Anion-binding polymers and uses thereof

[0001] Ion-selective sorbents are used to treat electrolyte imbalances in humans in conditions such as hyperphosphatemia / hyperphosphate in the blood, hyperoxaluria, hypercalcemia and hyperkalemia / excess of potassium in the blood. Excess phosphate in the blood occurs in patients with kidney failure whose kidneys do not excrete enough phosphate ions to equalize the intake of exogenous phosphate ions with the diet. This condition leads to a high concentration of phosphate ions in the blood serum and a high product of calcium and phosphate concentration. Although the etiology is not fully illustrated, it is believed that a high product of calcium and phosphate concentration is responsible for soft tissue calcification and cardiovascular disease. Cardiovascular disease is the cause of death for almost half of all patients on dialysis.

[0002] Aluminum salts, calcium salts and recently lanthanum salts are used to regulate the absorption of phosphate ions in the gastrointestinal tract (GI) and to restore the systemic level of phosphate ions in the body to normal. However, these salts release soluble aluminum and calcium cations in GI, which are then partially absorbed into the blood stream. Aluminum ion absorption can cause serious side effects such as aluminum osteopathy and dementia; high calcium absorption leads to hypercalcaemia and exposes patients to the risk of coronary calcification.

[0003] Metal-free phosphate binders, such as highly basic exchangers, have been proposed for use as phosphate binders.

Cholestyramine. However, ionic Dowex resins require high doses due to their low binding capacity, which are not well tolerated by patients.

[0004] Polymers containing amine functional groups have been described as phosphate or oxalate binder binders. For example: see patents 5,985,938; 5,980,881; 6,180,094; 6,423,754 and WO 95/05184 PCT patent application. Renagel, a cross-linked polyallylamine resin, is a phosphate masking material, marketed as a phosphate binder that does not contain metals. The in vitro binding of phosphate by Renagel is approximately 6 mmol / g in water and 2.5 mmol / g measured in a solution of 100 mM (millimoles) sodium chloride and 20 mM phosphate ions at neutral pH. The recommended dosage for the target patient population to maintain phosphate levels below 6 mg / dL is typically between 5 g / day and 15 g / day. Published Phase I clinical studies for Renagel in healthy volunteers showed that 15 g Renagel reduces the amount of phosphate ions excreted in the urine from a normal level of 25mmol to 17mmol, with the remaining amount being excreted in the faeces in free or polymer-bound form . Based on this data, the in vivo binding capacity range can be estimated at 0.5-1 mmol / g, which is much less than the measured in vitro brine capacity of 6 mmol / g. If you take pod

- only the Renagel binding capacity, measured in vitro in saline solution, a dose of 15 g phosphate binder would bind more than the total phosphate content of the average American diet, i.e. 37 mmol / day. The discrepancy between in vitro binding capacity and documented low in vivo yield has a negative effect on the therapeutic benefits of the drug because more resin is needed to bring plasma phosphate concentrations to a safe range.

[0005] When used in a complex environment that is the gastrointestinal tract, such a reduction in the ion exchange capacity of resins is not limited to Renagel. Despite general safety from a toxicological point of view, the high dose and inconvenience of consuming multi-gram quantities of resin speaks for the need to improve the ion exchange capacity of the resin. For example, even in Renagel's documented safety studies, patients experienced gastrointestinal upset at doses as low as 1.2-2.0 g / day for an 8-week treatment period. Patients receiving 5.4 g Renagel / day in 8.9% of cases discontinued treatment due to adverse symptoms such as gastrointestinal complaints (Slatapolsky et al., Kidney Int. 55: 299307, 1999; Chertow et al., Nephrol Dial Transplant 14: 29072914, 1999). Thus, improving in vivo binding ability, which translates into smaller, better tolerated dosing, is a desirable improvement in resin-based therapy.

[0006] The result of these considerations is still a great need to produce safe high-performance binders that selectively remove ions from the body, with a lower dosage and a better patient compliance profile.

[0007] Patient compliance is currently recognized as one of the main factors limiting patients' compliance with K / DOQI recommendations: increasing the dose means that patients must take ten or more tablets of 800 mg daily. Renagel pills are swallowed tablets and are given with a minimum amount of fluid, which is an additional burden for ESRD / end stage renal disease patients who need to maintain fluid intake. A pharmaceutical preparation in a form that would be easier to take would be desirable: especially chewable tablets are becoming increasingly popular among the geriatric and pediatric patient populations, and for treatment requiring the intake of tablets containing a higher dose of the active ingredient: chewable tablets allow the preparation of tablets with higher potency and ultimately reduce the number of tablets per dose. Since the active substance contained in the chewable tablet is first comminuted under the influence of chewing and saliva before swallowing, the requirements for both the shape and weight of the tablet are much less stringent than those imposed on swallowing tablets. However, up to now it has not been possible to form a hydrogel, such as Renagel, to form a chewable tablet due to the strong swelling properties of this polymer. Renagel usually swells very quickly in

- isotonic solution in the range up to about 10 times greater than its mass. This has two undesirable effects: first, during swelling in the mouth, the polymer causes very unpleasant sensations (dry mouth, choking sensation); secondly, even if the patient overcomes discomfort in the mouth, the introduction of swollen gel into the esophagus can be dangerous. What's more, it is also well known that highly swelling gels, when administered in multigram quantities, cause side effects such as bloating, constipation or diarrhea.

SUMMARY OF THE INVENTION [0008] In one embodiment, the invention provides anion-binding polymers. In certain embodiments, the invention provides an anion-binding polymer, wherein the polymer binds to a target anion (e.g., phosphate or oxalate), wherein the polymer has at least two of the following features: a) a swelling ratio of less than about 5; b. a gel pore volume distribution, 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 molecular weight of the target anion occupies less than about 20% of the gel; and c) disrupting the ion binding process for the target anion in measurements in a mixture mimicking the gastrointestinal tract content of less than about 60% 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

- 6 2.5. 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. 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- (3-aminopropyl) 1,4-diaminobutane, 1,2,3,4-tetraaminobutane, a compound of formula 1 and a compound of formula 2 when what Formula 1 and Formula 2 represent the following structures:

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[0009] In certain embodiments, the invention provides an anion binding polymer comprising crosslinked polyamines, wherein the polymer is obtained by inverted suspension, wherein the degree of swelling of the polymer is less than 5.

[0010] In certain embodiments, the invention 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) gel pore volume distribution measured in a physiological environment characterized by

- 7 in that the pore fraction with a volume available for non-interacting solutes with a molecular weight greater than about 200 takes less than about 20% of the gel; 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. 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.

[0011] In certain embodiments, the invention 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 at neutral pH. In embodiments 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.

[0012] In certain embodiments, the invention provides an anion-binding polymer, wherein the polymer binds to a target anion (for example, phosphate or oxalate) and the polymer has at least two of the following features: a) a swelling ratio of less than about 5; b) gel pore volume distribution measured in a physiological environment, characterized in that the pore fraction with a volume available for non-interacting solutes with a molecular weight greater than about twice the MC molecular weight of the target anion takes less than about 20% gel; 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 is produced in a process in which the amine is in the solvent before cross-linking in an amine ratio: a solvent 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, average number of connections with amine monomers (NC) is between about 2.05 and about 6, or between about 2.2 and about 4.5. In certain 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 the factor

- 9 crosslinking; c) performing a crosslinking reaction; id) elution of the target ion.

[0013] In certain embodiments, the invention provides anion-binding polymer, wherein the polymer binds to a target anion (for example, phosphate or oxalate) and the polymer has at least two of the following features: a) a swelling ratio of less than about 5; b) gel pore volume distribution measured in a physiological environment, characterized in that the pore fraction with a volume available for non-interacting solutes with a molecular mass greater than about twice the MC molecular mass of the target anion takes less than about 20% of the mass gel; 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 wherein the polymer is produced by a process involving: a) preparing a soluble prepolymer by adding all of the amine monomer component followed by the continuous addition of a crosslinker fraction to form a syrup; b) emulsifying the syrup in oil; and

c) adding the remaining amount of crosslinker to form crosslinked beads.

[0014] In certain embodiments, the invention provides an anion-binding polymer, wherein the polymer binds to a target anion (e.g., phosphate or oxalate) and the polymer has at least two of the following characteristics: a) a swelling ratio less than

- 10 around 5; b) gel pore volume distribution measured in a physiological environment, characterized in that the pore fraction with a volume available for non-interacting solutes with a molecular weight greater than about twice the MC molecular weight of the target anion takes less than about 20% gel; 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 wherein the polymer produced by 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.

[0015] In certain embodiments, the invention provides a phosphate-binding polymer comprising one or more amine monomers and one or more crosslinkers, wherein the polymer is made by a process in which the total content of crosslinkers added to the reaction mixture is such that the average number of connections with amine monomers is between 2.2 and

4,5.

[0016] In some of these 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 wherein the crosslinker is selected from

- 11 groups consisting of 1,3-dichloropropane and epichlorohydrin. In the examples, the invention provides an ion-binding polymer comprising N, N, N ', N'-tetrakis- (3aminopropyl) -1,4-diaminobutane cross-linked with epichlorohydrin, wherein the polymer is produced by a process in which the ratio of the initial concentration of N, N' -tetrakis- (3aminopropyl) -1,4-diaminobutane to water is from about 1: 3 to about 4: 1, or from about 1.5: 1 to about 4: 1.

[0017] In some embodiments, the invention provides a phosphate-binding polymer comprising N, N, N ', N'-tetrakis- (3-aminopropyl) -1,4-diaminobutane monomers and an epichlorohydrin crosslinker, wherein the polymer is prepared in process wherein the total amount of epichlorohydrin crosslinker added to the reaction mixture is from about 200% to about 300 mol% or from about 230 to about 270 mol% or about 250 mol% of the total amount of N, N, N ', N'-tetrakis (3-aminopropyl) -1,4diaminobutanu. 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.

[0018] In certain embodiments, the invention 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.

[0019] In certain embodiments, the invention provides a phosphate-binding polymer comprising a prepolymer comprising 1,3-diaminopropane and a crosslinker in the form of 1,3-dichloropropane, in a molar ratio of 1: 1, wherein the prepolymer is then subjected to a crosslinking reaction with a crosslinker - epichlorohydrin and the total amount of crosslinker - epichlorohydrin added to the reaction mixture is about 200 mole% of the total amount of prepolymer and the ratio of prepolymer: water in the reaction mixture is from about 1.1 : 1 to about 1.7: 1.

[0020] The invention further 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.

[0021] In another embodiment, the invention 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 formulation in which the polymer is dispersed in a liquid carrier in the form of water and appropriate excipients. In certain embodiments, the invention 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, wherein the polymer has a degree of swelling

When 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 having a transition temperature greater than about 50 ° C.

[0022] 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 to form a solid phase 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 is more than about 1.6 g of the total weight of the tablet. In certain types of chewable tablets of the invention, 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 having an average diameter less than about μm. In some of these embodiments, the sweetener is selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose and sorbitol and combinations thereof.

[0023] In a further embodiment, the invention provides a method of measuring 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 GI and / or the collection of gastrointestinal 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 decrease in the concentration of the target ion before and after its addition; and d) calculation of the degree of interference in the binding process in the form of a fractional decrease in the binding capacity of the target ion, expressed as a percentage, observed between the measurement of binding capacity in a non-interfering buffer environment and in a digested meal or in ex-vivo aspirates at the same equilibrium ion concentration.

[0024] In a still further embodiment, the invention provides a method for selecting an ion binding polymer, said polymer comprising a monomer and a crosslinking agent, wherein said polymer has at least one of the following properties: a) a swelling ratio less than about 5; b) gel pore volume distribution measured in a physiological environment, characterized in that the pore fraction with a volume available for non-interacting solutes with a molecular weight greater than about twice the weight

- the molecular MC of the target anion takes up less than about 20% of the gel mass; 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, which includes the steps of: i) changing the following composition and process variables: 1) 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) a hydrophilic / hydrophobic balance of the polymer backbone; ii) assessment of swelling capacity, 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 invention 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 is from about 2.05 to about 6; and / or b) producing the polymer by a method in which polyamine is initially present in water in a polyamine: water ratio of from about 3: 1 to about 1: 3.

[0025] According to another embodiment, the invention 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

- 16 by the following two features: (a) a swelling ratio less than about 5; b. a polymer fraction of less than 20% of its mass available to non-interacting solutes with a molecular weight greater than about twice the MC of the target anion, the above percentage being measured in a physiological environment; and c) ion binding disruption 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 amine monomer is polyallylamine. In some embodiments, the crosslinker is epichlorohydrin.

[0026] In another aspect, the invention provides an anion-binding polymer that binds to a target ion, wherein the polymer is made by a process comprising crosslinking polyallylamine in a non-homogeneous process, said polymer having at least two of the following characteristics: a) a swelling ratio of less than around 5; b. a polymer fraction of less than 20% of its mass available to non-interacting solutes with a molecular weight greater than about twice the MC of the target anion, the above percentage being measured in a physiological environment; and c) ion binding disruption 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 one embodiment, the polyallylamine is cross-linked with epichlorohydrin.

[0027] In another aspect, the invention provides a method of removing anion from an animal's body by administering to the animal an effective amount of the polymer of the invention. In some embodiments, the polymer is an anion-binding polymer, wherein the polymer binds to the target anion (e.g. phosphate or oxalate), the polymer having at least two of the following features: a) a swelling ratio of less than about 5; b. a gel pore volume distribution, 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 molecular weight of the target anion occupies 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 GI gastrointestinal tract content relative to the non-interfering buffer. In some embodiments, the target anion for the polymer is phosphate; in some examples, 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 extremes stage renal failure (ESRD). In certain embodiments, the animal is a human.

[0028] 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 a phosphate binder, for example a carbonate phosphate binder. aluminum, calcium carbonate, calcium acetate, lanthanum carbonate or sevelamer hydrochloride.

LITERATURE REFERENCES [0029] All publications and patent applications cited herein are incorporated herein by reference in the same manner as if each independent publication or patent application has been specifically and separately indicated as related material.

BRIEF DESCRIPTION OF THE DRAWINGS [0030] Fig. 1 is a graph illustrating the determination of disruption of the binding process by comparing the target ion binding isotherm by the polymer in a non-interfering buffer environment against the binding of the target ion by the polymer in the interfering environment (for example, a mixture of gastrointestinal (GI) or gastrointestinal content (ex vivo).

[0031] Fig. 2 is a graph illustrating the inaccessible gel volume depending on the radius of the dissolved test substance.

[0032] Fig. 3 is a graph illustrating the determination of binding interference for a phosphate binding polymer (EC172A).

- from the test weight, binding substance molecular illustrating substance FR-005-144 [0033] Fig. 4 is a graph illustrating the determination of binding interference for a phosphate-binding polymer (RENAGEL).

[0034] Fig. 5 is a graph of the relationship of inaccessible volume to the non-interfering substance difference between phosphate polymer according to the invention (EC 172A) and binding phosphate ions commercially available (RENAGEL).

[0035] Fig. 6 is a graph of the dependence of the inaccessible volume versus the radius of a test substance molecule for a non-interfering test substance, illustrating the difference between the phosphate-binding polymer according to the invention (EC 172A) and a commercially available binder phosphate ions (RENAGEL).

[0036] Fig. 7 is a graph illustrating a change in binding capacity for a chloropropylamine modified; hydrochloride.

[0037] New embodiments of the invention are presented with particular regard to examples found in the appended claims. A better understanding of the embodiments and advantages of the invention will be possible by reference to the following detailed description summarizing illustrative embodiments in which the principles of the invention are used, and the accompanying figures in which:

DETAILED DESCRIPTION OF THE INVENTION

I. Introduction

[0038] 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 invention provides pharmaceutical compositions from anion-binding polymers, which pharmaceutical compositions are in the form of chewable tablets or fluid preparations. Another embodiment of the invention 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 in vivo, low interference by interfering ions, and / or specific porosity. Still a further embodiment of the invention are methods of using the anion-binding polymers of the invention to treat 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, oxalate phosphate. 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

[0039] The polymers of the invention are characterized by their ion binding capacity. Preferably, the polymers of the invention bind anions, more preferably bind phosphates and / or oxalates, and most preferably bind phosphate ions. For illustration, anion binding polymers will be described, especially phosphate binding polymers; however, it is understood that this description, with appropriate modifications that are apparent to one skilled in the art, also applies to all ions and solutes. The terms used herein, such as an "ion-binding" polymer, e.g. an anion, or an "ion-binding" polymer (e.g., a "phosphate-binding" polymer) are used when the polymer binds to the ion, generally, but not necessarily in a non-covalent way, with sufficiently strong association power, so that at least a portion of the ion remains bound in vitro or in vivo while using the 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. The polymer may bind more than one target ion. "Anion" bond means more than minimal binding, 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, most preferably at least about 0.5 mmol anion / g polymer The polymers of the invention are

- 22 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, and most preferably less than about 0.1 mmol / g. In certain 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 most preferably less than about 0.1 mmol / g.

A. Characteristics [0040] The polymers of the invention have one or more of the following properties: 1) low swelling; 2) small disruption of the binding process in the physiological environment; 3) a porosity suitable 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 examples, 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 in that the pore fraction with a volume below 20% is available for non-interacting substances dissolved in water with a molecular weight greater than

- about twice the molecular weight MC of the target anion; and 3) ion binding disruption for the target ion of less than about 60% when measured in a medium imitating 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 in that the pore fraction with a volume less than about 20% is available for non-interacting solutes with a molecular weight greater than about 200; and 3) ion binding interference for phosphate ions less than about 60% when measured in a medium that mimics the content of the gastrointestinal tract, relative to the non-interfering buffer. In some 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. The "physiological environment" is an isotonic environment with a neutral pH. In certain embodiments, the invention provides a phosphate-binding polymer having a swelling ratio, 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 binding capacity of phosphate ion of greater than about 0.5 mol / g. In some 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 examples

In one embodiment, 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 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 most preferably less than about 0.1 mmol / g. Preferably the polymers consist of amine monomers.

[0041] In general, these features are achieved by changing one or more parameters during polymer production.

[0042] 1) Degree of swelling. The polymers of the invention are crosslinked materials, which means that they do not dissolve in solvents and, at most, swell in solvents.

[0043] The degree of swelling in an isotonic physiological buffer characteristic of the environment of use, 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 has been carried out for a given polymer, it is assumed that the degree of swelling is the average of the measurements.

[0044] Swelling rates can be measured using various 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 from about 6.5 to

7.5. The dry polymer (e.g., phosphate-binding polymer) is generally used in completely protonated form with a counterionone, such as chloride. The polymer is soaked in a liquid until equilibrium is reached. The soaked gel is then 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 follows: mass of wet gel minus mass of dry polymer, divided by mass of dry polymer.

[0045] Another method is the dye method, in which a dye with a very high molecular weight, which does not interact with the gel, dissolves in water and to the resulting

An aliquot of the dry polymer sample is introduced into the solution. The ratio of the solution to mass ratio is slightly higher than Because the dye has a polymer with a similar value and the expected degree of swelling, very high molecular weight (e.g. above 200,000 g / mol), it does not penetrate the gel, while water penetrates its interior. which leads to an increase in the current concentration of dye, from which the degree of swelling can be determined. An example of a useful dye is Fluorescein Isothiocyanate (FITC) dextran.

[0046] The degree of polymer swelling depends on several variables, such as temperature, ionic strength, polymer charge density, Flory-Huggins polymer-solvent ratio and crosslinking density. Since the ion-binding polymers of the invention are typically charged polymers (e.g., phosphate-binding polyamines occur in protonated form at an pH value that is present in the digestive system), their swelling behavior is typical of polyelectrolyte gels. Although the swelling ratio and pore size are somewhat related to each other, i.e. large swelling ratio is usually accompanied by large pore sizes, there is no theoretical basis to accurately determine the exclusion limit of polyelectrolyte gels.

[0047] 2) Disruption of the binding process. In certain embodiments, the polymers of the invention 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%,

Even more preferably less than about 40%, even more preferably less than about 30%, and most preferably less than about 20%. The phosphate-binding polymers of the invention when measured in a 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%, more preferably less than about 40 %, even more preferably less than about 30% and most preferably less than about 20%.

[0048] The terms "degree of interference with the binding process or interference with the binding process" as used herein

is the fractional decrease in target ion binding capacity, expressed as a percentage, observed between the binding efficiency in a non-interfering buffer environment and in a mixture mimicking 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 chloride and bicarbonate ions commonly found in the digestive tract, which, if present, may be present in a concentration such as under physiological conditions. An example of a non-interfering buffer

- 28 is given in example 1. The term "mixture imitating gastrointestinal tract (GI) content" as used herein means a system intended 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 study. The degree of interference can be easily illustrated by plotting the two appropriate binding isotherms, i.e. for the mixture mimicking the content of the GI conduit and for the non-interfering buffer environment, as shown in Figure 1. An example of measuring the disruption of the binding process using a mixture imitating the content of the GI cable is given in Example 1.

[0049] Measurement of binding interference can also be performed by comparing the binding of the target ion in the collected nutrient 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.

[0050] It has been found that, by carefully choosing the degree of swelling and / or setting the limiting molecular weight of the gel excluded molecules, the binding capacity measured by competing methods can be significantly increased (i.e.

- 29 is in vivo or in a mixture that mimics the content of the GI wire) compared to other gels with the same polymer composition but not optimized porosity.

[0051] 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 ion binding capacity (e.g., phosphate) than polymers with less crosslinking and / or entanglement. Without wishing to be bound by theory, it has been hypothesized that the polymers of the invention exert a sieve effect and only bind solutes with specific dimensions from the solution, and exclude other substances with larger particles that would otherwise compete for binding sites within the polymer. Higher molecular weight substances include, but are not limited to, inorganic and organic anions, oligopeptides, carbohydrates, bilirubins, lipid micelles, and lipid vesicles.

[0052] 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.

[0053] The pore size distribution of polymer gels is obtained using various methods such as mercury porosimetry, nitrogen adsorption, differential scanning calorimetry, or substance permeation separation techniques

- 30 dissolved. The latter method, the technique of permeation separation of the solute, is the most advantageous, since the test is subjected to a completely hydrated gel, i.e. in a condition identical to that prevailing in the environment of use. The solute permeation technique is an indirect method introduced by Kuga (Kuga SJ, J. of Chromatography, 1986, 206: 449-461) and involves measuring the partition of solutes with known molecular weights in the 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. The solutes will diffuse 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. For the calculation of the gel pore size distribution, the concentration of each solute is reduced from its initial concentration.

in order to get rid of the exclusion effects by attraction / repulsion, the dissolved substances are selected from polymers or oligomers that have little or no interaction with the gel polymer; neutral hydrophilic polymers with narrow weight distribution [0054] In caused molecular,

Molecular compounds such as polyethylene glycol, polyethylene oxide or dextran are most suitable. Thus, unless otherwise indicated herein, volumes for excluding solutes of particular sizes (also referred to herein as "critical permeation volume") refer to volumes measured using solutes that do not interact with the polymer for which the measurements were made.

[0055] According to the experimental protocol and data provided by Kremer et al., Macromolecules, 1994, 27, 2965-73, the pore size distribution can be represented as shown in Figure 2. In Figure 2, the Y axis is the volume of swollen gel , which is not available for solutes with 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.

[0056] 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. E.g:

Radius (angstroms) = 0.217M^0,498 dextran

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

Radius (angstreams) = 0.166M^0,573 poly (ethylene oxide)

[0057] 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: 4.4 angstrom particle radius

Sucrose: 5.3 angstrom particle radius [0058] Thus, the molecular weight of the solute can be calculated from molecular weight and vice versa.

[0059] 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.

[0060] A direct way to characterize the particle exclusion limit is: (i) quantifying the particle distribution of the probe; (ii) calculating the available volume (or mass) as described above; and (iii) normalizing the data obtained to the total gel volume (or weight).

[0061] The desired exclusion limit for molecules is achieved by changing production variables such as entanglement of polymer chains and the concentration of crosslinker (see below). In general, polymers are produced that have an exclusion limit for molecules that depend on the size of the ion (e.g., anion) to be bound, and likely interfering substances to be excluded, as well as the allowable amount of polymer swelling depending on

- 33 intended use. In certain example embodiments of this invention, the ion-binding polymer is characterized by a gel pore volume distribution (critical permeation volume) determined by the method described 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 molecular weight MC the target anion occupies less than about 60%, less than about 40%, or less than about 20% of the polymer pore volume. In some embodiments, 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 1.8 times the molecular weight of the target ion MC is less than about 60 %, less than about 40% or less than about 20% of the polymer pore volume. In some embodiments, 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 MC of the target ion occupies less than about 60%, less than about 40% or less than about 20% of the polymer pore volume. In some embodiments, 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 1.4 times the molecular weight of the MC of the target ion occupies less than

- about 60%, less than about polymer pore volume.

40% or less than about 20% In some embodiments, 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 1.2 times the molecular weight The target ion MC occupies less than about 60%, less than about 40% or less than about 20% of the polymer pore volume. In certain embodiments, the invention provides a phosphate-binding polymer, characterized by a gel pore volume distribution (critical permeation volume) determined by the method described 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 pores.

[0062] 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) is 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 brine solution, or in vivo, e.g. in urine excreted for

- ion (e.g. phosphate), or ex vivo, e.g. using fluids taken from the body, such as food content taken from laboratory animals, patients or volunteers. Measurements may be made 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, 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.

[0063] The ion binding capacity of the polymer can be calculated from the formula V * (Cstart-Ceq) / P, expressed in mmol / g, where V is the volume of solution used, expressed in l; Cstart is the initial concentration of the target ion in solution, expressed in mM; Ceq is the equilibrium concentration of the target ion in solution, expressed in mM, after adding the polymer with a mass of P in grams to equilibrium.

[0064] 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 binding capacity measurements do not always reflect in vivo binding capacity. Therefore, it is useful to define binding capacity both in vitro and in vivo.

[0065] The in vitro phosphate binding capacity of polymers of the invention, in a non-interfering buffer environment, can be higher 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 the 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, yet more preferably above about 4 mmol / g and even more preferably above about 6 mmol / g. In some embodiments, the phosphate ion 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. Several methods are known in the art for determining phosphate ion binding capacity. The in vitro binding capacity of the phosphate ions of the polymers of the invention is measured as described in Example 1 to measure the binding capacity in a non-interfering buffer environment.

[0066] 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 dietary feeds were obtained as described in Example 1 from normal individuals and the binding ability was measured in a non-interfering buffer. Average values ​​were obtained from about 5-15 or about 15-30 or about 30-60 individuals. IN

- 37 certain embodiments, measurements were carried out on 6-12 individuals.

[0067] The term "average phosphate ion binding capacity in vivo" as used herein, unless otherwise specified, refers to 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 in vivo average phosphate ion binding capacity of the polymers of 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> 0,5</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> 1,0</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> 2,0</td><td>mmol / g</td><td>What</td>

<td>least</td><td>about</td><td> 3,</td><td> 0</td><td>mmol / g</td><td>What</td><td>least</td><td>about</td><td> 4,0</td><td>mmol / g</td><td>What</td>

<td>least</td><td>conc</td><td>about</td><td> 5</td><td>, 0 mmol</td><td>/ g</td><td>or what</td><td>najmn</td><td>iej</td><td>about</td><td> ,0</td>

mmol / g.

[0068] The in vivo binding capacity of a polymer can preferably be determined by measuring the equilibrium of the target ion (e.g., phosphate ion) in mammals, preferably in humans: subjects were given a meal with a controlled content of phosphate and a binding polymer, followed by monitoring of phosphate ion uptake and its excretion with feces and urine. The examination covers the period of getting rid of the previously used drug from the system before administration of the next, after

At which time subjects were given a daily dose, preferably three times a day, of a phosphate binding agent, 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 reference, divided by the weight of the binding agent administered, gives the ability to bind 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 along 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. The actual binder concentration is then calculated based on the initial concentration in the meal and the dilution level measured using the marker. The total phosphate content is analyzed in the food sample. The "dissolved" phosphate is measured by centrifuging the sample, decanting the clarified liquid and analyzing the phosphate content. The "bound" phosphate content is obtained from the difference between the total phosphate content and the amount of soluble phosphate.

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

B. Preparation of polymers [0069] The polymers of the invention are 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.

[0070] Polymers are obtained by normal or inverse suspension, 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.

[0071] Sizes, such as swelling ratio, disruption of the binding process, binding capacity, and the molecular weight limit of the particles excluded by the gel are affected, among others, by the following variables regarding the composition and the production process:

- 40 1- Density of chemical cross-links of polymer chains.

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

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

- Hydrophilic / hydrophobic balance of the polymer backbone.

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

[0072] The following are, by way of example, 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.

[0073] 1) Thickening of chemical crosslinks of polymer chains. The densification of chemical crosslinking is one important feature that regulates the swelling properties and polymer pore size distribution. One convenient way to describe the polymers of the invention is to define the amino repeating member and the average number of bonds of these members with the rest of the polymer. "A" means amino repeating member and "NC" means average number of connections from A; NC can take values ​​such as 2, 3, 4 and higher. To produce

- 41 insoluble gel, the NC should generally be greater than 2.

[0074] The NC values ​​can then be translated into stoichiometric ratios of the amine to the crosslinking agent by the following equations:

[0075] 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 number of moles of crosslinker, Fb is the number of B groups reacting with A to form a covalent bond and A is the amount of moles of the amine.

[0076] 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 connections that bind monomer repeat members within the polymer backbone. The equation then takes the form: NC = (2 ^ A + B * Fb) / A.

[0077] Conversely, the molar ratio of crosslinker to amine can be calculated from the desired NC value, using the equations as above:

[0078] Low molecular weight amine:

B / A = NC'Fb [0079] High molecular weight amine:

B / A = (NC-2) Tb [0080] The table below shows examples of transformations between NC values ​​and the actual ratio of crosslinker to amine in which the amine is a high or low weight substance

- 42 molecular linkages, and the cross-linking agent is a bi-or tri-functional substance.

<td>Amine</td><td>Type amine</td><td>Means cross-linking</td><td>fb</td><td>desired and value NC</td><td>Relations in k molar B / A</td><td>applied e equation</td>

<td>polialliloa face</td><td>big m.w.</td><td>epichlorohydr ina</td><td> 2</td><td> 2,2</td><td> 0, 10</td><td>b</td>

<td>polyvinyl face</td><td>big m.w.</td><td>1,3dichloropropa n</td><td> 2</td><td> 2,5</td><td> 0,25</td><td>b</td>

<td>polyethylene imine</td><td>big m.w.</td><td>N-tris (2-chloroethyl) and face</td><td> 3</td><td> 2,2</td><td> 0,07</td><td>b</td>

<td>1,3diaminoprop an</td><td>amine about small m.w.</td><td>1,3dichloropropa n</td><td> 2</td><td> 2</td><td> 1,00</td><td>and</td>

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

<td>N, N, N ', N'tetrakis (3aminopropyl a) -1,4diaminobutan</td><td>amine about small m.w.</td><td>N-tris (2-chloroethyl) and face</td><td> 3</td><td> 4</td><td> 1,33</td><td>and</td>

<td colspan="7">(a): B / A = NC / Fb (b): B / A = (NC-2) / Fb</td>

[0081] It has surprisingly been found that the binding selectivity, which reflects the in vivo efficiency, passes through the optimum with respect to NC: in the low NC range, the material tends to swell significantly, resulting in a lot of disruption of the process in the GI-mimicking mixture bond. However, in the range of high values, a significant decrease in the binding capacity was observed inside the material, which of course negatively affected the overall in vivo effect.

- 43 It was found that the optimal NC values ​​are between 2.05 and 5 depending on the amine / crosslinker systems.

[0082] 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 subject of routine experimentation.

[0083] In certain 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%.

[0084] In certain embodiments of the invention providing a phosphate-binding polymer containing one or more low molecular weight amine monomers and one or more crosslinking agents, NC is greater than about 2, or greater than about 3, or greater than about at 4. In some embodiments, the polymers are composed of monomers in the form of N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane (low molecular weight MC monomers) crosslinked with epichlorohydrin (Fb = 2), where B / A is from about 2.0 (mole / mole) to about 3.0 (mole / mole) (i.e., NC is from about 4 to about 6), or from about 2.3 (mole / mole) 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 with 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 B / A ratio takes values ​​from about 2.0 (mol / 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 / mole) (i.e., NC is about 5.0).

[0085] 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).

[0086] This condition essentially depends on the concentration in the reaction medium of both the monomer (e.g. amine) and the crosslinker. In certain embodiments, the concentration of monomer and crosslinker in the reaction medium is greater than about 20% by weight,

Preferably above 40% by weight, more preferably above 60% by weight. In some embodiments, a ratio (monomer + crosslinker): solvent (e.g., water) of from about 3: 1 to about 1: 3 (by weight) is used. In some embodiments, a ratio (monomer + crosslinker): solvent (e.g., water) of from about 3: 1 to about 1: 1 (by weight) is used. In some embodiments, a ratio (monomer + crosslinker): solvent (e.g., water) of 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 addition of 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 mole% and about 400 mole% of the initial monomer content or between about 200 mole% and about 300 mole% of the initial monomer content. In some embodiments, monomers in the form of N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane are used, and the crosslinker is epichlorohydrin, with the initial monomer: water ratio being between about 4: 1 and 1: 1, or from about 3: 1 to about 1: 1, or about 1.7 or about 1.73; wherein the crosslinker is added in an amount of from about 200 mole% to about 300 mole% monomer content, or about 230 mole% to about 270 mole% or about 250 mole%.

[0087] In certain embodiments, e.g., 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 crosslinker, and even more by weight) and the above ratios can be expressed as monomer: solvent ratios, ignoring the crosslinker. 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 about 3: 1 to about 1: 3, and epichlorohydrin is added to the reaction mixture in

10 mole% of the total amount to about polyallylamine.

[0088] Where possible, it is even more advantageous to run the process without solvent: in one embodiment, the amine and crosslinker are mixed rapidly, 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 spheres.

[0089] 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.

- [0090] chain

Main hydrophilic / hydrophobic polymer balance. The hydrophilic / hydrophobic balance of the polymer makes it possible to some extent independently control the chemical crosslinking density and swelling ratio. The degree of swelling is very sensitive to the interaction between the polymer and the solvent, determined by the parameter χίj, as described in Flory-Huggins (Flory PJ "Principles of Polymer Chemistry, Cornell Ithaca Pub. 1953)). Increasing the xij value up to 0.4 and above creates very poor solvent conditions for the polymer, which then attempts to minimize the interaction of monomer and solvent (water) and, consequently, significantly less swell. 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 is from about 0.5 mol% to about 50 mol%, preferably from about 20% to 50%.

[0091] In preferred methods, absolute hydrophobicity is quantified as the absolute difference in log P values ​​of the monomers. The quantitative 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 partition coefficient in the octanol-water system. 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, on the market as well as in

- 48 computer programs are available online 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 by simply entering a CAS registration number or chemical record. Log P for hydrophobic monomers typically have 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.

[0092] 5) The presence of a core-shell structure in which the shell component limits the extent of swelling of the core forming material. Gel particles with a core-shell structure 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 significantly greater extent. 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 the description of the patent application St. Ser. North America No. 10 / 814.789.

[0093] The coating material may be chemically bonded to the core forming material or may physically cover it. In the first case, the coating may grow on the core using chemical methods, for example: chemical grafting of the polymer forming the coating on the core, using polymerization on a living polymer, using active sites anchoring 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.

[0094] 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.

[0095] 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 then filled with core-forming precursors to form a core inside the capsule shell.

[0096] In certain embodiments using the block copolymerization method, an amphiphilic block copolymer is used as the dispersant to form core particles in the process of producing particles by normal or inverse suspension. In the inverted water-in-oil suspension process, the block copolymer contains the first block soluble in the continuous oil phase, and the other hydrophilic block contains functional groups that can react with the core polymer. When added to the aqueous phase together with the precursor of the core formation reaction and the oil phase, the block copolymer is located on the water / oil interface and acts as a dispersing agent. The hydrophilic block reacts with the core forming material or with the core forming precursors. After separating the particles from the oil phase, the 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.

[0097] 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 only acts 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.

[0098] Thus, in one aspect, the invention provides a method of 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 of: a) a swelling ratio of less than about 5; b. gel pore volume distribution measured in a physiological environment characterized in that a pore fraction with a volume available to non-interacting solutes with a molecular weight greater than about twice the MC molecular weight 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:

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.

[0099] In another aspect, the invention 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 [0100] Any suitable monomers and crosslinkers can be used to prepare the polymers of the invention. For phosphate or oxalate binding polymers, the polymer usually contains polyamine and a crosslinker. Polyamines include amine functional monomers such as 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. Nos. 10 / 806,495 and 10 / 701,385. These patents and patent applications are hereby incorporated in their entirety as related material.

[0101] In certain embodiments, the invention provides an ion binding polymer that comprises crosslinked

- 53 amine units. In some of these examples, 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 crosslinked amine repeating members are referred to herein as crosslinked amine polymers. Polymeric repeatable amine members can be separated by repeating connecting (or intermediate) units of the same or varying lengths. In some embodiments, the polymers contain amine repeating members and intermediary linking group units. In other embodiments, multiple amine members are separated by one or more linking group units.

[0102] One monomer useful for preparation

<img file="PL2009042T3_D0002.tif" />

3; m is equal to or greater than 1; and each R1 is independently H or optionally substituted alkyl or aryl; or is linked to the adjacent R1 substituent to form an optionally substituted alicyclic, aromatic or heterocyclic group. In one embodiment, the invention is a crosslinked amine polymer containing an amine of formula I as described above, wherein the amine is crosslinked using a crosslinker.

[0103] Preferred amines of formula I include:

/ ^ηΛ

H₃N-ξ-C-NH₂

<img file="PL2009042T3_D0003.tif" />

[0105] The second monomer useful according to the invention is an amine of formula [0104] In one embodiment, the invention provides methods of treating living organisms, including humans, using the polymers of the invention. 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

AND.

polymer production

II:

(Π)

<img file="PL2009042T3_D0004.tif" />

where p is 1, 2, 3 or 4; each R1, is independently H or optionally substituted alkyl or aryl, or is bonded to the adjacent R1 substituent to form an optionally substituted alicyclic,

- 55 aromatic or heterocyclic groups; R2 and

R3, each independently, are H or optionally substituted alkyl or aryl, with the proviso that if p = 1, then R2 and R3 are not both H and if p = 2, 3 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 amines in which p is greater than 4. In various 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 an embodiment of the invention is a crosslinked amine polymer containing an amine of formula II as described above, wherein the amine is crosslinked using a crosslinker.

[0106] Preferred amines of formula II include:

<img file="PL2009042T3_D0005.tif" />

[0107] One embodiment of this invention is a method for 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 II.

[0108] A third monomer useful for preparing the polymers of the invention is the amine of formula III:

<img file="PL2009042T3_D0006.tif" />

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

[0109] Preferred amines of formula III include:

<img file="PL2009042T3_D0007.tif" />

[0110] One embodiment of this invention is a method for 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 III.

[0111] A fourth monomer useful for preparing the polymers of the invention is an amine of formula IV:

<img file="PL2009042T3_D0008.tif" />

where each n, independently, is equal to or greater than 3; each r is independently 0, 1 or 2; each R1 is independently H or optionally substituted alkyl or aryl, or is linked to the adjacent R1 substituent to form an optionally substituted alicyclic, aromatic or heterocyclic group. In one embodiment, the invention is a crosslinked amine polymer containing an amine of formula IV as described above, wherein the amine is crosslinked using a crosslinker.

<img file="PL2009042T3_D0009.tif" />

[0113] One embodiment of this invention is a method for 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 IV.

[0114] A fifth monomer useful for preparing the polymers of the invention is an amine of formula V:

<img file="PL2009042T3_D0010.tif" />

where each n, independently, is equal to or greater than 3; each r is independently 0, 1 or 2; each R1 is independently H or optionally substituted alkyl or aryl, or is linked to the adjacent R1 substituent to form an optionally substituted alicyclic, aromatic or heterocyclic group. In one embodiment, the invention is a crosslinked amine polymer comprising an amine of formula V as described above, wherein the amine is crosslinked using a crosslinker.

[0115] Preferred amines of formula V include:

<img file="PL2009042T3_D0011.tif" />

[0116] One embodiment of this invention is a method for 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 V.

[0117] A sixth monomer useful for preparing the polymers of the invention is an amine of formula VI:

<img file="PL2009042T3_D0012.tif" />

than 3. In one embodiment, the invention is a crosslinked amine polymer containing an amine of formula VI as described above, wherein the amine is crosslinked using a crosslinker.

[0118] One embodiment of this invention 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 VI.

[0119] 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 issued by WileyVCH Verlag GmbH &amp; Co. KGaA) . Several small amine monomers and / or amines with intermediate linking units are also commercially available.

[0120] In one embodiment, the useful amine of the invention is the tetramethylenetetramine shown below, which is prepared by catalytic hydrogenation of commercially available diaminomaleonitrile (DAMN):

- 60 η₂ν

ΝΗ₂ catalyst

<td>/ h₂</td><td></td><td></td>

<td> \</td><td></td><td> 1</td>

CN

NH₂ NH₂ NH_? NRS

NC [0121] Amines for use in the present invention are not limited to those described, but typically are small molecules that serve as monomers or portions 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.

[0122] In the embodiments of the invention, 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 members that are actually or conceptually derived from relatively low molecular weight molecules.

[0123] Examples of amines suitable for the synthesis of polymers of the invention 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>

<td>B-SM-20-TeA</td><td>TetraMin</td><td>.ŃH, \ / h₃n '</td><td> 316,54</td>

<td>B-SM-22-DA</td><td>diamine</td><td></td><td> 61,1</td>

<td>B-SM-23-DA</td><td>diamine</td><td>h₂n -</td><td> 88,15</td>

<td>B-SM-24-DA</td><td>diamine</td><td>r7 H_;N MH_FROM</td><td> 74,13</td>

<td>B-SM-25-DA</td><td>diamine</td><td>77 H₂N NH_and</td><td> 88,15</td>

<td>B-SM-26-DA</td><td>diamine</td><td>/ - \ HM Μ — 1 hhj</td><td> 129,21</td>

<td>B-SM-27-DA</td><td>diamine</td><td> "07 ^λ-^from of NH</td><td> 114,19</td>

<td>B-SM-28-TA</td><td>triamine</td><td>WM_andTNmh, AA 2HC! and nh₄</td><td> 196,08</td>

<td>B-SM-29-TA</td><td>triamine</td><td>Η ^ ^ γ γΝ »! Νγ " NH,</td><td> 125,13</td>

<td>B-SM-31-DA</td><td>diamine</td><td>N— SUCI</td><td> 184,07</td>

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

[0124] apply

Additional amine monomers that can be used in the polymers according to adjacent amine fragments. The polymer may be a homopolymer comprising repeating members of adjacent amino groups or a copolymer comprising one or more repeating members of adjacent amino groups and other monomers such as acrylates, methacrylates, acrylamides, methacrylamides, vinyl esters, vinyl amides, olefins, styrene monomers and others. The molecular weight of the polymer may vary, for example from about 500 to about 1,000,000 daltons.

contain [0125] One amino monomer, adjacent amino groups, useful for the polymers of the invention is the monomer of formula containing

VII:

<img file="PL2009042T3_D0013.tif" />

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

- 63 [0126]

In another embodiment, the polymer is characterized by a repeating member of the formula:

R-M⁺-R

<img file="PL2009042T3_D0014.tif" />

X 'or a copolymer thereof, 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, and X^- means a negatively charged organic or inorganic counterion.

<img file="PL2009042T3_D0015.tif" />

also include polymers having a repeating unit of the formula:

<img file="PL2009042T3_D0016.tif" />

where 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.

[0129] 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="PL2009042T3_D0017.tif" />

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

[0130] In the polymers described herein, n is zero, one or more than 1. In preferred embodiments, n

- 65 assumes values ​​0-5, even more preferably n is zero or 1.

[0131] The value of n 'depends on the desired polymer properties, the potential use of the polymer and the synthetic techniques used.

[0132] 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, hydrazine group, diazo, imino, amidine, guanidine, sulfamate, phosphoramidate and heterocycle.

[0133] 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.

[0134] The substituents of the R '' groups may be ionic units containing oxygen, nitrogen, phosphorus or sulfur atoms. Examples of substituents are carboxylate, sulfonate, sulfamate, sulfonate 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 hydroxyl, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanadine, urea and carboxylic acid esters.

[0135] Preferred R groups include H and the following groups:

<img file="PL2009042T3_D0018.tif" />

τ (alkyl or aryl)

T (alkyl or aryl)

T (alkyl or aryl)

II

OH

OH

HJN

<img file="PL2009042T3_D0019.tif" />

NH

H₂N

AND.

: nh

C = O

OH

<img file="PL2009042T3_D0020.tif" />

(alkyl or aryl) / V^OH θ OH

- binding points with R groups [0136] Counterions X^-, negatively charged, they can 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, peroxyde sulfate 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.

[0137] In a preferred embodiment, the counterion does not cause harmful side effects and is selected such that

- 67 to bring for the patient.

therapeutic or nutritional benefits [0138] for preparing formula XI:

A further polymer monomer according to the invention applicable to the invention is illustrated below

<img file="PL2009042T3_D0021.tif" />

where R "'is H or CH3 and R has the same meaning as described above. Monomers of formula XI wherein R = H are preferred.

[0139] In one embodiment, the polymer is a copolymer in which one of the repeating members is the monomer described herein.

[0140] The copolymers of the invention may be alternating or random copolymers. Generally, monomers that can be copolymerized with amino precursors include one or more target monomers selected from the group consisting of styrene, substituted styrene, alkyl acrylate, substituted alkyl acrylate, alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, N-methacrylamide .

N, Nizopren,

N-alkylmethacrylamide, dialkylacrylamide, N, N-dialkylmethacrylamide, butadiene, ethylene, vinyl acetate, N-vinylamide, maleic acid derivatives, vinyl ether, allyl monomers, methyl allyl monomers and combinations thereof. The above monomers with additional groups can also be used

- 68 functional. Specific monomers or comonomers that can be used according to the invention 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-dimethylaminoethyl methacrylate, N-dimethylaminoethyl, methacrylate ), 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, Nn.-butylmethacrylamide, N-methylmethacrylamide , Nt.-butylacrylamide, Nn-butylacrylamide, N-methylolacrylamide, N-ethylacrylamide, 4-acryloylmorpholine, vinylbenzoic acid (all isomers), diethylaminostyrene (all isomers), α-methylvinylbenzoic acid (all isomers), diethylamino-α-methylstyrene (all isomers), p-vinylbenzenesulfonic acid, sodium phenylbenzenesulfonic acid, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, methacrylate

- 69 tributoksysililopropylu, dimetoksymetylosililopropylu, dietoksymetylosililopropylu, metylosililopropylu, diizopropoksymetylosililopropylu methacrylate methacrylate methacrylate methacrylate methacrylate dibutoksy dimetoksysililopropylu methacrylate dietoksysililopropylu 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, Nfenylomaleimid, N-butylmaleimid, N-vinylformamide, Nwinyloacetamid, allyl amine, methyl allyl amine, allyl alcohol, methyl vinyl ether, ethyl vinyl ether , butyl vinyl ether, butadiene, isoprene, chloroprene, ethylene, vinyl acetate and combinations thereof, but are not limited to them. Preferred monomers or comonomers are acrylamide, dimethylacrylamide, N-vinylformamide, N-vinylacetamide, vinyl acetate, methyl acrylate and butyl acrylate.

[0141] Further monomers that can be used in the polymer of the invention include:

<img file="PL2009042T3_D0022.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, such as ethylamino) or aryl (e.g. phenyl);

<img file="PL2009042T3_D0023.tif" />

wherein each R is independently 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 ) and each X^- means an exchangeable negative charge counterion.

[0142] Another suitable monomer has a structure illustrated by the formula:

( / 1 -¹ where R is H or substituted or unsubstituted alkyl (e.g. containing 1-5 carbon atoms), alkylamino (e.g. containing 1-5 atoms)

- 71 carbon inclusive, such as an ethylamino group) or an aryl group (e.g. phenyl).

[0143] Another suitable monomer has the structure illustrated by the formula:

X '

<img file="PL2009042T3_D0024.tif" />

wherein R1 and R2 are each independently 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) and each X^- means an exchangeable negative charge counterion. In one embodiment, at least one of the R groups is hydrogen.

[0144] Another suitable monomer has a structure illustrated by the formula:

<img file="PL2009042T3_D0025.tif" />

wherein R1 and R2 are each independently H, substituted or unsubstituted alkyl, 120 carbon atoms, alkylamino (e.g., containing 1-5 carbon atoms inclusive, such as ethylamino) or aryl containing 6-12 atoms (e.g. phenyl).

[0145] Another suitable monomer has a structure illustrated by the formula:

<img file="PL2009042T3_D0026.tif" />

and R3 is independently H, a substituted or unsubstituted alkyl group having 1-20 carbon atoms, an alkylamino group (e.g., containing 1-5 carbon atoms inclusive, such as an ethylamino group) or an aryl group containing 6-12 atoms (e.g. phenyl) and every X^- means an exchangeable negative charge counterion.

[0146] For each of these monomers, the R groups may contain one or more substituents. Suitable substituents include therapeutic anions, e.g., quaternary ammonium or amino groups, e.g., primary 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.

[0147] 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, peroxyde sulfate and sulfite. Suitable ions

Organic compounds include acetate, ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate, tartrate, taurocholate, glycocholate and cholate.

[0148] Polymers containing guanidine groups are also useful as compositions that can be prepared using the processes described herein because they have the desired properties and bind to 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 related 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. 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 through some forms of moieties, acting as a "spacer", through which the guanidine residue is attached to the backbone of the polymer. Various attachment forms can be used, with preferred types

- 74 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.

[0149] 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 RL Schnaar and YC Lee, 1975, Biochemistry 14, 1535-1541, incorporated herein in its entirety as a related 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.

[0150] Preferred monomers of 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:

<img file="PL2009042T3_D0027.tif" />

[0151] In certain embodiments, the polymers of the invention consist of one or more amine monomers and one or more crosslinkers, wherein the polymer is made by a process in which the amine is in a solvent prior to crosslinking in an amine: solvent ratio of from about 3 : 1 to about 1: 3 and the total content of crosslinkers added to the reaction mixture is such that 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 by a process in which the total content of crosslinkers added to the reaction mixture is such that the average the number of bonds to amine monomers ranged 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 1,3-dichloropropane and epichlorohydrin. In certain embodiments, the polymers of the invention consist of one or more amine monomers and one or more crosslinkers, wherein the amine monomers are not

- 76 polyallylamine monomers and / or the crosslinker is not epichlorhydrin.

[0152] In certain 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. Crosslinking agents [0153] Crosslinking agents include those set forth 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 of St. Ser. Nos. 10 / 806,495 and 10 / 701,385 [0154] Crosslinking 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 the synthesis of polymers of the invention include, but are not limited to, compounds as shown in Table 2.

Table 2

<td>Mark</td><td>Building</td><td>Molecular weight</td>

<td>X-EP-1</td><td>ABOUT-.., L&gt; \ ^^CI</td><td> 92,52</td>

<td>X-EP-2</td><td colspan="2">^174,19</td>

<td>X-EP-3</td><td colspan="2"></td>

<td>X-EP-4</td><td></td><td> 302,37</td>

<td>X-EP-5</td><td>° 7Ί RY °. &gt; Γ! Χ ^ &lt;Γ xl °</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> 0</td><td> 202,25</td>

<td>X-Cl-1</td><td>ΊΥ □</td><td> 184,41</td>

<td>X-Cl-2</td><td>Ml · "</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></td><td>+ Cl ^^&gt; ^^ C1 cl</td><td></td>

<td>X-Cl-5</td><td>cl J</td><td> 240,99</td>

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

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

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

- 78 X-AC-1

X-AC-2

<img file="PL2009042T3_D0028.tif" />

203,02

203,02

X-AC-3

<img file="PL2009042T3_D0029.tif" />

265,48

X-AC-4

<img file="PL2009042T3_D0030.tif" />

154,98

X-AH-1

<img file="PL2009042T3_D0031.tif" />

198,13

X-AH-2

<img file="PL2009042T3_D0032.tif" />

X-AH-3

<img file="PL2009042T3_D0033.tif" />

112,08

X-Mc-1

<img file="PL2009042T3_D0034.tif" />

168,2

X-Mc-2

<img file="PL2009042T3_D0035.tif" />

118,16

X-Mc-3

<img file="PL2009042T3_D0036.tif" />

249,27

X-IC-1

<img file="PL2009042T3_D0037.tif" />

168,19

X-IC-2

<img file="PL2009042T3_D0038.tif" />

174,16

X-IC-3

<img file="PL2009042T3_D0039.tif" />

188,18

<td>X-IC-4</td><td>OCN. &gt; γ</td><td> 222,28</td>

<td>X-ME-1</td><td> 0</td><td> 86,09</td>

<td>X-ME-2</td><td> 0</td><td> 158,16</td>

<td>X-ME-3</td><td> 0 --^Ο% γ-_Ο·' 0</td><td> 146,14</td>

<td>X-ME-4</td><td>about ού; 0</td><td> 194,19</td>

<td>X-ME-5</td><td>o -A o oo 1</td><td> 234,2</td>

<td>X-ME-6</td><td>and ^ 0 0</td><td> 252,22</td>

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

<td>X-ME-8</td><td> -°_Ttv 0 OH</td><td> 178,14</td>

<td>X-ME-9</td><td>ΑΛ 0</td><td> 108,53</td>

[0155] Examples of suitable crosslinkers are diacrylates and dimethacrylates (e.g., ethylene glycol diacrylate, propylene glycol diacrylate, diacrylate

- 80 ethylene glycol, poly (propylene glycol dimethacrylate, poly (glycol dimethacrylate

1,41,21,2ether butylene ether, butylene glycol dimethacrylate, butylene glycol dimethacrylate, ethylene diacrylate), methylene bisacrylamide, methylene bismethacrylamide, ethylene bisacrylamide, ethylene bismethacrylamide, ethylidene bisacryrylene, di-diacrylene benzene diacyl, dianhydrides and dimethyl esters.

[0156] Examples of preferred crosslinkers include epichlorohydrin, butanedioliglycidyl, ethanedioliglycidyl; 1,3-dichloropropane, dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethyl succinate, toluene diisocyanate, acryloyl chloride, methyl acrylate, ethylene bisacrylamide and pyromellitic anhydride.

E. Polymerization [0157] 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.

[0158] 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:

[0159] 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 cross-linking reaction is obtained in the form of a mass or gel suspension forms 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 that remain in suspension in the form of dispersed particles are formed.

[0160] 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 rather takes the form of dispersed droplets or particles and then undergoes a cross-linking reaction, forming balls or particles irregularly shaped suspended in the above continuous phase.

[0161] Homogeneous processes may be impractical for crosslinked materials with limited swelling rates, such as the polymers of the invention: level

82 crosslinking typical for the desired range of swelling ratio and pore size distribution usually induces a very short gelation time and high local viscosity, which is impractical for large-scale processes.

[0162] A preferred method for the synthesis of polymers of the present invention is the use of heterogeneous processes. These processes are also referred to as polymerization in dispersion media and include inverse suspension, normal 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. Water can be used for processes carried out by normal suspension or in emulsion, although brines are also useful for "desalting" reagents in the form of amines and crosslinkers in a separate droplet phase as indicated in U.S. Patent No. 5,414,068. Monomeric 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 at

- 83 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) enabling the cross-linking reaction to complete it vi) removing water by distillation vii) separating the beads by filtration viii) washing and drying [0163] In this process polymer particles are obtained in the form of spherical beads with preferably a controlled diameter in the range from 5 to 500 microns , preferably from 25 to 250 microns. In some of these embodiments, balls with an average diameter of less than 40 microns are obtained.

[0164] In one aspect, the invention provides a method of making 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: 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 representing less than 20% of its mass available for non-interacting solutes with a molecular weight greater than

- about twice the molecular weight MC of the target anion, the above percentage being measured in a physiological environment; 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 amine monomer is polyallylamine. In some embodiments, the crosslinker is epichlorohydrin.

[0165] In another aspect, the invention provides an anion-binding polymer that binds to a target ion, wherein the polymer is made by a process comprising crosslinking polyallylamine in a non-homogeneous process, said polymer having at least two of the following characteristics: 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 of less than 20% of its mass available to non-interacting solutes with a molecular weight greater than about twice the MC of the target anion, the above percentage being measured in a physiological environment; 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 one embodiment, the polyallylamine is cross-linked with epichlorohydrin.

[0166] As discussed above, the molar ratios of crosslinker to amine regulate the extent of gel material formation as well as its crosslinking density. Too small

The 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. examples in which low molecular weight monomers crosslinked with crosslinkers having an Fb value of 2 are used, 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 on the Fb value of the crosslinker (see discussion and table above).

[0167] 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 (1 to 100 parts) is added to the solution containing polyethyleneimine (100 parts) and heated to

- 86 reaction temperatures. 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, ionizing radiation exposure, ultraviolet radiation, electron beam bombardment, radical-based operation and pyrolysis.

[0168] 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 the 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, followed by a continuous crosslinking agent fraction 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.

[0169] 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 crosslinking 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.

[0170] 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 crosslinking. This method is known as "significance" and aims to increase the chemical affinity of the gel for the anion by creating "shaped" pockets within the gel that recognize and bind the given 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 ACS Symposium Series 703, "Molecular and Ionic Recognition with Imprinted Polymers, Bartsch RA and Maeda M. [ed. ], 1998, ch. 22, 315. Typically, the anion is present in a molar ratio to the amine (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., phosphoric acid, oxalic acid) and the amine in the form of the free base to form, in situ, the ammonium / anionic salt. Cross-linking 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 gel formed is carefully washed with a strong acid (e.g. pH &lt;2) or strongly basic (e.g. pH&gt; 12) solution to remove the marked anion, and then washed with a neutral solution. If all parameters have the same values ​​(e.g. ratio of amine to cross-linking agent, ratio of monomers to solvents), then the meaning method described here usually increases the binding efficiency by 1.1-, 1.3- or even 1.5-fold.

III. Pharmaceutical compositions [0171] In another embodiment, the invention provides pharmaceutical compositions. In one embodiment, the pharmaceutical compositions are chewable tablets. In another embodiment, the pharmaceutical compositions are liquid preparations.

[0172] The pharmaceutical compositions of the present invention include compositions that comprise 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. The actual amount effective for a particular application will depend on the patient (e.g. age, weight) and the condition being treated and the method of administration. Determining an effective amount is not difficult for those skilled in the art, particularly in light of the present disclosure.

[0173] The effective amount for use in humans can be determined from animal models. For example, the dose

- 89 for humans can be formulated so as to obtain an adequate concentration of the active substance in the circulatory and / or digestive system which has been found to be effective in animals.

[0174] The pharmaceutical compositions comprise a polymer, e.g. crosslinked amine polymers, one or more pharmaceutically acceptable carriers, diluents or excipients and optionally additional therapeutic agents.

[0175] 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 adjuvants 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 incorporated herein in its entirety as a material related.

[0176] 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., phosphate-binding polymer, may be alone, mixed with a carrier, diluted with a carrier, or encapsulated within a carrier, which may be in the form of capsules, sachets, tissue paper, or other containers. When the carrier serves as a diluent, it can

- 90 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, sachets, wafer capsules, 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.

[0177] In another aspect of the invention, the binding polymer is prepared as free 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. It has been shown (Brezina B. et al., Kidney International, vol. LXVI, supl. XC (2004), 39-45) that sevelamer hydrochloride (trade name of the pharmaceutically active ingredient Renagel) induces acid production, which causes acidosis. Acidosis can have serious side effects in this group of patients. In another, an amine anion (e.g. phosphate) free of

- 91 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 [0178] In certain embodiments, the polymers of the invention are provided as pharmaceutical compositions in the form of chewable tablets.

[0179] Patient compliance is currently recognized as one of the main factors limiting patient compliance with recommendations for the treatment of ionic imbalances, such as excess phosphate ions in the blood / 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 compliance due to high daily doses stands out as a factor that clearly affects the intake of this class of drugs.

[0180] A pharmaceutical preparation of an easier to take form would be desirable. Although a drug delivered in the form of a chewable tablet would in many cases be very beneficial, the limited use of this form is due to the difficulty of 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.

[0181] 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 needs to be optimized to facilitate the chewing process and a "hardness" suitable for chewing is used. Round-shaped tablets with bevelled edges, with height / diameter ratios ranging from about 0.3 to

0,4.

[0182] 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; lubricant to minimize friction effects

- 93 matrix walls and facilitating tablet ejection; in some preparations, 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 sweeteners make up the volume of inactive ingredients.

[0183] 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 low 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, which can result in choking or even rupture of the esophagus. Psyllium is not indicated for patients with dysphagia and / or narrow esophagus.

[0184] The present invention provides chewable tablets that contain the polymer or polymers of the invention and

- one or more pharmaceutical excipients, suitable for the formulation in the form of a chewable tablet. 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 appropriate excipients provides acceptable organoleptic properties, such as mouthfeel, taste and penetration into interdental crevices, while at the same time it does not cause the esophagus to clog after chewing and in contact with saliva.

[0185] In certain aspects of the invention, the polymer (s) provide such mechanical and thermal properties as would typically be obtained after the introduction of suitable excipients, which allows reducing the amount of excipients in the formulations of the invention. 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., a polymer

- anion-binding, it comprises 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 provide the same properties for which excipients were often used, such as, for example, proper hardness, desired mouth feel, compressibility and the like. The polymer particles 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.

[0186] Pharmaceutical excipients useful in the chewable tablets of 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 starch glycolate. Other additives may include plasticizers, pigments, talc and others. Such additives and other suitable ingredients are well known in the art; see, e.g., Gennaro AR [ed.], Remington's Pharmaceutical Sciences, 20th Edition.

[0187] In certain embodiments, the invention provides a pharmaceutical composition in the form of a chewable tablet, comprising a phosphate binding polymer and a suitable excipient. In certain embodiments, the invention provides a pharmaceutical composition in the form of a chewable tablet, comprising a phosphate binding polymer, a filler, and a lubricant. In certain embodiments, the invention provides a pharmaceutical composition in the form of a chewable tablet, comprising a phosphate-binding polymer, filler and lubricant, wherein the filler is selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose and sorbitol, and a lubricant is a magnesium salt of a fatty acid such as magnesium stearate.

[0188] The tablet may be of any size and shape suitable for chewing and grinding in the mouth, preferably cylindrical, with a diameter of from about 10 mm to about 40 mm and a height from about 2 mm to about 10 mm, most preferably with a diameter of about 22 mm and a height of about 6 mm.

[0189] In one embodiment, the polymer transition temperature to brittleness / glass transition temperature is above about 30 ° C, preferably above about 50 ° C.

[0190] 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 and low drying are useful

- 97 temperature, freeze drying or wet granulation. Indications of the level of mixing are obtained by known physical methods such as differential scanning calorimetry or dynamic mechanical analysis.

[0191] Methods for making chewable tablets containing pharmaceutical components, including polymers, are known in the art. See, e.g., European Patent Application No. EP-373852A2, US Patent Ser. No. 6,475,510 and Remington's Pharmaceutical Sciences, which are hereby incorporated in their entirety as related material.

B. Liquid preparations [0192] 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 for example

Remington's Pharmaceutical Sciences.

IV. Methods of treatment [0193] In another aspect, the invention provides methods of treating ion balance disorders. The term "ionic imbalance" as used herein refers to conditions in which the ion concentration in the body is abnormal. In one embodiment, the invention provides methods for treating phosphate imbalance. 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.

- herein the term "hyperphosphataemia" refers to a condition in which the elemental phosphorus is present in the body in an increased concentration. Typically, the patient is diagnosed with hyperphosphataemia when the blood phosphate concentration exceeds e.g. about 4.5 milligrams per deciliter of blood and / or the value of glomerular filtration is reduced, for example, by more than about 20%.

[0194] Thus, for example, the invention provides methods for removing anion from an animal's body by administering to the animal an effective amount of the polymer of the invention. In some embodiments, the polymer is an anion-binding polymer, wherein the polymer binds to the target anion (e.g. phosphate or oxalate), the polymer having at least two of the following features: a) a swelling ratio of less than about 5; b. a gel pore volume distribution, 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 molecular weight of the target anion occupies 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 GI gastrointestinal tract content 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

- 99 consisting of hyperphosphataemia, hypocalcemia, hyperthyroidism, reduction of renal calcitriol synthesis, tetany associated with hypocalcemia, renal failure, ectopic foci of soft tissue calcification and end stage renal disease (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 gel pore volume distribution, measured in a physiological environment, characterized in that the pore fraction with a volume available for non-interacting solutes with a molecular weight greater than about 200 takes less than about 20% of the gel; and c) disruption of the phosphate ion binding process in measurements in a mixture imitating 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.

[0195] Other conditions in which the methods, compositions and kits of the invention may be used include hypocalcaemia, hyperparathyroidism, "hunger bones" syndrome, decreased kidney calcitriol synthesis, tetanus caused by hypocalcemia, renal failure and ectopic

- 100 foci of calcifications in soft tissues, including calcifications in the joints, lungs, kidneys, conjunctiva and myocardium. In addition, the present invention may be used to treat end stage renal disease (ESRD) and dialysis patients, including for the prophylaxis of any of the above diseases.

[0196] In addition, the polymers described herein can be used as an adjuvant in other therapies, e.g. those using dietary phosphorus control, dialysis of inorganic metal salts and / or other polymeric resins.

[0197] The compositions of the invention are also useful in removing chlorides, hydrogen carbonates, 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, acidosis, heartburn, acid reflux into the esophagus, hyperacidity or gastritis. In some embodiments, the compositions of the invention 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.

[0198] The present invention provides methods, pharmaceutical compositions and kits for treating animals.

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

[0199] As used herein, the term "treatment" and its grammatical equivalents include the achievement of therapeutic benefits and / or prophylactic benefits. The term therapeutic benefit is understood to mean curing, alleviating or preventing an underlying disorder in the animal being treated. For example, a patient with hyperphosphatemia has a 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 seen in the patient despite the underlying disorder being present. For example, administering 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 comorbidities renal failure and / or hyperphosphataemia, such as e.g. ectopic foci of calcification and renal osteodystrophy. For the benefit of preventive treatment, crosslinked amine polymers can, for example, be administered to a patient at risk of

- 102 occurrence of hyperphosphataemia, or a patient reporting one or more symptoms of hyperphosphataemia, even if hyperphosphataemia has not been diagnosed. For example, the polymers of the invention can be administered to a patient with chronic kidney disease without the diagnosis of hyperphosphataemia.

[0200] The dosage of the crosslinked polymer, e.g., amine polymers, in animals will depend on the condition being treated, the mode of administration and the physical characteristics of the animal being treated. In some embodiments in which crosslinked amine polymers are used, the dosage amount of the crosslinked 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 below about 50 g / day, preferably below about 40 g / day, more preferably below about 30 g / day, more preferably below about 20 g / day, and particularly preferably below 10 g / day.

[0201] Preferably, the ion-binding polymers, for example cross-linked amine polymers used for therapeutic and / or prophylactic benefits, can be administered alone or in the form of a pharmaceutical composition as described herein. For example, crosslinked amine polymers of the invention can be administered

- 103 along with other pharmaceutically active ingredients depending on the condition being treated. Examples of pharmaceutical agents that can be administered simultaneously include, but are not limited to, proton pump inhibitors, calcimetics (e.g., cinacalcet), vitamin D and analogues, as well as phosphate binding agents. Examples of phosphate binding agents that find use herein include, but are not limited to: aluminum carbonate, calcium carbonate, calcium acetate (PhosLo), lanthanum carbonate (Fosrenol) and Renagel. Co-administration may mean simultaneous administration of two agents in the same dosage form, simultaneous administration in independent dosage forms, as well as independent administration. For example, when treating hyperphosphatemia / excess phosphate in the blood, crosslinked amine polymers can be administered concurrently with calcium salts used to treat hypocalcemia resulting from hyperphosphatemia. The calcium salt and the polymer can be used in the same dosage form or administered simultaneously. Alternatively, the calcium salt and the polymer may be administered simultaneously, both substances being independent preparations. Alternatively, the calcium salt may be administered just before or just after the polymer. In the case of independent administration, the polymer and calcium salt may be administered with a several-minute, several-hour or several-day interval.

[0202] The polymer can be administered by 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 powder, tablet, capsule,

- 104 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.

[0203] The invention also provides methods for removing anionic impurities from wastewater by bringing the wastewater into contact with the anion-binding polymer of the invention, wherein the anionic impurities, i.e. phosphates, are absorbed by the polymer.

V. Kits [0204] In yet another aspect, the invention provides kits for treating electrolyte imbalance, eg, for treating phosphate imbalance. These kits contain the polymer or polymers described herein and instructions for using the kit for the various methods and approaches described herein. Such kits may also contain information, such as references to scientific literature, package leaflets, clinical test results and / or their summaries and the like, which indicate the action and / or determine the extent 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 majors, pharmacy employees, and the like. The delivery, distribution and / or promotion of cosmetic kits may be aimed directly at consumers.

[0205] All publications and patent applications cited herein are incorporated herein by reference in the same manner as if each independent publication or patent application were specifically and separately identified as related material.

[0206] 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 [0207] This example describes various protocols for measuring polymer anion (in this case phosphate) binding performance measurements.

Measurements of phosphate binding capacity in non-interfering buffer [0208] A dry polymer sample of P (g) was gently mixed in a fixed volume V (l) of the following buffer: 20 mM H3PO4, 80 mM NaCl, 100 mM sodium MES (acid morpholinoethanesulfonic acid) and a pH of 6.5. For single binding measurements, a second buffer was used. If the measurements were carried out repeatedly, e.g. when plotting the binding isotherms, different phosphate concentrations in buffer were used. Baseline phosphate ion concentration was determined as Pstart (mM). The solution can be described as a non-interfering buffer because it does not contain other competing solutes that could compete with phosphate ions for binding to

- 106 polymer resin. After the resin reached equilibrium, the solution was decanted by centrifugation and the concentration of remaining Peq phosphate ions (mM) in the supernatant liquid was analyzed using ion chromatography. Binding capacity was calculated as V * (Pstart-Peq) / P reported 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 [0209] This study was designed to mimic the conditions for the use of phosphate-binding polymer in the gastrointestinal tract and to measure the polymer-phosphate binding properties (solute target) in the presence of other metabolites ( competing solutes). The liquid meal was subjected to artificial digestion in the presence of pepsin and pancreatic juice to create a medium that mimics the content of the gastrointestinal tract. The order of enzyme addition and the pH profile of the mixture were controlled to simulate digestion to the level of jejunum.

[0210] 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 liter of double distilled H2O until 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 H2O. 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

- 107 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 10 mM 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 a stock solution of pancreatin and bile salts in 100 mM NaHCO3, pH 8.4 was added to achieve 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.

[0211] A sample of the gastrointestinal (GI) environment mimicking mixture was centrifuged and the supernatant 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 [0212] 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.

[0213] Participants of the study 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 fluoroscope control, one of the legs of the catheter with the hole

- 108 aspirators were placed in the stomach, and the other near the Treitz ligament (in the upper part of the jejunum).

[0214] 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 rate of 22 ml per minute. Approximately 25 minutes were needed to enter the entire volume into the stomach, simulating the time required to eat a normal meal.

[0215] 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.

[0216] A phosphate binding assay was performed on ex-vivo aspirates. The phosphate binding procedure was similar to that described above with the 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 binding capacity of phosphate ions in ex-vivo aspirate was calculated in the same way as in experiments using a mixture mimicking the content of the gastrointestinal tract.

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

Creating polymer libraries

[0217] Each of the following five examples each includes a library of up to 24 crosslinked polymers. Polymers were prepared in batch reactors arranged in a 4x6 system format. Magnetic stirring and temperature control were applied to each 350 microliter or 3 mL reactor. 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. The reactor system was then dismantled and the feeds in the form of crosslinked polymers were transferred to the glass milled, washed several times, freeze-dried. Five libraries were identified, which are shown below in Table 3 together with the appropriate reaction conditions used to generate them.

Table 3 vials followed by deionized water and

<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 ion binding capacity in a non-interfering buffer [0218] Binding properties of phosphate ion have been determined for each polymer in the library. See the procedure in Example 1.

Results [0219] 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-Cl3</td><td>NaOH</td><td>DMSO</td><td>Tie ions phosphate (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> 21,52</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

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

<td>Government</td><td>Column</td><td>Water</td><td>B-SM-</td><td>X-EP-</td><td>X-EP-4</td><td></td><td>Tie</td>

<td></td><td></td><td></td><td>20-TeA</td><td> 1</td><td></td><td></td><td>ions phosphate (Mmol / g)</td>

<td> 1</td><td> 1</td><td> 123,69</td><td> 110,75</td><td> 12,95</td><td> 0, 00</td><td>DMF</td><td></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-C</td><td>X-C</td><td></td><td>Tie</td>

<td></td><td></td><td></td><td>20-TeA</td><td> 3</td><td> 2</td><td></td><td>ions phosphate (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> 1</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> 1</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> 1</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> 1</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> 1</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> 2</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> 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> 2</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> 2</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> 2</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>

- 112 -

<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) unit: mg

<td>Column</td><td>B-SM20-tea</td><td>B-SM-22-DA</td><td>X-Cl3</td><td>NaOH</td><td></td><td>Tie ions phosphate (Mmol / g)</td>

<td> 1</td><td> 142,77</td><td> 11,14</td><td> 33,97</td><td> 24,05</td><td></td><td></td>

<td> 2</td><td> 117,71</td><td> 9,19</td><td> 44,82</td><td> 31,73</td><td></td><td></td>

<td> 3</td><td> 100,13</td><td> 7,82</td><td> 52,42</td><td> 37,12</td><td></td><td> 5, 838</td>

<td> 4</td><td> 87, 12</td><td> 6,80</td><td> 58,05</td><td> 41, 10</td><td></td><td> 5, 38</td>

<td> 5</td><td> 77, 10</td><td> 6,02</td><td> 62,39</td><td> 44, 17</td><td></td><td> 5, 549</td>

<td> 6</td><td> 69, 15</td><td> 5,40</td><td> 65,83</td><td> 46, 61</td><td></td><td> 5, 826</td>

<td> 1</td><td> 64,71</td><td> 5,05</td><td> 67,75</td><td> 47,97</td><td></td><td> 5, 452</td>

<td> 2</td><td> 57, 99</td><td> 4,53</td><td> 70,66</td><td> 50, 03</td><td></td><td> 3,358</td>

<td> 3</td><td> 52,54</td><td> 4,10</td><td> 73,01</td><td> 51,70</td><td></td><td> 3,45</td>

<td> 4</td><td> 48, 02</td><td> 3,75</td><td> 74,97</td><td> 53, 08</td><td></td><td> 4,27</td>

<td> 5</td><td> 44,22</td><td> 3,45</td><td> 76,61</td><td> 54,24</td><td></td><td> 3,469</td>

<td> 6</td><td> 40, 98</td><td> 3,20</td><td> 78,02</td><td> 55, 24</td><td></td><td> 4, 058</td>

<td> 1</td><td> 111,71</td><td> 26,16</td><td> 39,87</td><td> 28,23</td><td></td><td></td>

<td> 2</td><td> 89, 37</td><td> 20,93</td><td> 51,04</td><td> 36, 14</td><td></td><td></td>

<td> 3</td><td> 74,48</td><td> 17,44</td><td> 58,49</td><td> 41,41</td><td></td><td> 5, 154</td>

<td> 4</td><td> 63, 85</td><td> 14,95</td><td> 63,81</td><td> 45, 18</td><td></td><td> 5,784</td>

<td> 5</td><td> 55, 87</td><td> 13,08</td><td> 67,80</td><td> 48, 01</td><td></td><td> 5, 596</td>

<td> 6</td><td> 4 9,66</td><td> 11,63</td><td> 70,91</td><td> 50,20</td><td></td><td> 5,287</td>

<td> 1</td><td> 46, 24</td><td> 10,83</td><td> 72,62</td><td> 51,42</td><td></td><td> 5,261</td>

<td> 2</td><td> 41,13</td><td> 9,63</td><td> 75,17</td><td> 53,23</td><td></td><td> 4,743</td>

<td> 3</td><td> 37,04</td><td> 8,67</td><td> 77,22</td><td> 54, 67</td><td></td><td> 4,076</td>

<td> 4</td><td> 33, 69</td><td> 7,89</td><td> 78,90</td><td> 55, 86</td><td></td><td> 3, 924</td>

<td> 5</td><td> 30, 90</td><td> 7,24</td><td> 80,29</td><td> 56, 85</td><td></td><td> 2,896</td>

<td> 6</td><td> 0, 00</td><td> 0,00</td><td> 0,00</td><td> 0, 00</td><td></td><td> 5,287</td>

Table 8

Library: plate 1 (designation: 100384) unit: mg

I Column IX-CI-3 IB-SM- I Water and NaOH II Binding

- 113 -

<td> 1</td><td> 1</td><td> 643,88</td><td>DA-22 422.44</td><td> 1752,36</td><td> 227,94</td><td></td><td>ions phosphate (Mmol / g)</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> 4</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 [0220] A 3-liter reaction vessel was used, which was a three-necked round-bottomed flask with four side partitions. The reaction flask was equipped with a heating oil bath, reflux condenser with cold water and a mechanical stirrer with a 3 inch propeller. A solution of 1,3-diaminopropane (90.2 g, (1.21 mol)) dissolved in 90.2 g of water, a surfactant (sodium branched dodecylbenzenesulfonic acid sodium, 6.4 g of salt dissolved in 100 ml) was introduced into such a reaction vessel. g of water) and 1 kg of toluene. output

The reaction mixture was stirred at up to 600 rpm for 2 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.

[0221] A solution of epichlorohydrin in toluene at a concentration of 40% by weight was prepared in a separate vessel. 1.2 equivalents of epichlorohydrin (134.7 g, (1.45 mol)) were added to the initial reaction mixture over a period of 3 hours using a syringe pump. 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.

[0222] After this time, the beads formed were purified by toluene removal, washed with 1000 ml acetone, then with methanol, 20% NaOH (to remove surfactant) and then twice 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 system

1,3-Diaminopropane / 1,3-dichloropropane

[0223] 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 20 ml scintillation vial. The reaction mixture was stirred with a magnetic stirrer and kept at 80 ° C overnight, then at 90 ° C for two additional hours.

The 34% by weight (1716mg) reaction mixture was purified by 3 washes with water / centrifugation to give 144.7 mg of polymer according to the present example in the form of a powder.

Example 5: Synthesis of crosslinked polymer from system

1,3-diaminopropane / 1,3-dichloropropane [0224] Using water as the solvent, 2000 mg B-SM22-DA was mixed with 3048 mg X-Cl-3 and 5048 mg water in a 20 ml scintillation vial. The reaction mixture was stirred with a magnetic stirrer and kept at 80 ° C overnight.

[0225] After a reaction time of 3 hours, 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 [0226] The reaction vessel used was a 250 ml, two-necked round-bottomed flask equipped with

- 116 cold water reflux condenser, magnetic stirrer and working under 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 throughout the experiment. Then, 1 equivalent (47.47 g; 40.0 mL; 0.42 mol) of 1,3-dichloropropane (Aldrich 99%) was added with a syringe pump over 2 hours. 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 to obtain a solid product, easily soluble in water.

Purification [0227] Water was added to the solid product and washed with 200 mL water and 200 mL MeOH. The whole was then introduced into a 1 L beaker containing the solution

MeOH / isopropyl alcohol in a 50/50 ratio. A white polymer precipitate formed in the vessel. After centrifugation of the suspension, the clarified liquid was removed using a centrifuge. 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. Mass of separated polymer: Mn

- 117 (determined by GPC permeation gel chromatography in relation to the polyethyleneimine standard) was ~ 600.

Synthesis of cross-linked particles [0228] 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 containing 20% ​​by weight of polymer dispersed in toluene was obtained. The polymer was then ground to micron sized particles with 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 turned on (500 rpm). After 3 hours of stirring at this temperature, 112.2 mg (0.0012 mol) of epichlorohydrin was added over a period of 1.5 hours. The reaction was continued for another 2 hours before adding 224.4 mg (0.0056 mol) of sodium hydroxide (as an 40% by weight aqueous solution), 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 by removing toluene, washed with methanol, then with 20% NaOH (to remove surfactant) and twice with deionized water. The balls were freeze dried for 3 days to give a fine white powder. Capacity

118 non-interfering binding buffer measured at 3.85 mmol / g.

Example 7: Synthesis and isolation of low molecular weight polymer (prepolymer) made 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 [0230] This example shows the effect of changing the ratio of the amount of monomer (in this case prepolymer) to the amount of solvent in the reaction mixture on the binding capacity and swelling ratio. This example describes a process comprising two stages: the first stage, the synthesis of the adduct - a 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 is an inverted suspension process using different ratios of water to prepolymer. The influence of these variables on the binding effect and swelling was estimated.

Synthesis of the prepolymer [0231] Step 1 (preparation of the prepolymer): The reaction vessel used was a 250 ml two-necked round-bottomed flask equipped with a reflux condenser with cold water, a magnetic stirrer and an argon atmosphere.

A solution of 1,3-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 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 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.

[0232] 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 50/50 MeOH / isopropyl alcohol solution. A white polymer precipitate formed in the vessel. After centrifugation of the suspension, the clarified liquid was removed using a centrifuge. 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.

[0233] 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.

[0234] 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 was then comminuted into 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 different ratios of water content to prepolymer. After 3 hours of stirring at this temperature, the desired amount of epichlorohydrin was added over 1.5 hours (in this example the amount of epichlorohydrin added was equal to 20% by weight of the dry prepolymer). 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 purified by removing toluene, washing with methanol followed by a 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.

- 121 The balls were freeze dried for 3 days to give a fine white powder.

[0235] Polymer spheres synthesized by this method were analyzed for binding capacity (BC) in a non-interfering buffer environment and in a mixture mimicking the content of the gastrointestinal tract and for the degree of swelling. The results are summarized in Table 9.

[0236]

Table 9

<td colspan="4">Gel balls made from 1,3-diaminopropane / 1, 3- system</td>

<td colspan="4">dichloropropane / ECH. Influence of the ratio of monomer to water on</td>

<td colspan="4">binding capacity and swelling</td>

<td>Ratio</td><td>BC (mmol / g)</td><td>BC (mmol / g)</td><td>Swell</td>

<td>monomer to</td><td>not interfere</td><td>mixture</td><td>(GH2O / g</td>

<td>water</td><td>buffer</td><td>mimicking the content of the gastrointestinal tract (GI)</td><td>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>

[0237] These results show that the binding capacity in both the non-interfering buffer and in the GI 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 24-chamber parallel polymerization reactor [0238] This example shows the effect of changing the ratio of crosslinker to monomer on binding capacity and degree of swelling.

[0239] The following stock solution was prepared: 2 molar equivalents of concentrated HCl solution was added to 1 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 using a high shear homogenizer (trade mark: IKA. Model: Ultra-Turax T8). The particles were purified by removing water, washing with methanol and 20% solution

NaOH and then with HCl solution to protonate the amine functional groups. 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.

[0240] The results of the binding and swelling tests are summarized in Table 10.

Table 10

<td colspan="4">BTA / ECH gel: results of swelling ratio and binding capacity</td>

<td colspan="4">depending on the content of the crosslinker. That by volume (the ratio of monomer to water is 75% by weight (2HCl) in water). The amount of monomer to Water is in the range of 3.5 (ECH: BTA = 0.85) to 4.8 (ECH: BTA = 6.4)</td>

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

- 123 -

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

<td> 0,70</td><td> 0,00</td><td> 0, 00</td><td colspan="2"></td>

<td> 0,85</td><td> 2,23</td><td> 0,35</td><td colspan="2"></td>

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

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

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

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

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

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

<td> 1,98</td><td> 0,00</td><td> 0,98</td><td colspan="2"> 2,77</td>

<td> 2,00</td><td> 2,46</td><td> 1,00</td><td colspan="2"> 2,55</td>

<td> 2,00</td><td> 2,46</td><td> 1,00</td><td colspan="2"> 2,55</td>

<td> 2,16</td><td> 2,73</td><td> 0,99</td><td colspan="2"> 2,46</td>

<td> 2,35</td><td> 2,67</td><td> 0,96</td><td colspan="2"> 2,20</td>

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

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

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

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

<td> 3,20</td><td> 1,63</td><td> 0,73</td><td colspan="2"> 1,84</td>

<td> 3,20</td><td> 1,63</td><td> 0,73</td><td colspan="2"> 1,84</td>

<td> 3,60</td><td> 1,28</td><td> 0,64</td><td colspan="2"> 1,57</td>

<td> 3,60</td><td> 1,28</td><td> 0,64</td><td colspan="2"> 1,57</td>

<td> 4,00</td><td> 1,09</td><td> 0,58</td><td colspan="2"> 1,57</td>

<td> 4,00</td><td> 1,09</td><td> 0,58</td><td colspan="2"> 1,57</td>

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

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

<td> 4,90</td><td> 0,42</td><td> 0,35</td><td colspan="2"> 1,47</td>

<td> 4,90</td><td> 0,42</td><td> 0,35</td><td colspan="2"> 1,47</td>

<td> 5,40</td><td> 0,42</td><td> 0,28</td><td colspan="2"> 1,50</td>

<td> 5,40</td><td> 0,42</td><td> 0,28</td><td colspan="2"> 1,50</td>

<td> 5, 90</td><td> 0, 07</td><td> 0,27</td><td colspan="2"> 1,55</td>

<td> 5, 90</td><td> 0, 07</td><td> 0,27</td><td colspan="2"> 1,55</td>

<td> 6,40</td><td> 0, 06</td><td> 0,22</td><td colspan="2"> 1,55</td>

<td> 6,40</td><td> 0, 06</td><td> 0,22</td><td colspan="2"> 1,55</td>

[0241] 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 system, optimal binding capacity is observed in the mixture that mimics the content of the GI conductor for the degree of crosslinking from

1.8 to 2.8, which corresponds to an NC value of respectively

- 124 from 3.6 to 5.6. The swelling ratio is minimal in this crosslinking range. 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.

Example 9: Synthesis of micron sized cross-linked beads from the BTA / ECH system by inverse suspension [0242] The following stock solution was prepared: 2 molar equivalents of concentrated HCl solution was added to 1 molar equivalent of BTA over a period of 2 hours. To the solution, water and surfactant (branched dodecylbenzene sulfonic acid sodium, 30% by weight in water) were then added in such quantities 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.

[0243] The reaction vessel used was a three-necked round-bottom flask with four 0.25-liter side baffles, equipped with an oil heating bath, cold water reflux condenser, mechanical stirrer with 1-inch propeller. 25 g of the prepared stock solution and 75 g of toluene were introduced into such a vessel.

[0244] A solution of epichlorohydrin in toluene at a concentration of 40% by weight was prepared in a separate vessel. Then the required amount of ECH was added with a syringe pump over 90 minutes. The reaction was continued for an additional 2 hours, after which water was removed using a Dean Stark apparatus. The reaction ended with the deletion of all

- 125 water content from the system. The beads were purified by removing toluene, washing with methanol followed by a 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.

[0245] The results of the binding and swelling tests are summarized in Table 11.

Table 11

<td colspan="4">BTA / ECH gel balls: swelling ratio and binding capacity depending on the content of crosslinking agent</td>

<td>ECH: BTA molar ratio</td><td>BC (mmol / g) not interfere buffer</td><td>BC (mmol / g) digested meal</td><td>Degree swelling (g of water / g polymer)</td>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0246] 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 amount

- 126 to amine. In this particular arrangement, optimal binding capacity is observed in the mixture that mimics the content of the GI conductor for a crosslinking degree of 1.75 to 3, which corresponds to an NC value of 3.5 to 3, respectively

6. The swelling ratio is minimal in this crosslinking range. 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.

Example 10: Synthesis of micron-sized crosslinked particles from a polyallylamine / ECH bulk gel gel in a 24-chamber parallel polymerization reactor [0247] This example illustrates polymer synthesis 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 (MC = 60,000 g / mol) was used instead of BTA. The ratio of ECH to repeat members of allylamine 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, crosslinked polyallylamine separated from Renagel tablets was used.

<td>Amine molar ratio into the water</td><td>BC (mmol / g) not interfere buffer</td><td>BC (mmol / g) digested meal</td><td>Degree swelling (g of water / g 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>

[0248] 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 mimicking 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.

Example 11: Measurement of the binding interference level [0249] This example illustrates the measurement of binding interference using a polymer according to the invention and, for comparison, a prior art polymer. A crosslinked polyamine material (EC172A) 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.

[0250] The terms "degree of binding interference" or "disruption of the binding process" as used herein refer to the fractional decrease 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, the binding isotherm in a non-interfering buffer was obtained, plotting the dependence of the binding capacity on the equilibrium phosphate concentration for different phosphate concentration values. This isotherm was then fitted to the exponential function to predict binding capacity for any phosphate concentration. Then on

- 128 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 isothermal plot environment. The degree of interference was calculated from the expression: (BCNI-BCGI) / BCNI * 100.

[0251] The interference with the binding process for the EC127A polymer is shown in the table below and in Figure 3.

<td>Pstart (mM)</td><td>Peq (mM)</td><td>BC (mmol / g)</td><td>BC expected (mmol / g)</td><td>Disturbance (%)</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>

[0252] Interference with the binding process for RENAGEL is shown in the table below and in Figure 4.

<td>Pstart (mM)</td><td>Peq (mM)</td><td>BC (mmol / g)</td><td>BC expected (mmol / g)</td><td>Disturbance (%)</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>

[0253] 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 [0254] Cross-linked polyamine material (EC172A) was prepared according to the procedure described in Example 4, with a BTA: ECH molar ratio of 2.5 and a ratio (BTA + ECH) to water of 1.73. The material was tested

Followed by binding of phosphate ions in food contents collected from humans as described in example 1.

[0255] Phosphate binding for EC172A was compared to the pharmaceutically active crosslinked polyallylamine separated from Renagel (Genzyme). The EC172A 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></td><td>Average Peq (mM)</td><td>SD (mM)</td><td>Medium BC (Mmol / g )</td><td>SD (Mmol / g )</td><td>Envisaged ne BC (Mmol / g)</td><td>(%) Abnormal ia</td>

<td>rena gel 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>EC 17 2A</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>

[0256] In a subsequent experiment, both materials, EC172A and Renagel, were used ex-vivo in various food contents 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.

- 130 -

<td></td><td>[PO4]</td><td>BC (PO4)</td><td>[lemons ian]</td><td>BC (lemons ian)</td><td>(acid Bile y)</td><td>BC (bile)</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>system counterrevolutionary olny (lack Polim eru)</td><td> 5,722</td><td></td><td> 1,667</td><td></td><td> 4,928</td><td></td>

<td>Renage El</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 AND</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 [0257] This example illustrates the gel porosity measurement. The measurements were carried out for the polymer particles according to the invention and for comparison with the commercially available phosphate binding polymer. As the polymer of the invention, cross-linked polyamine material (EC172A) 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.

[0258] The probing substances were 8 poly (ethylene glycol) (PEG) samples with MC molecular weights ranging from 200 to 20,000 daltons and 4 poly (ethylene oxide) (PEO) samples (from 30,000 to 230,000 daltons).

[0259] 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 washed with HCl (15 ml / g dry gel); and

Then the whole was shaken for 4 days on a shaker

Vortexer.

[0260] Probing solutions were diluted 10-fold prior to LC / liquid chromatography analysis using a light scattering detector by evaporated particles from Polymer Lab (to be placed in the detector's linear operating range, ensuring that the peak area ratio is equal to the weight ratio).

[0261]

Calculation of the unavailable volume = msw + [1 - cbef / cpo] ^msolv^; where:

msw amount of water absorbed by the gel [g / g dry gel] msolv amount of water in which the probe was initially dissolved [g / g dry gel] cbefore and cpo: concentrations of the probing substances before and after reaching equilibrium. The cprzed / cpo ratio is equal to the peak area ratio obtained during LC analysis.

[0262] 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 EC127A polymer indicates constant molecular exclusion for solutes for MC 200, while Renagel shows a reduction in exclusion for particles of MC 1000.

Example 14: Subsequent modification of the beads with chloropropylamine hydrochloride [0263] Preparation of the stock solution:

- 132 • 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 [0264] Synthesis:

[0265] 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 (BTA + ECH) to water ratio of 1.73, was used as a raw material for further amination reactions (introduction of amino groups): The FR0005-144 beads were transferred to 4 ml vials (two 4x6 plates, each containing approximately 21 vials) and water, chloropropylamine hydrochloride stock solution and sodium hydroxide stock solution were added using a liquid dispensing automaton. The plate vials were transferred to the heating reactors and individual corked and stirred.

[0266] Heating and stirring were turned on for 12 hours: the reactor temperature was set to 85 ° C and the stirring speed was 1200 rpm.

[0267] Purification:

[0268] 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.

[0269] The product was then dried in a freeze dryer and analyzed for action in a digested meal in

- 133 non-interfering buffer and swelling ratio was measured. The results are shown below in Table 12 and Figure 7.

Table 12

<td colspan="9">Properties of polymers produced as a result of modification of the beads with chloropropylamine hydrochloride</td>

<td>FR0005144</td><td>Water</td><td>SM34-B-A</td><td>NaOH</td><td>Weight ratio BSM-34-A to FR0005-144</td><td>Ratio moth. NaOH to B-SM-34DA</td><td>BC masked DM (Mmol / g)</td><td>BC mask Kwan e NI (mMO l / g)</td><td>Stop ttings Spec lifted present (g water / g gel )</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>

<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>

- 134 -

<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> 0,00</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> 61,9</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>

[0270] 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 [0271] 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 contained the following composition by weight: N, N '- (tetra-3-aminopropyl) -1,4-diaminobutane 42% by weight, H3PO4 13% by weight, water 45% by weight. A 24-chamber reactor was used containing 5 ml flasks, each equipped with a magnetic stirrer. 0.6-0.7 g of the prepared stock solution was placed in each flask. Blending enabled. The desired amount of epichlorohydrin in pure form was added to each vial. The reactor was heated to 60 ° C for 1 hour and then heated to 80 ° C for 8 hours. The reactor was allowed to cool. Water was added to each vial

- 135 in order to transfer the swelling of the resulting gel. Gel for 4X6 plate with 10 ml test tubes. The gel was then ground to micron sized particles with a mechanical chopper (trade mark: 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 chloride and replace the bound H3PO4. 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 Table 13.

Table 13

<td colspan="7">Synthesis of phosphoric acid labeled gels</td><td colspan="4">m. ID 102776</td>

<td>Government</td><td>Kolu me</td><td>B-SM20TeA (Mg)</td><td>B-SM20-tea (Moles)</td><td>Acid phosphorus pink (Mg)</td><td>Water (Mg)</td><td>X-EP1 (Mg)</td><td>X-EP-1 (Moles)</td><td>B-SM-20TE / H3PO 4</td><td>XEP1 / BSM20TeA</td><td>Gel present in chamber</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>FROM</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>FROM</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>FROM</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>from</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>from</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>from</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>from</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>from</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>from</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>from</td>

- 136 -

<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>FROM</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>FROM</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>FROM</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>from</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>from</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>from</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>from</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>from</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>from</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>from</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>from</td>

[0272] Polymers prepared as described above bind phosphate.

[0273] 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 invention. It is understood that the various alternative embodiments described herein can be used in practicing it. It is intended that the invention be defined by the following claims. Methods and structures falling within the scope of these claims and their equivalents are the subject of the invention.

[0274] The following is a list of embodiments of the invention:

Embodiment 1. Anion-binding polymer, wherein the polymer binds to the target anion, wherein the polymer has at least two of the following characteristics:

a. a swelling ratio of less than about 5;

b) a polymer fraction representing less than 20% of its mass available for non-interacting solutes o

- 137 molecular weight greater than about twice the molecular weight MC of the target anion, the above percentage being measured in a physiological environment; and

c) disrupting the ion binding process for the target anion in measurements in a mixture mimicking the content of the gastrointestinal tract of less than about 60% relative to the non-interfering buffer.

Embodiment 2. A polymer with the properties of Embodiment 1 wherein the polymer binds bile acids or citrate ions with a yield of less than about 2 mmol / g.

Embodiment 3. A polymer with the properties of embodiment 1, wherein the swelling ratio is measured in isotonic solution and / or at neutral pH.

Embodiment 4. The polymer with the features of embodiment 1, wherein the polymer comprises amino groups.

Embodiment 5. A polymer with the properties of embodiment 4, wherein the amine monomers are selected from the group consisting of allylamine, vinylamine, ethyleneimine, of formula 1 and formula 2, wherein formula 1

<img file="PL2009042T3_D0040.tif" />

structure:

Embodiment 6. The polymer with the features of embodiment 4, wherein the amine monomers are non-polymeric amine monomers selected from the group consisting of 1,3-diaminopropane and N, N, N ', N'-tetrakis- (3 aminopropyl) -1,4-diaminobutane;

1,2,3,4 tetraaminobutane.

Embodiment 7. The polymer with the features of embodiment 1, wherein the polymer comprises a non-polymeric amine monomer and a crosslinker.

Embodiment 8. The polymer with the features of embodiment 1, wherein the polymer comprises amine monomers and a crosslinker, wherein the crosslinker is present in an amount greater than 50 mole%. total amine content of monomers.

Embodiment 9. Anion-binding polymer comprising a non-polymeric amine monomer and a crosslinking agent, wherein the polymer is obtained in a heterogeneous process and the swelling ratio of the polymer is less than 5.

Embodiment 10. A pharmaceutical composition comprising the polymer with the features of embodiment 1 or 9 and a pharmaceutically acceptable excipient.

Embodiment 11. The composition with the features of embodiment 1, wherein the target anion is selected from the group consisting of phosphate and oxalate.

Embodiment 12. The composition with the features of embodiment 1, wherein the target anion is phosphate.

Embodiment 13. A phosphate-binding polymer comprising a non-polymeric amine monomer and a crosslinking agent, wherein the polymer has at least one of the following features:

a. a swelling ratio of less than about 5;

b. a gel fraction representing less than about 20% of its mass available for non-interacting solutes with a molecular weight greater than about 200, wherein the above percentage is measured in a physiological environment; 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.

Embodiment 14. A phosphate-binding polymer comprising a non-polymeric amine monomer and a crosslinking agent, wherein the polymer has at least one of the following characteristics:

a. a swelling ratio of less than about 2.5;

b. a gel fraction representing less than about 20% of its mass available for non-interacting solutes with a molecular weight greater than about 200, wherein the above percentage is measured in a physiological environment; 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.

Embodiment 15. A phosphate-binding polymer, wherein the polymer has at least one of the following characteristics:

(a) a gel fraction of less than about 20% of its mass available to non-interacting solutes with a molecular weight greater than about 200, with the above percentage being measured in a physiological environment; and

b) ion binding disruption for phosphate ions of less than about 60% when measured in a medium that mimics the content of the gastrointestinal tract relative to the non-interfering buffer.

Embodiment 16. The polymer with the features of embodiment 15, wherein the polymer comprises amine monomers and a curative, wherein the curtail is present in an amount greater than 50 mole%. total amine content of monomers.

Embodiment 17. A polymer with the features of embodiment 14, wherein the polymer binds bile acids or citrate with a yield of less than 2 mmol / g.

Embodiment 18. The polymer with the properties of embodiment 14, wherein the swelling ratio is measured in isotonic solution and / or at physiological pH.

Embodiment 19. The polymer with the features of embodiment 15, wherein the polymer has an average in vivo phosphate binding capacity greater than about 0.5 mole / g.

Embodiment 20. The polymer with the features of embodiment 15, wherein 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.

Embodiment 21. A polymer with the properties of embodiment 1, consisting of one or more amine monomers and one or more crosslinkers, wherein the polymer is prepared by a process in which the amine is in a solvent prior to crosslinking in an amine: solvent ratio of from about 3: 1 to about 1: 3 and the total content of crosslinkers added to the reaction mixture is such that that the average amount of bond to amine monomers (NC) is from about 2.05 to about 6.

Embodiment 22. The composition with the features of embodiment 21, wherein the total amount of crosslinkers added to the reaction mixture is such that the NC value is between about 2.05 and about 4.5.

Embodiment 23. The polymer with the characteristics of embodiment 1, wherein the polymer is produced by a process in which the target anion is in a reaction medium during a crosslinking reaction.

Embodiment 24. The polymer with the features of embodiment 23, wherein the crosslinking reaction comprises the following steps:

a) adding the amine monomer as the free base and adding the target anion in its acid form;

b) adding a crosslinker;

- 142 c) conducting the crosslinking reaction; and

d) elution of the target ion.

Embodiment 25. The polymer with the features of embodiment 1, consisting of one or more amine monomers and one or more crosslinkers, wherein the polymer is prepared by a process comprising the following steps:

a) preparation of a soluble prepolymer by:

i) adding the amine monomer followed by ii) adding the crosslinker fraction to make a syrup;

b) emulsifying the syrup in oil; and

c) adding the remaining amount of crosslinker to form crosslinked beads.

Embodiment 26. The polymer with the properties of embodiment 1, consisting of one or more amine monomers and one or more crosslinkers, the polymer is prepared by a process comprising the following steps:

a) conducting a first reaction between the amine monomer and the crosslinker to form a gel; next

b) reacting the gel with an aminoalkyl halide, during which the alkylamino groups chemically attach to the gel by substituting a halide.

Embodiment 27. A pharmaceutical composition comprising the polymer with the features of embodiment 21 and a pharmaceutically acceptable excipient.

Embodiment 28. The polymer with the features of embodiment 1, wherein the polymer is in the form of particles that are surrounded by an outer coating.

Embodiment 29. A phosphate-binding polymer comprising one or more amine monomers and one or more crosslinkers, wherein the polymer is made by a process in which the total content of crosslinkers added to the reaction mixture is such that the average number of bonds to the amine monomers is between about 2.2 and about 4.5.

Embodiment 30. The polymer with the features of embodiment 29, wherein 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 wherein the crosslinker is selected from the group consisting of 1,3-dichloropropane and epichlorohydrin.

Embodiment 31. A pharmaceutical composition comprising the polymer with the features of embodiment 29 and a pharmaceutically acceptable excipient.

Embodiment 32. An ion-binding polymer containing 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, N'tetrakis- (3-aminopropyl-1,4-diaminobutane to water is from about 1: 3 to about 4: 1.

Embodiment 33. The polymer with the features of embodiment 32, wherein

- 144 the ratio of the initial concentration of N, N, N ', N'-tetrakis (3-aminopropyl) -1,4-diaminobutane to water is from about

1.5: 1 to about 4: 1.

Embodiment 34. A pharmaceutical composition comprising the polymer with the features of embodiment 32 and a pharmaceutically acceptable excipient.

Embodiment 35. A phosphate-binding polymer comprising N, N, N ', N'-tetrakis- (3-aminopropyl) 1,4-diaminobutane monomers and an epichlorohydrin crosslinker, wherein the polymer is produced by a process in which all the total amount of epichlorohydrin crosslinker added to the reaction mixture is from about 200% to about 300 mole% of the total amount of N, N, N ', N'-tetrakis- (3-aminopropyl) -1,4-diaminobutane.

Embodiment 36. The polymer with the features of embodiment 35, wherein 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.

Embodiment 37. The polymer with the features of embodiment 35, wherein the total amount of epichlorohydrin crosslinker added to the reaction mixture is from about 230 to about

270 mole% of the total amount of N, N, N ', N'-tetrakis- (3aminopropyl) -1,4-diaminobutane.

Embodiment 38. The polymer with the features of embodiment 35, wherein the total amount of crosslinker epichlorohydrin added to the initial reaction mixture is about 250%

- 145 molar total amount of N, N, N ', N'-tetrakis- (3aminopropyl) -1,4-diaminobutane.

Embodiment 39. The polymer with the properties of embodiment 38, wherein the polymer is prepared by a process in which a (N, N, N ', N'tetrakis- (3-aminopropyl) -1,4-diaminobutane + epichlorohydrin ratio ) to water is about 1.73.

Embodiment 40. The polymer with the features of embodiment 35, wherein the polymer is in the form of round spheres.

Embodiment 41. A phosphate-binding polymer comprising polyallylamine monomers and a crosslinker - epichlorohydrin, wherein the polymer is prepared by dissolving polyallylamine monomers in water in a monomer: water ratio of from about 3: 1 to about 1: 3.

Embodiment 42. The polymer with the properties of embodiment 41, wherein the total amount of crosslinker epichlorohydrin added to the reaction mixture is about 10 mol% of polyallylamine content.

Embodiment 43. A phosphate-binding polymer comprising a prepolymer containing 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 crosslinking reaction with an epichlorohydrin crosslinker, with the amount of epichlorohydrin crosslinker added The reaction amount is about 200 mole% of the total amount of prepolymer, wherein the ratio of prepolymer: water in the reaction mixture is from about 1.1: 1 to about 1.7: 1.

Embodiment 44. A pharmaceutical composition with the features of embodiment 10, 24, 31 or 34, wherein the composition is a liquid formulation containing water and pharmaceutically acceptable excipients.

Embodiment 45. A pharmaceutical composition comprising an anion-binding polymer that binds to a target anion and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of a chewable tablet and / or orodispersible tablet, the polymer having a degree of swelling in the for less than about 5 time to pass through the mouth and esophagus.

Embodiment 46. A pharmaceutical composition comprising an anion-binding polymer that binds to the target anion, and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of a chewable tablet and / or orodispersible tablet, the polymer having the following properties:

(a) a gel fraction of less than 20% of its mass available for non-interacting solutes with a molecular weight greater than about twice the MC of the target anion, the above percentage being measured in a physiological environment; and

b) disrupting the ion binding process of the target anion in measurements in a mixture mimicking the content of the gastrointestinal tract less than about 60% relative to the non-interfering buffer.

Embodiment 47. The composition with the features of embodiment 46, wherein the polymer has a transition temperature greater than about 50 ° C.

Embodiment 48. The composition with the features of embodiment 46, wherein the pharmaceutical excipients are selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose, sorbitol and combinations thereof, the composition being prepared by a process in which the polymer is previously mixed with an excipient to form a solid phase solution.

Embodiment 49. The composition with the features of embodiment 46, wherein the polymer target anion is phosphate.

Embodiment 50. A composition with the features of embodiment 46, wherein the polymer binds the target ion in vivo with a binding capacity greater than 0.5 mmol / g.

Embodiment 51. The composition with the features of embodiment 46, wherein the anion-binding polymer comprises more than about 50% of the weight of the tablet.

Embodiment 52. The composition with the features of embodiment 46, wherein 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 is more than about 1.6 g.

Embodiment 53. A pharmaceutical composition with the features of embodiment 46, wherein the excipients are selected from the group consisting of

- 148 sweeteners, binders, lubricants and tablet disintegrating agents.

Embodiment 54. A pharmaceutical composition with the features of embodiment 53, wherein the polymer is in the form of particles with an average diameter less than about 40 μη.

Embodiment 55. The pharmaceutical composition with the features of embodiment 53, wherein the sweetener is selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose and sorbitol and combinations thereof.

Embodiment 56. A method of measuring interference of the target ion binding process by an ion binding polymer, comprising:

a) adding the ion binding polymer to a non-interfering buffer containing the target ion and measuring the polymer binding capacity of the target ion;

b) preparing a disturbing buffer by artificially digesting a normalized meal using digestive enzymes of the GI mammalian gastrointestinal tract and / or collecting digestive tract from the upper gastrointestinal tract of mammals given a normalized meal; wherein the normalized meal contains a target ion;

c) adding the ion binding polymer to the interfering buffer and measuring the binding capacity of the target ion, said ability being measured by changing the concentration of the target ion in the interfering buffer before and after adding the ion binding polymer; and

- d) calculating the degree of interference in the binding process in the form of a fractional decrease in the binding capacity of the target ion observed between the measurement of binding capacity in a non-interfering buffer environment and in a interfering buffer environment at the same ion concentration in equilibrium.

Embodiment 57. A method for selecting an ion-binding polymer that binds to a target ion, wherein the polymer comprises a monomer and a crosslinker, wherein the polymer has at least one of the following properties:

a. a swelling ratio of less than about 5;

b) a gel fraction of less than about 20% of its mass available for non-interacting solutes with a molecular weight greater than about twice the MC of the target anion, the above percentage being measured in a physiological environment, and

c) disrupting the ion binding process of the target anion in measurements in a mixture mimicking the gastrointestinal tract content of less than about 60% relative to the non-interfering buffer;

wherein the method includes: i) differentiation:

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

- 150 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 having at least one of the following characteristics.

Embodiment 58. 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 binding sites with the polyamine monomer 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.

Embodiment 59. 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, wherein the phosphate-binding polymer has at least two of the following features:

a) a swelling ratio less than approximately by 5;

b. a polymer fraction of less than about 20% of its mass available to non-interacting solutes with a molecular weight greater than about twice the MC of the target anion, the above percentage being measured in a physiological environment, and

151 c) interfering with the ion binding process for the target anion in measurements in a mixture mimicking the content of the gastrointestinal tract of less than about 60% relative to the non-interfering buffer.

Embodiment 60. The method with the features of embodiment 59, wherein the amine monomer is a non-polymeric amine monomer.

Embodiment 61. The method with the features of embodiment 59, wherein the polymer comprises amine monomers and a crosslinker, wherein the crosslinker is present in an amount greater than 50 mole%. total amine content of monomers.

Embodiment 62. The method with the features of embodiment 59, wherein the amine monomer is polyallylamine.

Embodiment 63. The method with the features of embodiment 62, wherein the crosslinker is epichlorohydrin.

Embodiment 64. An anion-binding polymer that binds to a target ion, wherein the polymer is prepared by a process comprising crosslinking an amine monomer using a crosslinker in a non-homogeneous process, said polymer having at least two of the following characteristics:

a. a swelling ratio of less than about 5;

b. A polymer fraction of less than about 20% of its mass available for non-interacting solutes with a molecular weight greater than about twice the MC of the target anion, wherein

- 152 the above percentage is measured in a physiological environment, and

c) disrupting the ion binding process for the target anion in measurements in a mixture mimicking the content of the gastrointestinal tract of less than about 60% relative to the non-interfering buffer.

Embodiment 65. The method with the features of embodiment 64, wherein the amine monomer is a non-polymeric amine monomer.

Embodiment 66. The polymer with the features of embodiment 64, wherein the polymer comprises amine monomers and a crosslinker, wherein the crosslinker is present in an amount greater than 50 mole%. total amine content of monomers.

Embodiment 67. The polymer with the features of embodiment 64, wherein the amine monomer is polyallylamine.

Embodiment 68. The polymer with the features of embodiment 64, wherein the polyallylamine is cross-linked with epichlorohydrin.

Embodiment 69. A method of removing anion from an animal's body by administering to the animal an effective amount of a polymer, wherein the polymer is an anion-binding polymer that binds to the target ion, wherein the polymer has at least two of the following properties:

a. a swelling ratio of less than about 5;

b) a gel fraction of less than 20% of its mass available for non-interacting solutes with a molecular weight greater than about twice the mass

- 153 molecular MC of the target anion, the above percentage being measured in a physiological environment; and

c) disrupting the ion binding process for the target anion in measurements in a mixture mimicking the content of the gastrointestinal tract less than about 60% relative to the non-interfering buffer.

Embodiment 70. The method with the features of embodiment 69, wherein the polymer comprises a non-polymeric amine monomer and a crosslinker.

Embodiment 71. The method with the features of embodiment 69, wherein the polymer comprises amine monomers and a curative, wherein the curtail is present in an amount greater than 50 mole%. total amine content of monomers.

Embodiment 72. The method with the features of embodiment 69, wherein the anion is phosphate.

Embodiment 73. The method with the features of embodiment 72, wherein the animal suffers from at least one of the following conditions selected from the group consisting of hyperphosphataemia, hypocalcaemia, hyperthyroidism, reduction of kidney calcitriol synthesis, tetany associated with hypocalcemia, renal failure , ectopic foci of calcification in soft tissues and end stage renal disease (ESRD).

- Embodiment 74.

A method with the features of embodiment 72, wherein the animal is a human.

Embodiment 75. The method with the features of embodiment 72, wherein the phosphate is removed from the gastrointestinal tract.

Embodiment 76. The method with the features of embodiment 72, wherein the formulation is administered orally.

Embodiment 77. The method with the features of embodiment 72, wherein the polymer is administered in parallel with at least one of the following: a proton pump inhibitor, calcimimetic drug, vitamin, and analogs thereof, or a phosphate binder.

Embodiment 78. The method with the features of embodiment 77, wherein the phosphate binder is at least one of the following: aluminum carbonate, calcium carbonate, calcium acetate, lanthanum carbonate, or sevelamer hydrochloride.

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