A sample of the gastrointestinal (GI) environment mimicking mixture was centrifuged and the clarified liquid was tested for phosphate. The phosphate binding assay used was the same as that described above with the non-interfering buffer, except that the liquid fraction of the gastrointestinal (GI) mimicking mixture was used.

Degree of binding in ex-vivo aspirates [00213] Using a catheter placed in the lumen of the small intestine, healthy patients were given a meal with the same composition as made to mimic the gastrointestinal tract content described above, followed by duodenal samples.

[0014] Study participants were introduced into the gastrointestinal tract of a polyvinyl catheter with two separate lights with a mercury-loaded capsule attached at the end of the catheter to facilitate movement of the catheter in the small intestine. Under the fluoroscope, one of the legs of the catheter with the aspiration hole was placed in the stomach, and the other - near the Treitz ligament (in the upper part of the small intestine).

[00215] After placing the catheter in the right place, 550 ml of liquid gastrointestinal content (with the addition of a marker, poly (ethylene glycol) (PEG) - 2 g / 550 ml) was fed into the stomach through the catheter opening in the stomach at a speed of 22 ml per minute. Approximately 25 minutes were needed to enter the entire volume into the stomach, which simulated the time required to eat a normal meal.

[00216] The digestive tract was collected from the jejunum via a branch of the catheter ending near the Treitz ligament. This fluid was drawn continuously at 30-minute intervals for two and a half hours. As a result, 5 samples were obtained, which were mixed, measured for volume and lyophilized.

[00217] A phosphate binding assay was performed on aspirates taken ex-vivo. The procedure for binding phosphate ions was similar to that described above with a non-interfering buffer, except that an ex-vivo fluid was used (after reconstitution from the lyophilized material with the appropriate amount of deionized water). The phosphate binding capacity was calculated in ex-vivo aspirate in the same manner as in experiments using a mixture mimicking the content of the gastrointestinal tract.

Example 2: Libraries of cross-linked polymers formed using bulk processes and measurements of phosphate ion binding capacity

Creating polymer libraries [00218] Each of the following five examples each includes a library of up to 24 crosslinked polymers.

dismantled moved

Polymers were prepared in batch reactors arranged in a 4x6 format. In each reactor with a volume of 350 microliters or 3 ml, magnetic stirring was applied and the temperature controlled. In a typical procedure, the amine, crosslinkers, solvents and optionally the base were automatically dosed into the reactor, optionally by stirring. The reactors were then sealed and heated at the indicated temperature for 15 hours. Then, the reactor system and charges in the form of crosslinked polymers in glass vials, then ground, repeatedly washed with deionized water and lyophilized. Five libraries were identified, which are shown below in Table 3 together with the appropriate reaction conditions used to generate them.

Table 3

<td>Example</td><td>Mark libraries</td><td>Reaction temperature (° C)</td><td>Volume reactor (microliters)</td>

<td> 1</td><td> 100275</td><td> 85</td><td> 350</td>

<td> 2</td><td> 100277</td><td> 60</td><td> 350</td>

<td> 3</td><td> 100279</td><td> 80</td><td> 350</td>

<td> 4</td><td> 100353</td><td> 80</td><td> 350</td>

<td> 5</td><td> 100384</td><td> 80</td><td> 3000</td>

Measurements of phosphate binding capacity in non-interfering buffer [00219] Phosphate ion binding capacity was determined for each polymer in the library. See the procedure in Example 1.

Results [00220] Tables 4-8 provide the materials and amounts used to make all polymers for each of the 5 libraries, as well as the measured phosphate ion binding capacity in a non-interfering buffer environment for the polymers obtained. The data entered correspond to the masses of chemicals used in each reactor, expressed in mg, and the phosphate ion binding capacity of the resulting polymer gel (empty spots show that no crosslinked gel was obtained in a given reaction).

Table 4

Library: plate 3 (designation: 100275) unit: mg

<td>Government</td><td>Column</td><td>Water</td><td>B-SM-22-DA</td><td>X-Cl-3</td><td>NaOH</td><td>DMSO</td><td>Binding of phosphate ions (Mmol / g)</td>

<td> 1</td><td> 1</td><td> 128,51</td><td> 67,74</td><td> 51, 63</td><td> 9, 14</td><td> 0, 00</td><td></td>

<td> 1</td><td> 2</td><td> 130,70</td><td> 57,94</td><td> 61, 82</td><td> 10, 94</td><td> 0, 00</td><td></td>

<td> 1</td><td> 3</td><td> 132,33</td><td> 50, 61</td><td> 69, 43</td><td> 12,29</td><td> 0, 00</td><td></td>

<td> 1</td><td> 4</td><td> 133,59</td><td> 44,93</td><td> 75, 33</td><td> 13,33</td><td> 0, 00</td><td> 3, 042</td>

<td> 1</td><td> 5</td><td> 134,60</td><td> 40,39</td><td> 80, 04</td><td> 14, 17</td><td> 0, 00</td><td> 0</td>

<td> 1</td><td> 6</td><td> 135,43</td><td> 36, 69</td><td> 83, 89</td><td> 14, 85</td><td> 0, 00</td><td> 0</td>

<td> 2</td><td> 1</td><td> 136,42</td><td> 32,26</td><td> 88,50</td><td> 15, 66</td><td> 0, 00</td><td> 3,703</td>

<td> 2</td><td> 2</td><td> 137,05</td><td> 29,41</td><td> 91,45</td><td> 16, 19</td><td> 0, 00</td><td> 3, 624</td>

<td> 2</td><td> 3</td><td> 137,58</td><td> 27,03</td><td> 93, 93</td><td> 16, 63</td><td> 0, 00</td><td> 2,858</td>

<td> 2</td><td> 4</td><td> 138,03</td><td> 25, 00</td><td> 96, 03</td><td> 17, 00</td><td> 0, 00</td><td> 2,566</td>

<td> 2</td><td> 5</td><td> 138,42</td><td> 23,26</td><td> 97,84</td><td> 17,32</td><td> 0, 00</td><td> 2,761</td>

<td> 2</td><td> 6</td><td> 138,76</td><td> 21,74</td><td> 99, 42</td><td> 17, 60</td><td> 0, 00</td><td> 2,82</td>

<td> 3</td><td> 1</td><td> 132,04</td><td> 64,98</td><td> 49, 52</td><td> 17,53</td><td> 34, 60</td><td></td>

<td> 3</td><td> 2</td><td> 134,77</td><td> 55, 13</td><td> 58,82</td><td> 20, 82</td><td> 47,26</td><td></td>

<td> 3</td><td> 3</td><td> 136,79</td><td> 47, 87</td><td> 65, 67</td><td> 23,25</td><td> 57,22</td><td></td>

<td> 3</td><td> 4</td><td> 138,34</td><td> 42,30</td><td> 70, 93</td><td> 25, 11</td><td> 65, 27</td><td> 3, 087</td>

<td> 3</td><td> 5</td><td> 139,57</td><td> 37,90</td><td> 75, 09</td><td> 26, 58</td><td> 71,91</td><td> 2,946</td>

<td> 3</td><td> 6</td><td> 140,56</td><td> 34,32</td><td> 78,47</td><td> 27,78</td><td> 77,48</td><td> 2,535</td>

<td> 4</td><td> 1</td><td> 141,75</td><td> 30, 06</td><td> 82,48</td><td> 29,20</td><td> 79, 73</td><td> 2, 674</td>

<td> 4</td><td> 2</td><td> 142,50</td><td> 27,35</td><td> 85, 04</td><td> 30, 11</td><td> 90,45</td><td> 3, 038</td>

<td> 4</td><td> 3</td><td> 143,13</td><td> 25, 09</td><td> 87, 18</td><td> 30, 86</td><td> 97,98</td><td> 2,895</td>

<td> 4</td><td> 4</td><td> 143,66</td><td> 23, 17</td><td> 88,99</td><td> 31,50</td><td> 103,56</td><td> 2,571</td>

<td> 4</td><td> 5</td><td> 144,12</td><td> 2152</td><td> 90,54</td><td> 32,05</td><td> 107,86</td><td> 2, 636</td>

<td> 4</td><td> 6</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 5, 374</td>

Table 5

Library: plate 1 (designation: 100277) unit: mg

<td>Government 1</td><td>Column 1</td><td>Water 123.69</td><td>B-SM20-tea 110.75</td><td>X-EP-1 12.95</td><td>X-EP-4 0.00</td><td>DMF</td><td>Binding of phosphate ions (mmol / g)</td>

<td> 1</td><td> 2</td><td> 124,02</td><td> 107,66</td><td> 16,36</td><td> 0, 00</td><td> 0, 00</td><td></td>

<td> 1</td><td> 3</td><td> 124,33</td><td> 104,74</td><td> 19, 59</td><td> 0, 00</td><td> 0, 00</td><td></td>

<td> 1</td><td> 4</td><td> 124,63</td><td> 101,98</td><td> 22, 65</td><td> 0, 00</td><td> 0, 00</td><td></td>

<td> 1</td><td> 5</td><td> 124,91</td><td> 99, 35</td><td> 25, 55</td><td> 0, 00</td><td> 0, 00</td><td> 4, 183</td>

<td> 1</td><td> 6</td><td> 125,17</td><td> 96, 86</td><td> 28,31</td><td> 0, 00</td><td> 0, 00</td><td> 4,237</td>

<td> 2</td><td> 1</td><td> 125,59</td><td> 92,98</td><td> 32, 61</td><td> 0, 00</td><td> 0, 00</td><td> 4, 631</td>

<td> 2</td><td> 2</td><td> 125,89</td><td> 90, 08</td><td> 35, 81</td><td> 0, 00</td><td> 0, 00</td><td> 4,594</td>

<td> 2</td><td> 3</td><td> 126, 18</td><td> 87,37</td><td> 38,81</td><td> 0, 00</td><td> 0, 00</td><td> 4, 667</td>

<td> 2</td><td> 4</td><td> 126, 45</td><td> 84, 81</td><td> 41 , 64</td><td> 0, 00</td><td> 0, 00</td><td> 4,586</td>

<td> 2</td><td> 5</td><td> 126,71</td><td> 82,40</td><td> 44,31</td><td> 0, 00</td><td> 0, 00</td><td> 4,535</td>

<td> 2</td><td> 6</td><td> 126,95</td><td> 80, 12</td><td> 46, 83</td><td> 0, 00</td><td> 0, 00</td><td> 4,311</td>

<td> 3</td><td> 1</td><td> 0, 00</td><td> 181,12</td><td> 0, 00</td><td> 34, 60</td><td> 0, 00</td><td></td>

<td> 3</td><td> 2</td><td> 0, 00</td><td> 159,58</td><td> 0, 00</td><td> 47,26</td><td> 104,77</td><td></td>

<td> 3</td><td> 3</td><td> 0, 00</td><td> 142,63</td><td> 0, 00</td><td> 57,22</td><td> 118,23</td><td> 3, 112</td>

<td> 3</td><td> 4</td><td> 0, 00</td><td> 128,93</td><td> 0, 00</td><td> 65, 27</td><td> 128,56</td><td> 2,991</td>

<td> 3</td><td> 5</td><td> 0, 00</td><td> 117,63</td><td> 0, 00</td><td> 71,91</td><td> 136,73</td><td> 2,798</td>

<td> 3</td><td> 6</td><td> 0, 00</td><td> 108,15</td><td> 0, 00</td><td> 77,48</td><td> 143,35</td><td> 3,271</td>

<td> 4</td><td> 1</td><td> 0, 00</td><td> 104,33</td><td> 0, 00</td><td> 79, 73</td><td> 148,83</td><td> 3,258</td>

<td> 4</td><td> 2</td><td> 0, 00</td><td> 86, 08</td><td> 0, 00</td><td> 90,45</td><td> 156,12</td><td> 3, 062</td>

<td> 4</td><td> 3</td><td> 0, 00</td><td> 73,27</td><td> 0, 00</td><td> 97,98</td><td> 160,76</td><td> 2,176</td>

<td> 4</td><td> 4</td><td> 0, 00</td><td> 63,77</td><td> 0, 00</td><td> 103,56</td><td> 164,62</td><td> 2,228</td>

<td> 4</td><td> 5</td><td> 0, 00</td><td> 56,46</td><td> 0, 00</td><td> 107,86</td><td> 167,88</td><td> 2,407</td>

<td> 4</td><td> 6</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 170,67</td><td> 5, 224</td>

<td> 4</td><td> 6</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td></td>

Table 6

Library: plate 3 (designation: 100279) unit: mg

<td>Government</td><td>Column</td><td>Water</td><td>B-SM-</td><td>X-Cl-3</td><td>X-Cl-2</td><td></td><td>Tie</td>

<td></td><td></td><td></td><td>20-TeA</td><td></td><td></td><td></td><td>ions</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>phosphate</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>(Mmol / g)</td>

<td> 1</td><td> 1</td><td> 123,95</td><td> 108,47</td><td> 15,49</td><td> 0, 00</td><td></td><td></td>

<td>Column</td><td>Water</td><td>B-SM-</td><td>X-Cl-3</td><td>X-Cl-2</td><td></td><td>Tie</td>

<td></td><td></td><td>20-TeA</td><td></td><td></td><td></td><td>ions</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>phosphate</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(Mmol / g)</td>

<td> 2</td><td> 124,34</td><td> 104,88</td><td> 19, 47</td><td> 0, 00</td><td></td><td></td>

<td> 3</td><td> 124,70</td><td> 101,51</td><td> 23, 19</td><td> 0, 00</td><td></td><td></td>

<td> 4</td><td> 125,04</td><td> 98,36</td><td> 26, 68</td><td> 0, 00</td><td></td><td></td>

<td> 5</td><td> 125,36</td><td> 95,40</td><td> 29, 97</td><td> 0, 00</td><td></td><td> 3, 958</td>

<td> 6</td><td> 125,66</td><td> 92, 61</td><td> 33, 06</td><td> 0, 00</td><td></td><td> 4,309</td>

<td> 1</td><td> 126, 13</td><td> 88,30</td><td> 37,82</td><td> 0, 00</td><td></td><td> 4,417</td>

<td> 2</td><td> 126, 47</td><td> 85, 14</td><td> 41,33</td><td> 0, 00</td><td></td><td> 4,424</td>

<td> 3</td><td> 126,78</td><td> 82,19</td><td> 44,59</td><td> 0, 00</td><td></td><td> 4,392</td>

<td> 4</td><td> 127,08</td><td> 79, 44</td><td> 47, 64</td><td> 0, 00</td><td></td><td> 4,407</td>

<td> 5</td><td> 127,36</td><td> 76, 87</td><td> 50,49</td><td> 0, 00</td><td></td><td> 4, 14</td>

<td> 6</td><td> 127,62</td><td> 74,46</td><td> 53, 16</td><td> 0, 00</td><td></td><td> 4,314</td>

<td> 1</td><td> 0, 00</td><td> 118,41</td><td> 0, 00</td><td> 26, 19</td><td></td><td></td>

<td> 2</td><td> 0, 00</td><td> 102,78</td><td> 0, 00</td><td> 29, 56</td><td></td><td></td>

<td> 3</td><td> 0, 00</td><td> 90, 80</td><td> 0, 00</td><td> 32,14</td><td></td><td></td>

<td> 4</td><td> 0, 00</td><td> 81,32</td><td> 0, 00</td><td> 34,18</td><td></td><td></td>

<td> 5</td><td> 0, 00</td><td> 73, 64</td><td> 0, 00</td><td> 35, 84</td><td></td><td></td>

<td> 6</td><td> 0, 00</td><td> 67,28</td><td> 0, 00</td><td> 37,21</td><td></td><td> 2,237</td>

<td> 1</td><td> 0, 00</td><td> 58,81</td><td> 0, 00</td><td> 39, 03</td><td></td><td> 2,403</td>

<td> 2</td><td> 0, 00</td><td> 53,43</td><td> 0, 00</td><td> 40, 19</td><td></td><td> 2,704</td>

<td> 3</td><td> 0, 00</td><td> 48,96</td><td> 0, 00</td><td> 41, 15</td><td></td><td> 2, 614</td>

<td> 4</td><td> 0, 00</td><td> 45, 17</td><td> 0, 00</td><td> 41,97</td><td></td><td> 1,714</td>

<td> 5</td><td> 0, 00</td><td> 41,93</td><td> 0, 00</td><td> 42, 67</td><td></td><td> 2,294</td>

<td> 6</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td></td><td> 5,295</td>

Table 7

Library: plate 1 (designation: 100353)

<td>Column</td><td>B-SM-</td><td>B-SM-</td><td>X-Cl-3</td><td>NaOH</td>

<td></td><td>20-TeA</td><td>DA-22</td><td></td><td></td>

unit: mg Phosphate ion binding (mmol / g)

<td>B-SM20-tea</td><td>B-SM-22-DA</td>

<td> 142,77</td><td> 11, 14</td>

<td> 117,71</td><td> 9, 19</td>

<td> 100,13</td><td> 7, 82</td>

<td> 87,12</td><td> 6, 80</td>

<td> 77,10</td><td> 6, 02</td>

<td> 69,15</td><td> 5,40</td>

<td> 64,71</td><td> 5, 05</td>

<td> 57,99</td><td> 4,53</td>

<td> 52,54</td><td> 4, 10</td>

<td> 48,02</td><td> 3,75</td>

<td> 44,22</td><td> 3,45</td>

<td> 40,98</td><td> 3,20</td>

<td> 111,71</td><td> 26,16</td>

<td> 89,37</td><td> 20, 93</td>

<td> 74,48</td><td> 17,44</td>

<td> 63,85</td><td> 14,95</td>

<td> 55,87</td><td> 13, 08</td>

<td> 49,66</td><td> 11, 63</td>

<td> 46,24</td><td> 10, 83</td>

<td> 41,13</td><td> 9, 63</td>

<td> 37,04</td><td> 8, 67</td>

<td> 33,69</td><td> 7, 89</td>

<td> 30,90</td><td> 7,24</td>

<td> 0,00</td><td> 0, 00</td>

<td>X-Cl-3</td><td>NaOH</td>

<td> 33,97</td><td> 24,05</td>

<td> 44,82</td><td> 31,73</td>

<td> 52,42</td><td> 37,12</td>

<td> 58,05</td><td> 41, 10</td>

<td> 62,39</td><td> 44, 17</td>

<td> 65,83</td><td> 46, 61</td>

<td> 67,75</td><td> 47,97</td>

<td> 70,66</td><td> 50, 03</td>

<td> 73,01</td><td> 51,70</td>

<td> 74,97</td><td> 53, 08</td>

<td> 76,61</td><td> 54,24</td>

<td> 78,02</td><td> 55, 24</td>

<td> 39,87</td><td> 28,23</td>

<td> 51,04</td><td> 36, 14</td>

<td> 58,49</td><td> 41,41</td>

<td> 63,81</td><td> 45, 18</td>

<td> 67,80</td><td> 48, 01</td>

<td> 70,91</td><td> 50,20</td>

<td> 72,62</td><td> 51,42</td>

<td> 75,17</td><td> 53,23</td>

<td> 77,22</td><td> 54, 67</td>

<td> 78,90</td><td> 55, 86</td>

<td> 80,29</td><td> 56, 85</td>

<td> 0,00</td><td> 0, 00</td>

Binding of phosphate ions (mmol / g)

5,838

5,38

5,549

5,826

5,452

3,358

3,45

4,27

3,469

4,058

5,154

5,784

5,596

5,287

5,261

4,743

4,076

3,924

2,896

5,287: plate 1 (designation: 100384) unit: mg

<td>Government</td><td>Column</td><td>X-Cl-3</td><td>JB-SM</td><td>Water</td><td>NaOH</td><td></td><td>Tie</td>

<td></td><td></td><td></td><td>DA-22</td><td></td><td></td><td></td><td>ions</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>phosphate</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>(Mmol / g)</td>

<td> 1</td><td> 1</td><td> 643,88</td><td> 422,44</td><td> 1752,36</td><td> 227,94</td><td></td><td></td>

<td> 1</td><td> 2</td><td> 692,40</td><td> 378,56</td><td> 1743,80</td><td> 245,12</td><td></td><td> 4,362</td>

<td> 1</td><td> 3</td><td> 731,79</td><td> 342,94</td><td> 1736,85</td><td> 259,06</td><td></td><td> 4, 09</td>

<td> 1</td><td> 4</td><td> 764,40</td><td> 313,44</td><td> 1731,10</td><td> 270,61</td><td></td><td> 3, 198</td>

<td> 1</td><td> 5</td><td> 791,85</td><td> 288,62</td><td> 1726, 26</td><td> 280,33</td><td></td><td> 2,951</td>

<td> 1</td><td> 6</td><td> 815,27</td><td> 267,44</td><td> 1722,12</td><td> 288,62</td><td></td><td> 2,005</td>

<td> 2</td><td> 1</td><td> 643,88</td><td> 422,44</td><td> 1752,36</td><td> 227,94</td><td></td><td></td>

<td> 2</td><td> 2</td><td> 692,40</td><td> 378,56</td><td> 1743,80</td><td> 245,12</td><td></td><td></td>

<td> 2</td><td> 3</td><td> 731,79</td><td> 342,94</td><td> 1736,85</td><td> 259,06</td><td></td><td></td>

<td> 2</td><td> 4</td><td> 764,40</td><td> 313,44</td><td> 1731,10</td><td> 270,61</td><td></td><td> 4,794</td>

<td> 2</td><td> 5</td><td> 791,85</td><td> 288,62</td><td> 1726, 26</td><td> 280,33</td><td></td><td></td>

<td> 2</td><td> 6</td><td> 815,27</td><td> 267,44</td><td> 1722,12</td><td> 288,62</td><td></td><td> 4,332</td>

<td> 3</td><td> 1</td><td> 643,88</td><td> 422,44</td><td> 1752,36</td><td> 227,94</td><td></td><td></td>

<td> 3</td><td> 2</td><td> 692,40</td><td> 378,56</td><td> 1743,80</td><td> 245,12</td><td></td><td></td>

<td> 3</td><td> 3</td><td> 731,79</td><td> 342,94</td><td> 1736,85</td><td> 259,06</td><td></td><td></td>

<td> 3</td><td> 4</td><td> 764,40</td><td> 313,44</td><td> 1731,10</td><td> 270,61</td><td></td><td> 4,511</td>

<td> 3</td><td> 5</td><td> 791,85</td><td> 288,62</td><td> 1726, 26</td><td> 280,33</td><td></td><td> 5, 086</td>

<td> 3</td><td> 6</td><td> 815,27</td><td> 267,44</td><td> 1722,12</td><td> 288,62</td><td></td><td> 4, 61</td>

<td>AND</td><td> 1</td><td> 643,88</td><td> 422,44</td><td> 1752,36</td><td> 227,94</td><td></td><td></td>

<td> 4</td><td> 2</td><td> 692,40</td><td> 378,56</td><td> 1743,80</td><td> 245,12</td><td></td><td></td>

<td> 4</td><td> 3</td><td> 731,79</td><td> 342,94</td><td> 1736,85</td><td> 259,06</td><td></td><td></td>

<td> 4</td><td> 4</td><td> 764,40</td><td> 313,44</td><td> 1731,10</td><td> 270,61</td><td></td><td></td>

<td> 4</td><td> 5</td><td> 791,85</td><td> 288,62</td><td> 1726, 26</td><td> 280,33</td><td></td><td> 4,816</td>

<td> 4</td><td> 6</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td> 0, 00</td><td></td><td> 5, 17</td>

Example 3: Synthesis of cross-linked beads from the 1,3-diaminopropane / epichlorohydrin system produced in a slurry process [00221] A 3-liter reaction vessel was used, which was a three-necked round-bottom flask with four side partitions. The reaction flask was equipped with a heating oil bath, reflux condenser with cold water and a vessel stirrer (90.2 g; water center) and 1 kg of toluene. mixed at speed to mechanical with a 3 inch propeller. To this reaction solution was introduced a solution of 1,3-diaminopropane 1.21 mol dissolved in 90.2 g of water, a surface-active (sodium branched dodecylbenzenesulfonic acid, 6.4 g salt dissolved in 100 g. The initial reaction mixture 600 rpm for minutes then the stirring speed was reduced to 300 rpm and stirring continued for 10 minutes before adding epichlorohydrin. A stirring speed of 300 rpm was maintained for the remainder of the experiment. The solution was heated to 80 ° C and kept at this temperature throughout the experiment.

[00222] In a separate vessel, a solution of epichlorohydrin in toluene at a concentration of 40% by weight was prepared. Using a syringe pump, 1.2 equivalents of epichlorohydrin (134.7 g, (1.45 mol)) was added to the initial reaction mixture over a period of 3 hours. The reaction was continued for an additional 2 hours before adding 0.75 equivalents of sodium hydroxide (36.5 g (0.91 mol)) as a 40% by weight solution. The sodium hydroxide solution was added over a period of 2.5 hours to the reaction mixture using a syringe pump. The reaction mixture was kept at 80 ° C for a further 8 hours.

[00223] After this time, the beads formed were purified by removing toluene, washed with 1000 methanol (20% surfactant NaOH) and then twice more with deionized water. The balls were freeze dried for 3 days to give a fine white powder weighing 160 g (92% yield), with an average diameter of 93 pm.

Example 4: Synthesis of crosslinked polymer from 1,3-diaminopropane / 1,3-dichloropropane system [00224] Using water as the solvent, 1000 mg B-SM-22-DA was mixed with 1524 mg X-Cl-3 and 2524 mg water in a scintillation vial with a capacity of 20 ml. The reaction mixture was stirred per ml of acetone, then to remove the agent with a magnetic stirrer, and kept at 80 ° C overnight, then at 90 ° C for two additional hours. The 34% by weight (1716 mg) reaction mixture was purified by washing / centrifugation 3 times to obtain 144.7 mg of polymer according to the present example in the form of a powder.

Example 5: Synthesis of cross-linked polymer from 1,3-diaminopropane / 1,3-dichloropropane system [00225] Using water as the solvent, 2000 mg B-SM-22-DA was mixed with 3048 mg X-C1-3 and 5048 mg water in a scintillation vial with a capacity of 20 ml. The reaction mixture was stirred with a magnetic stirrer and kept at 80 ° C overnight.

[00226] After 3 hours of reaction, 3597 mg of 30% by weight aqueous NaOH solution was added to the reaction mixture to neutralize the acid formed during the reaction, as the crosslinking agent used was an alkyl halide. The 20.3% (2773.5 mg) reaction mixture was purified by 3 washes with water / centrifugation to give 591.3 mg of polymer according to the present example in the form of a powder.

Example 6: Synthesis of cross-linked beads from a 1,3-diaminopropane / 1,3-dichloropropane system using a prepolymer

Preparation of the prepolymer [00227] The reaction vessel used was a 250 ml two-necked round-bottomed flask equipped with a reflux condenser with cold water and a magnetic stirrer operating under an argon atmosphere. A solution of 1,3-diaminopropane (31.15 g; 0.42 mol) in 30.15 g of water was introduced into this reaction vessel. The initial reaction mixture was stirred at up to 300 rpm. The solution was heated to 80 ° C and kept at this temperature for the duration of the experiment. Then, 1 equivalent (47.47 g; 40.0 mL; 0.42 mol) of 1,3-dichloropropane (Aldrich 99%) was added over a 2 hour period using a syringe pump. The reaction was continued for an additional 2 hours after which 10 mol% (w

100 relative to 1,3-diaminopropane) sodium hydroxide (1.68 g (0.042 mol) NaOH as an aqueous solution up to 40% by weight). The sodium hydroxide solution was added to the reaction mixture over a 2 minute period via a pipette. The reaction mixture was kept at 80 ° C for a further 4 hours. The solution at 80 ° C had a high viscosity and after cooling to 25 ° C it solidified to obtain a solid product, easily soluble in water.

Purification [00228] Water was added to the solid product and washed with 200 mL water and 200 mL MeOH. Then all was introduced into a 1 L beaker containing a 50/50 MeOH / isopropyl alcohol solution. A white polymer precipitate formed in the vessel. After centrifugation of the suspension with a centrifuge, the supernatant liquid was removed. This process was repeated two more times using isopropyl alcohol. The white precipitate was then dried under reduced pressure at room temperature to remove isopropyl alcohol. The mass of the separated polymer: Mn (determined by GPC permeation chromatography in relation to the polyethyleneimine standard) was ~ 600.

Synthesis of crosslinked particles [00229] A white prepolymer (8.7 g) was placed in a flask containing 1.3 g of branched dodecylbenzenesulfonic acid sodium salt (30 wt% solution in water) and 34.8 g toluene. A solution was obtained containing 20% ​​by weight of polymer dispersed in toluene. The polymer was then ground to micron sized particles using a mechanical mill (trademark: IKA. Model: Ultra -Turax T8). 2.2 g of the resulting suspension was introduced into a 10 ml reaction flask equipped with a heating mantle, mechanical stirrer and syringe pump. The reaction flask was filled with an additional portion of 3779 mg toluene. The flask was then heated to 80 ° C and the stirrer was started (500 rpm). After 3 hours of stirring at this temperature, 112.2 mg were added over 1.5 hours

101 (0.0012 mol) epichlorohydrin. The reaction was continued for another 2 hours, after which 224.4 mg (0.0056 mol) of sodium hydroxide (in the form of an aqueous solution at 40% by weight) was added, which was added over a period of 2 hours. The reaction mixture was allowed to cool to room temperature and stirring was stopped. The beads were cleaned to remove toluene, washed with methanol then 20% NaOH (to remove surfactant) and twice with deionized water. The balls were freeze dried for 3 days to give a fine white powder. Binding capacity measured in non-interfering buffer was 3.85 mmol / g.

Example 7: Synthesis and isolation of low molecular weight polymer (prepolymer) prepared from 1,3-diaminopropane / 1,3-dichloropropane 1 system. Abbreviations used in further examples: Epichlorohydrin: ECH

N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane: BTA BC: binding capacity In this example, the effect of changing the ratio of the amount of monomer (in this case, prepolymer) to the amount is shown solvent in the reaction mixture for binding capacity and degree of swelling. This example describes a process comprising two stages: the first stage, the synthesis of the adduct - soluble prepolymer from 1,3-diaminopropane and 1,3-dichloropropane, and the second stage, the production of insoluble spheres by crosslinking the prepolymer with ECH. The second reaction contains a process inverse suspension in which different ratios of water to prepolymer were used. The influence of these variables on the binding effect and swelling was estimated.

Synthesis of prepolymer [00232] Step 1 (preparation of prepolymer): The reaction vessel used was a 250 ml round bottomed flask equipped with a reflux condenser with cold water, a magnetic stirrer, and operating under an argon atmosphere. A solution of 1,3102 diaminopropane (31.15 g; 0.42 mol) dissolved in 30.15 g of water was introduced into such a reaction vessel. The initial reaction mixture was stirred at up to 300 rpm. The solution was heated to 80 ° C and kept at this temperature throughout the experiment. Then, one equivalent (47.47 g; 40.0 mL; 0.42 mol) was added over a period of 2 hours using a syringe pump.

1,3-dichloropropane (Aldrich 99%). The reaction was continued for an additional 2 hours before adding 10 mol% (relative to 1,3-diaminopropane) sodium hydroxide (1.68 g (0.042 mol) NaOH prepared as a 40% by weight aqueous solution). The sodium hydroxide solution was added to the reaction mixture by pipette over 2 minutes. The reaction mixture was kept at 80 ° C for a further 4 hours. The solution at 80 ° C had a high viscosity and after cooling to 25 ° C it solidified as a solid product, easily soluble in water.

[00233] Step 2 (Purification): Water was added to the solid product and washed with 200 mL water and 200 mL MeOH. Then all was introduced into a 1 L beaker containing a 50/50 MeOH / isopropyl alcohol solution.

A white polymer precipitate formed in the vessel. After centrifugation of the suspension with a centrifuge, the supernatant liquid was removed. This process was repeated two more times using isopropyl alcohol. The white precipitate was then dried under reduced pressure at room temperature to remove isopropyl alcohol. The molecular weight of the separated polymer: Mn (determined by GPC permeation gel chromatography relative to the polyethyleneimine standard) was ~ 600. [00234] Synthesis of micron-sized crosslinked particles from a prepolymer obtained from a 1,3-diaminopropane / 1,3-dichloropropane system in a semi-continuous process in a 24-chamber parallel polymerization reactor.

[00235] White prepolymer 1 (8.7 g) was placed in a flask containing 1.3 g of branched dodecylbenzenesulfonic acid sodium salt (30 wt% solution in water) and 34.8 g of toluene. A solution was obtained containing 20% ​​by weight of polymer dispersed in toluene. The emulsion

103 was then ground to micron-sized droplets using a high shear homogenizer (trade mark:

IKA.

model:

Ultra-Turax

T8). 2.2 g of the resulting emulsion was introduced into 24 10 ml reaction flasks placed in a reactor equipped with a heating jacket, mechanical stirrer and syringe pump. Each reaction flask was filled with an additional portion of 3779 mg toluene. The flasks were then heated to 80 ° C and the stirrer was turned on (500 rpm). Water was added to the flasks in an amount necessary to achieve adequate water-prepolymer ratios. After 3 hours of stirring at this temperature, the desired amount was added over 1.5 hours (in this example, an amount of added equal to 20% by weight of dry weight, the amount of epichlorohydrin was prepolymer). The reaction was continued for another 2 hours, after which 224.4 mg (0.0056 mol) of sodium hydroxide (40% by weight aqueous solution) was added, which was introduced for a period of 2 and allowed to cool, stirring was stopped. Balls of hours. The reaction mixture to room temperature and purified by removing toluene, washing with methanol followed by 20% NaOH solution (to remove surfactant) and HCl solution to protonate the beads. The beads were then washed twice with deionized water to remove excess HCl. The balls were freeze dried for 3 days to give a fine white powder.

[00236] Polymer beads synthesized by this method were analyzed for binding capacity (BC) in a non-interfering buffer and in a mixture that mimics the content of the gastrointestinal tract and the degree of swelling. The results are summarized in table 9.

Table 9

Gel balls made from 1,3-diaminopropane / 1,3-dichloropropane / ECH system. Effect of monomer to water ratio on binding capacity and swelling

104

<td>Ratio monomer to water</td><td>BC (Mmol / g) not interfere buffer</td><td>BC (Mmol / g) imitation mixture cable content (GI)</td><td>Swell (g H2O / g polymer)</td>

<td> 1,67</td><td> 3,85</td><td> 1,54</td><td> 2,92</td>

<td> 1,42</td><td> 3, 68</td><td> 1,43</td><td> 3,34</td>

<td> 1,25</td><td> 3, 61</td><td> 1,34</td><td> 3,50</td>

<td> 1, 11</td><td> 3,55</td><td> 1,34</td><td> 3,70</td>

<td> 0, 83</td><td> 3,31</td><td> 1,16</td><td> 5, 22</td>

<td> 0,55</td><td> 2,90</td><td> 0, 91</td><td> 14, 00</td>

[00228] These results show that the binding capacity in both the non-interfering buffer and in the GI content mimicking mixture increases with increasing monomer to water ratio, while the swelling ratio decreases and reaches the desired range.

Example 8: Synthesis of micron-sized cross-linked particles from a crushed BTA / ECH bulk gel in a parallel polymerization chamber reactor [00239] In this example the effect of changing the ratio of crosslinker to monomer ratio on the swelling capacity is shown.

[00240] The following stock solution was prepared:

molar equivalents of concentrated HCl were added to the molar equivalent of BTA over a period of 2 hours. Water was then added to the solution in such an amount that the resulting solution contained the following composition by weight: BTA 45% by weight, HCl 10% by weight, water 45% by weight. 0.6 g of the prepared stock solution was placed in each 5 ml flask out of 24 contained in the reactor. The desired amount of epichlorohydrin was then added to each vial to achieve the appropriate ratio of monomer to crosslinker. The reactor was heated to 80 ° C for 9 hours. The reactor was allowed to cool. Water was added to each vial to swell the resulting gel. The gel was then ground to micron sized particles

105 using a high-shear homogenizer (trade mark: IKA. model: Ultra-Turax T8). The particles were purified by removing water, washing with methanol and 20% NaOH solution and then with HCl solution to protonate the amine functional groups of the particles. The particles were then washed twice with deionized water to remove excess HCl. The resulting particles were freeze dried for 3 days to give a fine white powder.

[00241] The results of the binding and swelling tests are summarized in Table 10.

Table 10

BTA / ECH gel: Results of swelling ratio and binding capacity depending on the content of crosslinking agent. Bulk gels (the amount of monomer to water is 75% by weight (2HCl) in water, triple ratio). The monomer to water ratio ranges from 3.5 (ECH: BTA = 0.85) to 4.8 (ECH: BTA = 6.4)

<td>Stack</td><td>kiss</td><td>BC</td><td>BC</td><td>Degree</td>

<td>moth</td><td>pink</td><td>(Mmol / g)</td><td>(Mmol / g)</td><td>swelling</td>

<td>ECH</td><td>: BTA</td><td>not interfere</td><td>imitation mixture</td><td>(g water /</td>

<td></td><td></td><td>buffer</td><td>GI cable content</td><td>g polymer)</td>

<td> 0,</td><td> 70</td><td> 0, 00</td><td> 0, 00</td><td></td>

<td> 0,</td><td> 85</td><td> 2,23</td><td> 0,35</td><td></td>

<td> 1,</td><td> 00</td><td> 2,46</td><td> 0,49</td><td> 16, 68</td>

<td> 1,</td><td> 15</td><td> 2,57</td><td> 0,49</td><td> 10, 98</td>

<td> 1,</td><td> 30</td><td> 2,84</td><td> 0,58</td><td> 6, 15</td>

<td> 1,</td><td> 45</td><td> 2,91</td><td> 0, 65</td><td> 4, 69</td>

<td> 1,</td><td> 60</td><td> 2,91</td><td> 0,77</td><td> 3, 85</td>

<td> 1,</td><td> 79</td><td> 2,88</td><td> 0, 85</td><td> 3, 13</td>

<td> 1,</td><td> 98</td><td> 0, 00</td><td> 0, 98</td><td> 2,77</td>

<td> 2,</td><td> 00</td><td> 2,46</td><td> 1, 00</td><td> 2,55</td>

<td> 2,</td><td> 00</td><td> 2,46</td><td> 1, 00</td><td> 2,55</td>

<td> 2,</td><td> 16</td><td> 2,73</td><td> 0, 99</td><td> 2,46</td>

<td> 2,</td><td> 35</td><td> 2, 67</td><td> 0, 96</td><td> 2,20</td>

<td> 2,</td><td> 40</td><td> 2,17</td><td> 0, 93</td><td> 1,97</td>

106

<td> 2,40</td><td> 2,17</td><td> 0, 93</td><td> 1,97</td>

<td>Ratio</td><td>BC</td><td>BC</td><td>Degree</td>

<td>molar</td><td>(Mmol / g)</td><td>(Mmol / g)</td><td>swelling</td>

<td>ECH: BTA</td><td>not interfere buffer</td><td>mixture imitating the content of the GI wire</td><td>(g water / g polymer)</td>

<td> 2,80</td><td> 1,86</td><td> 0, 82</td><td> 1, 81</td>

<td> 2,80</td><td> 1,86</td><td> 0, 82</td><td> 1, 81</td>

<td> 3,20</td><td> 1, 63</td><td> 0,73</td><td> 1, 84</td>

<td> 3,20</td><td> 1, 63</td><td> 0,73</td><td> 1, 84</td>

<td> 3, 60</td><td> 1,28</td><td> 0, 64</td><td> 1,57</td>

<td> 3, 60</td><td> 1,28</td><td> 0, 64</td><td> 1,57</td>

<td> 4, 00</td><td> 1, 09</td><td> 0,58</td><td> 1,57</td>

<td> 4, 00</td><td> 1, 09</td><td> 0,58</td><td> 1,57</td>

<td> 4,40</td><td> 0, 88</td><td> 0,45</td><td> 2,03</td>

<td> 4,40</td><td> 0, 88</td><td> 0,45</td><td> 2,03</td>

<td> 4,90</td><td> 0,42</td><td> 0,35</td><td> 1,47</td>

<td> 4,90</td><td> 0,42</td><td> 0,35</td><td> 1,47</td>

<td> 5,40</td><td> 0,42</td><td> 0,28</td><td> 1,50</td>

<td> 5,40</td><td> 0,42</td><td> 0,28</td><td> 1,50</td>

<td> 5, 90</td><td> 0, 07</td><td> 0,27</td><td> 1,55</td>

<td> 5, 90</td><td> 0, 07</td><td> 0,27</td><td> 1,55</td>

<td> 6,40</td><td> 0, 06</td><td> 0,22</td><td> 1,55</td>

<td> 6,40</td><td> 0, 06</td><td> 0,22</td><td> 1,55</td>

[00242] These data show that the binding capacity in the mixture that mimics the content of the GI duct goes through its maximum when the ratio of crosslinker to amine changes. In this particular arrangement, the optimum binding capacity in the mixture that mimics the content of the GI wire is observed at a crosslinking degree of 1.8 to 2.8 corresponding to an NC value of 3.6 to 5.6, respectively. The swelling ratio is minimal in this crosslinking range. Similar tests can routinely be carried out for other monomers and crosslinkers using the polymerization process described to determine the ratio that gives the desired results for the particular applications to which the polymer is targeted.

107

Example 9: Synthesis of micron sized crosslinked beads from the BTA / ECH system by inversion suspension [00243] The following stock solution was prepared: 2 molar equivalents of concentrated HCl solution was added to the molar equivalent of BTA over a period of 2 hours. To the solution, water and surfactant were then added in such amounts (branched dodecylbenzenesulfonic acid sodium, 30% by weight in water) so that the resulting solution had the following weight percentage: BTA 41.8% by weight, HCl 9.4% by weight, water 41.1% by weight, surfactant (30% by weight in water) 7.7% by weight. [00244] The reaction vessel used was a three-necked round-bottom flask with four 0.25-liter side partitions, equipped with an oil heating bath, reflux condenser with cold water and a mechanical stirrer with a 1 inch propeller. 25 g of the prepared stock solution and 75 g of toluene were introduced into such a reaction vessel.

[00245] In a separate vessel, a solution of epichlorohydrin in toluene at a concentration of 40% by weight was prepared. Then, using the syringe pump, the desired amount of ECH was added over 90 minutes. The reaction was continued for an additional hour, after which water was removed using a Dean Stark apparatus. The reaction ended with the removal of all water content from the system. The beads were purified by removing toluene, washing with methanol followed by 20% NaOH solution (to remove surfactant) and HCl solution to protonate the beads. The beads were then washed twice with deionized water to remove excess HCl. The balls were freeze dried for 3 days to give a fine white powder.

[00245] The results of binding and swelling performance tests are summarized in Table 11.

Table 11

BTA / ECH gel balls: Values ​​of swelling ratios and binding ability depending on the content of crosslinking agent

108

<td colspan="2">Ratio molar ECH: BTA</td><td>BC (Mmol / g) not interfere buffer</td><td>BC (Mmol / g) digested meal</td><td>Swelling rate (g water / g polymer)</td>

<td colspan="2"> 1, 00</td><td> 2,50</td><td> 0,58</td><td> 25,29</td>

<td> 1,</td><td> 00</td><td> 2,77</td><td> 0,55</td><td> 13, 01</td>

<td> 1,</td><td> 25</td><td> 2,97</td><td> 0, 65</td><td> 7, 69</td>

<td> 1,</td><td> 25</td><td> 3, 03</td><td> 0, 61</td><td> 7, 07</td>

<td> 1,</td><td> 50</td><td> 3, 13</td><td> 0,71</td><td> 4,41</td>

<td> 1,</td><td> 50</td><td> 3, 14</td><td> 0, 69</td><td> 3, 99</td>

<td> 1,</td><td> 75</td><td> 3, 13</td><td> 0,78</td><td> 3, 06</td>

<td> 1,</td><td> 75</td><td> 3, 10</td><td> 0, 87</td><td> 3,41</td>

<td> 2,</td><td> 00</td><td> 3, 07</td><td> 0, 99</td><td> 3, 13</td>

<td> 2,</td><td> 00</td><td> 2,80</td><td> 1, 00</td><td> 2,82</td>

<td> 2,</td><td> 00</td><td> 2,82</td><td> 0,73</td><td> 3, 17</td>

<td> 2,</td><td> 50</td><td> 2,76</td><td> 1, 03</td><td> 2,48</td>

<td> 3,</td><td> 00</td><td> 2,56</td><td> 0, 82</td><td> 2,40</td>

<td> 3,</td><td> 50</td><td> 0, 00</td><td> 0,71</td><td> 2,28</td>

<td> 3,</td><td> 00</td><td> 2,32</td><td> 0,70</td><td> 2,25</td>

<td> 3,</td><td> 00</td><td> 2, 61</td><td> 0, 80</td><td> 2,03</td>

<td> 3,</td><td> 50</td><td> 2,81</td><td> 0,59</td><td> 1, 85</td>

<td> 4,</td><td> 00</td><td> 0, 00</td><td> 0,58</td><td> 1,99</td>

<td> 4,</td><td> 00</td><td> 2,19</td><td> 0,77</td><td> 1,93</td>

<td> 4,</td><td> 50</td><td> 2,11</td><td> 0,30</td><td> 1,99</td>

<td> 5,</td><td> 00</td><td> 1,96</td><td> 0,55</td><td> 1,72</td>

[00247] These results show that the binding capacity in the mixture that mimics the content of the GI duct goes through the maximum when the ratio of crosslinker to amine changes. In this particular arrangement, optimal binding capacity is observed in a mixture that mimics the content of the GI conduit for a crosslinking degree of 1.75 to 3, which corresponds to an NC value of 3.5 to 6, respectively. In this crosslinking range, the swelling ratio is minimal.

Similar tests can routinely be carried out for other monomers and crosslinkers using this described process

109 polymerization to determine the ratio that gives the desired results for the particular applications to which the polymer is targeted.

Example 10: Synthesis of 5 micron crosslinked particles from a polyallylamine / ECH comminuted volumetric gel in a 24 chamber parallel polymerization reactor [00248] This example illustrates the synthesis of a polymer using a high molecular weight monomer and varying monomer to water ratios . The conditions identical to those described in Example 8 were used, except that polyallylamine (Mw = 60,000 g / mol) was used instead of BTA. The ratio of ECH to allylamine repeat units was 1: 0.106 (corresponding to an NC of 2.2). Initial polyallylamine to water ratios took different values ​​from 1: 1 to

1.4. As a comparative example, cross-linked polyallylamine isolated from Renagel tablets was used.

<td>Ratio</td><td>BC (mmol / g)</td><td>BC (mmol / g)</td><td>Degree of swelling</td>

<td>molar amine</td><td>not interfere</td><td>digested</td><td>(g water / g</td>

<td>into the water</td><td>buffer</td><td>meal</td><td>polymer)</td>

<td> 0,20</td><td> 3, 66</td><td> 0, 92</td><td> 19, 00</td>

<td> 0,33</td><td> 4, 12</td><td> 1,36</td><td> 6, 00</td>

<td> 0,50</td><td> 4,20</td><td> 1, 62</td><td> 4, 00</td>

<td>Renagel</td><td> 3, 85</td><td> 1,40</td><td> 9, 00</td>

[00249] These data show that a higher value of the ratio of amine to water leads to a reduction in the degree of swelling and an increase in binding capacity in the mixture that mimics the content of the GI tract. Similar tests can routinely be carried out for other monomers and crosslinkers using the polymerization method described to determine the ratio that gives the desired results for the particular applications to which the polymer is targeted.

110

Example 11: Measurement of the binding interference level [00250] This example illustrates the measurement of binding interference using the polymer from the inventive idea and, for comparison, a polymer from the known art. A crosslinked polyamine material (EC 172A) was prepared according to the procedure described in Example 4, with a BTA: ECH molar ratio of 2.5 and a (BTA + ECH) to water ratio of 1.73. Disruption of the binding process was compared with Renagel.

[00251] As used herein, the terms "degree of binding disruption" or "disruption of the binding process" refer to the fractional reduction in target ion binding capacity observed in a binding experiment in a non-interfering buffer and in a mixture that mimics the content of the GI tract, for the same equilibrium concentration of the target anion. First, a binding isotherm in a non-interfering buffer was obtained by plotting the dependence of the binding capacity on the phosphate concentration at equilibrium for different phosphate concentration values. This isotherm was then fitted to the exponential function to predict binding capacity for any phosphate concentration. Then, on the graph of the same isotherm, the binding capacity measured in the mixture imitating the content of the GI conduit was marked, plotting phosphate concentration points depending on the phosphate ion binding at equilibrium for the mixture imitating the content of the GI conduit and extending the vertical line through this point to intersect with the interfering isotherm plot environment. The degree of interference was calculated by computer from the expression:

(BCNI -BCGI) / BCNI * 100.

[00252] The interference with the binding process for the EC127A polymer is shown in the table below and in Figure 3.

<td>Pstart</td><td>peq</td><td>BC</td><td>BC predicted</td><td>Disruption</td>

<td>(MM)</td><td>(MM)</td><td>(Mmol / g)</td><td>(Mmol / g)</td><td> (%)</td>

<td> 6, 25</td><td> 3,31</td><td> 1, 18</td><td> 2,17</td><td> 45, 7</td>

<td> 6, 25</td><td> 3,28</td><td> 1, 19</td><td> 2,16</td><td> 45, 0</td>

<td> 6, 25</td><td> 3,24</td><td> 1,21</td><td> 2,15</td><td> 44, 0</td>

111 [00253] The interference with the binding process for RENAGEL is shown in the table below and in Figure 4.

<td>Pstart</td><td>peq</td><td>BC</td><td>BC predicted</td><td>Disruption</td>

<td>(MM)</td><td>(MM)</td><td>(Mmol / g)</td><td>(Mmol / g)</td><td> (%)</td>

<td> 6, 25</td><td> 2,70</td><td> 1,42</td><td> 4,53</td><td> 68,7</td>

<td> 6, 25</td><td> 2,54</td><td> 1,48</td><td> 4,46</td><td> 66, 7</td>

[00254] The interference with the binding process for the EC127A polymer is about 34% lower than for Renagel.

Example 12: Ex-vivo ion binding properties of human aspirates [00255] Cross-linked polyamine material (EC 172A) was prepared according to the procedure described in Example 4, for a BTA: ECH molar ratio of 2.5 and a ratio (BTA + ECH) to water of 1.73. The material was then tested for binding of phosphate ions in food contents collected from humans as described in Example 1.

[00256] Phosphate binding for EC 172 A was compared to the pharmaceutically active crosslinked polyallylamine separated from Renagel (Genzyme). The EC 172A polymer exhibits a much lower level of interference as well as a significantly lower degree of swelling (2.5 compared to 9 for Renagel)

<td rowspan="2"></td><td rowspan="2">Medium peq (MM)</td><td rowspan="2">SD (MM)</td><td rowspan="2">Medium BC (Mmol / g)</td><td colspan="2">predicted</td><td rowspan="2">(%) Noise</td>

<td>SD (Mmol / g)</td><td>BC (Mmol / g)</td>

<td>Renagel API</td><td> 2,37</td><td> 0, 01</td><td> 1,32</td><td> 0, 00</td><td> 4,37</td><td> 70</td>

<td>EC172A</td><td> 1,55</td><td> 0, 04</td><td> 1, 64</td><td> 0, 02</td><td> 1, 68</td><td> 2,5</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

[00257] In a subsequent experiment, both materials, EC 172A and Renagel, were used ex-vivo in different food contents

112 taken from humans to quantify the degree of interference of phosphate ion binding caused by competing solutes such as citrate anions and bile acids. Citrate anions and bile acids were determined by ion chromatography and enzymatic tests, respectively. The results presented below (average of results obtained for six volunteers) indicate that the polymer of the present invention is characterized by much better selectivity and overall phosphate binding.

<td></td><td>[PO4]</td><td>BC (PO4)</td><td>[zither sulfonate]</td><td>BC (citrate)</td><td>(bile acid)</td><td>BC (yellow)</td>

<td></td><td>mM</td><td>mmol / g</td><td>mM</td><td>mmol / g</td><td>mM</td><td>mmol / g</td>

<td>control system (no polymer)</td><td> 5, 722</td><td></td><td> 1, 667</td><td></td><td> 4,928</td><td></td>

<td>Renagel</td><td> 3, 019</td><td> 1, 078</td><td> 0,596</td><td> 0,429</td><td> 1,32</td><td> 1,443</td>

<td>EC172A</td><td> 1,78</td><td> 1,573</td><td> 1,316</td><td> 0, 141</td><td> 4, 65</td><td> 0, 109</td>

Example 13: Gel porosity measurement using a solute partitioning technique [00258] This example illustrates the gel porosity measurement. The measurements were carried out for polymer particles according to the inventive idea and for comparison for commercially available phosphate binding polymers. As the polymer of the invention, cross-linked polyamine material (EC 172A) was prepared using the procedure described in Example 10, with a BTA: ECH molar ratio of 2.5 and a (BTA + ECH) to water ratio of 1.73. For comparison, the same porosity measurements were carried out for Renagel.

[00259] The probes were 8 samples, polyethylene glycol (PEG) with molecular weights ranging from 200 to 20,000 daltons, and 4 samples of polyethylene oxides (PEO) (from 30,000 to 230,000 daltons).

[00260] All probes were dissolved in 30 mM ammonium acetate buffer pH 5.5 (concentration 5 g / L). Probing solutions were added to previously weighed polymer samples, washed with HCl, EC172A (5 ml / g) and Renagel

113 washed HCl (15 ml / g dry gel); and then it was shaken for 4 days on a Vortexer shaker.

[00261] Probing solutions were diluted 10-fold before LC / liquid chromatography analysis using a light scattering detector by evaporated particles, by Polimer Lab (for being in the detector's linear operating range, ensuring that the peak area ratio is equal to the weight ratio).

[00262] Calculation of unavailable volume = ^ms^{+ [1-c}FOR IN _d/ c_after] m_solv; Where's m_s amount of water absorbed by the gel [g / g dry gel] m_solv amount of water in which the probe was initially dissolved [g / g dry gel]

C_{in front of} and C._after : concentrations of probing substances before and after reaching equilibrium. Ratio C_{in front of}/ C_after is equal to the peak area ratio obtained during LC analysis.

[00263] The results of this comparative example are shown in Figures 5 and 6; Figure 5 shows the results depending on the molecular weight, while Figure 6 shows the results depending on the particle size of the solutes. The EC 127A polymer indicates constant molecular exclusion for solutes down to MW 200, while Renagel shows a reduction in exclusion for particles as large as 1000 MW.

Example 14: Subsequent modification of the beads with chloropropylamine hydrochloride.

[00264] Preparation of the stock solution:

• Chloropropylamine, hydrochloride (B-SM-34-A) in water at 50% by weight, d = 1,132 • Aqueous solution of sodium hydroxide at 30% by weight (obtained by diluting a solution at 50% by weight), d = 1,335 [00265] Synthesis:

[00266] FR-0005-144, a phosphate-binding polymer prepared according to the procedure described in Example 9, with a BTA: ECH molar ratio of 2.5 and a ratio of (BTA + ECH)

114 to water of 1.73, was used as a raw material for further amination (introduction of amino groups): FR0005-144 beads were transferred to 4 ml vials (two 4x6 plates, each containing 21 vials) and water, chloropropylamine hydrochloride stock solution and sodium hydroxide stock solution using a liquid dispensing automaton. The vials were capped and the plates transferred to reactors equipped with a heating system and individual mixing.

[00267] Heating and stirring were turned on for 12 hours: the reactor temperature was set to 85 ° C and the stirring speed was 1200 rpm.

[00268] Purification:

[00269] Each product was transferred to disposable culture tubes (16x100 mm) and washed once with methanol, twice with a 1M hydrochloric acid solution and three times with water. The balls were separated by centrifugation each time.

[00270] The product was then dried in a lyophilizer and analyzed for action in a digested meal in a non-interfering buffer and the swelling ratio was measured. The results are shown below in Table 12 and Figure 7.

TABLE 12

Properties of polymers produced as a result of modification of the beads with chloropropylamine hydrochloride

<td>FR-</td><td>Water</td><td>B-SM-</td><td>NaOH</td><td>Relations in</td><td>Ratio</td><td>BC</td><td>BC</td><td>Degree</td>

<td> 0005-</td><td></td><td>34-A</td><td></td><td>k mol.</td><td>moth.</td><td>masking</td><td>masking</td><td>sp ê -</td>

<td> 144</td><td></td><td></td><td></td><td>B-SM-</td><td>NaOH to</td><td>Wani</td><td>Wani</td><td>swelling</td>

<td></td><td></td><td></td><td></td><td>34-A to</td><td>B-SM-34-</td><td>DM</td><td>NI</td><td>(g water /</td>

<td></td><td></td><td></td><td></td><td>FR-</td><td>DA</td><td>(Mmol /</td><td>(Mmol /</td><td>g gel)</td>

<td></td><td></td><td></td><td></td><td> 0005-</td><td></td><td>g)</td><td>g)</td><td></td>

<td></td><td></td><td></td><td></td><td> 144</td><td></td><td></td><td></td><td></td>

<td> 222,1</td><td> 864,5</td><td> 22,2</td><td> 1,71</td><td> 0,1</td><td> 0,25</td><td> 0, 94</td><td> 2,84</td><td> 2,91</td>

<td> 233,3</td><td> 883, 0</td><td> 46,7</td><td> 3,59</td><td> 0,2</td><td> 0,25</td><td> 0, 91</td><td> 2,94</td><td> 2, 69</td>

<td> 203,7</td><td> 749, 0</td><td> 61, 1</td><td> 4,70</td><td> 0,3</td><td> 0,25</td><td> 0, 95</td><td> 2,85</td><td> 2,83</td>

<td> 209, 1</td><td> 746, 3</td><td> 83, 6</td><td> 6, 43</td><td> 0,4</td><td> 0,25</td><td> 0, 97</td><td> 2,91</td><td> 2, 64</td>

115

<td>FR-</td><td>Water</td><td>B-SM-</td><td>NaOH</td><td>Relations in</td><td>Ratio</td><td>BC</td><td>BC</td><td>Degree</td>

<td> 0005-</td><td></td><td>34-A</td><td></td><td>k mol.</td><td>moth.</td><td>masking</td><td>masking</td><td>spe-</td>

<td> 144</td><td></td><td></td><td></td><td>B-SM-</td><td>NaOH to</td><td>Wani</td><td>Wani</td><td>swelling</td>

<td></td><td></td><td></td><td></td><td>34-A to</td><td>B-SM-34-</td><td>DM</td><td>NI</td><td>(g water /</td>

<td></td><td></td><td></td><td></td><td>FR-</td><td>DA</td><td>(Mmol /</td><td>(Mmol /</td><td>gel)</td>

<td></td><td></td><td></td><td></td><td> 0005-</td><td></td><td>g)</td><td>g)</td><td></td>

<td></td><td></td><td></td><td></td><td> 144</td><td></td><td></td><td></td><td></td>

<td> 209</td><td> 723,5</td><td> 104,5</td><td> 8, 04</td><td> 0,5</td><td> 0,25</td><td> 0, 97</td><td> 2,89</td><td> 2,58</td>

<td> 0</td><td> 0, 0</td><td> 0, 0</td><td> 0, 00</td><td></td><td></td><td></td><td></td><td></td>

<td> 227</td><td> 761,3</td><td> 136, 2</td><td> 10,48</td><td> 0, 6</td><td> 0,25</td><td> 0, 96</td><td> 2,90</td><td> 2, 60</td>

<td> 235</td><td> 762,8</td><td> 164,5</td><td> 12, 65</td><td> 0,7</td><td> 0,25</td><td> 1, 00</td><td> 2,97</td><td> 2, 67</td>

<td> 231,3</td><td> 725, 9</td><td> 185, 0</td><td> 14,23</td><td> 0, 8</td><td> 0,25</td><td> 0, 99</td><td> 2,88</td><td> 2,86</td>

<td> 278,5</td><td> 844, 1</td><td> 250,7</td><td> 19,28</td><td> 0, 9</td><td> 0,25</td><td> 0, 99</td><td> 2,90</td><td> 3,38</td>

<td> 236, 2</td><td> 690,4</td><td> 236, 2</td><td> 18, 17</td><td> 1,0</td><td> 0,25</td><td> 1, 00</td><td> 2,96</td><td> 2,73</td>

<td> 0</td><td> 0, 0</td><td> 0, 0</td><td> 0, 00</td><td></td><td></td><td></td><td></td><td></td>

<td> 204,1</td><td> 792,9</td><td> 20,4</td><td> 3, 14</td><td> 0,1</td><td> 0,5</td><td> 0, 92</td><td> 2,81</td><td> 2,85</td>

<td> 271</td><td> 1021,5</td><td> 54,2</td><td> 8,34</td><td> 0,2</td><td> 0,5</td><td> 0, 95</td><td> 2,81</td><td> 2,74</td>

<td> 247</td><td> 902,5</td><td> 74, 1</td><td> 11,40</td><td> 0,3</td><td> 0,5</td><td> 0, 97</td><td> 2,85</td><td> 2,85</td>

<td> 225, 5</td><td> 797,9</td><td> 90,2</td><td> 13, 87</td><td> 0,4</td><td> 0,5</td><td> 0, 97</td><td> 2,93</td><td> 2, 61</td>

<td> 238,2</td><td> 815, 4</td><td> 119, 1</td><td> 18,32</td><td> 0,5</td><td> 0,5</td><td> 1, 01</td><td> 2,84</td><td> 2, 68</td>

<td> 270,7</td><td> 0, 0</td><td> 0, 0</td><td> 0, 00</td><td></td><td></td><td> 0, 89</td><td> 2,73</td><td> 2,98</td>

<td> 199, 7</td><td> 660,5</td><td> 119, 8</td><td> 18,43</td><td> 0, 6</td><td> 0,5</td><td> 0, 98</td><td> 2,91</td><td> 2,70</td>

<td> 230, 6</td><td> 736, 1</td><td> 161,4</td><td> 24,83</td><td> 0,7</td><td> 0,5</td><td> 1, 01</td><td> 3, 03</td><td> 2,46</td>

<td> 221,3</td><td> 680, 9</td><td> 177, 0</td><td> 27,23</td><td> 0, 8</td><td> 0,5</td><td> 0, 98</td><td> 2,92</td><td> 2,58</td>

<td> 212,5</td><td> 629, 3</td><td> 191,3</td><td> 29, 42</td><td> 0, 9</td><td> 0,5</td><td> 1, 02</td><td> 3, 04</td><td> 2, 61</td>

<td> 200,4</td><td> 570,4</td><td> 200,4</td><td> 30, 83</td><td> 1,0</td><td> 0,5</td><td> 1, 06</td><td> 2,93</td><td> 2,46</td>

<td> 0</td><td> 0</td><td> 0</td><td> 0</td><td></td><td></td><td></td><td></td><td></td>

<td> 213,1</td><td> 826, 17</td><td> 21,3</td><td> 4,92</td><td> 0,1</td><td> 0,75</td><td> 0,94</td><td> 2,80</td><td> 2,92</td>

<td> 203,7</td><td> 764,66</td><td> 40,7</td><td> 9,40</td><td> 0,2</td><td> 0,75</td><td> 0,94</td><td> 2,81</td><td> 2,82</td>

<td> 212,4</td><td> 771,18</td><td> 63,7</td><td> 14,70</td><td> 0,3</td><td> 0,75</td><td> 0,97</td><td> 2,84</td><td> 3,04</td>

<td> 218,2</td><td> 765,38</td><td> 87,3</td><td> 20,14</td><td> 0,4</td><td> 0,75</td><td> 1,00</td><td> 2,88</td><td> 2,99</td>

<td> 203,4</td><td> 688,43</td><td> 101,7</td><td> 23,47</td><td> 0,5</td><td> 0,75</td><td> 1,03</td><td> 2,90</td><td> 2,64</td>

<td> 0</td><td> 0</td><td> 0, 0</td><td> 0, 00</td><td></td><td></td><td></td><td></td><td></td>

<td> 214,3</td><td> 698,95</td><td> 128,6</td><td> 29,67</td><td> 0,6</td><td> 0,75</td><td> 1,05</td><td> 2,94</td><td> 2,50</td>

<td> 228,8</td><td> 718,09</td><td> 160,2</td><td> 36,95</td><td> 0,7</td><td> 0,75</td><td> 1,04</td><td> 2,95</td><td> 2,60</td>

116

<td>FR-</td><td>Water</td><td>B-SM-</td><td>NaOH</td><td>Relations in</td><td>Ratio</td><td>BC</td><td>BC</td><td>Degree</td>

<td> 0005-</td><td></td><td>34-A</td><td></td><td>k mol.</td><td>moth.</td><td>masking</td><td>masking</td><td>sp ê -</td>

<td> 144</td><td></td><td></td><td></td><td>B-SM-</td><td>NaOH to</td><td>Wani</td><td>Wani</td><td>swelling</td>

<td></td><td></td><td></td><td></td><td>34-A to</td><td>B-SM-34-</td><td>DM</td><td>NI</td><td>(g water /</td>

<td></td><td></td><td></td><td></td><td>FR-</td><td>DA</td><td>(Mmol /</td><td>(Mmol /</td><td>g gel)</td>

<td></td><td></td><td></td><td></td><td> 0005-</td><td></td><td>g)</td><td>g)</td><td></td>

<td></td><td></td><td></td><td></td><td> 144</td><td></td><td></td><td></td><td></td>

<td> 235,2</td><td> 709,23</td><td> 188,2</td><td> 43,41</td><td> 0,8</td><td> 0,75</td><td> 1,08</td><td> 3,02</td><td> 2,55</td>

<td> 216,8</td><td> 627,06</td><td> 195,1</td><td> 45,02</td><td> 0,9</td><td> 0,75</td><td> 1,00</td><td> 2,95</td><td> 2,65</td>

<td> 206,7</td><td> 572,41</td><td> 206,7</td><td> 47,69</td><td> 1,0</td><td> 0,75</td><td> 1,00</td><td> 3,03</td><td> 2,48</td>

<td> 0</td><td> 0</td><td> 0, 0</td><td> 0, 00</td><td></td><td></td><td></td><td></td><td></td>

<td> 199,7</td><td> 772,69</td><td> 20,0</td><td> 6,14</td><td> 0,1</td><td> 1,0</td><td> 0,97</td><td> 2,75</td><td> 2,85</td>

<td> 206,4</td><td> 771,62</td><td> 41,3</td><td> 12,70</td><td> 0,2</td><td> 1,0</td><td> 0,97</td><td> 2,77</td><td> 3,30</td>

<td> 216</td><td> 779,26</td><td> 64, 8</td><td> 19, 94</td><td> 0,3</td><td> 1,0</td><td> 0, 98</td><td> 2,83</td><td> 2,93</td>

<td> 213,3</td><td> 741,63</td><td> 85,3</td><td> 26,25</td><td> 0,4</td><td> 1,0</td><td> 1,00</td><td> 2,85</td><td> 3,43</td>

<td> 212,9</td><td> 712,4</td><td> 106, 5</td><td> 32,75</td><td> 0,5</td><td> 1,0</td><td> 1, 04</td><td> 2,95</td><td> 2, 66</td>

<td> 193,3</td><td> 0</td><td> 0, 0</td><td> 0, 0</td><td></td><td></td><td> 0, 95</td><td> 2,73</td><td> 2,95</td>

<td> 240,6</td><td> 773,63</td><td> 144,4</td><td> 44,41</td><td> 0,6</td><td> 1,0</td><td> 1,02</td><td> 2,94</td><td> 2,88</td>

<td> 294,5</td><td> 908,43</td><td> 206,2</td><td> 63,42</td><td> 0,7</td><td> 1,0</td><td> 1,07</td><td> 2,94</td><td> 2,58</td>

<td> 214,1</td><td> 632,43</td><td> 171,3</td><td> 52,69</td><td> 0,8</td><td> 1,0</td><td> 1,06</td><td> 3,05</td><td> 2,60</td>

<td> 205,5</td><td> 580,15</td><td> 185,0</td><td> 56,90</td><td> 0,9</td><td> 1,0</td><td> 1,08</td><td> 3,04</td><td> 2,66</td>

<td> 201,2</td><td> 541,7</td><td> 201,20</td><td> 61,90</td><td> 1,0</td><td> 1,0</td><td> 1, 09</td><td> 3, 07</td><td> 2,91</td>

<td> 0</td><td> 0</td><td> 0, 00</td><td> 0, 00</td><td></td><td></td><td></td><td></td><td></td>

[00271] Example 15: Synthesis of crosslinked particles with micron dimensions marked with a phosphate matrix from the N, N '- (tetra-3-aminopropyl) -1,4-diaminobutane / epichlorohydrin system [00272] The following stock solution was prepared: 1 molar equivalent of phosphoric acid (Aldrich, 85% by weight in water) was added over a period of 2 hours to 1 molar equivalent of N, N '- (tetra-3-aminopropyl) -1,4-diaminobutane.

Then, water was added to the solution in such an amount that the resulting solution had the following composition in% by weight: N, N '(tetra-3-aminopropyl) -1,4-diaminobutane 42% by weight, H₃AFTER₄13% by weight, water 45% by weight. 24-chamber was used

117 a reactor containing 5 ml flasks, each equipped with a magnetic stirrer 0.6-0.7 g of prepared mixing. For any cooling temperature.

Stock solution was placed in each flask. Included vials added the desired amount of epichlorohydrin in pure form. The reactor was heated to 60 ° C for 1 hour and then heated to 0 ° C for 8 hours. The reactor was allowed to add water to each vial to swell the resulting gel. The gel was transferred to a 4X6 plate with 10 ml test tubes. The gel was then ground to micron sized particles with a mechanical chopper (trademark: IKA; model: Ultra-Turax T8). The particles were purified by removal of water, washing with methanol and further washing with a 20% NaOH solution. The gel particles were then washed with 1.0 molar HCl solution, stirred for 30 minutes, then allowed to settle and the clarified liquid was decanted. This process was repeated 5 times to protonate the amine functional groups of the particles with HCl, and replace the bound H₃AFTER₄. The gel particles were then washed with a 20% NaOH solution to deprotonate the amine functional groups of the gel particles. The gel particles were washed twice with deionized water to remove excess NaOH / NaCl. The gel particles were freeze dried for 3 days to give a fine white powder. The synthesis is summarized in the table

13.

TABLE 13

Synthesis of phosphoric acid labeled gels. ID 102776

<td>Government</td><td>Kolu</td><td>B-SM-</td><td>B-SM-</td><td>Acid</td><td>Water</td><td>X-EP-1</td><td>X-EP-1</td><td>B-SM-</td><td>X-EP-</td><td>Gel</td>

<td></td><td>me</td><td> 20-</td><td>20-TeA</td><td>phospho</td><td>(Mg)</td><td>(Mg)</td><td>(Moles)</td><td> 20-</td><td>1 / B-</td><td>present</td>

<td></td><td></td><td>TeA</td><td>(Moles)</td><td>trenches</td><td></td><td></td><td></td><td>Tea /</td><td>SM-20</td><td>in</td>

<td></td><td></td><td>(Mg)</td><td></td><td>(Mg)</td><td></td><td></td><td></td><td>H3PO4</td><td>TeA</td><td>ventricular</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>sculpture</td>

<td> 1,0</td><td> 1,0</td><td> 347,5</td><td> 0,0011</td><td> 107,7</td><td> 369, 8</td><td> 71, 1</td><td> 0,0008</td><td> 1, 00</td><td> 0,70</td><td>x</td>

<td> 1,0</td><td> 2,0</td><td> 339, 5</td><td> 0,0011</td><td> 105, 2</td><td> 361,4</td><td> 79, 4</td><td> 0,0009</td><td> 1, 00</td><td> 0, 80</td><td>x</td>

<td> 1,0</td><td> 3, 0</td><td> 337,7</td><td> 0,0011</td><td> 104, 6</td><td> 359, 4</td><td> 88, 8</td><td> 0,0010</td><td> 1, 00</td><td> 0, 90</td><td> 5</td>

<td> 1,0</td><td> 4,0</td><td> 352,1</td><td> 0,0011</td><td> 109, 1</td><td> 374,8</td><td> 102,9</td><td> 0,0011</td><td> 1, 00</td><td> 1, 00</td><td> 5</td>

118

<td>Government</td><td>Kolu me</td><td>B-SM20TeA (Mg)</td><td>B-SM20-tea (Moles)</td><td>Acid phosphoric (Mg)</td><td>Water (Mg)</td><td>X-EP-1 (Mg)</td><td>X-EP-1 (Moles)</td><td>B-SM20TeA / H3PO4</td><td>X-EP- 1 / BSM-20TE</td><td>Gel present in chamber</td>

<td> 1,0</td><td> 5, 0</td><td> 355, 4</td><td> 0,0011</td><td> 110, 1</td><td> 378,2</td><td> 114,3</td><td> 0,0012</td><td> 1, 00</td><td> 1, 10</td><td>AND</td>

<td> 1,0</td><td> 6, 0</td><td> 366, 1</td><td> 0,0012</td><td> 113,4</td><td> 389, 6</td><td> 128,4</td><td> 0,0014</td><td> 1, 00</td><td> 1,20</td><td>AND</td>

<td> 2,0</td><td> 1,0</td><td> 355, 3</td><td> 0,0011</td><td> 110, 1</td><td> 378,1</td><td> 135, 0</td><td> 0,0015</td><td> 1, 00</td><td> 1,30</td><td>AND</td>

<td> 2,0</td><td> 2,0</td><td> 338, 6</td><td> 0,0011</td><td> 104,9</td><td> 360,4</td><td> 138, 6</td><td> 0,0015</td><td> 1, 00</td><td> 1,40</td><td>AND</td>

<td> 2,0</td><td> 3, 0</td><td> 356, 2</td><td> 0,0011</td><td> 110,4</td><td> 379, 1</td><td> 156, 2</td><td> 0,0017</td><td> 1, 00</td><td> 1,50</td><td>AND</td>

<td> 2,0</td><td> 4,0</td><td> 349, 7</td><td> 0,0011</td><td> 108,3</td><td> 372,2</td><td> 163,5</td><td> 0,0018</td><td> 0, 99</td><td> 1, 61</td><td>AND</td>

<td> 2,0</td><td> 5, 0</td><td> 342,2</td><td> 0,0011</td><td> 106, 0</td><td> 364,2</td><td> 170, 0</td><td> 0,0018</td><td> 1, 00</td><td> 1,70</td><td>AND</td>

<td> 2,0</td><td> 6, 0</td><td> 351,4</td><td> 0,0011</td><td> 108,9</td><td> 374,1</td><td> 184,9</td><td> 0,0020</td><td> 1, 00</td><td> 1, 80</td><td>AND</td>

<td> 3, 0</td><td> 1,0</td><td> 364,1</td><td> 0,0012</td><td> 112,8</td><td> 387,5</td><td> 212,8</td><td> 0,0023</td><td> 1, 00</td><td> 2,00</td><td>AND</td>

<td> 3, 0</td><td> 2,0</td><td> 351,2</td><td> 0,0011</td><td> 108, 8</td><td> 373, 8</td><td> 246, 4</td><td> 0,0027</td><td> 1, 00</td><td> 2,40</td><td>AND</td>

<td> 3, 0</td><td> 3, 0</td><td> 358,3</td><td> 0,0011</td><td> 111, 0</td><td> 381,4</td><td> 293,2</td><td> 0,0032</td><td> 1, 00</td><td> 2,81</td><td>AND</td>

<td> 3, 0</td><td> 4,0</td><td> 340,2</td><td> 0,0011</td><td> 105, 4</td><td> 362,1</td><td> 318,2</td><td> 0,0034</td><td> 1, 00</td><td> 3,20</td><td>AND</td>

<td> 3, 0</td><td> 5, 0</td><td> 368,9</td><td> 0,0012</td><td> 114,3</td><td> 392, 6</td><td> 388,2</td><td> 0,0042</td><td> 1, 00</td><td> 3,59</td><td>AND</td>

<td> 3, 0</td><td> 6, 0</td><td> 360,5</td><td> 0,0011</td><td> 111,7</td><td> 383,7</td><td> 421,5</td><td> 0,0046</td><td> 1, 00</td><td> 4, 00</td><td>AND</td>

<td> 4,0</td><td> 1,0</td><td> 345, 3</td><td> 0,0011</td><td> 107, 0</td><td> 367,5</td><td> 444, 0</td><td> 0,0048</td><td> 1, 00</td><td> 4,40</td><td>AND</td>

<td> 4,0</td><td> 2,0</td><td> 364,0</td><td> 0,0012</td><td> 112,8</td><td> 387,4</td><td> 510,7</td><td> 0,0055</td><td> 1, 00</td><td> 4, 80</td><td>AND</td>

<td> 4,0</td><td> 3, 0</td><td> 351,2</td><td> 0,0011</td><td> 108, 8</td><td> 373,7</td><td> 533,7</td><td> 0,0058</td><td> 1, 00</td><td> 5,20</td><td>AND</td>

<td> 4,0</td><td> 4,0</td><td> 365, 5</td><td> 0,0012</td><td> 113,2</td><td> 389, 0</td><td> 598,3</td><td> 0,0065</td><td> 0, 99</td><td> 5, 63</td><td>AND</td>

<td> 4,0</td><td> 5, 0</td><td> 358,5</td><td> 0,0011</td><td> 111, 1</td><td> 381, 6</td><td> 628,8</td><td> 0,0068</td><td> 1, 00</td><td> 6, 02</td><td>AND</td>

[00273] Polymers prepared as described above bind phosphate.

[00274] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that they are provided by way of example only. It will also be obvious to a person skilled in the art that many changes and modifications can be made to the solutions presented without departing from the inventive idea. It is understood that the various described here

119 use alternative forms of the idea in its practical implementation. The invention is defined by the following inventive claims

As intended, patent pending.

120