WO2009097127A1 - Pharmaceutical compositions - Google Patents

Abstract

This invention relates to pharmaceutically acceptable compositions and polymers or residues thereof for binding target ions, and more specifically relates to polymer particles for binding target ions. These pharmaceutically acceptable compositions are comprised of crosslinked polyamine particles, said crosslinked polyamine derived from an amine compound and a crosslinking agent, where the crosslinked polyamine particles have a particle size distribution greater than 10 vol.% of the particles having a particle size greater than 500 μm.

Description

PHARMACEUTICAL COMPOSITIONS

CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of priority from U.S. Provisional Application No. 61/006,791, filed January 31, 2008. This application, in its entirety, is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to pharmaceutically acceptable compositions and polymers or residues thereof for binding target ions, and more specifically relates to polymer particles for binding target ions.

BACKGROUND OF THE INVENTION

[0003] Hyperphosphatemia frequently accompanies diseases associated with inadequate renal function such as end stage renal disease (ESRD), hyperparathyroidism, and certain other medical conditions. The condition, especially if present over extended periods of time, leads to severe abnormalities in calcium and phosphorus metabolism and can be manifested by aberrant calcification in joints, lungs, and eyes. [0004] Therapeutic efforts to reduce serum phosphate include dialysis, reduction in dietary phosphate, and oral administration of insoluble phosphate binders to reduce gastrointestinal absorption. Many such treatments have a variety of unwanted side effects and/or have less than optimal phosphate binding properties, including potency and efficacy. Accordingly, there is a need for compositions and treatments with good phosphate-binding properties and good side effect profiles.

DEFINITIONS

[0005] The following definitions apply herein unless otherwise specifically noted: [0006] Aggregate particle: an aggregate particle is a particle that is assembled from, formed from or comprises distinct constituent particles.

[0007] d₁₀: the particle size within a distribution of particles where 10 vol.% of the particles have a smaller particle size.

[0008] d₅₀: the particle size within a distribution of particles where 50 vol.% of the particles have a particle size that is larger and where 50 vol.% of the particles have a particle size that is smaller.

[0009] d₉₀: the particle size within a distribution of particles where 90 vol.% of the particles have a smaller particle size. [0010] Crosslinked polyamine particles: particles comprising at least one crosslinked polyamine for example particles that comprise at least a substantial portion, by weight, of crosslinked polyamine, wherein the substantial portion is at least 50 wt.%, 60 wt.%, 70 wt.%, 80 wt.%, 90 wt.%, 95 wt.%, 98 wt.%, or 99 wt. % as well as 100 wt.%.

BRIEF SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention relates to crosslinked polyamine particles and/or pharmaceutical compositions comprising, at least in part, crosslinked polyamine particles. Compositions can comprise one or more crosslinked polyamines. Several embodiments of the invention are described in further detail as follows. Generally, each of these embodiments can be used in various and specific combinations, and with other aspects and embodiments unless otherwise stated herein.

[0012] In addition to the crosslinked polyamine particles of the present invention as described herein, other forms of the crosslinked polyamine particles are within the scope of the invention including pharmaceutically acceptable salts, solvates, hydrates, prodrugs, polymorphs, clathrates, and isotopic variants and mixtures thereof of the crosslinked polyamine particles.

[0013] In addition, crosslinked polyamine particles of the invention may have optical centers or chiral centers and the crosslinked polyamine particles of the present invention include all of the isomeric forms of these crosslinked polyamine particles, including optically pure forms, racemates, diastereomers, enantiomers, tautomers and/or mixtures thereof.

[0014] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles where the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas I to XXXII and a crosslinking agent or comprise repeat units according to Formula XXXIII and where the crosslinked polyamine particles have one or more of the particle size characteristics described herein, such as for example, a particle size distribution such that greater than 5 vol.% of the crosslinked polyamine particles have a particle size greater than 500 μm, such as between 500 μm and 2 mm. [0015] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, particles where the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas I to XXXII and a crosslinking agent or comprise repeat units according to Formula XXXIII and where the crosslinked polyamine particles have a mean gray value of greater than 180.

[0016] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of a crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, particles where the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas I to XXXII and a crosslinking agent or comprise repeat units according to Formula XXXIII and where the crosslinked polyamine particles comprise 2 or more constituent particles comprising or derived from an amine compound according to any of Formulas I to XXXII and a crosslinking agent or comprising repeat units according to Formula XXXIII.

[0017] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of a crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, where the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas I to XXXII and a crosslinking agent or comprise repeat units according to Formula XXXIII, the crosslinked polyamine particles being formed by aggregating 2 or more constituent particles comprising or derived from an amine compound according to any of Formulas I to XXXII and a crosslinking agent or comprising repeat units according to Formula XXXIII. [0018] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, where the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas I to XXXII and a crosslinking agent or comprise repeat units according to Formula XXXIII, the crosslinked polyamine particles having an in vitro competitive phosphate binding capacity of greater than 1.2 mmol/g at 60 minutes.

[0019] In some embodiments, crosslinked polyamine particles according to the invention may have one or more of or any combination of the following characteristics: a) a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm; b) a particle size distribution where from 5 vol.% to 100 vol.% of the crosslinked polyamine particles have a particle size of greater than 500 μm; c) a particle size distribution such that no more than 20 vol.% of the crosslinked polyamine particles have a particle size less than 300 μm; d) a particle size distribution such that the crosslinked polyamine particles have a dio value that is between 250 μm and 750 μm e) a particle size distribution such that the crosslinked polyamine particles have a dgo value that is between 900 μm and 1600 μm; f) a particle size distribution such that the crosslinked polyamine particles have a d₅o between 450 μm and 1100 μm; g) from 75 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is -5/+60; h) from 5 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is +35; i) no more than 20 wt.% of the crosslinked polyamine particles have a mesh size that is -50; j) from 40 wt.% to 60 wt.% of the crosslinked polyamine particles have a mesh size that is -16/+40; k) a mean gray value greater than 180; 1) comprises 2 or more constituent particles; and/or m) a competitive phosphate binding capacity at 60 minutes of greater than 1.2.

[0020] In some embodiments, the crosslinked polyamine particles described herein may comprise aggregates of constituent particles of the crosslinked polyamine polymers. In some embodiments, the constituent particles may have a particle size distribution such that greater than 70% of the constituent particles have a particle size between 50 μm and 850 μm. In some embodiments, the constituent particles may have a particle size distribution such that the constituent particles have a d₁₀ value between about 20 μm and about 100 μm and/or a d₉₀ value that is between about 150 μm and about 450 μm. In some embodiments, the constituent particles may have a d₅o between 50 μm and 200 μm. In some embodiments, the crosslinked polyamine particles comprise aggregates of from about 2 to about 10,000 constituent particles.

[0021] In some embodiments, the invention provides methods of treating an animal, including a human. The method generally involves administering an effective amount of crosslinked polyamine particles or a composition (e.g., a pharmaceutical composition) comprising the same to the animal as described herein.

[0022] In some embodiments, the crosslinked polyamine particles have an in vitro competitive phosphate binding capacity of greater than 0.4 mmol/g throughout a physiologically significant time period. In some embodiments, the crosslinked polyamine particles have an in vitro competitive phosphate binding capacity of greater than 0.5 mmol/g at 60 minutes. In some embodiments, the crosslinked polyamine particles have an in vitro competitive binding capacity at 60 minutes that is greater than 20% of the in vitro non-competitive phosphate binding capacity of said polymer at 300 minutes. [0023] Another aspect of the invention is a pharmaceutical composition comprising crosslinked polyamine particles of the present invention and at least one pharmaceutically acceptable excipient. In some embodiments, the composition is a liquid formulation in which the crosslinked polyamine particles are dispersed in a liquid vehicle, such as water, and suitable excipients. In some embodiments, the invention provides a pharmaceutical composition comprising crosslinked polyamine particles for binding a target compound or ion, and one or more suitable pharmaceutical excipients, where the composition is in the form of a tablet, sachet, slurry, food formulation, troche, capsule, elixir, suspension, syrup, wafer, chewing gum or lozenge. In some embodiments the composition contains a pharmaceutical excipient selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose, sorbitol, and combinations thereof. In some embodiments the target anion of the crosslinked polyamine particles is an organophosphate and/or phosphate. In some embodiments the crosslinked polyamine particles are more than about 50% of the weight of the tablet. In some embodiments, the tablet is of cylindrical shape with a diameter of from about 12 mm to about 28 mm and a height of from about 1 mm to about 8 mm and the crosslinked polyamine particles comprise more than 0.6 to about 2.0 gm of the total weight of the tablet.

[0024] In some of the compositions of the invention, the excipients are chosen from the group consisting of sweetening agents, binders, lubricants, and disintegrants. In some of these embodiments, the sweetening agent is selected from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose, and sorbitol, and combinations thereof. [0025] The crosslinked polyamine particles described herein have several therapeutic applications. For example, the crosslinked polyamine particles are useful in removing compounds or ions such as anions, for example phosphorous-containing compounds or phosphorous containing ions such as organophosphates and/or phosphates, from the gastrointestinal tract, such as from the stomach, small intestine and/or large intestine. In some embodiments, the crosslinked amine polymers are used in the treatment of phosphate imbalance disorders and renal diseases.

[0026] In yet another aspect, the crosslinked polyamine particles are useful for removing other solutes, such as chloride, bicarbonate, and/or oxalate containing compounds or ions. Crosslinked polyamine particles removing oxalate compounds or ions find use in the treatment of oxalate imbalance disorders. Crosslinked polyamine particles removing chloride compounds or ions find use in treating acidosis, for example. In some embodiments, the crosslinked polyamine particles are useful for removing bile acids, citrate and related compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0027] In one aspect, the present invention provides crosslinked polyamine particles, compositions and methods of using crosslinked polyamine particles, where the crosslinked polyamine comprises or is derived from an amine compound and a crosslinking agent. In addition, some embodiments may include multiple repeat units or residues thereof that repeat in a copolymer or polymer.

[0028] As used herein, unless otherwise stated, the term "derived from" is understood to mean: produced or obtained from another substance by chemical reaction, especially directly derived from the reactants, for example a crosslinked polyamine may be derived from the reaction of an amine compound and a linking agent, such as a crosslinking agent resulting in a crosslinked polyamine that is derived from the amine compound and the crosslinking agent.

[0029] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, where the crosslinked polyamine particles comprise or are derived from an amine compound or residue thereof and a crosslinking agent or residue thereof, said amine compound represented by the following Formula I:

"A- — ^ ^A N

RA Formula I

[0030] where each R_A, independently, represents a hydrogen radical, — R or -R-N(Ri)_2-m-(R-N(Ri)_2-n-(R-N(Ri)2)n)m; each n and each m, independently, represents an integer from 0 to 2, such as 0, 1 or 2; each R, independently, represents a branched or unbranched, substituted or un-substituted alkyl radical, for example a Ci to C₂o alkyl radical such as a Cj, C₂, C₃, C₄, C₅, or C₆ alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical, a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇ aryl or heteroaryl radical, which may contain from 0 to 4, such as 1 , 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇, alicyclic or heterocyclic radical, which may contain from 0 to 4, such as 1 , 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms; and each Ri, independently, represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical, for example a Ci to C₂₀ alkyl radical such as a Ci, C₂, C₃, C₄, C₅, or C₆ alkyl radical; a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical, a substituted or unsubstituted C₄ to C]₀, such as a C₄, C₅, C₆, or C₇ aryl or heteroaryl radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or a substituted or unsubstituted C₄ to Cio, such as a C₄, C₅, C₆, or C₇, alicyclic or heterocyclic radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or two Ri 's may combine to form a substituted or unsubstituted heteroaryl or heterocyclic radical, which may contain from 0 to 4, such as 1 , 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, with the proviso that at least one R_A, such as 1, 2, or 3 R_A's, is not a hydrogen radical, where the crosslinked polyamine particles have one or more of the following characteristics: a) a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm; b) a particle size distribution where from 5 vol.% to 100 vol.% of the crosslinked polyamine particles have a particle size of greater than 500 μm; c) a particle size distribution such that no more than 20 vol.% of the crosslinked polyamine particles have a particle size less than 300 μm; d) a particle size distribution such that the crosslinked polyamine particles have a d₁₀ value that is between 250 μm and 750 μm e) a particle size distribution such that the crosslinked polyamine particles have a dc>o value that is between 900 μm and 1600 μm; f) a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 450 μm and 1100 μm; g) from 75 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is -5/+60; h) from 5 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is +35; i) no more than 20 wt.% of the crosslinked polyamine particles have a mesh size that is -50; j) from 40 wt.% to 60 wt.% of the crosslinked polyamine particles have a mesh size that is -16/+40; k) a mean gray value greater than 180; 1) comprises 2 or more constituent particles; and/or m) a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g. [0031] Preferred embodiments of the amine compounds according to Formula I include:

Formula II Formula III

Formula IV Formula V

Formula VI

Formula VII,

[0032] where R and Rj are as defined above and where R₂ and R₃ each, independently, represents a branched or unbranched, substituted or un-substituted alkyl radical, for example a C₁ to C₂₀ alkyl radical such as a Ci, C₂, C₃, C₄, C₅, or C₆ alkyl radical; a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical, a substituted or unsubstituted C₄ to Qo, such as a C₄, C₅, C₆, or C₇ aryl or heteroaryl radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or a substituted or unsubstituted C₄ to C₁₀, such as a C₄, C₅, C₆, or C₇, alicyclic or heterocyclic radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or two Ri 's may combine to form a substituted or unsubstituted heteroaryl or heterocyclic radical, which may contain from 0 to 4, such as 1 , 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms. Some examples of such amine compounds include, for example,

Formula VIII Formula IX Formula X

Formula XI Formula XII

[0033] including amine compounds such as:

Formula XIII Formula XIV Formula XV

Formula XVI Formula XVII

Formula XVIII

Formula XIX

Formula XX

Formula XXIII

Formula XXV

Formula XXVI

[0034] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, where the crosslinked polyamine particles comprise or are derived from an amine compound or residue thereof and a crosslinking agent or residue thereof, said amine compound represented by the following Formula XXVII:

Formula XXVII where R, independently, represents a branched or unbranched, substituted or un- substituted alkyl radical, for example a C₁ to C₂₀ alkyl radical such as a Ci, C₂, C₃, C₄, C₅, or C₆ alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical, a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇ aryl or heteroaryl radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇, alicyclic or heterocyclic radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, where the crosslinked polyamine particles have one or more of the following characteristics: a) a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm; b) a particle size distribution where from 5 vol.% to 100 vol.% of the crosslinked polyamine particles have a particle size of greater than 500 μm; c) a particle size distribution such that no more than 20 vol.% of the crosslinked polyamine particles have a particle size less than 300 μm; d) a particle size distribution such that the crosslinked polyamine particles have a dio value that is between 250 μm and 750 μm e) a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 900 μm and 1600 μm; f) a particle size distribution such that the crosslinked polyamine particles have a d₅o between 450 μm and 1100 μm; g) from 75 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is -5/+60; h) from 5 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is +35; i) no more than 20 wt.% of the crosslinked polyamine particles have a mesh size that is -50; j) from 40 wt.% to 60 wt.% of the crosslinked polyamine particles have a mesh size that is -16/+40; k) a mean gray value greater than 180; 1) comprises 2 or more constituent particles; and/or m) a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

[0035] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, where the crosslinked polyamine particles comprise or are derived from an amine compound or residue thereof and a crosslinking agent or residue thereof, said amine compound represented by the following Formula XXVIII:

Formula XXVIII

[0036] where each RB, independently, represents hydrogen, -R₄, or -R₄-N(R₅)_2-m-(R-N(R₅)₂._n-(R₄-N(R₅)₂)_n)_m; each n and each m, independently, represents an integer from 0 to 2, such as 0, 1 or 2; each R₄, independently, represents a branched or unbranched, substituted or un-substituted alkyl radical, for example a Ci to C₂₀ alkyl radical such as a Ci, C₂, C₃, C₄, C₅ or C₆ alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical, a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇ aryl or heteroaryl radical, which may contain from 0 to 4, such as 1 , 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇, alicyclic or heterocyclic radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms; and each R₅, independently, represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical, for example a Ci to C₂₀ alkyl radical such as a Ci, C₂, C₃, C₄, C₅, or C₆ alkyl radical; a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical, a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇ aryl or heteroaryl radical, which may contain from 0 to 4, such as 1, 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or a substituted or unsubstituted C₄ to Ci₀, such as a C₄, C₅, C₆, or C₇, alicyclic or heterocyclic radical, which may contain from 0 to 4, such as 1 , 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, or two R₃ 's may combine to form a substituted or unsubstituted heteroaryl or heterocyclic radical, which may contain from 0 to 4, such as 1 , 2, 3 or 4 heteroatoms such as nitrogen and/or sulfur atoms, with the provisio that at least one R_B, such as 1 , 2, or 3 R_B'S, is not a hydrogen radical, where the crosslinked polyamine particles have one or more of the following characteristics: a) a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm; b) a particle size distribution where from 5 vol.% to 100 vol.% of the crosslinked polyamine particles have a particle size of greater than 500 μm; c) a particle size distribution such that no more than 20 vol.% of the crosslinked polyamine particles have a particle size less than 300 μm; d) a particle size distribution such that the crosslinked polyamine particles have a dio value that is between 250 μm and 750 μm e) a particle size distribution such that the crosslinked polyamine particles have a d₉o value that is between 900 μm and 1600 μm; f) a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 450 μm and 1100 μm; g) from 75 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is -5/+60; h) from 5 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is +35; i) no more than 20 wt.% of the crosslinked polyamine particles have a mesh size that is -50; j) from 40 wt.% to 60 wt.% of the crosslinked polyamine particles have a mesh size that is -16/+40; k) a mean gray value greater than 180; 1) comprises 2 or more constituent particles; and/or m) a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

[0037] Preferred embodiments of the amine compounds according to Formula XXVIII include:

Formula XXIX Formula XXX Formula XXXI

Formula XXXII

[0038] In some embodiments, the invention is, consists essentially of, or comprises crosslinked polyamine particles, a pharmaceutical composition comprising crosslinked polyamine particles or a method for removing a compound or ion, such as a phosphorous- containing compound or a phosphorous-containing ion (e.g. phosphate), from the gastrointestinal tract of an animal by administering an effective amount of crosslinked polyamine particles or a pharmaceutical composition comprising crosslinked polyamine particles, where the crosslinked polyamine particles comprise repeat units represented by the following Formula XXXIII:

Formula XXXIII

[0039] where s is an integer; and Rc independently represents a hydrogen radical, R₇, -N(Re)₂, -N⁺(R^)₃X^', -R₇-N(Rs)₂ Or -R₇-N⁺(Re)₃X^"; R₆ independently represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical, for example a Ci to C₂₀ alkyl radical such as a Cj, C₂, C₃, C₄, C₅, or C₆ alkyl radical or a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical; R₇ independently represents a branched or unbranched, substituted or un-substituted alkyl radical, for example a Ci to C₂₀ alkyl radical such as a Ci, C₂, C₃, C₄, C₅, or C₆ alkyl radical or a branched or unbranched, substituted or un-substituted alkenyl radical, for example a C₂ to C₂₀ alkenyl radical such as a C₂, C₃, C₄, C₅, C₆, or C₇ alkenyl radical, with the proviso that at least one Rc, such as 1, 2, or 3 Re's, is not a hydrogen radical, where the crosslinked polyamine particles have one or more of the following characteristics: a) a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm; b) a particle size distribution where from 5 vol.% to 100 vol.% of the crosslinked polyamine particles have a particle size of greater than 500 μm; c) a particle size distribution such that no more than 20 vol.% of the crosslinked polyamine particles have a particle size less than 300 μm; d) a particle size distribution such that the crosslinked polyamine particles have a dio value that is between 250 μm and 750 μm e) a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 900 μm and 1600 μm; f) a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 450 μm and 1 100 μm; g) from 75 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is -5/+60; h) from 5 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is +35; i) no more than 20 wt.% of the crosslinked polyamine particles have a mesh size that is -50; j) from 40 wt.% to 60 wt.% of the crosslinked polyamine particles have a mesh size that is -16/+40; k) a mean gray value greater than 180;

1) comprises 2 or more constituent particles; and/or m) a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

[0040] In some embodiments, the crosslinked polyamine particles are crosslinked with epichlorohydrin. In other embodiments, the crosslinked polyamine particles are crosslinked with dichloropropane.

[0041] In some embodiments, the composition includes a mixture of particles of more than one crosslinked polyamine of the invention, for example 2-20 such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 crosslinked polyamines of the invention.

[0042] In some embodiments, it has been found that the size and/or size distribution of the crosslinked polyamine particles of the invention affect the ion binding, such as the phosphate binding properties of the polymers. In some embodiments, crosslinked polyamine particles of the invention may exhibit enhanced phosphate binding in the presence of competing organic ions throughout a physiologically significant time period while having similar equilibrium phosphate binding properties when compared to smaller particles of the same polymer.

[0043] The particle size of the crosslinked polyamine particles may be determined according to the procedure detailed in the Test Procedures. In some embodiments, crosslinked polyamine particles have a particle size distribution such that 75 vol.% or greater, such as 80 vol.% or greater, 85 vol.% or greater, 90 vol.% or greater, 95 vol.% or greater, 99 vol.% or greater, or 100 vol.% of the crosslinked polyamine particles have a particle size between 250 μm and 4 mm, such as between 275 μm and 3.5 mm, between 300 μm and 3.0 mm, between 300 μm and 2.5 mm, between 300 μm and 2.0 mm, between 325 μm and 2.5 mm, between 350 μm and 2.0 mm, between 375 μm and 1.75 mm, between 400 μm and 1500 μm, between 425 μm and 1400 μm, between 450 μm and 1300 μm, between 475 μm and 1200 μm, between 500 μm and 1100 μm, or between 525 μm and 1075 μm.

[0044] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that greater than 5 vol.%, greater than 10 vol.%, greater than 20 vol.%, greater than 30 vol.%, greater than 40 vol.%, greater than 50 vol.%, greater than 60 vol.%, greater than 70 vol.%, greater than 80 vol.%, greater than 90 vol.% or greater than 95 vol.% of the crosslinked polyamine particles have a particle size of greater than 450 μm, such as greater than 500 μm, greater than 525 μm, greater than 550 μm, greater than 575 μm, greater than 600 μm, greater than 625 μm, greater than 650 μm, greater than 675, greater than 700 μm, greater than 725 μm, greater than 750 μm or greater than 775 μm.

[0045] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that greater than 5 vol.%, greater than 10 vol.%, greater than 20 vol.%, greater than 30 vol.%, greater than 40 vol.%, greater than 50 vol.%, greater than 60 vol.%, greater than 70 vol.%, greater than 80 vol.%, greater than 90 vol.% or greater than 95 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 2.0 mm, such as between 525 μm and 1800 μm, between 550 μm and 1600 μm, between 575 μm and 1550 μm, between 600 μm and 1500 μm, between 625 μm and 1475 μm, between 650 μm and 1450 μm, between 675 μm and 1425 μm, between 700 μm and 1400 μm, between 725 μm and 1375 μm, between 750 μm and 1350 μm or between 775 μm and 1300 μm. [0046] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that from 5 to 100 vol.%, 10 to 90 vol.%, 20 to 80 vol.%, 30 to 70 vol.%, 40 to 60 vol.% or 50 vol.% of the crosslinked polyamine particles have a particle size of greater than 450 μm, such as greater than 500 μm, greater than 525 μm, greater than 550 μm, greater than 575 μm, greater than 600 μm, greater than 625 μm, greater than 650 μm, greater than 675 μm, greater than 700 μm, greater than 725 μm, greater than 750 μm or greater than 775 μm.

[0047] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that from 5 to 100 vol.%, 10 to 90 vol.%, 20 to 80 vol.%, 30 to 70 vol.%, 40 to 60 vol.% or 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 2.0 mm, such as between 525 μm and 1800 μm, between 550 μm and 1600 μm, between 575 μm and 1550 μm, between 600 μm and 1500 μm, between 625 μm and 1475 μm, between 650 μm and 1450 μm, between 675 μm and 1425 μm, between 700 μm and 1400 μm, between 725 μm and 1375 μm, between 750 μm and 1350 μm or between 775 μm and 1300 μm.

[0048] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that no more than 0 to 20 vol.%, such as no more than 5 to 15 vol.%, such as no more than 5 vol.%, 10 vol.%, 15 vol.% or 20 vol.% of the crosslinked polyamine particles have a particle size of less than about 300 μm. In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that no more than 0 to 25 vol.%, such as no more than 5 to 20 vol.%, such as no more than 5 vol.%, 10 vol.%, 15 vol.%, 20 vol.% or no more than 25 vol.% of the crosslinked polyamine particles have a particle size of less than about 350 μm. In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that no more than 0 to 35 vol.%, such as no more than 5 to 30 vol.%, such as no more than 10 vol.%, 15 vol.%, 20 vol.%, 25 vol.% or no more than 30 vol.% of the crosslinked polyamine particles have a particle size of less than about 400 μm. In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that no more than 0 to 40 vol.%, such as no more than 5 to 35 vol.%, such as no more than 10 vol.%, 15 vol.%, 20 vol.%, 25 vol.%, 20 vol.%, 35 vol.% or no more than 40 vol.% of the crosslinked polyamine particles has a particle size of less than about 450 μm.

[0049] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that dio is greater than 225 μm, such as greater than 250 μm, greater than 275 μm, greater than 300 μm, greater than 325 μm, greater than 350 μm, greater than 375 μm, greater than 400 μm, greater than 425, μm, greater than 450 μm, greater than 475 μm, greater than 500 μm, greater than 525 μm, or greater than 550 μm. [0050] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that dio is between 275 μm and 725 μm, between 300 μm and 700 μm, between 325 μm and 675 μm, between 350 μm and 650 μm, between 375 μm and 625 μm.

[0051] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that d₉₀ is less than 1650 μm, such as less than 1600 μm, less than 1550 μm, less than 1500 μm, less than 1475 μm, less than 1450 μm, less than 1425 μm, less than 1400 μm, less than 1350 μm, less than 1300 μm. [0052] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that d₉o is between 900 μm and 1600 μm, such as between 925 μm and 1550 μm, between 950 μm and 1525 μm, between 975 μm and 1500 μm, between 1000 μm and 1475 μm, between 1025 μm and 1450 μm, between 1050 μm and 1425 μm, between 1075 μm and 1400 μm, between 1100 μm and 1400 μm, between 1100 μm and 1375 μm, between 1100 μm and 1350 μm or between 1100 μm and 1325 μm.

[0053] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that dio is greater than 225 μm, such as greater than 250 μm, greater than 275 μm, greater than 300 μm, greater than 325 μm, greater than 350 μm, greater than 375 μm, greater than 400 μm, greater than 425, μm, greater than 450 μm, greater than 475 μm, greater than 500 μm, greater than 525 μm, or greater than 550 μm and d₉₀ is less than 1650 μm, such as less than 1600 μm, less than 1550 μm, less than 1500 μm, less than 1475 μm, less than 1450 μm, less than 1425 μm, less than 1400 μm, less than 1350 μm, less than 1300 μm.

[0054] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that d₁₀ is greater than 225 μm, such as greater than 250 μm, greater than 275 μm, greater than 300 μm, greater than 325 μm, greater than 350 μm, greater than 375 μm, greater than 400 μm, greater than 425, μm, greater than 450 μm, greater than 475 μm, greater than 500 μm, greater than 525 μm, or greater than 550 μm and d₉₀ is between 900 μm and 1600 μm, such as between 925 μm and 1550 μm, between 950 μm and 1525 μm, between 975 μm and 1500 μm, between 1000 μm and 1475 μm, between 1025 μm and 1450 μm, between 1050 μm and 1425 μm, between 1075 μm and 1400 μm, between 1100 μm and 1400 μm, between 1100 μm and 1375 μm, between 1100 μm and 1350 μm or between 1100 μm and 1325 μm.

[0055] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that d₁₀ is between 275 μm and 725 μm, between 300 μm and 700 μm, between 325 μm and 675 μm, between 350 μm and 650 μm, between 375 μm and 625 μm and d₉₀ is less than 1650 μm, such as less than 1600 μm, less than 1550 μm, less than 1500 μm, less than 1475 μm, less than 1450 μm, less than 1425 μm, less than 1400 μm, less than 1350 μm, less than 1300 μm.

[0056] In some embodiments of the invention, the crosslinked polyamine particles have a particle size distribution such that d₁₀ is between 275 μm and 725 μm, between 300 μm and 700 μm, between 325 μm and 675 μm, between 350 μm and 650 μm, between 375 μm and 625 μm and d₉₀ is between 900 μm and 1600 μm, such as between 925 μm and 1550 μm, between 950 μm and 1525 μm, between 975 μm and 1500 μm, between 1000 μm and 1475 μm, between 1025 μm and 1450 μm, between 1050 μm and 1425 μm, between 1075 μm and 1400 μm, between 1100 μm and 1400 μm, between 1 100 μm and 1375 μm, between 1100 μm and 1350 μm or between 1100 μm and 1325 μm. [0057] In some embodiments of the invention, the crosslinked polyamine particles have a d₅₀ that is greater than 450 μm, such as greater than 475 μm, greater than 500 μm, greater than 525 μm, greater than 550 μm, greater than 575 μm, greater than 600 μm, greater than 625 μm, greater than 650 μm, greater than 675 μm or greater than 700 μm. [0058] In some embodiments of the invention, the crosslinked polyamine particles have a d₅₀ between 450 μm and 1100 μm, such as between 475 μm and 1050 μm, between 500 μm and 1025 μm, between 525 μm and 1000 μm, between 550 μm and 975 μm, between 575 μm and 950 μm, between 600 μm and 925 μm, between 625 μm and 900 μm, between 650 μm and 875 μm, between 675 μm and 850 μm or between 700 μm and 825 μm. In some embodiments, the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm.

[0059] In some embodiments, crosslinked polyamine particles of the invention may be sized according to sieve size with a "+" indicating that the crosslinked polyamine particles are held back by a sieve of the indicated mesh size and a "-" indicating that the crosslinked polyamine particles pass through a sieve of the indicated mesh size. Thus a crosslinked polyamine particle that passes through a No. 5 mesh sieve but is held back by a No. 20 mesh sieve is designated as being -5/+20. All references to mesh size described herein refer to mesh sizes that are U.S. Standard and in conformance with ASTM E-I l . In some embodiments, from 75 wt.% to 100 wt.%, such as 80 wt.%, 85 wt.%, 90 wt.% or 95 wt.% of the crosslinked polyamine particles have a mesh size that is -5, -6, -7, -8, -10, 12, -14, - 16, -18, -20, or -25. In some embodiments from 50 to 100 wt.% such as 55 wt.%, 60 wt.%, 65 wt.%, 70 wt.%, 75 wt.%, 80 wt.%, 85 wt.%, 90 wt.% or 95 wt.% of the crosslinked polyamine particles have a mesh size that is +60, +50, +45, +40, +35 or +30. In some embodiments, from 50 wt.% to 100 wt.% such as 55 wt.%, 60 wt.%, 65 wt.%, 70 wt.%, 75 wt.%, 80 wt.%, 85 wt.%, 90 wt.% or 95 wt.% of the crosslinked polyamine particles have a mesh size that is -5/+60, such as -6/+60, -7/+60, -8/+60, -10/+60, -12/+60, -14/+60, -16/+50, -18/+50, -20/+50, -25/+45, -25/+40, -25/+35 or -25/+30. In some embodiments, from 40 wt.% to 60 wt.% of the crosslinked polyamine particles have a mesh size that is -16/+40 mesh, such as -18/+35, -20/+35, -20/+30 or -20/+25. [0060] In some embodiments of the invention, from 5 to 100 wt.% of the crosslinked polyamine particles, such as 10 to 90 wt.%, 20 to 80 wt.%, 30 to 70 wt.%, 40 to 60 wt.% or 50 wt.% of the crosslinked polyamine particles have a mesh size that +35 mesh, such as +30, +25, +20, +18, +16, or +14 mesh.

[0061] In some embodiments of the invention, greater than 10 wt.%, greater than 20 wt.%, greater than 30 wt.%, greater than 40 wt.%, greater than 50 wt.%, greater than 60 wt.%, greater than 70 wt.%, greater than 80 wt.%, greater than 90 wt.% or greater than 95 wt.% of the crosslinked polyamine particles have a mesh size that +35 mesh, such as +30, +25, +20, +18, +16, or +14 mesh.

[0062] In some embodiments of the invention, no more than 0 to 20 wt.%, such as no more than 5 to 15 wt.%, such as no more than 10 wt.% of the crosslinked polyamine particles have a mesh size that is -50. In some embodiments of the invention, no more than 0 to 25 wt.%, such as no more than 5 to 20 wt.%, such as no more than 10 wt.% or no more than 15 wt.% of the crosslinked polyamine particles have a mesh size that is -45. In some embodiments of the invention, no more than 0 to 35 wt.%, such as no more than 5 to 35 wt.%, such as no more than 10 wt.%, 15 wt.%, 20 wt.%, 25 wt.% or no more than 20 wt.% of the crosslinked polyamine particles have a mesh size that is -40. In some embodiments of the invention, no more than 0 to 45 wt.%, such as no more than 5 to 30 wt.%, such as no more than 10 wt.%, 15 wt.%, 20 wt.%, 25 wt.%, 30 wt.%, 35 wt.%, or no more than 40 wt.% have a mesh size that is -35.

[0063] In some embodiments, crosslinked polyamine particles of the invention may have any one or more of the particle size characteristics described herein prior to being formulated into a final dosage form, while in other embodiments, crosslinked polyamine particles of the invention may have any one or more of the particle size characteristics described herein when in a final dosage form. In some embodiments, any of the particle size characteristics described above may be determined prior to tableting. In other embodiments, any of the particle size characteristics described above may be determined after tableting has occurred.

[0064] Any suitable method of controlling or achieving the desired particle size may be used. For example, the particle size of the crosslinked polyamine particles may be controlled by controlling various polymerization process parameters such as temperature, monomer and crosslinker concentration, solvent, monomer to solvent ratio, pH, infusion rate, mixing rate, and by selecting the downstream process and processing parameters. For example, the particle size may be affected by the orifice size of a spray dryer nozzle and the height of a spray drying tower or the drying temperature. In addition, after polymerization, the crosslinked polyamine particles may be further processed to achieve the desired particle size such as ground using a grinder or a mill or selectively sieved. Any suitable method of controlling or achieving the desired particle size may be used. Specific suitable downstream processing methods include, but are not limited to grinding, wet or dry milling, spray drying, sieving, precipitation, and spray-freezing. In some embodiments, the down stream processing methods comprise wet milling. [0065] In some embodiments, it has been found that the size and/or size distribution of the crosslinked polyamine particles of the invention affect the ion binding, such as the phosphate binding properties of the polymers. In some embodiments, crosslinked polyamine particles of the invention may exhibit enhanced phosphate binding in the presence of competing organic ions throughout a physiologically significant time period while having similar equilibrium phosphate binding properties when compared to smaller particles of the same polymer.

[0066] Accordingly, in some embodiments, the crosslinked polyamine particles may have one or more of the following particle size characteristics, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or even all 10 of the following particle size characteristics as discussed above: a) a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm; b) a particle size distribution where from 5 vol.% to 100 vol.% of the crosslinked polyamine particles have a particle size of greater than 500 μm; c) a particle size distribution such that no more than 20 vol.% of the crosslinked polyamine particles have a particle size less than 300 μm; d) a particle size distribution such that the crosslinked polyamine particles have a diQ value that is between 250 μm and 750 μm e) a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 900 μm and 1600 μm; f) a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 450 μm and 1100 μm; g) from 75 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is -5/+60; h) from 5 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is +35; i) no more than 20 wt.% of the crosslinked polyamine particles have a mesh size that is -50; and/or j) from 40 wt.% to 60 wt.% of the crosslinked polyamine particles have a mesh size that is -16/+40.

[0067] Thus, by way of example, in some embodiments, the crosslinked polyamines may have 3 of the above particle size characteristics such as a, e and h (or aeh) and would thus have a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm, a particle size distribution such that the crosslinked polyamine particles have a d₉o value that is between 900 μm and 1600 μm and from 5 wt.% to 100 wt.% of the crosslinked polyamine particles have a mesh size that is +35. Accordingly it should be understood that the crosslinked polyamine particles may have any one or more of the above characteristics in any combination. Similarly, when any characteristics herein are provided in a list that includes "and/or" it should be understood that each and every possible permutation of combinations of those characteristics are specifically disclosed and included herein.

[0068] In addition, it should be understood that each of the characteristics identified herein by a letter such as "a)" may be any permutation of that same characteristic as discussed in the various detail paragraphs herein. For example, characteristic "a)" refers to a particle size distribution such that 75 vol.% or greater of the crosslinked polyamine particles have a size of between 250 μm and 4 mm. This reference however should be understood to encompass the detailed discussion of this characteristic above where it is shown that characteristic "a)" refers to particles having a particle size distribution such that 75 vol.% or greater, such as 80 vol.% or greater, 85 vol.% or greater, 90 vol.% or greater, 95 vol.% or greater, 99 vol.% or greater, or 100 vol.% of the crosslinked polyamine particles have a particle size between 250 μm and 4 mm, such as between 275 μm and 3.5 mm, between 300 μm and 3.0 mm, between 300 μm and 2.5 mm, between 300 μm and 2.0 mm, between 325 μm and 2.5 mm, between 350 μm and 2.0 mm, between 375 μm and 1.75 mm, between 400 μm and 1500 μm, between 425 μm and 1400 μm, between 450 μm and 1300 μm, between 475 μm and 1200 μm, between 500 μm and 1100 μm, or between 525 μm and 1075 μm. Each of the individual characteristics identified by letters in this application should be understood to refer to their detail paragraph or paragraphs discussed elsewhere in this application.

[0069] In some embodiments, crosslinked polyamine particles according to the invention exhibit special optical characteristics, such as optical density. In some embodiments, the crosslinked polyamine particles may have a mean gray value of greater than 180, such as a mean gray value of greater than 185, greater than 190, greater than 195, greater than 200, greater than 205, greater than 210, greater than 215 or greater than 220. In some embodiments, crosslinked polyamine particles according to the invention have a mean gray value that is between 180 and 230, such as between 185 and 225, between 190 and 215, between 190 and 210, between 195 and 205 or between 195 and 200. The mean gray value may be measured according to the techniques described in the Test Methods section below.

[0070] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles of the crosslinked polyamine polymers. In some embodiments, the constituent particles may have a particle size distribution such that greater than 70%, such as greater than 80 vol.%, such as greater than 85 vol.%, greater than 90 vol.%, greater than 95 vol.%, greater than 99 vol.% or 100 vol.% of the constituent particles have particle size between 10 μm and 850 μm, such as between 10 μm and 800 μm, between 10 μm and 750 μm, between 10 μm and 650 μm, between 10 μm and 550 μm, between 10 μm and 450 μm, between 10 μm and 400 μm, between 20 μm and 650 μm, between 30 μm and 550 μm, between 40 μm and 450 μm, between 50 μm and 400 μm, between 55 μm and 750 μm, between 55 μm and 650 μm, between 55 μm and 550 μm, between 55 μm and 500 μm, between 55 μm and 450 μm, between 55 μm and 400 μm, between 60 μm and 350 μm, between 65 μm and 300 μm, between 70 μm and 250 μm, between 75 μm and 200 μm, between 85 μm and 150 μm, between 90 μm and 125 μm or between 90 μm and 105 μm. [0071] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a dj₀ value between 20 μm and 100 μm, such as between 20 μm and 70 μm, between 25 μm and 60 μm, between 28 μm and 53 μm, or between 30 μm and 50 μm. [0072] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a d₁₀ value greater than 20 μm, greater than 25 μm, greater than 28 μm or greater than 30 μm.

[0073] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a dgo value that is between 120 μm and 450 μm, such as between 150 μm and 400 μm, between 175 μm and 350 μm, between 175 μm and 300 μm, between 175 μm and 275 μm or between 175 μm and 250 μm.

[0074] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a d₉₀ value that is less than 450 μm, such as less than 425 μm, less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm, less than 300 μm, less than 275 μm or less than 250 μm.

[0075] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a dio value between 20 μm and 100 μm, such as between 20 μm and 70 μm, between 25 μm and 60 μm, between 28 μm and 53 μm, or between 30 μm and 50 μm and a dgo value that is between 120 μm and 450 μm, such as between 150 μm and 400 μm, between 175 μm and 350 μm, between 175 μm and 300 μm, between 175 μm and 275 μm or between 175 μm and 250 μm.

[0076] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a djo value between 20 μm and 100 μm, such as between 20 μm and 70 μm, between 25 μm and 60 μm, between 28 μm and 53 μm, or between 30 μm and 50 μm and a d₉o value that is less than 450 μm, such as less than 425 μm, less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm, less than 300 μm, less than 275 μm or less than 250 μm.

[0077] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a d₁₀ value greater than 20 μm, greater than 25 μm, greater than 28 μm or greater than 30 μm and a d₉₀ value that is between 120 μm and 450 μm, such as between 150 μm and 400 μm, between 175 μm and 350 μm, between 175 μm and 300 μm, between 175 μm and 275 μm or between 175 μm and 250 μm.

[0078] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a d₁₀ value greater than 20 μm, greater than 25 μm, greater than 28 μm or greater than 30 μm and a d₉₀ value that is less than 450 μm, such as less than 425 μm, less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm, less than 300 μm, less than 275 μm or less than 250 μm.

[0079] In some embodiments, the crosslinked polyamine particles described herein may comprise constituent particles or may comprise aggregates of constituent particles where the constituent particles have a d₅₀ between 50 μm and 200 μm, such as between 50 μm and 175 μm, between 50 μm and 150 μm, between 50 μm and 120 μm, between 70 μm and 120 μm or between 70 μm and 100 μm.

[0080] In some embodiments, the crosslinked polyamine particles comprise 2 or more constituent particles, such as from 2 to 10,000 constituent particles, such as from 10 to 9000 constituent particles, from 100 to 8000 constituent particles, from 150 to 7000 constituent particles, from 200 to 6000 constituent particles, from 250 to 5000 constituent particles, from 275 to 4000 constituent particles, from 300 to 3500 constituent particles, from 350 to 3000 constituent particles, from 400 to 2500 constituent particles, from 450 to 2000 constituent particles, from 500 to 1500 constituent particles, from 600 to 1250 constituent particles, from 700 to 1000 constituent particles. In some embodiments, the crosslinked polyamine particles comprise from 500 to 1000 constituent particles. [0081] In some embodiments, the crosslinked polyamine particles comprise aggregates of 2 or more constituent particles, such as from 2 to 10,000 constituent particles, such as from 10 to 9000 constituent particles, from 100 to 8000 constituent particles, from 150 to 7000 constituent particles, from 200 to 6000 constituent particles, from 250 to 5000 constituent particles, from 275 to 4000 constituent particles, from 300 to 3500 constituent particles, from 350 to 3000 constituent particles, from 400 to 2500 constituent particles, from 450 to 2000 constituent particles, from 500 to 1500 constituent particles, from 600 to 1250 constituent particles, from 700 to 1000 constituent particles. In some embodiments, the crosslinked polyamine particles comprise aggregates of from 500 to 1000 constituent particles.

[0082] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles. In some embodiments, the constituent particles may have a particle size distribution such that greater than 70%, such as greater than 80 vol.%, such as greater than 85 vol.%, greater than 90 vol.%, greater than 95 vol.%, greater than 99 vol.% or 100 vol.% of the constituent particles have particle size between 10 μm and 850 μm, such as between 10 μm and 800 μm, between 10 μm and 750 μm, between 10 μm and 650 μm, between 10 μm and 550 μm, between 10 μm and 450 μm, between 10 μm and 400 μm, between 20 μm and 650 μm, between 30 μm and 550 μm, between 40 μm and 450 μm, between 50 μm and 400 μm, between μm 55 μm and 750 μm, between 55 μm and 650 μm, between 55 μm and 550 μm, between 55 μm and 500 μm, between 55 μm and 450 μm, between 55 μm and 400 μm, between 60 μm and 350 μm, between 65 μm and 300 μm, between 70 μm and 250 μm, between 75 μm and 200 μm, between 85 μm and 150 μm, between 90 μm and 125 μm or between 90 μm and 105 μm.

[0083] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a dio value between 20 μm and 100 μm, such as between 20 μm and 70 μm, between 25 μm and 60 μm, between 28 μm and 53 μm, or between 30 μm and 50 μm. [0084] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a dio value greater than 20 μm, greater than 25 μm, greater than 28 μm or greater than 30 μm.

[0085] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a O₉₀ value that is between 120 μm and 450 μm, such as between 150 μm and 400 μm, between 175 μm and 350 μm, between 175 μm and 300 μm, between 175 μm and 275 μm or between 175 μm and 250 μm.

[0086] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a d₉₀ value that is less than 450 μm, such as less than 425 μm, less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm, less than 300 μm, less than 275 μm or less than 250 μm.

[0087] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a djo value between 20 μm and 100 μm, such as between 20 μm and 70 μm, between 25 μm and 60 μm, between 28 μm and 53 μm, or between 30 μm and 50 μm and a d₉₀ value that is between 120 μm and 450 μm, such as between 150 μm and 400 μm, between 175 μm and 350 μm, between 175 μm and 300 μm, between 175 μm and 275 μm or between 175 μm and 250 μm.

[0088] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a dio value between 20 μm and 100 μm, such as between 20 μm and 70 μm, between 25 μm and 60 μm, between 28 μm and 53 μm, or between 30 μm and 50 μm and a d₉₀ value that is less than 450 μm, such as less than 425 μm, less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm, less than 300 μm, less than 275 μm or less than 250 μm.

[0089] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a dio value greater than 20 μm, greater than 25 μm, greater than 28 μm or greater than 30 μm and a d₉₀ value that is between 120 μm and 450 μm, such as between 150 μm and 400 μm, between 175 μm and 350 μm, between 175 μm and 300 μm, between 175 μm and 275 μm or between 175 μm and 250 μm. [0090] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a particle size distribution such that the constituent particles have a d₁₀ value greater than 20 μm, greater than 25 μm, greater than 28 μm or greater than 30 μm and a dgo value that is less than 450 μm, such as less than 425 μm, less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm, less than 300 μm, less than 275 μm or less than 250 μm.

[0091] In some embodiments, the crosslinked polyamine particles described herein may comprise particles which are formed by aggregating 2 or more constituent particles where the constituent particles have a d₅₀ between 50 μm and 200 μm, such as between 50 μm and 175 μm, between 50 μm and 150 μm, between 50 μm and 120 μm, between 70 μm and 120 μm or between 70 μm and 100 μm.

[0092] In some embodiments, may comprise particles which are formed by aggregating 2 or more constituent particles, such as from 2 to 10,000 constituent particles, such as from 10 to 9000 constituent particles, from 100 to 8000 constituent particles, from 150 to 7000 constituent particles, from 200 to 6000 constituent particles, from 250 to 5000 constituent particles, from 275 to 4000 constituent particles, from 300 to 3500 constituent particles, from 350 to 3000 constituent particles, from 400 to 2500 constituent particles, from 450 to 2000 constituent particles, from 500 to 1500 constituent particles, from 600 to 1250 constituent particles, from 700 to 1000 constituent particles. In some embodiments, the crosslinked polyamine particles comprise from 500 to 1000 constituent particles. [0093] In some embodiments, aggregating 2 or more constituent particles includes hydrating constituent particles, such as suspending, forming a suspension of or forming a re-suspension of constituent particles in water. In some embodiments, forming a suspension of or forming a re-suspension of constituent particles includes protonating, such as carbonating, at least a portion of the crosslinked polyamine particles. In some embodiments, forming includes making a gel from constituent particles. In some embodiments, the gel may be dried and/or the gel may be ground, milled or wet milled. Polymerization and Production

[0094] In some embodiments, the crosslinked polyamines may be formed by crosslinking amine compounds in a bulk solution (i.e. using the amine compounds and neat crosslinking agents) or in dispersed media. When a bulk process is used, solvents are selected so that they co-dissolve the reactants and do not interfere with the crosslinking reaction. Suitable solvents include water, low boiling alcohols (methanol, ethanol, butanol), acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, methylethylketone, and the like.

[0095] Other polymerization methods may include a single polymerization reaction, stepwise addition of individual monomers via a series of reactions, the stepwise addition of blocks of monomers, combinations of the foregoing, or any other method of polymerization, such as, for example, direct or inverse suspension, condensation, phase transfer, emulsion, precipitation techniques, polymerization in aerosol or using bulk polymerization/crosslinking methods and size control processes such as extrusion and grinding. Processes can be carried out as batch, semi-continuous and continuous processes. For processes in dispersed media, the continuous phase can be selected from apolar solvents such as toluene, benzene, hydrocarbon, halogenated solvents, supercritical carbon dioxide, and the like. With a direct suspension process, water can be used, although salt brines are also useful to "salt out" the amine compounds and crosslinking agents in a droplet separate phase.

[0096] Examples of some suitable polymerization methods may be found, for example, in the following patents and patent applications each of which is incorporated herein by reference in their entirety: US 4,605,701; US 5,496,545; US 5,618,530; US 5,679,717; US 5,693,675; US 5,702,696; US WO 96/21454; WO 98/57652; EP 7372352; DE 4227019.

[0097] A non-limiting example of polymerization or crosslinking of an amine compound with epichlorohydrin may occur as follows. The amine compound may be emulsified with epichlorohydrin using a static or high shear mixer. The resulting oil-in- water emulsion may be polymerized using a batch reactor or a single screw or twin screw kneading or LIST reactor. The temperature, amine compound concentration, ratio of amine compound units to crosslinking agent, rotor speed, and/or work supplied to the reacting polymer may be controlled to help achieve the desired particle size. The polymer leaving the reactor may be suspended in a solvent, such as water, ethanol, ethanol/water mixtures, isopropanol, isopropanol/water mixtures and mixtures thereof followed by filtering and optionally re-suspending one or multiple times, may be milled, wet milled, neutralized and/or protonated using a suitable source such as HCl, CO₂ or carbonic acid, may be milled and/or may be separated before drying using centrifugal force, such as using hydrocyclones or centrifuges. The polymer may be dried using any suitable method such as using a convection oven, a vacuum oven or a fluidized bed and then may be ground, milled and/or sieved or fractionated to a particular desired mesh or particle size after drying. Alternatively, when a solvent that comprises ethanol, ethanol/water mixtures, isopropanol or isopropanol/water mixtures is used, the polymer may not need to be dried prior to grinding, milling and/or sieving or fractionating. In some embodiments, the solvent is water and the polymer is dried prior to grinding.

[0098] In some embodiments, the crosslinking reaction can be run in any suitable vessel or reactor and may be run batch-wise or in a continuous fashion. In some embodiments, the crosslinking reaction is run in a reactor designed for high viscosity processing which has agitation means capable of mixing the reactants prior to gelation and breaking the gel into small pieces or crumb after gelation. Examples of such reactors are LIST reactors, such as the LIST-DISCOTHERM B manufactured by LIST Inc. LIST reactors may be supplied for batch or continuous operation and are particularly useful for thermal processes such as drying or reactions, where mixing or kneading is necessary to process viscous, pasty, crusting or gelatinous materials such as cross-linked polyamine polymer. In some embodiments, such a reactor may include a horizontal, cylindrical housing, and a concentric agitator shaft with disc elements perpendicular to the axis carrying peripheral mixing/kneading bars. Stationary hook-shaped bars may be set in the shell and may interact with, and clean, the shaft and disk elements as they rotate. Shell, shaft, and disc elements, all of which contribute to heat transfer can be heated or cooled. The unit generally operates with a fill level of 60 to 75 percent reactor capacity. Typical shaft speeds range from 5 to 100 rotations per minute ("rpm") with high installed torque. The combined effect of the intensive mixing and kneading action and the self cleaning of the heat exchange surfaces results in high heat and mass transfer rates. In batch units the mixing bars may be arranged to perform optional mixing. For continuous operation, the arrangement of the internal geometry provides a forward plug flow movement of the material. However, the axial conveying rate is nearly independent of agitator rotation speed, making it possible to operate at high agitator rotation speeds optimizing heat and mass transfer. Furthermore, the positioning of the disc elements enables the processing of liquid feed stocks directly through to a solid free flowing material without recycling of dry product. The unique design of the LIST reactor eliminates the formation of a single, continuous, congealed mass. As gelation occurs, the self-wiping concentric agitator shaft and disc elements create easy to handle clumps of gel.

[0099] In some embodiments, after polymerization, the polymer may be hydrated and/or suspended in water, stirred until a gel forms and allowed to cure for a period of time, such as from 30 minutes to 30 hours, from 1 hour to 29 hours, from 3 hours to 28 hours, from 6 hours to 27 hours, from 9 hours to 26 hours, from 12-25 hours, such as 15- 21 hours or 17-19 hours. After curing, the gelled polymer may be broken into pieces using any suitable instrument, diluted with water and/or wet milled to a desired constituent particle size. The wet milling may use any known wet milling method and may include using a blender or homogenizer. In some embodiments, after wet milling, or after curing, the gel may be neutralized and/or washed multiple times until the gel (in suspension) has a conductivity of approximately 1 mS/cm or less. The polymer may then be protonated, for example carbonated using dry ice, CO₂ and/or carbonic acid or any other suitable carbonating system. After protonation, the gel may be dried using any suitable method such as using a convection oven, a vacuum oven and/or a fluidized bed and then may be ground, milled and/or sieved or fractionated to a particular desired particle or mesh size after drying. Alternatively, when a solvent that comprises ethanol, ethanol/water mixtures, isopropanol or isopropanol/water mixtures is used to wash the gel before or after carbonation, it may not be necessary to dry the gel prior to grinding, milling and/or sieving or fractionating. In some embodiments, the solvent is water and the polymer is dried prior to grinding.

[00100] In some embodiments, crosslinked polyamines of the invention may be formed from constituent particles of the crosslinked polyamine, which may be placed in a solvent, such as such as water, ethanol, ethanol/water mixtures, isopropanol, isopropanol/water mixtures and mixtures thereof, dried using any suitable method such as using a convection oven, a vacuum oven or a fluidized bed, and then ground, milled and/or sieved or fractionated to a particular desired particle or mesh size after drying. Alternatively, when a solvent that comprises ethanol, ethanol/water mixtures, isopropanol or isopropanol/water mixtures is used to wash the gel before or after carbonation, it may not be necessary to dry the gel prior to grinding, milling and/or sieving or fractionating. In some embodiments, the solvent is water and the polymer is dried prior to grinding.

[00101] In some embodiments, crosslinked polyamine polymers of the invention may be formed using or starting from epichlorohydrin crosslinked polyamine carbonate constituent particles. In some embodiments, epichlorohydrin crosslinked polyamine carbonate having an average particles size within the desired constituent particle size range may be suspended in a solvent such as water, ethanol, ethanol/water mixtures, isopropanol, isopropanol/water mixtures and mixtures thereof, stirred until forming a gel and then cured for from 30 minutes to 30 hours, such as from 1 hour to 29 hours, from 3 hours to 28 hours, from 6 hours to 27 hours, from 9 hours to 26 hours, from 12-25 hours, such as 15-21 hours or 17-19 hours. The gel may then be dried for from 30 minutes to 30 hours, such as from 1 hour to 29 hours, from 3 hours to 28 hours, from 6 hours to 27 hours, from 9 hours to 26 hours, from 12-25 hours, such as 15-21 hours or 17-19 hours and the dried gel may then be milled using any suitable milling or grinding equipment and sieved or fractionated to the desired particle size/particle size distribution. A solvent that comprises ethanol, ethanol/water mixtures, isopropanol or isopropanol/water mixtures may be used to wash the gel after curing and it may not be necessary to dry the gel prior to grinding, milling and/or sieving or fractionating. In some embodiments, the solvent is water and the polymer is dried prior to grinding.

[00102] In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises an ethanol/water mixture such as from 5 wt.% to 95 wt.% ethanol and from 5 wt.% to 95 wt.% water. In some embodiments, the solvent comprises an isopropanol/water mixture such as from 5 wt.% to 95 wt.% isopropanol and from 5 wt.% to 95 wt.% water.

[00103] In some embodiments, the gel may be cured at room temperature. In other embodiments, the gel may be cured at an elevated temperature such as from 30 °C to 65 °C. In some embodiments, the gel may be dried in a forced air oven. In other embodiments, the gel may be dried in a vacuum oven. In other embodiments, the gel may be dried in a fluidized bed. Any suitable drying temperature may be used. In some embodiments, the drying temperature may be from 15 °C to 75 °C, such as from 20 °C to 75 °C, from 25 °C to 70 °C from 30 °C to 70 °C, 35 ⁰C to 65 ⁰C, from 40 ⁰C to 65 °C, from 45 °C to 60 °C or from 50 ⁰C to 60 °C.

[00104] In some embodiments, the polymer or polymer gel may be ground, wet milled and/or milled. Any suitable grinding or milling equipment may be used including manual grinding techniques such as mortar and pestle, potato or other mashers and automated grinding or milling using equipment such as blenders, grinders and mills including coffee grinders, industrial or other commercial blenders. In some embodiments, the polymer or polymer gel may be milled or ground using a jet-mill, a fluidized jet-mill, a pin-mill, a cosmomizer, a cavitation-mill and/or a dispersion mill. Examples of some suitable milling techniques may be found in Lachman et al, The Theory and Practice of Industrial Pharmacy (1986), the entire contents of which is hereby incorporated by reference. In some embodiments, the grinding or milling may be conducted in the presence of various grinding media that may assist in the grinding. [00105] Any suitable method of controlling or achieving the desired particle size may be used. The particle size of the crosslinked polyamine polymers may be controlled by controlling various polymerization process parameters such as temperature, monomer and crosslinker concentration, solvent, monomer to solvent ratio, pH, infusion rate, mixing rate, and by selecting the downstream process and processing parameters. For example, the particle size may be affected by the orifice size of a spray dryer nozzle and the height of a spray drying tower or the drying temperature. In addition, after polymerization, the particles may be further processed to achieve the desired particle size such as ground using a grinder or a mill or selectively sieved. Specific suitable downstream processing methods include, but are not limited to grinding, milling, wet milling, spray drying, sieving, precipitation, suspension or re-suspension and filtration, separation using passive or active centrifugal forces, spray-freezing and any combination thereof. [00106] In some embodiments, the crosslinked polyamine particles may be formed using a ratio of (amine compound + crosslinker) : solvent of between about 10:1 to about 1 :10 (w/w), such as between about 7:1 to about 1 :7 (w/w), between about 5:1 to about 1 :5 (w/w), between about 4: 1 to about 1 :4 (w/w), between about 3.5:1 to about 1 :3.5 (w/w), between about 3:1 to about 1 :3 (w/w), between about 2.5:1 to about 1 :2.5 (w/w), between about 2:1 to about 1 :2 (w/w), or between about 1.5:1 to about 1 :1.5 (w/w). [00107] In some embodiments, crosslinked polyamine particles of the invention may not dissolve in solvents, and, at most, swell in solvents. The swelling ratio may be calculated according to the procedure in the Test Methods section below and is typically in the range of about 1 to about 150, such as about 2.5 to about 150, about 5 to about 150, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, or about 5 to about 20; for example, 1 to 20, 2.5 to 19, 5 to 18, 5 to 16 or 5 to 15, such as greater than 1 and less than 50, greater than 2.5 and less than 45, greater than 5 and less than 40, greater than 5 and less than 20, greater than 9 and less than 20, greater than 11 and less than 20, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or more.

[00108] Crosslinking agents are typically compounds having at least two functional groups that are selected from a halogen 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 carbon backbone or to a nitrogen of an amine polymer, amine monomer or residue thereof. [00109] Examples of crosslinking agents that are suitable for synthesis of the crosslinked polyamine particles of the present invention include, but are not limited to, one or more multifunctional crosslinking agents such as: dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl)amines, diepoxides, triepoxides, tetraepoxides, bis(halomethyl) benzenes, tri(halomethyl) benzenes, tetra(halomethyl) benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin, poly(epichlorohydrin), (iodomethyl)oxirane, bromo-l,2-epoxybutane, 1 ,2-dibromoethane, 1,3-dichloropropane, 1 ,2-dichloroethane, 1 -bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene diepoxide, methyl acrylate and the like. When the crosslinking agent is an alkylhalide compound, a base may be used to scavenge the acid formed during the reaction. Inorganic or organic bases are suitable. NaOH is preferred. The base to crosslinking agent ratio may be between about 0.5 to about 2. [00110] In some embodiments, the crosslinking agents may be used in the crosslinking reaction in an amount of from 7 wt.% to 70 wt%, such as from about 8 wt.% to about 65 wt.%, about 10 wt.% to about 65 wt.%, about 15 wt.% to about 60 wt. %, about 20 wt.% to about 60 wt.%, about 25 wt.% to about 60 wt. %, about 30 wt.% to about 60 wt.%, about 35 wt.% to about 55 wt. %, about 40 wt.% to about 55 wt.% or about 45 wt.% to about 55 wt.%. In some embodiments, the crosslinking agents may be used in the crosslinking reaction an amount of from about 8 wt.% to 11 wt.%, from about 9 wt.% to about 10.4 wt.% or from about 9.4 wt.% to about 10.2 wt.%, such as 8, 9, 9.4, 9.8 or 10 wt.%.

[00111] In some embodiments, the weight averaged molecular weight of the polymers and copolymers may be typically at least about 1000. For example, the molecular weight may be from about 1000 to about 1,000,000, such as about 2000 to about 750,000, about 3000 to about 500,000, about 5000 to about 250,000, about 10000 to about 100,000, such as from 15,000-80,000, 20,000 to 75,000, 25,000 to 60,000, 30,000 to 50,000, or 40,000 to 45,000.

[00112] The crosslinked polyamine polymers of some embodiments may be formed using a polymerization initiator. Generally, any initiator may be used including cationic and radical initiators. Some examples of suitable initiators that may be used include: the free radical peroxy and azo type compounds, such as azodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2'-azobis(isobutyronitrile), 2,2'- azobis(N,N'-dimethyleneisobutyramidine)dihydrochloride, 2,2'-azobis(2- amidinopropane)dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine), 1,1 '- azobis(l-cyclohexanecarbo-nitrile), 4,4'-azobis(4-cyanopentanoic acid), 2,2'- azobis(isobutyramide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2- methylbutyronitrile), VAZO 67, cyanopentanoic acid, the peroxy pivalates, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, dimethyl bis(butylperoxy) hexane.

[00113] In some embodiments, any of the nitrogen atoms within the crosslinked polyamine particles according to embodiments of the invention may optionally be quaternized to yield the corresponding positively charged tertiary nitrogen group, such as for example, an ammonium or substituted ammonium group. Any one or more of the nitrogen atoms in the crosslinked polyamines may be quaternized and such quaternization, when present, is not limited to or required to include terminal amine nitrogen atoms. In some embodiments, this quaternization may result in additional network formation and may be the result of addition of crosslinking, linking or amine reactive groups to the nitrogen. The ammonium groups may be associated with a pharmaceutically acceptable counterion.

[00114] In some embodiments, crosslinked polyamine particles of the invention may be partially or fully quaternized, including protonated, and may have a pharmaceutically acceptable counterion, which may be organic ions, inorganic ions, or a combination thereof. Examples of some suitable inorganic ions include halides (e.g., chloride, bromide or iodide) carbonates, bicarbonates, sulfates, bisulfates, hydroxides, nitrates, persulfates and sulfites. Examples of some suitable organic ions include acetates, ascorbates, benzoates, citrates, dihydrogen citrates, hydrogen citrates, oxalates, succinates, tartrates, taurocholates, glycocholates, and cholates. Preferred counterions include chlorides and carbonates.

[00115] In some embodiments, crosslinked polyamine particles of the invention may be protonated such that the fraction of protonated nitrogen atoms is from 1% to 100%, such as 10% to 75%, 20% to 60%, 25%% to 55%, 30% to 50%, 35% to 45% or about 40%. [00116] In one embodiment, the pharmaceutically acceptable crosslinked polyamine particles are in partially or fully protonated form and comprise a carbonate anion. In one embodiment, the pharmaceutically acceptable crosslinked polyamine particles are in partially or fully protonated form and comprise a mixture of carbonate and bicarbonate counterions. [00117] In some embodiments, crosslinked polyamine particles of the invention are characterized by their ability to bind compounds or ions. Preferably the crosslinked polyamine particles of the invention bind anions, more preferably they bind organophosphates, phosphate and/or oxalate, and most preferably they bind phosphate. For illustration, anion-binding crosslinked polyamine particles and especially organophosphate or phosphate-binding crosslinked polyamine particles will be described; however, it is understood that this description applies equally, with appropriate modifications that will be apparent to those of skill in the art, to other ions, compounds and solutes. While not wishing to be bound by any theory, crosslinked polyamine particles are believed to bind an ion, e.g., an anion, when they associate with the ion, generally though not necessarily in a noncovalent manner, with sufficient association strength that at least a portion of the ion remains bound under the in vitro or in vivo conditions in which the polymer is used for sufficient time to effect a removal of the ion from solution or from the body. A target ion may be an ion to which the crosslinked polyamine particles bind, and usually refers to the ion whose binding to the crosslinked polyamine particles is thought to produce the therapeutic effect of the crosslinked polyamine particles and may be an anion or a cation. Crosslinked polyamine particles of the invention may have more than one target ion.

[00118] For example, some of the crosslinked polyamine particles described herein exhibit organophosphate or phosphate binding properties. Phosphate binding capacity is a measure of the amount of phosphate ion a phosphate binder can bind in a given solution. Some embodiments of the crosslinked polyamine particles of the invention have an in vitro non-competitive phosphate binding capacity which is greater than about 0.2, 0.4, 0.5, 1.0, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, greater than about 12, or up to about 14, mmol/g. In some embodiments, the in vitro noncompetitive phosphate binding capacity of crosslinked polyamine particles of the invention is greater than about 0.4 mmol/g, greater than about 2.5 mmol/g, greater than about 3 mmol/g, greater than about 4.5 mmol/g or greater than about 6 mmol/g. In some embodiments, the in vitro non-competitive phosphate binding capacity can be between about 0.2 mmol/g and about 14 mmol/g, such as between about 0.4 mmol/g and about 10 mmol/g, between about 1.0 mmol/g and about 8 mmol/g, between about 1.5 mmol/g and about 8 mmol/g, between about 2.0 mmol/g and about 8 mmol/g, between about 2.5 mmol/g and about 8 mmol/g, between about 3 mmol/g and about 6 mmol/g or between about 3 mmol/g and about 5 mmol/g. The in vitro non-competitive phosphate binding capacity may be measured according to the techniques described in the Test Methods section below.

[00119] In some embodiments, the crosslinked polyamine particles according to the invention have an in vitro competitive phosphate binding capacity of between 0.4 mmol/g and 10 mmol/g, for example between 0.5 mmol/g and 7 mmol/g, between 0.6 mmol/g and 5 mmol/g, between 0.7 mmol/g and 4 mmol/g or between 0.8 mmol/g and 2.5 mmol/g throughout a physiologically significant time period. A physiologically significant time period may be the length of time during which significant uptake of a target ion occurs in a human. For example, for phosphate the physiologically significant time period may be from 0 to 5 hours, such as 0.5 to 5 hours, 1 to 4.5 hours, 1.5 to 4 hours, 2 to 3.5 hours or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 hours. The in vitro competitive phosphate binding capacity may be measured according to the techniques described in the Test Methods section below.

[00120] In some embodiments, the crosslinked polyamine particles of the present invention have an in vitro non-competitive phosphate binding capacity at 5 hours that is within 20%, for example within 15%, 12.5%, 10% or even 5% of that of sevelamer hydrochloride.

[00121] In some embodiments, the crosslinked polyamine particles according to the invention may have an in vitro competitive phosphate binging capacity at 60 minutes that is greater than 1.2 mmol phosphate/g of polymer, such as greater than 1.25 mmol/g, greater than 1.30 mmol/g, greater than 1.35 mmol/g, greater than 1.4 mmol/g, greater than 1.5 mmol/g, greater than 1.6 mmol/g, greater than 1.7 mmol/g, greater than 1.8 mmol/g, greater than 1.9 mmol/g or greater than 2.0 mmol/g. In some embodiments, the crosslinked polyamine particles according to the invention may have an in vitro competitive phosphate binging capacity at 60 minutes that is between 1.2 mmol/g and 10 mmol/g, such as between 1.2 mmol/g and 7.5 mmol/g, between 1.2 mmol/g and 5.0 mmol/g, between 1.2 mmol/g and 4.0 mmol/g, between 1.25 mmol/g and 4.0 mmol/g, between 1.3 mmol/g and 4.0 mmol/g, between 1.35 mmol/g and 4.0 mmol/g, between 1.4 mmol/g and 4.0 mmol/g, between 1.5 mmol/g and 4.0 mmol/g, between 1.6 mmol/g and 4.0 mmol/g, between 1.7 mmol/g and 4.0 mmol/g, or between 1.8 mmol/g and 4.0 mmol/g.

[00122] In some embodiments, the crosslinked polyamine particles of the present invention have an in vitro competitive phosphate binding capacity at 1 hour of greater than 20%, for example greater than 30%, greater than 35 %, greater than 40% or greater than 45% of the 5 hour or 300 minute in vitro non-competitive phosphate binding capacity of said polymer.

[00123] In some embodiments, the crosslinked polyamine particles of the invention have an in vivo phosphate binding capacity of between 0.2 mmol/g and 14 mmol/g, such as between 0.3 mmol/g and 14 mmol/g, between 0.4 mmol/g and 12.5 mmol/g, between 0.5 mmol/g and 10 mmol/g, between 0.75 mmol/g and 8 mmol/g, between 1.0 mmol/g and 6 mmol/g, between 1.25 mmol/g and 5 mmol/g, between 1.5 mmol/g and 4.5 mmol/g, between 2.0 mmol/g and 4.0 mmol/g or between 2.5 mmol/g and 3.5 mmol/g. The in vivo phosphate binding capacity may be measured in any animal, such as any mammal, such as humans or rats. The test methods detail a procedure for measuring the in vivo phosphate binding capacity in rats, which may be suitably modified as appropriate for measurement in humans.

[00124] In some embodiments, the crosslinked polyamine particles of the invention have an in vitro bile acid binding capacity of between 0.5 mmol/g and 14 mmol/g, such as between 0.3 mmol/g and 14 mmol/g, between 0.4 mmol/g and 12.5 mmol/g, between 0.5 mmol/g and 10 mmol/g, between 0.75 mmol/g and 8 mmol/g, between 1.0 mmol/g and 6 mmol/g, between 1.25 mmol/g and 6 mmol/g, between 1.5 mmol/g and 6 mmol/g, between 2.0 mmol/g and 6 mmol/g or between 2.5 mmol/g and 6 mmol/g, such as greater than 1.00, 1.5, 2.0, 2.5, 3.0, 3.5, 4, 4.5, 5.0, 5.5, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0 or greater than 13.0 mmol/g. The in vitro bile acid binding capacity may be determined according to the procedure detailed in the Test Procedures.

[00125] In some embodiments, the crosslinked polyamine particles of the invention have an in vivo bile acid binding capacity of between 0.5 mmol/g and 14 mmol/g, such as between 0.3 mmol/g and 14 mmol/g, between 0.4 mmol/g and 12.5 mmol/g, between 0.5 mmol/g and 10 mmol/g, between 0.75 mmol/g and 8 mmol/g, between 1.0 mmol/g and 6 mmol/g, between 1.25 mmol/g and 6 mmol/g, between 1.5 mmol/g and 6 mmol/g, between 2.0 mmol/g and 6 mmol/g or between 2.5 mmol/g and 6 mmol/g, such as greater than 1.00, 1.5, 2.0, 2.5, 3.0, 3.5, 4, 4.5, 5.0, 5.5, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0 or greater than 13.0 mmol/g. The in vivo bile acid binding capacity may be measured in any animal, such as any mammal, such as humans or rats. The test methods detail a procedure for measuring the in vivo bile acid binding capacity in rats, which may be suitably modified as appropriate for measurement in humans.

[00126] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a d₁₀ value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a dc>₀ value that is between 1100 μm and 1400 μm, and/or a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm. [00127] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a dio value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30. [00128] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a mean gray value greater than 190.

[00129] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and comprise 500 to 1000 constituent particles, the constituent particles having a d]₀ value between 20 μm and 70 μm, a d₉₀ value between 150 μm and 400 μm and/or a d₅₀ of between 70 μm and 120 μm.

[00130] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and comprise a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

[00131] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a dj₀ value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30, where the crosslinked polyamine particles further comprise a mean gray value of greater than 190. [00132] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a dio value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30, where the crosslinked polyamine particles further comprise or are formed from 500 to 1000 constituent particles, the constituent particles having a d₁₀ value between 20 μm and 70 μm, a d₉₀ value between 150 μm and 400 μm and/or a d₅₀ of between 70 μm and 120 μm. [00133] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a d]₀ value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30, where the crosslinked polyamine particles further comprise a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

[00134] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a di₀ value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30, where the crosslinked polyamine particles further comprise a mean gray value of greater than 190 and 500 to 1000 constituent particles, the constituent particles having a dio value between 20 μm and 70 μm, a d₉₀ value between 150 μm and 400 μm and/or a d₅₀ of between 70 μm and 120 μm.

[00135] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a di₀ value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30, where the crosslinked polyamine particles further comprise a mean gray value of greater than 190 and a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g. [00136] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a di₀ value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a dgo value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅₀ between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30, where the crosslinked polyamine particles further comprise a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g and 500 to 1000 constituent particles, the constituent particles having a d^ value between 20 μm and 70 μm, a d₉₀ value between 150 μm and 400 μm and/or a d₅o of between 70 μm and 120 μm. [00137] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a particle size distribution such that 90 vol.% or greater of the crosslinked polyamine particles have a size between 300 μm and 2000 μm, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a particle size of between 500 μm and 1500 μm, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a particle size less than 375 μm, a particle size distribution such that the crosslinked polyamine particles have a dio value that is between 350 μm and 650 μm, a particle size distribution such that the crosslinked polyamine particles have a d₉₀ value that is between 1100 μm and 1400 μm, a particle size distribution such that the crosslinked polyamine particles have a d₅o between 675 μm and 1000 μm, a particle size distribution such that 75 vol.% to 100 vol.% of the crosslinked polyamine particles have a mesh size that is -14/+50, a particle size distribution where greater than 50 vol.% of the crosslinked polyamine particles have a mesh size that is - 12/+35, a particle size distribution such that no more than 10 vol.% of the crosslinked polyamine particles have a mesh size that is -45 and/or a particle size distribution such that the crosslinked polyamine particles have an average mesh size of -18/+30, where the crosslinked polyamine particles further comprise a mean gray value of greater than 190, a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g and 500 to 1000 constituent particles, the constituent particles having a dio value between 20 μm and 70 μm, a dgo value between 150 μm and 400 μm and/or a d₅o of between 70 μm and 120 μm.

[00138] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a mean gray value greater than 190, where the crosslinked polyamine particles further comprise 500 to 1000 constituent particles, the constituent particles having a dio value between 20 μm and 70 μm, a d₉o value between 150 μm and 400 μm and/or a dso of between 70 μm and 120 μm.

[00139] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a mean gray value greater than 190, where the crosslinked polyamine particles further comprise a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

[00140] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and have a mean gray value greater than 190, where the crosslinked polyamine particles further comprise a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g and 500 to 1000 constituent particles, the constituent particles having a d₁₀ value between 20 μm and 70 μm, a dgo value between 150 μm and 400 μm and/or a d₅o of between 70 μm and 120 μm.

[00141] In some embodiments, the crosslinked polyamine particles comprise or are derived from an amine compound according to any of Formulas IX, XI, XII or XXVII, where each R, each R₂ and each R₃, independently, is a C₃, C₄, or C₅ alkyl radical, where the crosslinked polyamine particles are crosslinked with from 35 wt.% to 55 wt.% epichlorohydrin crosslinker, are in the form of a base and/or a hydrochloride or carbonate salt and 500 to 1000 constituent particles, the constituent particles having a dio value between 20 μm and 70 μm, a dg₀ value between 150 μm and 400 μm and/or a d₅₀ of between 70 μm and 120 μm and where the crosslinked polyamine particles further comprise a competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

[00142] One aspect of the invention is core-shell compositions comprising a polymeric core and shell. In some embodiments, the polymeric core comprises the crosslinked polyamine particles described herein. The shell material can be chemically anchored to the core material or physically coated. In the former case, the shell can be grown on the core component through chemical means, for example by: chemical grafting of shell polymer to the core using living polymerization from active sites anchored onto the core polymer; interfacial reaction, i.e., a chemical reaction located at the core particle surface, such as interfacial polycondensation; and using block copolymers as suspending agents during the core particle synthesis.

[00143] In some embodiments, the interfacial reaction and use of block polymers are the techniques used when chemical methods are used. In the interfacial reaction pathway, typically, the periphery of the core material is chemically modified by reacting small molecules or macromolecules on the core interface. For example, a crosslinked polyamine core is reacted with a polymer containing amine reactive groups such as epoxy, isocyanate, activated esters or halide groups to form a crosslinked shell around the core. [00144] When the shell material is physically adsorbed on the core material, well known techniques of microencapsulation such as solvent coacervation, fluidized bed spray coater, or multiemulsion processes can be used. One method of microencapsulation is the fluidized bed spray coater in the Wurster configuration. In yet another embodiment, the shell material is only acting temporarily by delaying the swelling of the core while in the mouth and esophagus, and optionally disintegrates in the stomach or duodenum. The shell may be selected in order to hinder the transport of water into the core, by creating a layer of high hydrophobicity and very low liquid water permeability.

[00145] In some embodiments, shell materials are polymers carrying negative charges in the pH range typically found in the intestine. Examples include, but are not limited to, polymers that have pendant acid groups such as carboxylic, sulfonic, hydrosulfonic, sulfamic, phosphoric, hydrophosphoric, phosphonic, hydrophosphonic, phosphoramidic, phenolic, boronic and a combination thereof. The polymer can be protonated or unprotonated; in the latter case the acidic anion can be neutralized with pharmaceutically acceptable cations such as Na, K, Li, Ca, Mg, and NH₄.

[00146] The shell polymers can be either linear, branched, hyperbranched, segmented (i.e. backbone polymer arranged in sequence of contiguous blocks of which at least one contains pendant acidic groups), comb-shaped, star-shaped or crosslinked in a network, fully and semi-interpenetrated network (IPN). The shell polymers are either random or blocky in composition and either covalently or physically attached to the core material. Examples of such shell polymers include, but are not limited to acrylic acid homopolymers or copolymers, methacrylic acid homopolymers or copolymers, and copolymers of methacrylate and methacrylic acid. Examples of such polymers are copolymers of methyl methacrylate and methacrylic acid and copolymers of ethyl acrylate and methacrylic acid, sold under the tradename Eudragit (Rohm GmbH & Co. KG): examples of which include Eudragit L100-55 and Eudragit LlOO (a methyl methacrylate- methacrylic acid (1 :1) copolymer, Degussa/Rohm), Eudragit L30-D55, Eudragit S 100-55 and Eudragit FS 30D, Eudragit S 100 (a methyl methacrylate-methacrylic acid (2:1) copolymer), Eudragit LD- 55 (an ethyl acrylate-methacrylic acid (1 :1) copolymer), copolymers of acrylates and methacrylates with quaternary ammonium groups, sold under the tradenames Eudragit RL and Eudragit RS, and a neutral ester dispersion without any functional groups, sold under the tradename Eudragit NE30-D.

[00147] Additional shell polymers include: poly(styrene sulfonate), polyacrylic acid(s); carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate as sold under the tradename HP-50 and HP-55 (Shin-Etsu Chemical Co., Ltd.), cellulose acetate trimellitate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, cellulose derivatives, such as hydroxypropylmethylcellulose, methylcelluose, hydroxylethylcellulose, hydroxyethylmethylcellulose, hydroxylethylethylcelluose and hydroxypropylethylcellulose and cellulose derivatives such as cellulose ethers useful in film coating formulations, polyvinyl acetate phthalate, carrageenan, alginate, or poly(methacrylic acid) esters, acrylic/maleic acid copolymers, styrene/maleic acid polymers, itaconic acid/acrylic copolymers, and fumaric/acrylic acid copolymers, polyvinyl acetal diethylaminoacetate, as sold under the tradename AEA (Sankyo Co., Ltd.), methylvinylether/maleic acid copolymers and shellac. [00148] In some embodiments the shell polymers are selected amongst pharmaceutically acceptable polymers such as Eudragit L 100-55 and Eudragit LlOO (a methylmethacrylate-methacrylic acid (1 :1) copolymer, Degussa/Rohm), Carbopol 934 (polyacrylic acid, Noveon), C-A-P NF (cellulose acetate phthalate — Eastman), Eastacryl (methacrylic acid esters — Eastman), Carrageenan and Alginate (FMC Biopolymer), Anycoat — P (Samsung Fine Chemicals — HPMC Phthalate), or Aqualon (carboxymethyl cellulose — Hercules), methylvinylether/maleic acid copolymers (Gantrez), and styrene/maleic acid (SMA).

[00149] The shell can be coated by a variety of methods. In one embodiment, the shell materials are added in the drug formulation step as an active excipient; for example, the shell material can be included in a solid formulation as a powder, which is physically blended with the crosslinked polyamine and other excipients, optionally granulated, and compressed to form a tablet. Thus, in some embodiments, the shell material need not cover the core material in the drug product. For example, the acidic shell polymer may be added together with the core formulated in the shape of a tablet, capsule, gel, liquid, etc, wafer, extrudates and the shell polymer can then dissolve and distribute itself uniformly as a shell coating around the core while the drug product equilibrates in the mouth, esophagus or ultimately in the site of action, /. e. , the GI tract.

[00150] In some embodiments, the shell is a thin layer of shell polymer. The layer can be a molecular layer of polyanion on the core material surface. The weight to core ratio can be between about 0.0001% to about 30%, preferably comprised between about 0.01% to about 5%, such as between about 0.1% to about 5%.

[00151] The shell polymers have a minimum molecular weight such that they do not freely permeate within the core pore volume nor elute from the core surface. In some embodiments, the molecular weight (Mw) of the shell acidic polymer is above about 1000 g/mole, such as above about 5000 g/mole, and or even above about 20,000 g/mole [00152] The anionic charge density of the shell material (as prevailing in the milieu of use) may be between 0.5 mEq/g to 22 mEq/g, such as 2 mEq/g to 15 mEq/g. If a coating process is used to form the shell on the crosslinked polyamine particles as part of the manufacture of the dosage form, then procedures known from those skilled-in-the-art in the pharmaceutical industry are applicable. In one embodiment, the shell is formed in a fluidized bed coater (Wurster coater). In an alternate embodiment, the shell is formed through controlled precipitation or coascervation, wherein the crosslinked amine polymer particles are suspended in a polymer solution, and the solvent properties are changed in such a way as to induce the polymer to precipitate onto or coat the crosslinked amine polymer particles.

[00153] Suitable coating processes include the procedures typically used in the pharmaceutical industry. Typically, selection of the coating method is dictated by a number of parameters, that include, but are hot limited to the form of the shell material (bulk, solution, emulsion, suspension, melt) as well as the shape and nature of the core material (spherical beads, irregular shaped, etc.), and the amount of shell deposited. In addition, the cores may be coated with one or more shells and may comprise multiple or alternating layers of shells.

[00154] The term "phosphate imbalance disorder" as used herein refers to conditions in which the level of phosphorus present in the body is abnormal. One example of a phosphate imbalance disorder includes hyperphosphatemia. The term "hyperphosphatemia" as used herein refers to a condition in which the element phosphorus is present in the body at an elevated level. Typically, a patient is often diagnosed with hyperphosphatemia if the blood phosphate level is, for example, above about 4.0 or 4.5 milligrams per deciliter of blood, for example above about 5.0 mg/dl, such as above about 5.5 mg/dl, for example above 6.0 mg/dl, and/or the patient has a severely impaired glomerular filtration rate such as, for example, less than about 20% of normal. The present invention may also be used to treat patients suffering from hyperphosphatemia in End Stage Renal Disease and who are also receiving dialysis treatment (e.g., hemodialysis or peritoneal dialysis). Also, the present invention can be used to treat Chronic Kidney Disease (CKD), to treat patients with CKD who are on dialysis and dialysis patients, including prophylactic treatment of any of the above.

[00155] Other diseases that can be treated with the methods, polymers, crosslinked polyamine particles, compositions and kits of the present invention include hypocalcemia, hyperparathyroidism, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, renal insufficiency, and ectopic calcification in soft tissues including calcifications in joints, lungs, kidney, conjuctiva, and myocardial tissues including prophylactic treatment of any of the above. [00156] The crosslinked polyamine particles and compositions described herein can be used as an adjunct to other therapies e.g. those employing dietary control of phosphorus intake, dialysis, inorganic metal salts and/or other polymer resins.

[00157] The compositions of the present invention are also useful in removing chloride, bicarbonate, oxalate, and bile acids from the gastrointestinal tract. Crosslinked polyamine particles removing oxalate compounds or ions find use in the treatment of oxalate imbalance disorders, such as oxalosis or hyperoxaluria that increases the risk of kidney stone formation. Crosslinked polyamine particles removing chloride compounds or ions find use in treating acidosis, heartburn, acid reflux disease, sour stomach or gastritis, for example. In some embodiments, the compositions of the present invention are useful for removing fatty acids, bilirubin, and related compounds. Some embodiments may also bind and remove high molecular weight molecules like proteins, nucleic acids, vitamins or cell debris.

[00158] The present invention provides methods, pharmaceutical compositions, and kits for the treatment of animals. The term "animal" or "animal subject" or "patient" as used herein includes humans as well as other mammals (e.g., in veterinary treatments, such as in the treatment of dogs or cats, or livestock animals such as pigs, goats, cows, horses) and other livestock animals such as chickens and the like. One embodiment of the invention is a method of removing phosphorous-containing compounds such as organophosphates or phosphate from the gastrointestinal tract, such as the stomach, small intestine or large intestine of an animal by administering an effective amount of the crosslinked polyamine particles described herein.

[00159] The term "treating" and its grammatical equivalents as used herein include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication, amelioration, or prevention of the underlying disorder being treated. For example, in a hyperphosphatemia patient, therapeutic benefit includes eradication or amelioration of the underlying hyperphosphatemia. Also, a therapeutic benefit is achieved with the eradication, amelioration, or prevention of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For example, administration of crosslinked polyamine particles, described herein, to a patient suffering from renal insufficiency and/or hyperphosphatemia provides therapeutic benefit not only when the patient's serum phosphate level is decreased, but also when an improvement is observed in the patient with respect to other disorders that accompany renal failure and/or hyperphosphatemia like ectopic calcification and renal osteodistrophy. For prophylactic benefit, for example, the crosslinked polyamine particles may be administered to a patient at risk of developing hyperphosphatemia or to a patient reporting one or more of the physiological symptoms of hyperphosphatemia, even though a diagnosis of hyperphosphatemia may not have been made.

[00160] The compositions may also be used to control serum phosphate in subjects with elevated phosphate levels, for example, by changing the serum level of phosphate towards a normal or near normal level, for example, towards a level that is within 10% of the normal level of a healthy patient.

[00161] Other embodiments of the invention are directed towards pharmaceutical compositions comprising at least one of the crosslinked polyamine particles or a pharmaceutically acceptable salt of the crosslinked polyamine particles, and one or more pharmaceutically acceptable excipients, diluents, or carriers and optionally additional therapeutic agents. The compositions may be lyophilized or dried under vacuum or oven before formulating.

[00162] The excipients or carriers are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations can conveniently be presented in unit dosage form and can be prepared by any suitable method. The methods typically include the step of bringing into association the agent with the excipients or carriers such as by uniformly and intimately bringing into association the crosslinked amine polymer with the excipients or carriers and then, if necessary, dividing the product into unit dosages thereof. [00163] The pharmaceutical compositions of the present invention include compositions wherein the crosslinked polyamine particles are present in an effective amount, i.e., in an amount effective to achieve therapeutic and/or prophylactic benefit. The actual amount effective for a particular application will depend on the patient (e.g. age, weight, etc.) the condition being treated; and the route of administration. [00164] In some embodiments, crosslinked polyamine particles and compositions of the invention may reduce urinary phosphorous of a patient in need thereof by 5 -100% of the elevation above normal urinary phosphorous levels, such as 10-75 %, 25-65%, or 45- 60%. Some embodiments may reduce urinary phosphorous by greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 45%, greater than 50% or greater than 60% of the elevation above normal urinary phosphorous levels. [00165] In some embodiments, crosslinked polyamine particles and compositions of the invention may reduce blood phosphate of a patient in need thereof by 5 -100% of the elevation above normal blood phosphate levels, such as 10-75 %, 25-65%, or 45-60% of the elevation above normal blood phosphate levels. Some embodiments may reduce blood phosphate levels by greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 45%, greater than 50% or greater than 60% of the elevation above normal blood phosphate levels.

[00166] The dosages of the crosslinked polyamine particles in animals will depend on the disease being, treated, the route of administration, and the physical characteristics of the animal being treated. Such dosage levels in some embodiments for either therapeutic and/or prophylactic uses may be from about 1 gm/day to about 30 gm/day, for example from about 2 gm/day to about 20 gm/day, from about 2 gm/day to about 10 gm/day, from about 3 gm/day to about 9 gm/day, from about 3 gm/day to about 8 gm/day, from about 3 gm/day to about 7 gm/day, from about 3 gm/day to about 6 gm/day, from about 3 gm/day to about 5 gm/day, from about 4 gm/day to about 7 gm/day or from about 4 gm/day to about 6 gm/day. The dose of the crosslinked amine polymers described herein can be less than about 50 gm/day, less than about 40 gm/day, less than about 30 gm/day, less than about 20 gm/day, and less than about 10 gm/day.

[00167] Typically, the crosslinked polyamine particles can be administered before or after a meal, or with a meal. As used herein, "before" or "after" a meal is typically within two hours, preferably within one hour, more preferably within thirty minutes, most preferably within ten minutes of commencing or finishing a meal, respectively. [00168] Generally, it is preferred that the crosslinked polyamine particles are administered along with meals. In some embodiments, the crosslinked polyamine particles may be administered one time a day, two times a day, or three times a day. In some embodiments, the crosslinked polyamine particles are administered once a day with the largest meal.

[00169] Preferably, the crosslinked polyamine particles may be used for therapeutic and/or prophylactic benefits and can be administered alone or in the form of a pharmaceutical composition. The pharmaceutical compositions comprise the crosslinked polyamine particles, one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally additional therapeutic agents. For example, the crosslinked polyamine particles of the present invention may be co-administered with other active pharmaceutical agents depending on the condition being treated. Examples of pharmaceutical agents that may be co-administered include, but are not limited to: [00170] Other phosphate sequestrants including pharmaceutically acceptable lanthanum, calcium, aluminum, magnesium, iron and zinc compounds, such as acetates, carbonates, oxides, hydroxides, citrates, alginates, and ketoacids thereof. [00171] Calcium compounds, including calcium carbonate, acetate (such as PhosLo^® calcium acetate tablets), citrate, alginate, and ketoacids;

[00172] Aluminium-based phosphate sequestrants, such as Amphojel^® aluminium hydroxide gel;

[00173] Lanthanide compounds such as lanthanum carbonate (Fosrenol^®). [00174] Other phosphate sequestrants suitable for use in the present invention include pharmaceutically acceptable magnesium compounds. Various examples of pharmaceutically acceptable magnesium compounds are described in U.S. Provisional Application No. 60/734,593 filed November 8, 2005, the entire teachings of which are incorporated herein by reference. Specific suitable examples include magnesium oxide, magnesium hydroxide, magnesium halides (e.g., magnesium fluoride, magnesium chloride, magnesium bromide and magnesium iodide), magnesium alkoxides (e.g., magnesium ethoxide and magnesium isopropoxide), magnesium carbonate, magnesium bicarbonate, magnesium formate, magnesium acetate, magnesium trisilicates, magnesium salts of organic acids, such as fumaric acid, maleic acid, acrylic acid, methacrylic acid, itaconic acid and styrenesulfonic acid, and a combination thereof. [00175] Other phosphate sequestrants suitable for co-administration include various examples of pharmaceutically acceptable zinc compounds are described in PCT Application No. PCT/US2005/047582 filed December 29, 2005, the entire teachings of which are incorporated herein by reference. Specific suitable examples of pharmaceutically acceptable zinc compounds include zinc acetate, zinc bromide, zinc caprylate, zinc carbonate, zinc chloride, zinc citrate, zinc formate, zinc hexafluorosilicate, zinc iodate, zinc iodide, zinc iodide-starch, zinc lactate, zinc nitrate, zinc oleate, zinc oxalate, zinc oxide, calamine (zinc oxide with a small proportion of ferric oxide), zinc p- phenolsulfonate, zinc propionate, zinc salicylate, zinc silicate, zinc stearate, zinc sulfate, zinc sulfide, zinc tannate, zinc tartrate, zinc valerate and zinc ethylenebis(dithiocarbamate). Another example includes poly(zinc acrylate). [00176] When referring to any of the above-mentioned phosphate sequestrants, it is to be understood that mixtures, polymorphs and solvates thereof are encompassed. [00177] In some embodiments, a mixture of the phosphate sequestrants described above can be used in the invention in combination with pharmaceutically acceptable ferric or ferrous iron salts.

[00178] In other embodiments, the phosphate sequestrant used in combination crosslinked polyamine particles of the present invention is not a pharmaceutically acceptable magnesium compound. In yet other embodiments, the phosphate sequestrant used in combination with the pharmaceutically acceptable crosslinked polyamine particles is not a pharmaceutically acceptable zinc compound.

[00179] The invention also includes methods and pharmaceutical compositions directed to a combination therapy of the crosslinked polyamine particles in combination with a phosphate transport inhibitor or an alkaline phosphatase inhibitor. Alternatively, a mixture of the crosslinked polyamine particles is employed together with a phosphate transport inhibitor or an alkaline phosphatase inhibitor.

[00180] Suitable examples of phosphate transport inhibitors can be found in co-pending

U.S. Application Publication Nos. 2004/0019113 and 2004/0019020 and WO

2004/085448, the entire teachings of each of which are incorporated herein by reference.

[00181] Examples of alkaline phosphatase (ALP) inhibitors may be found in, for example, U.S. Patent No. 5,948,630, the entire teachings of which are incorporated herein by reference. Examples of alkaline phosphatase inhibitors include orthophosphate, arsenate, L-phenylalanine, L-homoarginine, tetramisole, levamisole, L-p-

Bromotetramisole, 5,6-Dihydro-6-(2-naphthyl) imidazo-[2,l-b]thiazole (napthyl) and derivatives thereof. The preferred inhibitors include, but are not limited to, levamisole, bromotetramisole, and 5,6-Dihydro-6-(2-naphthyl)imidazo-[2,l-b]thiazole and derivatives thereof.

[00182] This co-administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, for the treatment of hyperphosphatemia, the crosslinked polyamine particles may be co-administered with calcium salts which are used to treat hypocalcemia resulting from hyperphosphatemia.

[00183] The pharmaceutical compositions of the invention can be formulated as tablets, chewable tablets, sachets, slurries, food formulations, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums or lozenges.

[00184] Preferably, the crosslinked polyamine particles or the pharmaceutical compositions comprising the crosslinked polyamine particles are administered orally. Illustrative of suitable methods, vehicles, excipients and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 19^th ed., the contents of which is incorporated herein by reference.

[00185] Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active crosslinked polyamine particles into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Suitable techniques for preparing pharmaceutical compositions are well known in the art. [00186] In some aspects of the invention, the crosslinked polyamine particles provide mechanical and thermal properties that are usually performed by excipients, thus decreasing the amount of such excipients required for the formulation. In some embodiments the crosslinked polyamine particles constitute over about 30 wt.%, for example over about 40 wt.%, over about 50 wt.%, preferably over about 60 wt.%, over about 70 wt.%, more preferably over about 80 wt.%, over about 85 wt.%, over about 90 wt.%, over about 95 wt.% or over about 99 wt.% of the composition, such as from about 80 wt.% to about 99 wt.% or from about 80 wt. % to about 95 wt.% of the composition, the remainder comprising suitable excipient(s).

[00187] In some embodiments, the dosage form of the composition is a tablet or tablets. In some embodiments, the compressibility of the tablets is strongly dependent upon the degree of hydration (moisture content) of the crosslinked polyamine particles. Preferably, the crosslinked polyamine particles have a moisture content of about 5% by weight or greater, more preferably, the moisture content is from about 5% to about 9% by weight, and most preferably about 7% by weight. It is to be understood that in embodiments in which the crosslinked polyamine particles are hydrated, the water of hydration is considered to be a component of the crosslinked polyamine particles. [00188] The tablet can further comprise one or more excipients, such as hardeners, glidants and lubricants, which are well known in the art. Suitable excipients include colloidal silicon dioxide, stearic acid, magnesium silicate, calcium silicate, sucrose, calcium stearate, glyceryl behenate, magnesium stearate, talc, zinc stearate and sodium stearylfumarate.

[00189] In some embodiments, the tablets may be prepared by a method comprising the steps of: (1) hydrating or drying the crosslinked polyamine particles to the desired moisture level; (2) blending the crosslinked polyamine particles with any excipients; and (3) compressing the blend using conventional tableting technology to form a tablet or a tablet core. In some embodiments, the tablet or tablet core may then be further processed, such as coated.

[00190] In some embodiments, the invention relates to a stable, swallowable coated tablet, such as a tablet comprising the crosslinked polyamine particles, as described above. In one embodiment, the coating composition comprises a cellulose derivative and a plasticizing agent. The cellulose derivative is, preferably, hydroxypropylmethylcellulose (HPMC). The cellulose derivative can be present as an aqueous solution. Suitable hydroxypropylmethylcellulose solutions include those containing HPMC low viscosity and/or HPMC high viscosity. Additional suitable cellulose derivatives include cellulose ethers useful in film coating formulations. The plasticizing agent can be, for example, an acetylated monoglyceride such as diacetylated monoglyceride. The coating composition can further include a pigment selected to provide a tablet coating of the desired color. For example, to produce a white coating, a white pigment can be selected, such as titanium dioxide.

[00191] In one embodiment, a coated tablet of the invention can be prepared by a method comprising the step of contacting a tablet core, as described above, with a coating solution comprising a solvent, at least one coating agent dissolved or suspended in the solvent and, optionally, one or more plasticizing agents. Preferably, the solvent is an aqueous solvent, such as water or an aqueous buffer, or a mixed aqueous/organic solvent. Preferred coating agents include cellulose derivatives, such as hydroxypropylmethylcellulose. Typically, the tablet core is contacted with the coating solution until the weight of the tablet core has increased by an amount ranging from about 4% to about 6%, indicating the deposition of a suitable coating on the tablet core to form a coated tablet.

[00192] Other pharmaceutical excipients useful in some compositions of the invention include a binder, such as microcrystalline cellulose, carbopol, providone and xanthan gum; a flavoring agent, such as mannitol, xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such as vegetable based fatty acids; and, optionally, a disintegrant, such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ether of cellulose, sodium starch glycolate. Such additives and other suitable ingredients are well-known in the art; see, e.g., Gennaro A R (Ed.), Remington 's Pharmaceutical Sciences, 19^l Edition. [00193] In one embodiment, the crosslinked polyamine particles are pre-formulated with a high Tg / high melting point low molecular weight excipient such as mannitol, sorbose, and sucrose in order to form a solid solution wherein the crosslinked polyamine particles and the excipient are intimately mixed. Methods of mixing such as extrusion, spray-drying, chill drying, lyophilization, or wet granulation are useful. Indication of the level of mixing is given by known physical methods such as differential scanning calorimetry or dynamic mechanical analysis.

[00194] In some embodiments the crosslinked polyamine particles of the invention may be provided as pharmaceutical compositions in the form of liquid formulations. In some embodiments the pharmaceutical composition contains crosslinked polyamine particles dispersed in a suitable liquid excipient. Suitable liquid excipients are known in the art; see, e.g., Remington's Pharmaceutical Sciences.

[00195] In some embodiments, the pharmaceutical compositions may be in the form of a powder formulation packaged as a sachet that may be mixed with water or other ingestible liquid and administered orally as a drink (solution or suspension). In order to ensure that such formulations provide acceptable properties to the patient such as mouth feel and taste, a pharmaceutically acceptable anionic stabilizer may be included in the formulation.

[00196] Examples of suitable anionic stabilizers include anionic polymers such as: an anionic polypeptide, an anionic polysaccharide, or a polymer of one or more anionic monomers such as polymers of mannuronic acid, guluronic acid, acrylic acid, methacrylic acid, glucuronic acid glutamic acid or a combination thereof, and pharmaceutically acceptable salts thereof. Other examples of anionic polymers include cellulose, such as carboxyalkyl cellulose or a pharmaceutically acceptable salt thereof. The anionic polymer may be a homopoloymer or copolymer of two or more of the anionic monomers described above. Alternatively, the anionic copolymer may include one or more anionic monomers and one or more neutral comonomers such as olefinic anionic monomers such as vinyl alcohol, acrylamide, and vinyl formamide.

[00197] Examples of anionic polymers include alginates (e.g. sodium alginate, potassium alginate, calcium alginate, magnesium alginate, ammonium alginate, and esters of alginate), carboxymethyl cellulose, polylactic acid, polyglutamic acid, pectin, xanthan, carrageenan, furcellaran, gum Arabic, karaya gum, gum ghatti, gum carob, and gum tragacanth. Preferred anionic polymers are alginates and are preferably esterified alginates such as a C₂-C₅-diol ester of alginate or a C₃-C₅ triol ester of alginate. As used herein an "esterified alginate" means an alginic acid in which one or more of the carboxyl groups of the alginic acid are esterified. The remainder of the carboxylic acid groups in the alginate are optionally neutralized (partially or completely) as pharmaceutically acceptable salts. For example, propylene glycol alginate is an ester of alginic acid in which some of the carboxyl groups are esterified with propylene glycol, and the remainder of the carboxylic acid groups is optionally neutralized with pharmaceutically acceptable salts. More preferably, the anionic polymer is ethylene glycol alginate, propylene glycol alginate or glycerol alginate, with propylene glycol alginate even more preferred.

TEST METHODS

Non-Competitive Phosphate Binding Capacity Buffer Preparation:

[00198] 0.680 g Of KH₂PO₄, 10.662 g of morpholinoethane sulfonic acid and 2.338 g of NaCl may be weighed into a 500 ml volumetric flask. 300 ml of deionized water and the solids may be dissolved. Additional deionized water may be added until the total volume of buffer is 500 ml. The pH is adjusted to 5.8 using 1 N NaOH. Sample Preparation:

[00199] The percent loss on drying (%LOD) by Thermogravimetric Analyzer (TGA) of 25 mg of each polymer may be determined on a Thermogravimetric Analyzer, TA Instruments, Model TGA Q 500, purged with nitrogen and using platinum pans. The following heating conditions may be used:

Heating rate: 10 °C/min

End temperature: 85 ⁰C

Hold time: 60 minutes

[00200] The % LOD may be determined as the % weight loss over 65 minutes and the result used to calculate the target sample weight with the following formula: Weight = 33.35 mg/ (1-(LODAOO))

Binding Procedure:

[00201] The calculated target sample weight per polymer is weighed into each of two 50 ml plastic sample bottles. A 25 ml aliquot of the 10 mM Phosphate Buffer Solution is transferred into each of the sample bottles. The solutions are mixed well by vortexing and then shaken in an orbital shaker at 37 °C and 250 RPMs for 60 minutes. During shaking it should be ensured that the polymer particles do not adhere to the walls or lid of the sample bottle. After 60 minutes the shaker is stopped and the polymer is allowed to settle. An aliquot of exactly 2.0 ml is taken from each solution. The aliquots are filtered into small vials using a disposable syringe and 25 mm syringe filter and then diluted at a ratio of 1 part solution to 9 parts DI water. The sample bottles are shaken for a further 4 hours (total of 5 hours altogether) and the sampling procedure is repeated. Four phosphate standards are prepared by diluting the 10 mM Phosphate Buffer Solution as follows:

[00202] The standards and samples are analyzed by ion chromatography using a Dionex ICS3000 instrument with conductivity detection. The 0.75 mM Standard is used as a check standard to verify the system suitability by re-injecting this standard after every 6 sample injections. The following instrument conditions are used:

Column: Dionex, ASl 1 -HC, 4 x 250 mm,

Guard Column: AGl 1 -HC, 4 X 50 mm,

Mobile Phase = 40 mM KOH (using eluent generator)

Conductivity detector current set at 200 mA

Column Temperature: 35 °C

Flow rate: 1.5 mL/min

Injection volume: 25 μL

Run time: 6 minutes

Retention time of phosphate: ~ 4 mins

[00203] A standard curve is prepared and the unbound phosphate (mM) for each test solution is calculated taking into account the 10-fold dilution. The bound phosphate is determined using the following equation:

Bound PO₄ (mmol/g) = [(10 - Unbound PO₄) X Vol. X 1000]/MassP where: Vol. = volume of test solution (L)

MassP = LOD adjusted mass of polymer (mg) The results from the duplicate analyses may be averaged. Competitive Phosphate Binding Capacity

Buffer Preparation:

[00204] 0.680 g Of KH₂PO₄, 10.662 g of morpholinoethane sulfonic acid and 2.338 g of NaCl are weighed into a 500 ml volumetric flask. 300 ml of deionized water and the solids are dissolved. Additional deionized water is added until the total volume of buffer is 500 ml. A lO mL aliquot of this solution is taken and stored for use in the preparation of standards. 3.537 g of Glycochenodeoxycholic acid, sodium salt ("GCDC")and 2.285 g of oleic acid, sodium salt are added to the remaining 490 ml of buffer solution and the pH was adjusted to pH 5.8 with 1 N NaOH. The solution was well mixed. (Note that oleic acid does not dissolve but forms a suspension. It is ensured that the solution is well mixed and the suspended oleic acid is mixed as homogenously as possible before taking aliquots.) Sample Preparation:

The %LOD drying is determined as set forth above. Binding Procedure:

[00205] The procedure as set forth above is repeated with a 25 ml aliquot of the 10 mM Phosphate Buffer Solution with Acids. Determination of Particle Size and Distribution

[00206] Particle size and distribution of particle sizes may be determined as vol.% using a Malvern Mastersizer 2000 equipped with a Scirocco 2000 dry powder dispensing unit. The Mastersizer is modified by removing the ball bearings and mesh basket positioned above the venturi from the feed tray and the sample is fed to the machine and the particle size and distribution are determined using the following parameters:

Measurement time: 20 sec

Measurement snaps: 20,000

Background measurement time: 15 sec

Background measurement snaps: 15,000

Obscuration limits: 0.1 to 6%

Feeding rate: 30%

Dispersion Air pressure: 1 bar Determination of Mean Gray Value Using Bright Field Microscopy [00207] After sieving to a mesh size that is -20/+50, a representative sample of the crosslinked polyamine particles may be sieved using a 35 mesh sieve. A representative sample of the particles retained on the sieve is spread over a glass slide. Images having 15-40 particles within the field of view are taken with an Olympus SZX 12 Stereomicroscope equipped with an Olympus QColor 5 digital camera and set with the following parameters: 0.5x objective lens, 10x total magnification, bright field setting, and open light filters (FR, LBD and ND25).

[00208] Mean Gray Value is determined using Microsuite Biological Suite 2.3 (Build 1121). Image magnification is set at 10x using software calibration. The images are converted from the full color to 8-bit format with 230 colors. Two color phases are used: Phase I (green for the background) is set from color value 0-112, and Phase II (red for the particles) is set from color value 114-250). The minimum particle size used in the analysis is set at 1000 pixels and the fill holes option is selected. A gray value for each pixel in every particle in the image is assigned, and a mean individual particle gray value is calculated, by the software. The mean gray value, which represents the arithmetic mean of the individual particles gray value means, is determined for the imaged collection of particles. Two additional representative samples of the particles retained on the 35 mesh sieve are analyzed and the mean gray values for each of the three images are averaged to establish the Mean Gray Value. Bile Acid Binding Capacity

[00209] After analyzing the competitive phosphate binding of a polymer sample by ion chromatography the bile acid binding capacity of the same samples may be analyzed using HPLC according to the following procedure: Standard Preparation

[00210] 0.177 g of GCDC is weighed into a 25 ml volumetric flask and diluted to the mark using a 100 mM morpholinoethane sulfonic acid stock solution to form a 15 mM GCDC stock solution. Four standards having the following concentrations are prepared by diluting the GCDC stock solution in volumetric flasks as follows:

[00211] A blank is prepared by diluting the MES buffer stock l-to-10.

[00212] For the HPLC determination, the following parameters are used:

• Column: Platinum EPS-Cl 8, 33 X 7 mm, 3 micron, rocket format

• MP: A = 15 mM ammonium acetate, pH 5.30

(adjust pH with an 8/2 by volume acetic acid/acetonitrile solution)

• MP: B = acetonitrile

• Flow rate: 2 ml/min

• Column Temp: 30 °C

• Injection Volume: 10 μl

• UV Detection: 210 nm Using the following gradient:

with stop run = 4.0 minutes and post run = 2.5 minutes.

[00213] The following injection format may be used: Blank twice, Standards twice,

Blank, then test samples once each with the 1.0 mM standard injected after every 9 sample injections for system suitability testing. The system is suitable if the difference between the original standards and the suitability standard is less than 5%.

[00214] A standard curve is set up and the unbound GCDC (mM) for each test solution is calculated. The bound GCDC is determined using the following equation:

Bound GCDC (mmol/g) = [(15 - Unbound GCDC) X Vol. X 1000]/MassP where: Vol. = volume of test solution (L) and

MassP = LOD adjusted mass of polymer (mg)

Crosslinked Amine Polymer Urinary Phosphorous Reduction (In Vivo-Rats) [00215] House male Sprague Dawley (SD) rats may be used for the experiments. The rats are placed singly in wire-bottom cages, fed with Purina 5002 diet, and allowed to acclimate for at least 5 days prior to experimental use.

[00216] To establish baseline phosphorus excretion, the rats are placed in metabolic cages for 48 hours. Their urine is collected and its phosphorus content analyzed with a Hitachi analyzer to determine phosphorus excretion in mg/day. Any rats with outlying values are excluded; and the remainder of the rats is distributed into groups. [00217] Purina 5002 is used as the standard diet. The crosslinked polyamine particles being tested in each group are mixed with Purina 5002 to result in the desired final crosslinked polyamine concentration for each group. Cellulose at 0.5% by weight is used as a negative control. For each rat, 20Og of diet is prepared.

[00218] Each rat is weighed and placed on the standard diet. After 4 days the standard diet is replaced with the treatment diet (or control diet for the control group). On days 5 and 6, urine samples from the rats at 24 hours (+/- 30 minutes) are collected and analyzed.

The test rats are again weighed, and any weight loss or gain is calculated. Any remaining food is also weighed to calculate the amount of food consumed per day. A change in phosphorus excretion relative to cellulose negative control is calculated. Percentage reduction of urinary phosphorous is determined using the following equation:

% Reduction of Urinary Phosphorous = [(urinary phosphorous of negative control

(mg/day) - urinary phosphorous of experimental (mg/day)) / urinary phosphorous of negative control (mg/day)] X 100.

Crosslinked Amine Polymer Fecal Bile Acid Increase (In K/vø-Rats)

[00219] House male Sprague Dawley (SD) rats may be used for the experiments. The rats are placed singly in wire-bottom cages, fed with Purina 5002 diet, and allowed to acclimate for at least 5 days prior to experimental use.

[00220] After acclimatization, the rats are split into test groups with 6 rats per group.

Purina 5002 with NaH₂PO₄ at a concentration of 0.4 wt% phosphate added is used as the standard diet. The crosslinked polyamine being tested in each group is mixed with the standard diet to result in the desired final crosslinked polyamine concentration for each group. Cellulose at 4.0% by weight is used as a negative control.

[00221] Each rat is weighed and placed on its respective treatment diet. On day six, the rats are placed in metabolism cages specifically designed to separate and collect fecal material for 24 hours. The fecal material is collected, freeze dried, weighed and ground into a powder. 500 mgs of the powder is added to an extraction vessel and heated to 100

°C at 1500 psi for 10 minutes in an extraction solvent consisting of 80% methanol/20%

500 mM KOH. 250 μls of the extract is evaporated in a speed vac at 45 °C for 2 hours and then is reconstituted in a 50% mixture of calf serum and saline. The bile acid concentration may be quantitated using a Total Bile Acids colorometric assay available from Diazyme Laboratories, Inc. at catalog number DZ092A. [00222] A change in fecal bile acid excretion relative to the cellulose negative control is calculated. Percentage increase of fecal bile acid was determined using the following equation:

% Increase in Fecal Bile Acid = [(Fecal Bile Acid of experimental (mg/day) - Fecal Bile

Acid of negative control (mg/day)) / Fecal Bile Acid of negative control (mg/day)] X 100.

In-Process Swelling Ratio (ml/g)

[00223] The in-process swelling ratio (SR) of polymers may be determined by the following equation:

SR = (weight of wet gel (g) - weight of dry polymer (g))/weight of dry polymer (g).

[00224] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[00225] While preferred embodiments of.the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

What is claimed is:

1. A pharmaceutical composition comprising: crosslinked polyamine particles, said crosslinked polyamine derived from a) at least one amine compound according to the following Formula I:

Formula I wherein: each R_A, independently, represents a hydrogen radical, -R or -R-N(R₁)_2-m-(R-N(R₁)_2-n-(R-N(R₁)₂)_π)_m; each n and each m, independently, represents an integer from 0 to 2; each R, independently, represents a branched or unbranched, substituted or un- substituted alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, a substituted or unsubstituted C₄ to Qo aryl or heteroaryl radical, or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical; each Ri, independently, represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical; a branched or unbranched, substituted or unsubstituted alkenyl radical; a substituted or unsubstituted C₄ to C₁₀ aryl or heteroaryl radical; or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical, with the proviso that at least one R_A is not a hydrogen radical; and b) a crosslinking agent; said crosslinked polyamine particles having a particle size distribution wherein greater than 10 vol.% of the particles have a particle size greater than 500 μm.

2. The pharmaceutical composition according to claim 1 , further comprising a pharmaceutically acceptable excipient.

3. The pharmaceutical composition according to any of claims 1-2, wherein said particles have a particle size distribution wherein greater than 50 vol.% of the particles have a particle size between 500 μm and 1500 μm.

4. The pharmaceutical composition according to any of claims 1-3, wherein said particles have a d₅₀ between 675 μm and 1000 μm.

5. The pharmaceutical composition according to any of claims 1-4, wherein said particles have a distribution such that the di₀ value is between 350 μm and 650 μm and/or the d₉₀ value is between 1100 μm and 1400 μm.

6. The pharmaceutical composition according to any of claims 1-5, wherein said crosslinked polyamine particles are at least partially protonated with carbonate, bicarbonate or a mixture thereof as the counterion.

7. The pharmaceutical composition according to any of claims 1-6, wherein said crosslinking agent comprises epichlorohydrin.

8. The pharmaceutical composition according to any of claims 1-7, wherein the compound according to Formula I is selected from the group consisting of:

Formula II Formula III

Formula IV Formula V

Formula VI

Formula VII

Formula VIII Formula IX Formula X

Formula XI Formula XII wherein each R, each R₂, and each R₃ independently, represents a branched or unbranched, substituted or un-substituted alkyl radical, a branched or unbranched, substituted or un- substituted alkenyl radical, a substituted or unsubstituted C₄ to C₁₀ aryl or heteroaryl radical, or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical; and each R₁, independently, represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical; a branched or unbranched, substituted or unsubstituted alkenyl radical; a substituted or unsubstituted C₄ to Ci₀ aryl or heteroaryl radical; or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical.

9. The composition according to any of claims 1-8, wherein the compound according to Formula I is selected from the group consisting of:

Formula XIII Formula XIV Formula XV

Formula XVI Formula XVII

Formula XVIII

Formula XIX

Formula XX

Formula XXIII

Formula XXIV

Formula XXV and

Formula XXVI

10. The pharmaceutical composition according to any of claims 1-9, wherein the compound according to Formula I comprises a compound according to the following Formula XXVII

Formula XXVII wherein each R, independently, represents a branched or unbranched, substituted or un-substituted alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, a substituted or unsubstituted C₄ to Ci₀ aryl or heteroaryl radical, or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical.

1 1. The pharmaceutical composition according to any of claims 1-10, wherein said crosslinked polyamine particles having a mean gray value of greater than 180.

12. The pharmaceutical composition according to claim 11 , wherein said particles have a mean gray value of between 190 and 230.

13. The pharmaceutical composition according to any of claims 1-12, wherein said crosslinked polyamine particles comprise aggregate particles comprising constituent particles.

14. The pharmaceutical composition according to claim 13, wherein said crosslinked polyamine particles comprise at least 2 constituent particles.

15. The pharmaceutical composition according to any of claims 13-14, wherein said aggregate particles comprise from 2 to 10,000 constituent particles.

16. The pharmaceutical composition according to any of claims 13-15, wherein said aggregate particles comprise from 500 to 1000 of said constituent particles.

17. The pharmaceutical composition according to any of claims 13-16, wherein said constituent particles have a d₅₀ between 70 and 120 μm.

18. The pharmaceutical composition according to any of claims 13-17, wherein said aggregate particles are formed by aggregating 2 or more constituent particles, said constituent particles comprising said crosslinked polyamine particles.

19. The pharmaceutical composition of claim 18, wherein said aggregating comprises hydrating said constituent particles.

20. The pharmaceutical composition of claims 18-19, wherein said aggregating comprises forming a suspension of said constituent particles.

21. The pharmaceutical composition of claims 18-20, wherein said forming comprises carbonating at least a portion of said constituent particles.

22. The pharmaceutical composition of claims 18-21, wherein said forming comprises making a gel from said constituent particles.

23. The pharmaceutical composition of claim 22, wherein said forming comprises milling said gel.

24. The pharmaceutical composition of claims 22-23, wherein said forming comprises drying said gel.

25. The pharmaceutical composition of claim 24, wherein said forming comprises wet milling said gel.

26. The pharmaceutical composition according to any of claims 1-25, wherein said crosslinked polyamine particles have an in vitro competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

27. A method of manufacturing a pharmaceutical composition comprising: forming constituent particles having a dso between 70 μm and 150 μm, said constituent particles comprising crosslinked polyamine particles, said crosslinked polyamine derived from a) at least one amine compound according to the following Formula I:

RA- — RA

N

RA Formula I wherein each R_A, independently, represents a hydrogen radical, -R or

-R-N(R,)_2-m-(R-N(R₁)2-n-(R-N(R₁)₂)n)m; each n and each m, independently, represents an integer from 0 to 2; each R, independently, represents a branched or unbranched, substituted or un- substituted alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, a substituted or unsubstituted C₄ to Qo aryl or heteroaryl radical, or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical; each Ri, independently, represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical; a branched or unbranched, substituted or unsubstituted alkenyl radical; a substituted or unsubstituted C₄ to Ci₀ aryl or heteroaryl radical; or a substituted or unsubstituted C₄ to Cio alicyclic or heterocyclic radical, with the proviso that at least one R_A is not a hydrogen radical; and b) a crosslinking agent; suspending said particles in a solvent; drying the suspended particles; and fractionating the dried particles into particles having a dso between 675 μm and 1000 μm.

28. The method according to claim 27, wherein the solvent comprises water.

29. The method according to any of claims 27-28, wherein said fractionated dried particles have a particle size distribution such that the dio value is between 350 μm and 650 μm and/or the d₉₀ value is between 1 100 μm and 1400 μm.

30. A method of treating hyperphosphatemia comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: crosslinked polyamine particles, said crosslinked polyamine derived from a) at least one amine compound according to the following Formula I:

Formula I wherein each R_A, independently, represents a hydrogen radical, -R or

-R-N(R,)_2-m-(R-N(R₁)_2-n-(R-N(R₁)2)n)m; each n and each m, independently, represents an integer from 0 to 2; each R, independently, represents a branched or unbranched, substituted or unsubstituted alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, a substituted or unsubstituted C₄ to Ci₀ aryl or heteroaryl radical, or a substituted or unsubstituted C₄ to Qoalicyclic or heterocyclic radical; each Ri, independently, represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical; a branched or unbranched, substituted or unsubstituted alkenyl radical; a substituted or unsubstituted C₄ to Cj₀ aryl or heteroaryl radical; or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical, with the proviso that at least one R_A is not a hydrogen radical; and b) a crosslinking agent; said crosslinked polyamine particles having a particle size distribution wherein greater than 10 vol.% of the particles have a particle size greater than 500 μm.

31. The method according to claim 30, said composition further comprising a pharmaceutically acceptable excipient.

32. The method according to any of claims 30-31 wherein said particles have a particle size distribution wherein greater than 50 vol.% of the particles have a particle size between 500 μm and 1500 μm.

33. The method according to any of claims 30-32, wherein said particles have a d₅₀ between 675 μm and 1000 μm.

34. The method according to any of claims 30-33, wherein said particles have a distribution such that the d]₀ value is between 350 μm and 650 μm and/or the dς_>o value is between 1100 μm and 1400 μm.

35. The method according to any of claims 30-34, wherein said crosslinked polyamine particles are at least partially protonated with carbonate, bicarbonate or a mixture thereof as the counterion.

36. The method according to any of claims 30-35, wherein said crosslinking agent comprises epichlorohydrin.

37. The method according to any of claims 30-36, wherein the compound according to Formula I is selected from the group consisting of: R

Formula II Formula III

Formula IV Formula V

Formula VI

Formula VII

NH,

/

N- -R

-R- / \ NH₂

H₂N^ ^"NH₉ H₅N' H₂N [J NH₂ Formula VIII Formula IX Formula X

Formula XI Formula XII wherein each R, each R₂, and each R₃ independently, represents a branched or unbranched, substituted or un-substituted alkyl radical, a branched or unbranched, substituted or un- substituted alkenyl radical, a substituted or unsubstituted C₄ to Ci₀ aryl or heteroaryl radical, or a substituted or unsubstituted C₄ to Ci₀ alicyclic or heterocyclic radical; and each R₁, independently, represents a hydrogen radical, a branched or unbranched, substituted or un-substituted alkyl radical; a branched or unbranched, substituted or un- substituted alkenyl radical; a substituted or unsubstituted C₄ to Ci₀ aryl or heteroaryl radical; or a substituted or unsubstituted C₄ to Cio alicyclic or heterocyclic radical.

38. The method according to any of claims 30-37, wherein the compound according to Formula I is selected from the group consisting of:

^^ NH₂ H₂N ^^ NH₂

H₂N ^^^ ^^^

Formula XIII Formula XIV Formula XV

Formula XVI Formula XVII

Formula XVIII

Formula XIX

Formula XX

Formula XXIII

Formula XXV and

Formula XXVI

39. The method according to any of claims 30-38, wherein the compound according to Formula I comprises a compound according to the following Formula XXVII

Formula XXVII wherein each R, independently, represents a branched or unbranched, substituted or un-substituted alkyl radical, a branched or unbranched, substituted or un-substituted alkenyl radical, a substituted or unsubstituted C₄ to Ci₀ aryl or heteroaryl radical, or a substituted or unsubstituted C₄ to C₁₀alicyclic or heterocyclic radical.

40. The method according to any of claims 30-39, wherein said crosslinked polyamine particles having a mean gray value of greater than 180.

41. The method according to claim 40, wherein said crosslinked polyamine particles have a mean gray value of between 190 and 230.

42. The method according to any of claims 30-41, wherein said crosslinked polyamine particles comprise aggregate particles comprising constituent particles.

43. The pharmaceutical composition according to claim 42, wherein said crosslinked polyamine particles comprise at least 2 constituent particles.

44. The pharmaceutical composition according to any of claims 42-43, wherein said aggregate particles comprise from 2 to 10,000 constituent particles.

45. The pharmaceutical composition according to any of claims 42-44, wherein said aggregate particles comprise from 500 to 1000 of said constituent particles.

46. The method according to any of claims 42-45, wherein said constituent particles have a d₅₀ between 70 and 120 μm.

47. The pharmaceutical composition according to any of claims 42-47, wherein said aggregate particles are formed by aggregating 2 or more constituent particles, said constituent particles comprising said crosslinked polyamine particles.

48. The method of claim 47, wherein said aggregating comprises hydrating said constituent particles.

49. The method according to any of claims 47-48, wherein said aggregating comprises forming a suspension of said constituent particles.

50. The method according to any of claims 47-49, wherein said forming comprises carbonating at least a portion of said constituent particles.

51. The method according to any of claims 47-50, wherein said forming comprises making a gel from said constituent particles.

52. The method according to claim 51, wherein said forming comprises milling said gel.

53. The method according to any of claims 51-52, wherein said forming comprises drying said gel.

54. The method according to claim 53, wherein said forming comprises wet milling said gel.

55. The method according to any of claims 30-54, wherein said crosslinked polyamine particles have an in vitro competitive phosphate binding capacity at 60 minutes of greater than 1.2 mmol/g.

56. The method according to any of claims 30-55, wherein said patient is suffering from one or more of the following conditions: End Stage Renal Disease, Chronic Kidney Disease, hypocalcemia, hyperparathyroidism, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, renal insufficiency, and ectopic calcification in soft tissues including calcifications in joints, lungs, kidney, conjuctiva, and myocardial tissues.