WO2013106086A1 - Compositions comprenant des polymères réticulés de liaison à des cations et utilisations associées - Google Patents

Compositions comprenant des polymères réticulés de liaison à des cations et utilisations associées Download PDF

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Publication number
WO2013106086A1
WO2013106086A1 PCT/US2012/047486 US2012047486W WO2013106086A1 WO 2013106086 A1 WO2013106086 A1 WO 2013106086A1 US 2012047486 W US2012047486 W US 2012047486W WO 2013106086 A1 WO2013106086 A1 WO 2013106086A1
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WIPO (PCT)
Prior art keywords
polymer
carboxylate groups
counterions
cations
magnesium
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PCT/US2012/047486
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English (en)
Inventor
Alan D. Strickland
George M. Grass
Original Assignee
Sorbent Therapeutics, Inc.
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Publication date
Priority claimed from PCT/US2012/020849 external-priority patent/WO2012097017A1/fr
Priority claimed from PCT/US2012/038908 external-priority patent/WO2013106072A1/fr
Application filed by Sorbent Therapeutics, Inc. filed Critical Sorbent Therapeutics, Inc.
Priority to CA2863240A priority Critical patent/CA2863240A1/fr
Publication of WO2013106086A1 publication Critical patent/WO2013106086A1/fr
Priority to IL233578A priority patent/IL233578A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present disclosure relates generally to crosslinked cation-binding polymers comprising monomers containing carboxylic acid groups, wherein the polymer contains i) calcium cations that are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer; or ii) calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer.
  • the present disclosure also relates to methods of preparation of the polymers or compositions, formulations, and/or dosage forms containing the polymers, and methods of using the polymers or compositions, formulations, and/or dosage forms containing the polymers to treat various diseases or disorders.
  • hyperkalemia hyperkalemia
  • hypercalcemia hypercalcemia
  • hypermagnesia increased retention of fluid
  • ESRD end stage renal disease
  • patients afflicted with an increased level of potassium may exhibit a variety of symptoms ranging from malaise, palpitations, muscle weakness and, in severe cases, cardiac arrhythmias.
  • patients afflicted with increased levels of sodium may exhibit a variety of symptoms including, lethargy, weakness, irritability, edema and in severe cases, seizures and coma.
  • edema e.g., pulmonary edema, peripheral edema, edema of the legs, etc.
  • waste products in the blood e.g., urea, creatinine, other nitrogenous waste products, and electrolytes or minerals such as sodium, phosphate and potassium.
  • Treatments for diseases or disorders associated with ion imbalances and/or an increased retention of fluid attempt to restore the ion balance and decrease the retention of fluid.
  • treatment of diseases or disorders associated with ion imbalances may employ the use of ion exchange resins to restore ion balance.
  • Treatment of diseases or disorders associated with an increased retention of fluid may involve the use of diuretics ⁇ e.g., administration of diuretic agents and/or dialysis, such as hemodialysis or peritoneal dialysis and remediation of waste products that accumulate in the body). Additionally or alternatively, treatment for ion imbalances and/or increased retention of fluid may include restrictions on dietary consumption of electrolytes and water. However, the effectiveness and/or patient compliance with present treatments is less than desired.
  • compositions comprising crosslinked cation- binding polymers comprising monomers containing carboxylic acid groups.
  • the present disclosure relates generally to crosslinked cation-binding polymers comprising monomers containing carboxyate groups, wherein the polymers further comprise calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, the polymers comprise calcium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), and wherein sodium cations are counterions to no more than about 5% (alternatively, no more than about 4%, about 3%, about 2%, or about 1 %, about 0.5%, about 0.05%, or about 0.01 %) of the carboxylate groups on the polymer.
  • the present disclosure also relates generally to crosslinked cation-binding polymers comprising monomers containing carboxyate groups, wherein the polymers further comprise calcium cations and magnesium cations (e.g., a mixture of calcium cations and magnesium cations), wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, the polymers comprise calcium and magnesium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and wherein sodium cations are counterions to no more than about 5% (alternatively, no more than about 4%, about 3%
  • At least a portion of the polymer is derived from acrylic acid monomers or acrylic acid derivative monomers. In some embodiments, all or substantially all of the polymer is derived from acrylic acid monomers or acrylic acid derivative monomers.
  • the present disclosure also relates to methods of preparation of crosslinked cation-binding polymers comprising monomers that comprise carboxylate groups, for example, crosslinked polyacrylic acid, wherein the polymers further comprise calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, the polymers comprise calcium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), and wherein the polymers may comprise sodium cations that are counterions to no more than about 5% (alternatively, no more than about 4%, about 3%, about 2%, or about 1 %, about 0.5%, about 0.1 %, or about 0.05%) of the carboxylate groups in the polymer.
  • the present disclosure also relates to methods of preparation of crosslinked cation-binding polymers comprising monomers that comprise carboxylate groups, for example, crosslinked polyacrylic acid, wherein the polymers further comprise calcium cations cations and magnesium cations (e.g., a mixture of calcium and magnesium cations), wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, the polymers comprise calcium and magnesium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymers may comprise sodium cations that are counterions to no more than about
  • compositions, formulations, and/or dosage forms comprising crosslinked cation-binding polymers comprising monomers that comprise carboxylate groups, for example, crosslinked polyacrylic acid, wherein the polymers further comprise calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, the polymers comprise calcium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), and wherein the polymer may optionally comprise sodium cations that are counterions to less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1 % of the carboxylate groups.
  • compositions, formulations, and/or dosage forms comprising crosslinked cation-binding polymers comprising monomers that comprise carboxylate groups, for example, crosslinked polyacrylic acid, wherein the polymers further comprise calcium cations and magnesium cations (e.g., a mixture of calcium and magnesium cations), wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, the polymers comprise calcium and magnesium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and wherein the polymer may optionally comprise sodium cations that
  • the present disclosure also relates to methods of preparation of the polymers and compositions, formulations, and/or dosage forms containing the polymers.
  • the present disclosure also relates to dosage forms ⁇ e.g., oral dosage forms) comprising one or more of the polymers, compositions and/or formulations disclosed herein.
  • the present disclosure also relates to methods of using the disclosed polymers, compositions, formulations, and/or dosage forms to treat various diseases or disorders, including those involving ion imbalances and/or fluid imbalances ⁇ e.g., overloads).
  • the disease is heart failure.
  • the disease is heart failure with chronic kidney disease.
  • the disease is end stage renal disease.
  • the disease is end stage renal disease with heart failure.
  • the disease is chronic kidney disease.
  • the disease is hypertension.
  • the disease is salt-sensitive hypertension.
  • the disease is refractory hypertension.
  • the disease involves an ion imbalance such as hyperkalemia, hypernatremia, hypercalcemia, etc.
  • the disease or disorder involves a fluid maldistribution or fluid overload state such as edema or ascites.
  • the disease or disorder is the result of, or is associated with, administration of another agent ⁇ e.g., drug).
  • compositions, formulations, and/or dosage forms according to the present disclosure are useful in treating an increase in a subject's potassium level when co-administered with an agent ⁇ e.g., drug) known to cause increases in potassium levels, such as an alpha-adrenergic agonist, a RAAS inhibitor, an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, an aldosterone antagonist, etc.
  • the present disclosure relates generally to crosslinked cation-binding polymers comprising monomers that comprise carboxylate groups, e.g., crosslinked polyacrylic acid, and compositions, formulations, and/or dosage forms that contain the polymers, wherein the polymers further comprise calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer ⁇ e.g., the polymer comprises an amount of calcium cations sufficient to provide calcium counterions to about 50% to about 70% of the carboxylate groups in the polymer).
  • the polymer comprises calcium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer.
  • the polymer comprises calcium cations that are counterions to about 50%, about 55%, about 60%, about 65%, or about 70% of the carboxylate groups in the polymer.
  • the polymers may comprise sodium cations that are counterions to up to about 5% of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to about 5% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 4% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 3% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 2% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 1 % of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to less than 1 % of the carboxylate groups on the polymer.
  • the polymer comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, sodium cations as counterions up to about 5% of the carboxylate groups on the polymer, and hydrogen cations ⁇ e.g., protons) as counterions to about 25% to about 45% of the carboxylate groups on the polymer.
  • the polymer comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer and hydrogen cations ⁇ e.g., protons) are counterions to the remainder or substantially the remainder of the carboxylate groups on the polymer ⁇ e.g., counterions that are not calcium or sodium are hydrogen).
  • hydrogen cations are essentially hydrogen and may include small amounts (e.g., less than about 10,000 ppm of non-hydrogen elements), such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • the present disclosure also relates generally to crosslinked cation-binding polymers comprising monomers that comprise carboxylate groups, e.g., crosslinked polyacrylic acid, and compositions, formulations, and/or dosage forms that contain the polymers, wherein the polymers further comprise calcium cations and magnesium cations ⁇ e.g., a mixture of calcium and magnesium cations), wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer ⁇ e.g., the polymer comprises an amount of calcium and magnesium cations sufficient to provide calcium and magnesium counterions to about 50% to about 70% of the carboxylate groups in the polymer), and wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer.
  • the polymers further comprise calcium cations and magnesium cations ⁇ e.g., a mixture of calcium and magnesium cations
  • the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in
  • the polymer comprises calcium and magnesium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer.
  • the polymer comprises calcium and magnesium cations that are counterions to about 50%, about 55%, about 60%, about 65%, or about 70% of the carboxylate groups in the polymer.
  • the polymers may comprise sodium cations that are counterions to up to about 5% of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to about 5% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 4% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 3% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 2% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 1 % of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to less than 1 % of the carboxylate groups on the polymer.
  • the polymer comprises calcium cations and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, sodium cations as counterions up to about 5% of the carboxylate groups on the polymer, and hydrogen cations ⁇ e.g., protons) as counterions to about 25% to about 45% of the carboxylate groups on the polymer, wherein magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • the polymer comprises calcium cations and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, and hydrogen cations ⁇ e.g., protons) are counterions to the remainder or substantially the remainder of the carboxylate groups on the polymer ⁇ e.g., counterions that are not calcium or sodium are hydrogen), wherein magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • these hydrogen cations are essentially hydrogen and may include small amounts (e.g., less than about 10,000 ppm of non-hydrogen elements), such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • non-hydrogen elements such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • crosslinked cation-binding polymers comprise monomers that comprise carboxylate groups, e.g., crosslinked polyacrylic acid, and compositions, formulations, and/or dosage forms that contain the polymers, wherein the polymers further comprise calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer ⁇ e.g., the polymer comprises an amount of calcium cations sufficient to provide calcium counterions to about 50% to about 70% of the carboxylate groups in the polymer).
  • the polymer comprises calcium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer.
  • the polymer comprises calcium cations that are counterions to about 50%, about 55%, about 60%, about 65%, or about 70% of the carboxylate groups in the polymer.
  • the polymers may comprise sodium cations that are counterions to up to about 5% of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to about 5% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 4% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 3% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 2% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 1 % of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to less than 1 % of the carboxylate groups on the polymer.
  • the polymer comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, sodium cations as counterions up to about 5% of the carboxylate groups on the polymer, and hydrogen cations ⁇ e.g., protons) as counterions to about 25% to about 45% of the carboxylate groups on the polymer.
  • the polymer comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer and hydrogen cations ⁇ e.g., protons) are counterions to the remainder or substantially the remainder of the carboxylate groups on the polymer ⁇ e.g., counterions that are not calcium or sodium are hydrogen).
  • hydrogen cations are essentially hydrogen and may include small amounts ⁇ e.g., less than about 10,000 ppm) of non-hydrogen elements, such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • crosslinked cation-binding polymers comprise monomers that comprise carboxylate groups, e.g., crosslinked polyacrylic acid, and compositions, formulations, and/or dosage forms that contain the polymers, wherein the polymers further comprise calcium cations and magnesium cations ⁇ e.g., a mixture of calcium and magnesium cations), wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer ⁇ e.g., the polymer comprises an amount of calcium and magnesium cations sufficient to provide calcium and magnesium counterions to about 50% to about 70% of the carboxylate groups in the polymer), and wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer.
  • the polymer comprises calcium and magnesium cations that are counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer.
  • the polymer comprises calcium and magnesium cations that are counterions to about 50%, about 55%, about 60%, about 65%, or about 70% of the carboxylate groups in the polymer.
  • the polymers may comprise sodium cations that are counterions to up to about 5% of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to about 5% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 4% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 3% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 2% of the carboxylate groups on the polymer. In some embodiments, the polymer comprises sodium cations that are counterions to about 1 % of the carboxylate groups on the polymer.
  • the polymer comprises sodium cations that are counterions to less than 1 % of the carboxylate groups on the polymer.
  • the polymer comprises calcium and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, sodium cations as counterions up to about 5% of the carboxylate groups on the polymer, and hydrogen cations ⁇ e.g., protons) as counterions to about 25% to about 45% of the carboxylate groups on the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • the polymer comprises calcium and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, and hydrogen cations ⁇ e.g., protons) are counterions to the remainder or substantially the remainder of the carboxylate groups on the polymer ⁇ e.g., counterions that are not calcium or sodium are hydrogen), wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • these hydrogen cations are essentially hydrogen and may include small amounts (e.g., less than about 10,000 ppm) of non-hydrogen elements, such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • the polymer comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, wherein counterions that are not calcium are hydrogen.
  • the polymer comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer and hydrogen cations ⁇ e.g., protons) are counterions to the remainder or substantially the remainder of the carboxylate groups on the polymer.
  • hydrogen cations are essentially hydrogen and may include small amounts (e.g., less than about 10,000 ppm) of non-hydrogen elements, such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • the polymer comprises calcium cations and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, wherein counterions that are not calcium or magnesium are hydrogen, and wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • the polymer comprises calcium cations and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, and hydrogen cations ⁇ e.g., protons) are counterions to the remainder or substantially the remainder of the carboxylate groups on the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • these hydrogen cations are essentially hydrogen and may include small amounts (e.g., less than about 10,000 ppm) of non-hydrogen elements, such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • non-hydrogen elements such as iron, copper, aluminum, arsenic, mercury, manganese, phosphorous, lead, selenium, titanium, and/or zinc.
  • the polymer comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, and sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer.
  • the polymer further comprises hydrogen cations (e.g., protons) as counterions to all or substantially all of the carboxylate groups to which calcium and sodium are not counterions (e.g., "free carboxylates"), for example about 95% of the free carboxylates, about 96% of the free carboxylates, about 97% of the free carboxylates, about 98% of the free carboxylates, about 99% of the free carboxylates, about 99.5% of the free carboxylates, or about 100% of the free carboxylates.
  • the polymer comprises calcium cations as counterions to about 50% to about 60% of the carboxylate groups on the polymer, sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer, and hydrogen cations (e.g., protons) as counterions to all or substantially all of the free carboxylates.
  • the polymer comprises calcium and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, and sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer, and further comprises hydrogen cations (e.g., protons) as counterions to all or substantially all of the carboxylate groups to which calcium, magnesium, or sodium are not counterions (e.g., "free carboxylates"), for example about 95% of the free carboxylates, about 96% of the free carboxylates, about 97% of the free carboxylates, about 98% of the free carboxylates, about 99% of the free carboxylates, about 99.5% of the free carboxylates, or about 100% of the free carboxylates, wherein magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • hydrogen cations e.g., protons
  • the polymer comprises calcium and magnesium cations as counterions to about 50% to about 60% of the carboxylate groups on the polymer, sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer, and hydrogen cations (e.g., protons) as counterions to all or substantially all of the free carboxylates, wherein magnesium cations are counterions to no more than about 35% of the carboxylate groups on the polymer.
  • the cross-linked polymer e.g., cross-linked polyacrylate polymer, comprising calcium and/or magnesium counterions as disclosed herein may absorb at least about 20- fold, 30-fold, or 40-fold or more of its mass in fluid, such as a sodium solution (e.g., a solution of sodium salts, such as a saline solution or a physiological saline solution, for example, 0.154 molar total sodium concentration).
  • a sodium solution e.g., a solution of sodium salts, such as a saline solution or a physiological saline solution, for example, 0.154 molar total sodium concentration.
  • saline holding capacity for a disclosed cross-linked cation-binding polymer is determined in a buffered saline solution, e.g., a buffered saline solution that maintains pH at about 7.
  • Polymers as described herein and compositions that contain the polymers have unexpected cation binding and/or removal, and/or fluid binding and/or removal properties when administered to an individual (e.g., a mammal, such as a human) and therefore are useful for the treatment of a variety of diseases or disorders, including those involving ion and/or fluid imbalances (e.g., overloads).
  • ranges of calcium ions have been discovered and are disclosed herein that maintain cation binding and/or fluid removal properties of the polymer (e.g., for potassium and/or sodium) and/or the fluid binding and/or removal properties of the polymer in individuals, for example, humans while minimizing or preventing a change in acid base balance from administration of the polymer.
  • a neutral or substantially neutral acid/base status is maintained in the body of a subject, for example, a human subject.
  • an acid/base status e.g., acid/base balance
  • an acid/base status associated with a subject does not change, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap, after administration of the polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer as described herein.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • the cation binding polymer selectively binds potassium (e.g. a K/Na binding ratio of about 2 or more). In some embodiments, the cation binding polymer (e.g., in various subject populations and/or in various diseases or disorders) bind potassium and sodium in similar amounts (e.g., a K/Na binding ratio of about 1 ).
  • the present disclosure also relates to methods of preparation of such polymers, and compositions, formulations, and dosage forms containing the polymers.
  • the present disclosure also relates to methods of using such polymers and/or compositions, for example, in dosage forms, for the treatment of various diseases or disorders as disclosed herein, including, for example, heart failure (e.g., with or without chronic kidney disease), end stage renal disease (e.g., with or without heart failure), chronic kidney disease, hypertension (including, e.g., salt sensitive and refractory), hyperkalemia (e.g., any origin), hypernatremia (e.g., any origin), and/or fluid overload states (e.g., edema or ascities).
  • heart failure e.g., with or without chronic kidney disease
  • end stage renal disease e.g., with or without heart failure
  • chronic kidney disease e.g., hypertension (including, e.g., salt sensitive and refractory)
  • hyperkalemia e.g., any origin
  • hypernatremia e.g., any origin
  • fluid overload states e.g., edema or asc
  • Non-limiting examples of suitable carboxylic acid-containing monomers for production of a polymer as described herein include, for example: acrylic acid and its salts, methacrylic acid and its salts, crotonic acid and its salts, tiglinic acid and its salts, 2-methyl- 2-butenoic acid (Z) and its salts, 3-butenoic acid (vinylacetic acid) and its salts, 1 - cyclopentene carboxylic acid and its salts, 2-cyclopentene carboxylic acid and its salts; and unsaturated dicarboxylic acids and their salts, such as maleic acid, fumaric acid, itaconic acid, glutaconic acid, and their salts.
  • Polymers may include copolymers of the above monomers.
  • cross-linked cation-binding polyelectrolyte polymers may be based on sulfonic acids and their salts, phosphonic acids and their salts, or amines and their salts, for example, acrylic acid with sulfonic acids or salts thereof, phosphonic acids or salts thereof, or amines and their salts.
  • polymers useful in the present disclosure contain a plurality of carboxylic acid (-C(O)OH) and/or carboxylate (-C(O)O ) groups.
  • Polymers of the present disclosure are crosslinked. Any crosslinker known in the art may be used.
  • Crosslinking agents contemplated for use in the present disclosure include, for example, diethelyeneglycol diacrylate (diacryl glycerol), triallylamine, tetraallyloxyethane, allylmethacrylate, 1 , 1 , 1-trimethylolpropane triacrylate (TMPTA), divinyl benzene, 1 ,7-octadiene, and divinyl glycol.
  • the amount of crosslinking agent used may vary depending on the absorbent characteristics desired. In general, increasing amounts of crosslinking agent will yield polymers with increasing degrees of crosslinking.
  • an amount of crosslinking may be chosen that yields a polymer with an in vitro saline holding capacity of greater than about 20 times its own weight.
  • saline holding capacity is measured for the polymer as the sodium salt (for example the sodium salt of polyacrylate) or equivalently the polymer with calcium counterions washed with acid to prepate the acid form polymer (e.g. polyacrylic acid) and then converted to the sodium salt (e.g.
  • the amount of crosslinker used to crosslink polymers according to the present disclosure may range from about 0.08 mol% to about 0.2 mol% or alternatively from about 0.025 mol% to about 3.0 mol%, including from about 0.025 mol% to about 0.3 mol%, from about 0.025 mol% to about 0.17 mol%, from about 0.025 mol% to about 0.34 mol%, or from about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol.% to about 3.0 mol.% including, for example, from about 0.025 mol.% to about 0.3 mol.%.
  • the crosslinked cation-binding polymer as described, for example, for inclusion in compositions, formulations, and/or dosage forms and/or for use in methods for treatment of various diseases or disorders as described herein, and/or for use in methods for cation binding and/or removal, and/or fluid binding and/or removal, as described herein, is a crosslinked polyacrylate polymer (e.g., derived from acrylic acid monomers or a salt thereof) that comprises calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, and wherein sodium cations (if present) are counterions to no more than about 5% of the carboxylate groups in the polymer.
  • a crosslinked polyacrylate polymer e.g., derived from acrylic acid monomers or a salt thereof
  • the polymer may be a polyacrylate polymer crosslinked with about 0.025 mol% to about 3.0 mol%, including from about 0.025 mol% to about 0.3 mol%, from about 0.025 mol% to about 0.17 mol%, from about 0.025 mol% to about 0.34 mol%, or from about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol.% to about 3.0 mol.% including, for example, from about 0.025 mol.% to about 0.3 mol.%., and for example, may comprise an in vitro saline holding capacity of at least about 20 times its weight (e.g., at least about 20 grams of saline per gram of polymer, or "g/g"), at least about at least about 30 times its weight, at least about 40 times its weight, at least about 50 times its weight, at least about 60 times its weight, at least about 70 times its weight, at least about 80 times its weight, at least about 90 times its
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 20 microns to about 125 microns, about 20 microns to about 150 microns, about 20 microns to about 200 microns, about 35 microns to about 150 microns, about 35 microns to about 125 microns, about 50 microns to about 125 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns, about 500 microns to about 1000 microns, about 1000 to about 5000 micron
  • a polymer including a polyacrylate polymer
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 100 microns.
  • no less than about 60% of the polymer is within a particle size range of about 212 microns to about 500 microns, a particle size range from about 75 microns to about 150 microns, or a particle size range of about 75 microns or less.
  • the polyacrylate polymer is in the form of small particles that flocculate to form agglomerated particles with a diameter of about 1 micron to about 10 microns or about 0.1 microns to about 20 microns.
  • Such polyacrylate polymers may include polymers derived from polycarbophil and/or calcium polycarbophil.
  • the crosslinked cation-binding polymer as described, for example, for inclusion in compositions, formulations, and/or dosage forms and/or for use in methods for treatment of various diseases or disorders as described herein, and/or for use in methods for cation binding and/or removal, and/or fluid binding and/or removal, as described herein, is a crosslinked polyacrylate polymer (e.g., derived from acrylic acid monomers or a salt thereof) that comprises calcium cations and magnesium cations (e.g., a mixture of calcium and magnesium cations), wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and wherein sodium cations (if present) are counterions to no more than about 5% of the carboxylate groups in the polymer.
  • a crosslinked polyacrylate polymer e.g., derived from acrylic acid monomers or
  • the polymer may be a polyacrylate polymer crosslinked with about 0.025 mol% to about 3.0 mol%, including from about 0.025 mol% to about 0.3 mol%, from about 0.025 mol% to about 0.17 mol%, from about 0.025 mol% to about 0.34 mol%, or from about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol.% to about 3.0 mol.% including, for example, from about 0.025 mol.% to about 0.3 mol.%., and for example, may comprise an in vitro saline holding capacity of at least about 20 times its weight (e.g., at least about 20 grams of saline per gram of polymer, or "g/g"), at least about at least about 30 times its weight, at least about 40 times its weight, at least about 50 times its weight, at least about 60 times its weight, at least about 70 times its weight, at least about 80 times its weight, at least about 90 times its
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 20 microns to about 125 microns, about 20 microns to about 150 microns, about 20 microns to about 200 microns, about 35 microns to about 150 microns, about 35 microns to about 125 microns, about 50 microns to about 125 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns, about 500 microns to about 1000 microns, about 1000 to about 5000 micron
  • a polymer including a polyacrylate polymer
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 100 microns.
  • no less than about 70% of the polymer has a particle size of about 212 microns to about 500 microns, a particle size from about 75 microns to about 150 microns, or a particle size of about 75 microns or less.
  • the polyacrylate polymer is in the form of small particles that flocculate to form agglomerated particles with a diameter of about 1 micron to about 10 microns or about 0.1 microns to about 20 microns.
  • Such polyacrylate polymers may include polycarbophil.
  • administration of such a crosslinked polyacrylate polymer, comprising calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer
  • an added base e.g., up to about 0.45 equivalents of added base per equivalents of carboxylate groups in the polymer
  • acid/base status e.g., acid/base balance
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, may be administered, optionally with added base as described herein, to an individual for removal of fluid and/or ions, for example, sodium and/or potassium cations, wherein such administration does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • administration of such a crosslinked polyacrylate polymer comprising calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, and wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, is administered with an added base (e.g., up to about 0.45 equivalents of added base per equivalents of carboxylate groups in the polymer), and such administration of the polymer and base does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • an added base e.g., up to about 0.45 equivalents of added base per equivalents of carboxylate groups in the polymer
  • acid/base status e.g., acid/base balance
  • an acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, and wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, may be administered, optionally with added base as described herein, to an individual for removal of fluid and/or ions, for example, sodium and/or potassium cations, wherein such administration does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the
  • cation refers to atomic, polyatomic, or molecular ions having a net positive charge, and may include one such cation or a combination of more than one cation.
  • Non-limiting examples of cations include: hydrogen cations (H + ), sodium cations (Na + ), potassium cations (K + ), magnesium cations (Mg 2+ ), calcium cations (Ca 2+ ), iron cations (e.g., Fe 2+ , Fe 3+ ), and combinations thereof.
  • non-hydrogen cation or “non-hydrogen cations” refers to cation(s) (e.g., as defined above) other than hydrogen (H + ; proton). Mixtures of more than one cation are within the scope of the terms cation or cations, as used herein.
  • Counterions to carboxylate groups on the polymers described herein are cations. Crosslinked cation-binding polymers as disclosed herein can be described by the percentage of carboxylate groups for which one or more cation serves as a counterion.
  • a polymer according to the present disclosure may be referred to as "50% calcium” to indicate that calcium cations are counterions to about 50% of the carboxylate groups in the polymer.
  • a "50% calcium” polymer according to the present disclosure includes about 25 moles of calcium cations (e.g., divalent Ca 2+ cations) per 100 moles of carboxylate groups in the polymer (e.g., a mole fraction with respect to calcium of 0.25).
  • a "35% magnesium" polymer according to the present disclosure indicates that magnesium cations ⁇ e.g., divalent Mg 2+ cations) are counterions to about 35% of the carboxylate groups in the polymer ⁇ e.g., a mole fraction with respect to magnesium of 0.175).
  • hydrogen cations ⁇ e.g., protons
  • crosslinked cation-binding polymers comprise: i) calcium cations that are counterions to about 50% to about 70% of the carboxylate groups in the polymer, and further comprise one or more additional cations; or ii.) calcium and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and further comprise one or more additional cations.
  • the one or more additional cations are monovalent cations such as sodium, potassium, ammonium, arginine, lysine, choline, histidine, serine, and the like.
  • the one or more additional cations are divalent cations such as iron(ll), zinc, a lanthanide, and the like. In some embodiments, the one or more cations are trivalent cations such as aluminum, iron(lll), and the like. Nomenclature of a polymer which comprises one or more additional cations thus depends on the identity of the one or more additional cations, the amount of each of the one or more additional cations, and the valency of each of the one or more additional cations.
  • a polymer according to the present disclosure denoted as “50% calcium/9% iron (III) " would indicate that calcium cations are counterions to about 50% of the carboxylate groups in the polymer, trivalent iron cations (Fe 3+ cations) are counterions to about 9% of the carboxylate groups in the polymer, and hydrogen cations ⁇ e.g., protons) are counterions to about 41 % of the carboxylate groups in the polymer.
  • a "50% calcium/9% trivalent iron" polymer according to the present disclosure comprises about 25 moles of calcium cations and about 3 moles of trivalent iron cations per 100 moles of carboxylate groups in the polymer ⁇ e.g., 0.50 equivalents of calcium cations and 0.09 equivalents of iron per equivalent of carboxylate groups).
  • Determination of the percentage of cations that serve as counterions to carboxylate groups in a polymer as disclosed herein can be accomplished by any suitable means known in the art.
  • the polymer comprises calcium as a counterion to the carboxylate groups of the polymer
  • the polymer may be referred to as Ca-CLP.
  • the polymer comprises calcium and magnesium as counterions to the carboxylate groups of the polymer
  • the polymer may be referred to as Ca/Mg-CLP.
  • the polymer comprises sodium as a counterion to the carboxylate groups of the polymer
  • the polymer may be referred to as Na-CLP.
  • the polymer may be analyzed with an inductively coupled plasma ("ICP") spectrometer ⁇ e.g., by mass spectroscopy (ICP- MS), atomic emission spectroscopy (ICP-AES), or optical emission spectroscopy (ICP- OES)) using methods known to those skilled in the art.
  • ICP- MS mass spectroscopy
  • ICP-AES atomic emission spectroscopy
  • ICP- OES optical emission spectroscopy
  • the percentage of cations serving as counterions to carboxylate groups in the polymer may be confirmed, for example, by ICP spectroscopy, atomic absorption spectroscopy, or other similar ICP methods. Such methods are well known in the art.
  • Cation content of polymers disclosed herein may be determined by ICP, including ICP-AES, ICP-MS, or ICP-OES (see, e.g., Example 7).
  • content of calcium, magnesium, sodium, potassium, and/or iron may be determined.
  • the ICP analysis may be reported in ⁇ g cation/g polymer, which may then be converted to weight percent (wt.%). Weight percent may be converted to % of cations that are counterions to the carboxylate groups in the polymer.
  • the % of cations that are counterions to the carboxylate groups in the polymer determined in different measurements may vary by ⁇ 5% or less.
  • the determination of 50% to 70% calcium cations or calcium and magnesium cations as counterions to carboxylate groups in the polymer may vary in different measurements by ICP [e.g., 50% ⁇ 5% (47.5 to 52.5) to 70% ⁇ 5% (66.5 to 73.5)].
  • an ICP analysis of a crosslinked cation-binding polyacrylate polymer as disclosed herein, comprising hydrogen cations (e.g., protons), calcium cations and acrylic acid monomers having carboxylate groups, reporting about 16 wt.% calcium cations corresponds to a polyacrylate polymer wherein about 70% of the carboxylate groups are bound to calcium counterions, as calculated by the following formula:
  • [x]%Ca-CLP (72.06)(wt.% Ca)/(20.05 - (0.19)(wt.% Ca))
  • an ICP analysis that reports calcium content at 16.44 wt.% calcium represents a polyacrylate polymer with about 70% of the carboxylate groups bound to calcium ⁇ e.g., calcium cations are counterions to about 70% of the carboxylate groups in the polymer), as calculated by the following formula:
  • an ICP analysis that reports calcium content at 16.44 wt.% represents a 70.0% Ca-CLP) polymer ⁇ e.g., calcium cations are counterions to about 70.0% of the carboxylate groups in the polymer).
  • a 70% Ca-CLP polyacrylate polymer has 16.4 wt% calcium according to the following equation:
  • an ICP analysis that reports magnesium content at 5.6 wt.% magnesium represents about 35% magnesium as counterions to carboxylate groups in a polyacrylate polymer (e.g., about 35% Mg-CLP), as calculated by the following formula for a polyacrylate polymer:
  • [x]%Mg-CLP (72.06)(wt.% Mg)/(12.15 - (0.1 1 )(wt.% Mg))
  • an ICP analysis that reports sodium content at 0.030 wt.% sodium represents about 0.09% sodium cations as counterions to carboxylate groups in the polymer, as calculated by the following formula for a polyacrylate polymer:
  • [x]%Na-CLP (72.06)(wt.% Na)/(23.0 - (0.23)(wt.% Na))
  • an ICP analysis that reports sodium content at 0.031 wt.% sodium represents a polacrylate polymer having sodium counterions to about 0.10% of the carboxylate groups in the polymer.
  • an ICP analysis that reports sodium content at 0.035 wt.% represents a polyacrylate polymer having sodium counterions to about 0.1 1 % sodium of the carboxylate groups in the polymer.
  • compositions, formulations, and/or dosage forms comprising a polymer as disclosed herein may optionally additionally comprise and/or be co-administered with an additional base (alternatively termed an alkali).
  • an additional base alternatively termed an alkali
  • the term base may refer to a suitable compound or mixture of compounds that is capable of increasing the pH of the blood or other bodily fluids.
  • Exemplary bases include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, aluminum hydroxide, calcium citrate.
  • Exemplary bases also include calcium acetate, calcium oxide, potassium citrate, and potassium acetate.
  • inorganic and organic bases can be used, provided they are physiologically and/or clinically acceptable.
  • the dose and route of administration of the specific base are important considerations. For example, oral administration of even small amounts of sodium hydroxide would cause local tissue damage and would not be acceptable on this basis while administration of intermittent, small amounts of sodium hydroxide intravenously is performed routinely. Similarly, though lithium carbonate or rubidium acetate would be an acceptable base, only small amounts could be used due to the effects of the lithium or the rubidium, regardless of the route of administration.
  • compositions, formulations, and/or dosage forms comprising a polymer as disclosed herein additionally comprise a base that may be present in an amount sufficient to provide up to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer.
  • the composition, formulation, and/or dosage form may contain a disclosed polymer that contains calcium and/or magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups (e.g., calcium and/or magnesium counterions that are added during manufacture of the polymer) and base that is added during preparation or formulation of the composition, formulation, and/or dosage form in an amount sufficient to provide up to about 0.45 equivalents per equivalent of carboxylate groups in the polymer.
  • compositions of the present disclosure comprise a monobasic base (e.g., one equivalent per mole) present in an amount sufficient to provide from up to about 0.45 moles of base per mole of carboxylic acid groups in the polymer, for example about 0.45 moles of base, about 0.1 moles of base, about 0.15 moles of base, about 0.2 moles of base, about 0.25 moles of base, about 0.3 moles of base, about 0.35 moles of base, about 0.4 moles of base, or about 0.45 moles of base per mole of carboxylic acid groups in the polymer.
  • a monobasic base e.g., one equivalent per mole
  • compositions of the present disclosure comprise a monobasic base present in an amount sufficient to provide from about 0.2 moles of base to about 0.45 moles of base, for example about 0.2 moles of base, about 0.25 moles of base, about 0.3 moles of base, about 0.35 moles of base, about 0.4 moles of base, or about 0.45 moles of base per mole of carboxylate groups in the polymer.
  • compositions of the present disclosure comprise a monobasic base present in an amount sufficient to provide from about 0.3 moles of base to about 0.45 moles of base, for example about 0.3 moles of base, about 0.35 moles of base, about or 0.4 moles of base, or about 0.45 moles of base per mole of carboxylate groups in the polymer. In some embodiments, compositions of the present disclosure comprise a monobasic base present in an amount sufficient to provide about 0.45 moles of base per mole of carboxylate groups in the polymer.
  • compositions of the present disclosure comprise a dibasic base (e.g., two equivalents per mole) present in an amount sufficient to provide from up to about 0.225 moles of base per mole of carboxylic acid groups in the polymer, for example about 0.05 moles of base, about 0.075 moles of base, about 0.1 moles of base, about 0.125 moles of base, about 0.15 moles of base, about 0.175 moles of base, about 0.2 moles of base, or about 0.225 moles of base per mole of carboxylic acid groups in the polymer.
  • a dibasic base e.g., two equivalents per mole
  • compositions of the present disclosure comprise a dibasic base present in an amount sufficient to provide from about 0.1 moles of base to about 0.225 moles of base, for example about 0.1 moles of base, about 0.125 moles of base, about 0.15 moles of base, about 0.175 moles of base, about 0.2 moles of base, or about 0.225 moles of base per mole of carboxylate groups in the polymer.
  • compositions of the present disclosure comprise a dibasic base present in an amount sufficient to provide from about 0.15 moles of base to about 0.225 moles of base, for example about 0.15 moles of base, about 0.175 moles of base, about 0.2 moles of base, or about 0.225 moles of base per mole of carboxylate groups in the polymer. In some embodiments, compositions of the present disclosure comprise a dibasic base present in an amount sufficient to provide from about 0.2 moles of base to about 0.225 moles of base, for example about 0.2 moles of base or about 0.225 moles of base per mole of carboxylate groups in the polymer. In some embodiments, compositions of the present disclosure comprise a dibasic base present in an amount sufficient to provide about 0.225 moles of base per mole of carboxylate groups in the polymer.
  • compositions of the present disclosure comprise a tribasic base (e.g., three equivalents per mole) present in an amount sufficient to provide up to about 0.15 moles of base per mole of carboxylic acid groups in the polymer, for example about 0.05 moles of base, about 0.065 moles of base, about 0.07 moles of base, about 0.075 moles of base, about 0.08 moles of base, about 0.085 moles of base, about 0.09 moles of base, about 0.095 moles of base, about 0.1 moles of base, about 0.105 moles of base, about 0.1 1 moles of base, about 0.1 15 moles of base, about 0.12 moles of base, about 0.125 moles of base, about 0.13 moles of base, about 0.135 moles of base, about 0.14 moles of base, about 0.145 moles of base, or about 0.15 moles of base per mole of carboxylic acid groups in the polymer.
  • a tribasic base e.g., three equivalents per mole
  • compositions of the present disclosure comprise a tribasic base present in an amount sufficient to provide from about 0.065 moles of base to about 0.15 moles of base, for example about 0.065 moles of base, about 0.07 moles of base, about 0.075 moles of base, about 0.08 moles of base, about 0.085 moles of base, about 0.09 moles of base, about 0.095 moles of base, about 0.1 moles of base, about 0.105 moles of base, about 0.1 1 moles of base, about 0.1 15 moles of base, about 0.12 moles of base, about 0.125 moles of base, about 0.13 moles of base, about 0.135 moles of base, about 0.14 moles of base, about 0.145 moles of base, or about 0.15 moles of base moles of base per mole of carboxylate groups in the polymer.
  • compositions of the present disclosure comprise a tribasic base present in an amount sufficient to provide from about 0.1 moles of base to about 0.15 moles of base, for example about 0.1 moles of base, about 0.105 moles of base, about 0.1 1 moles of base, about 0.1 15 moles of base, about 0.12 moles of base, about 0.125 moles of base, about 0.13 moles of base, about 0.135 moles of base, about 0.14 moles of base, about 0.145 moles of base, or about 0.15 moles of base per mole of carboxylate groups in the polymer.
  • compositions of the present disclosure comprise a tribasic base present in an amount sufficient to provide about 0.15 moles of base per mole of carboxylate groups in the polymer.
  • compositions, formulations, and/or dosage forms of the present disclosure comprise more than one base (e.g., one or more monobasic bases, one or more dibasic bases, one or more tribasic bases, etc.).
  • the compositions comprise an amount of each base such that the total number of equivalents of base present is up to about 0.45 equivalents per mole of carboxylic acid groups in the polymer, for example, about 0.25 equivalents to about 0.45 equivalents per mole of carboxylic acid groups in the polymer.
  • a composition according to the present invention that comprises 1 .0 mole of carboxylic acid groups and 0.15 moles of sodium bicarbonate may also comprise up to about 0.15 moles of a dibasic base such as magnesium carbonate.
  • a dibasic base such as magnesium carbonate.
  • the total equivalents of base would be equal to 0.15 + (2)(about 0.15), or about 0.45 equivalents of base.
  • the base is present in an amount sufficient to provide from up to about 0.45 equivalents of base, for example about 0.05 equivalents, about 0.1 equivalents, about 0.15 equivalents, 0.2 equivalents, about 0.25 equivalents, about 0.3 equivalents, about 0.35 equivalents, about 0.4 equivalents, or about 0.45 equivalents of base per equivalent of carboxylic acid groups in the polymer.
  • the base is present in an amount sufficient to provide from about 0.25 to about 0.30, about 0.25 to about 0.35, about 0.25 to about 0.40, about 0.25 to about 0.45, about 0.30 to about 0.35, about 0.30 to about 0.40, about 0.30 to about 0.45, about 0.35 to about 0.40, about 0.35 to about 0.45, or about 0.40 to about 0.45 of base per equivalent of carboxylate groups in the polymer.
  • the base is one or more of: an alkali metal hydroxide, an alkali metal acetate, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal oxide, an alkaline earth metal hydroxide, an alkaline earth metal acetate, an alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal oxide, and an organic base.
  • the base is choline, lysine, arginine, histidine, a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the base is an acetate, a butyrate, a propionate, a lactate, a succinate, a citrate, an isocitrate, a fumarate, a malate, a malonate, an oxaloacetate, a pyruvate, a phosphate, a carbonate, a bicarbonate, a lactate, a benzoate, a sulfate, a lactate, a silicate, an oxide, an oxalate, a hydroxide, an amine, a dihydrogen citrate, or a combination thereof.
  • the base is a bicarbonate, a carbonate, an oxide, or a hydrochloride.
  • the base is one or more of: calcium bicarbonate, calcium carbonate, calcium oxide, and calcium hydroxide.
  • the base is a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an aluminum salt, a rubidium salt, a barium salt, a chromium salt, a manganese salt, an iron salt, a cobalt salt, a nickel salt, a copper salt, a zinc salt, an ammonium salt, a lanthanum salt, a choline salt, or a serine salt of any of the foregoing anions or anion combinations.
  • the base may be selected to avoid increasing a level of a particular cation associated with the subject.
  • a method of treatment for hyperkalemia in a subject would preferably include administering a base that does not include potassium cations, in conjunction with a polymer or composition, formulation or dosage form containing a polymer as disclosed herein.
  • a composition according to the present disclosure intended to treat hypernatremia in a subject would preferably contain a base that does not include sodium cations
  • the base may be selected to specifically increase the amount of a particular cation important in the disease or condition of the subject.
  • a method of treatment for hyponatremia for example, in a subject suffering simultaneously from hyperkalemia and hyponatremia, would preferably contain a base that either includes sodium cations or alters the polymer binding in such a manner that fewer sodium cations are removed by the polymer.
  • the disclosed polymers and compositions, formulations, and/or dosage forms containing the polymers described herein have superior manufacturing and processing properties in comparison to analogous polymers, compositions, formulations, and/or dosage forms wherein the carboxylate groups of the polymer are bound to hydrogen cations (e.g., protons; H + ) instead of calcium cations at the levels described herein.
  • hydrogen cations e.g., protons; H +
  • polymers with predominantly unneutralized carboxylate groups e.g., more than about 95% of the carboxylates are bound to hydrogen cations
  • are very adhesive which may result in manufacturing difficulties and poor oral delivery or mucoadhesive properties.
  • certain methods for preparing the disclosed polymers, compositions, formulations, and/or dosage forms require transferring the polymer from one vessel to another, drying the polymer, grinding or milling to form a powder, filtering the polymer, etc.
  • the adhesive properties associated with polymer having predominantly unneutralized carboxylate groups may render one these exemplary processes difficult, time-consuming, cost-inefficient, or sub-optimal for scale up.
  • polymers disclosed herein have calcium counterions to about 50% to about 70% of the carboxylate groups in the polymer.
  • polymers disclosed herein have about calcium and magnesium counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer.
  • Such polymers are characterized by dramatically improved manufacturability due to greatly reduced adhesive properties.
  • polymers having predominantly unneutralized carboxylate groups lead to poor oral delivery properties as they generally hydrate rapidly when exposed to saliva, becoming bioadhesive.
  • the hydrated form of the polymer causes the material to adhere to oral tissue, including teeth, which can lead to irritation.
  • polymers disclosed herein, which have calcium counterions to about 50% to about 70% of the carboxylate groups in the polymer, or which have calcium and magnesium counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer possess improved oral delivery properties.
  • a polymer and/or composition of the present disclosure has an in vitro saline holding capacity of greater than or at least about 20 times its own weight ⁇ e.g., greater than or at least about 20 grams of saline per gram of composition, or "g/g").
  • the polymer and/or composition has an in vitro saline holding capacity of about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 55 times, about 60 times, about 65 times, about 70 times, about 75 times, about 80 times, about 85 times, about 90 times, about 95 times, or about 100 times its own weight, or more.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 50% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 55% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 60% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 65% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations that are counterions to about 70% of the carboxylate groups of said polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the magnesium cations are counterions to no more than 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 65% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 65% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 5% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 65% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 65% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 4% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 65% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 3% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 65% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 2% sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 35% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 20% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 30% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 25% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 25% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 30% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 20% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers ⁇ e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 35% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 15% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers
  • carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 40% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 10% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 70% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 65% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 65% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 60% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 60% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 55% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 55% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 50% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • a crosslinked cation-binding polymer comprising monomers (e.g., acrylic acid) comprising carboxylate groups is a crosslinked polyacrylate, wherein said polymer contains calcium cations and magnesium cations that are counterions to about 50% of the carboxylate groups of said polymer, wherein the calcium cations are counterions to about 45% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to about 5% of the carboxylate groups in the polymer, and wherein the polymer comprises no more than about 1 % sodium cations as counterions to the carboxylate groups of said polymer.
  • monomers e.g., acrylic acid
  • the crosslinked cation binding polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 20 microns to about 125 microns, about 20 microns to about 150 microns, about 20 microns to about 200 microns, about 35 microns to about 125 microns, about 35 microns to about 150 microns, about 50 microns to about 125 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns, about 500 microns to about 1000 microns, about 1000 to about 5000 microns (alter
  • a polymer including a polyacrylate polymer, may have a particle size of about 212 microns to about 500 microns, a particle size from about 75 microns to about 150 microns, or a particle size of about 75 microns or less.
  • no less than about 70% of the polymer has a particle size of about 212 microns to about 500 microns, a particle size from about 75 microns to about 150 microns, a particle size of about 100 microns, or a particle size of about 75 microns or less.
  • the polyacrylate polymer is in the form of small particles that flocculate to form agglomerated particles with a diameter of about 1 micron to about 10 microns or about 0.1 microns to about 20 microns.
  • Particle sizes, including mean diameters, distributions, etc. can be determined using techniques known to those of skill in the art.
  • U.S. Pharmacopeia (USP) ⁇ 429> discloses methods for determining particle sizes.
  • the crosslinked cation binding polymer particles also have less than about 4 volume percent of the particles that have a diameter of less than about 10 ⁇ ; particularly, less than about 2 volume percent of the particles that have a diameter of less than about 10 ⁇ ; more particularly, less than about 1 volume percent of the particles that have a diameter of less than about 10 ⁇ ; and even more particularly, less than about 0.5 volume percent of the particles that have a diameter of less than about 10 ⁇ .
  • specific ranges are less than about 4 volume percent of the particles that have a diameter of less than about 20 ⁇ ; less than about 2 volume percent of the particles that have a diameter of less than about 20 ⁇ ; less than about 1 volume percent of the particles that have a diameter of less than about 20 ⁇ ; less than about 0.5 volume percent of the particles that have a diameter of less than about 20 ⁇ ; less than about 2 volume percent of the particles that have a diameter of less than about 30 ⁇ ; less than about 1 volume percent of the particles that have a diameter of less than about 30 ⁇ ; less than about 1 volume percent of the particles that have a diameter of less than about 30 ⁇ ; less than about 1 volume percent of the particles that have a diameter of less than about 40 ⁇ ; or less than about 0.5 volume percent of the particles that have a diameter of less than about 40 ⁇ .
  • the crosslinked cation exchange polymer has a particle size distribution wherein not more than about 5 volume% of the particles have a diameter less than about 30 ⁇ (e.g., D(0.05) ⁇ 30 ⁇ ), not more than about 5 volume% of the particles have a diameter greater than about 250 ⁇ (e.g., D(0.05) > 250 ⁇ ), and at least about 50 volume% of the particles have a diameter in the range from about 70 to about 150 ⁇ .
  • the present disclosure also relates to methods of using the polymers, and compositions, formulations, and/or dosage forms containing the polymers disclosed herein, with or without added base, to treat various diseases and disorders, ion imbalances, and fluid imbalances.
  • the disease or disorder is one or more of: heart failure, a renal insufficiency disease, end stage renal disease, liver cirrhosis, chronic renal insufficiency, chronic kidney disease, fluid overload, fluid maldistribution, edema, pulmonary edema, peripheral edema, lymphedema, nephrotic edema, idiopathic edema, ascites, cirrhotic ascites, interdialytic weight gain, high blood pressure, hyperkalemia, hypernatremia, abnormally high total body sodium, hypercalcemia, tumor lysis syndrome, head trauma, an adrenal disease, hyporeninemic hypoaldosteronism, hypertension, salt- sensitive hypertension, refractory hypertension, renal tubular disease, rhabdomyolysis, crush injuries, renal failure, acute tubular necrosis, insulin insufficiency, hyperkalemic periodic paralysis, hemolysis, malignant hyperthermia, pulmonary edema secondary to cardiogenic pathophysio
  • the disease or disorder is the result of, or is associated with, administration of another drug.
  • compositions and/or dosage forms as disclosed herein are useful in treating an increase in a subject's potassium level when coadministered with a drug known to cause increases in potassium levels.
  • a drug is an alpha-adrenergic agonist, a RAAS inhibitor, an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, an aldosterone antagonist, etc.
  • Crosslinked cation-binding polymers including, for example, polyelectrolyte polymers, such as polyacrylate polymers, etc.
  • polyelectrolyte polymers such as polyacrylate polymers, etc.
  • Polymers with differential properties may be prepared that are useful as therapeutics for different diseases and disorders, including those involving an ion imbalance and/or a fluid imbalance.
  • polymeric material including for example polymeric beads
  • the polymeric material may be further processed by milling or grinding the polymeric material into particles.
  • a polymer as described herein may contain many carboxylic acid groups, for example, polyacrylic acid, which may be reacted with alkali metals to produce a polycarboxylate, for example, polyacrylate.
  • Many of these polycarboxylates act as superabsorbent polymers and have a saline holding capacity of over twenty times their mass in vitro ⁇ e.g., about 40 times its mass) as measured in 0.9% saline solution ⁇ e.g., 0.15 M sodium chloride solution) buffered to pH 7. Exemplary methods are provided below.
  • Cross-linked cation-binding polymers including cross-linked polyacrylate and/or polyacrylic acid polymers, may be prepared by commonly known methods in the art.
  • cross-linked polyelectrolyte polymers may be prepared as a suspension of drops of aqueous solution in a hydrocarbon, for example, a liquid hydrocarbon ⁇ e.g., by inverse suspension polymerization).
  • Cross-linked polyacrylate polymers may be prepared by polymerization of partially neutralized acrylic acid in an aqueous environment where an appropriate cross- linker is present in small quantities. Given that there is an inverse relationship between the amount of fluid the polymer will absorb and the degree of cross-linking of the polymer, it may be desirable to have a low level of cross-linking to obtain a fluid absorption capacity of at least 20 g/g (e.g. 20 g/g, 30 g/g, 40 g/g, 50 g/g, 60 g/g, 70 g/g, 80 g/g, 90 g/g, or 100 g/g polymer), for use in methods as described herein.
  • 20 g/g e.g. 20 g/g, 30 g/g, 40 g/g, 50 g/g, 60 g/g, 70 g/g, 80 g/g, 90 g/g, or 100 g/g polymer
  • Non-crosslinked polymer is soluble and may not contribute to the absorbency of the polymer since it dissolves in the fluid.
  • polyacrylates can be designed to absorb about 35 times their mass (e.g., with a saline holding capacity of 35 g/g) in pH 7 buffered physiological saline as a compromise between high absorbency and minimal soluble polymer.
  • the precise amount of each reactant used in the preparation of cross-linked polyelectrolyte polymer, such as polyacrylate may be determined by one of skill in the art. For example, in a five-hundred gallon reactor, about 190 to 200 pounds (roughly 85 to 90 kg) of acrylic acid may be used while in a three liter reactor 150 to 180 g of acrylic acid may be used. Accordingly, the amount of each reactant used for the preparation of an exemplary cross-linked polyacrylate may be expressed as a weight ratio to acrylic acid. Thus, acrylic acid weight may be taken as 1 .0000 and other compounds are represented in relation to this value. Exemplary amounts of reactants used for the preparation of such a cross-linked polyacrylate by an inverse suspension polymerization are presented in Table 1 .
  • Table 1 Exemplary amounts of reactants in an inverse suspension polymerization
  • An exemplary inverse suspension reaction to form a crosslinked polymer may involve preparation of two mixtures ⁇ e.g., a hydrophobic mixture and an aqueous mixture) in two different vessels followed by combination of the mixtures to form a reaction mixture.
  • One vessel may be designated as a hydrophobic compound vessel and the other may be designated as an aqueous solution vessel.
  • the hydrophobic compounds may be mixed in a larger vessel that will become a reaction vessel, while an aqueous solution may be prepared in a smaller vessel that may be discharged into the reaction vessel.
  • the hydrophobic mixture may contain solvent, surfactant, and crosslinking agent
  • the aqueous mixture may contain water, base, monomer (e.g., acrylic acid), initiator, and optional chelating agent.
  • a hydrophobic solvent may be introduced into the reaction vessel.
  • a hydrophobic solvent also referred to herein as the "oil phase”
  • oil phase may be chosen based upon one or more considerations, including, for example, the density and viscosity of the oil phase, the solubility of water in the oil phase, the partitioning of the neutralized and unneutralized ethylenically unsaturated monomers between the oil phase and the aqueous phase, the partitioning of the crosslinker and the initiator between the oil phase and the aqueous phase and/or the boiling point of the oil phase.
  • Hydrophobic solvents contemplated for use in the present disclosure include, for example, IsoparTM L (isoparaffin fluid), toluene, benzene, dodecane, cyclohexane, n- heptane and/or cumene.
  • IsoparTM L is chosen as a hydrophobic solvent due to its low viscosity, high boiling point and low solubility for neutralized monomers such as sodium acrylate and/or potassium acrylate.
  • One or more surfactants and one or more cross-linkers may be added to the oil (hydrophobic) phase.
  • the oil phase may then be agitated and sparged with an inert gas, such as nitrogen or argon to remove oxygen from the oil phase.
  • an inert gas such as nitrogen or argon to remove oxygen from the oil phase.
  • This addition of surfactant is designed to coat the water droplets formed in the initial reaction mixture before the reaction starts. Higher amounts of surfactant and higher agitation rates produce smaller droplets with more total surface area. It will be understood by those of skill in the art that an appropriate choice of cross-linker and initiator may be used to prepare spherical to ellipsoid shaped beads.
  • cross-linker choice depends on whether it needs to be hydrophobic or hydrophilic polymer or whether it needs to resist acidic or basic external conditions.
  • An amount of cross-linker depends on how much soluble polymer is permissible and how much saline holding capacity is desired.
  • Exemplary surfactants include hydrophobic agents that are solids at room temperature, including, for example, hydrophobic silicas (such as Aerosil ® or Perform-O- SilTM) and glycolipids (such as polyethylene glycol distearate, polyethylene glycol dioleate, sorbitan monostearate, sorbitan monooleate or octyl glucoside).
  • hydrophobic silicas such as Aerosil ® or Perform-O- SilTM
  • glycolipids such as polyethylene glycol distearate, polyethylene glycol dioleate, sorbitan monostearate, sorbitan monooleate or octyl glucoside.
  • Crosslinking agents with two or more vinyl groups, each group of which is independently polymerizable, may be used, allowing for a wide variety in molecular weight, aqueous solubility and/or lipid ⁇ e.g., oil) solubility.
  • Crosslinking agents contemplated for use in the present disclosure include, for example, diethyleneglycol diacrylate, diacryl glycerol, triallylamine, tetraallyloxyethane, allylmethacrylate, 1 , 1 , 1-trimethylolpropane triacrylate (TMPTA), divinyl benzene, 1 ,7-octadien, and divinyl glycol.
  • a heat activated crosslinker may be used in the preparation of crosslinked polymers according to the present disclosure.
  • heat-activated crosslinkers include hydroxyl-containing crosslinking agents, amine-containing crosslinking agents, or epoxy-containing crosslinking agents containing at least one functionality suitable to react with a carboxyl group on the polymer and containing at least two functional groups capable of forming covalent bonds with the polymer.
  • Some non-limiting examples of heat-activated crosslinkers suitable for such use is the class of compounds commonly referred to as polyols or polyhydroxy compounds.
  • polyols include: glycerin, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, 1 ,4-butanediol, 1 ,5-pentanediol, 1 ,6-hexanediol, neopentyl glycol, polyglycerin, trimethylolpropane, polyethylene glycol, and polypropylene glycol-polyethylene glycol copolymers.
  • Masked polyols such as ethyleneglycol diacetate may also be used.
  • heat-activated crosslinkers containing amine functionality are ethylenediamine, diethylenetriamine, triethylenetetramine, monoethanolamine, and aminoethylethanolamine.
  • heat- activated crosslinkers containing epoxy functionality are glycidyl acrylate, glycidylmethacrylate, and ethyleneglycol diglycidylether,
  • dimodal crosslinkers may be used in the preparation of crosslinked polymers according to the present disclosure.
  • Dimodal crosslinkers contain one or more carboxylic acid-reactive groups and one or more ethylenically unsaturated groups in the same compound.
  • Non-limiting examples of dimodal crosslinkers suitable for use to crosslink polymers according to the present disclosure include: 2- hydroxyethyl(meth)acrylate, polyethylene glycol monomethacrylate, glycidyl methacrylate, allyl glycidyl ether, hydroxypropyl methacrylate, hydroxyethyl methacrylate, and hexapropylene glycol monomethacrylate.
  • polyvinyl compounds may be used in the preparation of crosslinked polymers according to the present disclosure.
  • polyvinyl crosslinkers include divinyl compounds or polyvinyl compounds such as: divinyl glycol, divinyl benzene, 1 ,7, octadience (ODE), divinyl toluene, divinyl xylene, divinyl ether, divinyl ketone, trivinyl benzene; unsaturated polyesters that can be obtained by reacting an unsaturated acid such as maleic acid with polyols such as: ethylene glycol, glycerol, diethylene glycol, triethylene glycol, tetraethyleneglycol, propylene glycol, dipropyleneglycol, tripropyleneglycol, tetrapropyleneglycol, polyoxyethylene glycols and polyoxypropylene glycols, 1 ,4-butanediol, 1 ,5-pentaned
  • the crosslinker may be one or more compound consistent with the following formula:
  • R 1 is a straight-chain or branched-chain C1-C10 polyalkoxy radical, optionally substituted with one or more oxygen atoms in the backbone, having x valences;
  • each R 2 is independently a C 2 -C 4 alkylene group
  • each R 3 is independently a straight-chain or branched-chain C2-C10 alkenyl moiety
  • n is a positive integer from 1-20;
  • x is a positive integer from 2-8.
  • An aqueous phase mixture may be prepared in another vessel ⁇ e.g., a vessel that is separate from that used to prepare the hydrophobic phase) that contains water.
  • preparation of neutralized or partially neutralized polymer base and monomer are added to the water.
  • preparation of non-neutralized (acid form) polymer monomer is added to the water without base.
  • the amount of base used in the vessel is determined by the degree of neutralization of the monomer desired. For neutralized or partially neutralized polymer, a degree of neutralization between about 60% and 100% is preferred.
  • one-hundred percent neutralization minimizes the chance of suspension failure, but the highly charged monomer may not react as rapidly and may not pull hydrophobic crosslinkers into the forming polymer.
  • Considerations in choosing the degree of neutralization may be determined by one of skill in the art and include, for example, the effect of monomer charge ⁇ e.g., as determined by ionization of the cation from the neutralized molecules) on reaction rate, partitioning of the monomer and neutralized monomer between oil phase and aqueous phase and/or tendency of the aqueous droplets to coalesce during the reaction.
  • the solubilities of sodium acrylate and sodium methacrylate in water are limited and are lower at lower temperatures ⁇ e.g., sodium acrylate is soluble at about 45% at 70 °C but less than 40% at 20 °C).
  • This solubility may establish the lower limit of the amount of water needed in the neutralization step.
  • the upper limit of the amount of water may be based on reactor size, amount of oil phase needed to reliably suspend the aqueous phase as droplets and/or the desired amount of polymer produced per batch.
  • Bases contemplated for use in methods of making the crosslinked polymers of the present disclosure include, for example, hydroxides, bicarbonates, or carbonates. Use of these bases allows neutralization of the acid monomer without residual anions left in the reaction mixture as the anions react to form water or C0 2 . Frequently, sodium bases are chosen in the method of making the crosslinked polymers. However, potassium bases, ammonium bases, and bases of other cations, including calcium bases, are contemplated for use in the present disclosure.
  • the water used in the reaction may be purified water or water from other sources such as city water or well water. If the water used is not purified water, chelating agents may be needed to control metals, e.g., heavy metal ions, such as iron, calcium, and/or magnesium from destroying the initiator. Chelating agents contemplated for use with the present disclosure include, for example, diethylenetriaminepentaacetic acid pentasodium (VersenexTM 80). The amount of chelating agent added to the reaction mixture may be determined by one of skill in the art from a determination of the amount of undesirable metal in the water.
  • a metal may be added to catalyze the polymerization reaction ⁇ e.g., iron).
  • the aqueous phase solution may be cooled to remove the heat released from dilution of the base, and one or more classes of monomers may be added, to react with the base, for example, monomers which will be neutralized by the base. As will be appreciated by one of skill in the art, the monomers will be neutralized to the degree dictated by the amount of base in the reaction.
  • the aqueous phase solution may be kept cool ⁇ e.g., below 35 to 40 °C) and preferably around 20 °C to prevent formation of prepolymer strands, dimers and/or possible premature polymerization.
  • Monomers are dissolved in water at concentrations of 10-70 wt% or 20-40 wt% and polymerization may subsequently be initiated by free radicals in the aqueous phase.
  • Monomers may be polymerized either in the acid form or as a partially neutralized salt.
  • monomers in the acid form may be less desirable due to high solubility in the oil phase.
  • the amount of water used to dissolve the monomer is minimally set so that all of the monomer ⁇ e.g., sodium acrylate) is dissolved in the water rather than crystallizing and maximally set so that there is the smallest volume of reaction mixture possible (to minimize the amount of distillation and allow the maximum yield per batch).
  • Exemplary monomer units contemplated for use in the present disclosure include, for example, acrylic acid and its salts, methacrylic acid and its salts, crotonic acid and its salts, tiglinic acid and its salts, 2-methyl-2-butenoic acid (Z) and its salts, 3-butenoic acid (vinylacetic acid) and its salts, 1 -cyclopentene carboxylic acid, and 2-cyclopentene carboxylic acid and their salts; and unsaturated dicarboxylic acids and their salts, such as maleic acid, fumaric acid, itaconic acid, glutaconic acid, and their salts.
  • cross-linked polyelectrolyte superabsorbent polymers may be based on sulfonic acids and their salts, or phosphonic acids and their salts.
  • additional monomers may be contemplated for use.
  • the additional monomers are those from which the desired carboxylic acid, sulfonic acid, or phosphonic acid functionality may be derived by known chemical reactions, for example by hydrolysis.
  • the monomer for example, acrylonitrile, acrylamide, methacrylamide, lower alcohol esters of unsaturated, polymerizable carboxylic acids (such as those mentioned in the paragraph above) or their mixtures, and the like may be polymerized with a suitable crosslinker to an intermediate crosslinked polymer, which is then subjected to chemical reaction (so-called "polymer analogous reaction") to convert the functional groups of the polymer into carboxylic functionality.
  • ethyl acrylate may be polymerized with a non-hydrolysis- susceptible crosslinker (e.g.
  • tetraallyloxyethane to form a crosslinked intermediate polymer, which is then subjected to hydrolysis conditions to convert the ester functionality to carboxylic acid functionality by means known in the art.
  • acrylonitrile is graft polymerized to starch with a crosslinker as necessary to form a crosslinked starch- graft intermediate polymer, which is then treated with aqueous base to hydrolyze the nitrile functionality to carboxylic acid functionality (see, e.g., U.S. Patent Nos. 3,935,099, 3,991 ,100, 3,997,484, and 4, 134,863).
  • One or more initiators may be added to the aqueous phase just before the aqueous phase is transferred into the oil phase.
  • the initiator amount and type used in the polymerization reaction depends on oil versus water solubility and whether longer chain lengths are desired. For example, a lower amount of initiator may be used in the polymerization reaction when longer chain lengths are desired.
  • one of the initiators may be a thermally sensitive compound such as a persulfate, 2,2'-azobis(2-amidino-propane)-dihydrochloride, 2,2 - azobis (2-amidino-propane)-dihydrochloride and/or 2,2'-azobis (4-cyanopentanoic acid).
  • thermally sensitive initiators polymerization does not begin until an elevated temperature is reached. For persulfates, this temperature is approximately 50 to 55 °C. Since the reaction is highly exothermic, vigorous removal of the heat of reaction is required to prevent boiling of the aqueous phase. It is preferred that the reaction mixture be maintained at approximately 65 °C.
  • thermal initiators have the advantage of allowing control of the start of the reaction when the reaction mixture is adequately sparged of oxygen.
  • one of the initiators may be a redox pair such as persulfate/bisulfate, persulfate/thiosulfate, persulfate/ascorbate, hydrogen peroxide/ascorbate, sulfur dioxide/tert-butylhydroperoxide, persulfate/erythorbate, tert- butylhydroperoxide/erythorbate and/or tert-butylperbenzoate/erythorbate.
  • These initiators are able to initiate the reaction at room temperature, thereby minimizing the chance of heating the reaction mixture to the boiling point of the aqueous phase as heat is removed through the jacket around the reactor.
  • the reaction is not started immediately after the mixing of the aqueous phase into the oil phase in the final reactor because the aqueous phase still has an excessive amount of oxygen dissolved in the water. It will be appreciated by one of skill in the art that an excessive amount of oxygen may cause poor reactivity and inadequate mixing may prevent the establishment of uniform droplet sizes. Instead, the final reaction mixture is first sparged with an inert gas for ten to sixty minutes after all reagents (except the redox pair if that initiator system is used) have been placed in the reactor. The reaction may be initiated when a low oxygen content ⁇ e.g., below 15 ppm) is measured in the inert gas exiting the reactor.
  • a low oxygen content ⁇ e.g., below 15 ppm
  • the reaction may be continued for four to six hours after the peak exotherm is seen to allow for maximal consumption of the monomer into the polymer.
  • the polymeric material may be isolated by either transferring the entire reaction mixture to a centrifuge or filter to remove the fluids or by initially distilling the water and some of the oil phase ⁇ e.g., frequently as an azeotrope) until no further removal of water is possible and the distillation temperature rises significantly above 100 °C, followed by isolating the polymeric material by either centrifugation or filtering.
  • the isolated crosslinked cation-binding polymeric material is then dried to a desired residual moisture content ⁇ e.g., less than 5%).
  • An exemplary cross-linked cation-binding polymer, polyacrylate may be formed by copolymerizing an ethylenically unsaturated carboxylic acid with a multifunctional cross- linking monomer.
  • the acid monomer or polymer may be substantially or partially neutralized with an alkali metal salt such as an oxide, a hydroxide, a carbonate, or a bicarbonate and polymerized by the addition of an initiator.
  • an alkali metal salt such as an oxide, a hydroxide, a carbonate, or a bicarbonate
  • One such exemplary polymer gel is a copolymer of acrylic acid/sodium acrylate and any of a variety of cross-linkers.
  • cross-linked cation-binding polymer cross-linked polyacrylate
  • This cross-linked cation- binding polymer may be produced as a one-hundred kilogram batch in a five-hundred gallon vessel.
  • cation-binding polymers may be prepared by other methods known in the art ⁇ e.g., Buchholz, F. L. and Graham, A. T., "Modern Superabsorbent Polymer Technology,” John Wiley & Sons (1998)), for example by aqueous one-phase methods, by precipitation polymerization (see, e.g., European Patent Application No. EP0459373A2), and by crosslinking of soluble polymer using monomers, crosslinkers, surfactants, initiators, neutralizing agents, solvents, suspending agents, and chelators as described herein.
  • cation-binding polymers containing carboxyl groups formed from monomers as described herein may be polymerized to form soluble polymer which may then be crosslinked.
  • the crosslinker it may be possible to incorporate the crosslinker either into the intermediate polymer, or into the chemically-reacted carboxylic acid functional polymer.
  • crosslinker may be incorporated by copolymerization of the contemplated monomers with a crosslinker as described herein, and then the crosslinked polymer may be converted by, for example hydrolysis, to the desired crosslinked carboxylic acid-functional product.
  • the contemplated additional monomers may be polymerized to a non- crosslinked polymer, then converted to the carboxylic acid-functional polymer and subsequently reacted with a suitable crosslinker (for example, one of the heat-activated crosslinkers in the list) to provide the desired, crosslinked, carboxylic acid-functional polymer.
  • a suitable crosslinker for example, one of the heat-activated crosslinkers in the list.
  • the polymerization is accomplished in the normal way to yield an uncrosslinked polymer that also contains the molecularly dispersed, heat-activated crosslinker.
  • the polymer system is heated to a temperature that is suitable to cause the reaction between polymer functional groups and the crosslinker molecules, thereby crosslinking the polymer.
  • Partially neutralized or fully neutralized crosslinked cation-binding polymers may be acidified by washing the polymer with acid.
  • Suitable acids contemplated for use with the present disclosure include, for example, hydrochloric acid, acetic acid and phosphoric acid.
  • Acid-washed crosslinked cation-binding polymers may be additionally rinsed with water or other fluid (e.g. ethanol) and then dried in, for example, a vacuum oven or inert atmosphere until, for example, less than 5% moisture remains, to produce a substantially free acid form of cross-linked polyacrylic acid.
  • water or other fluid e.g. ethanol
  • Any particle form of partially or fully neutralized cross-linked cation-binding polymer may be used as the starting point, for example, particles, powders, or bead-form particles, or milled bead-form particles.
  • Acid form cross-linked cation-binding polymers may be prepared by any method known by those skilled in the art (e.g., Buchholz, F. L. and Graham, A. T., "Modern Superabsorbent Polymer Technology,” John Wiley & Sons (1998)), for example by inverse suspension, aqueous one-phase polymerization, by precipitation polymerization (see, e.g., European Patent Application No. EP0459373A2), and by crosslinking of soluble polymer. Any of the methods, monomers, crosslinkers, surfactants, initiators, neutralizing agents, solvents, suspending agents, chelators, catalysts, and other agents as described herein may be used.
  • Crosslinked cation-binding polymers may be prepared from monomers with unneutralized carboxylic acid groups.
  • a crosslinked polyacrylic acid can be prepared from acrylic acid.
  • a monomer solution is prepared in a reactor by dissolving an unsaturated carboxylic acid monomer (e.g., acrylic acid) in water.
  • a chelating agent e.g., VersenexTM 80
  • a metal added to catalyze the polymerization reaction e.g., iron
  • a suitable crosslinking agent e.g., trimethylolpropane triacrylate
  • the solution may be agitated and oxygen may be removed using nitrogen, argon or by other means known in the art.
  • the temperature of the solution may be adjusted as desired.
  • One or more polymerization initiators may be added to the reactor and the oxygen tension may be reduced or the temperature may be increased to initiate polymerization.
  • the reaction is allowed to proceed through the exothermic heating that occurs during reaction. Reaction heat can be removed and/or controlled as desired by methods known to those skilled in the art.
  • the reaction vessel may then be heated and oxygen tension in the reaction vessel may be kept low to continue the polymerization to low levels of residual monomer.
  • the polymerization reaction product can be removed from the reactor and the wet polymer may be reduced in size (e.g. by cutting or by methods known to those skilled in the art) into pieces of appropriate size for drying.
  • the polymer pieces can then be dried in a vacuum oven or other equipment known to those skilled in the art. Conditions during drying may be adjusted (e.g. humidity level, rate of drying) so that polymerization and reduction of residual monomer continues during the drying process. After drying, the particles can be separated by size and/or milled and/or sieved to produce the desired particle size.
  • Conditions during drying may be adjusted (e.g. humidity level, rate of drying) so that polymerization and reduction of residual monomer continues during the drying process.
  • the particles can be separated by size and/or milled and/or sieved to produce the desired particle size.
  • Other examples of the polymerization of aqueous acrylic acid solutions with crosslinkers are disclosed in Buchholz, F. L. and Graham, A. T., "Modern Superabsorbent Polymer Technology," John Wiley & Sons (1998), U.S. Patent No. 4,654,039; U.S. Patent No. 4,295,987; U.S. Patent No. 5, 145,906
  • Crosslinked, cation-binding polymers with calcium and/or magnesium ions may be prepared by ion-exchange from a partially neutralized crosslinked, cation-binding polymer, by the addition of a calcium and/or magnesium base to an acid form of a crosslinked, cation-binding polymer, by using a calcium or magnesium base to neutralize acrylic acid prior to polymerization, or by other methods known by those skilled in the art.
  • Any particle form of partially or fully neutralized cross-linked cation-binding polymer may be used as the starting point, for example, particles, powders, or bead-form particles, or milled bead-form particles.
  • Partially neutralized crosslinked cation-binding polymers may be hydrated and equilibrated with several washes of a salt solution of calcium and/or magnesium (e.g. CaCI 2 , MgCI 2 ) of a concentration high enough to exchange the original counterions on the polymer with the calcium and/or magnesium cations and remove the original counterions from the solution.
  • a salt solution of calcium and/or magnesium e.g. CaCI 2 , MgCI 2
  • an appropriate amount of acid may be added with the calcium and/or magnesium salt to bring the neutralization level down to the desired level.
  • the replacement of the counterions (ion- exchange), including cations such as sodium atoms, by calcium and/or magnesium cations can be performed with many different calcium and/or magnesium salts and salt concentrations.
  • the calcium and/or magnesium crosslinked cation-binding polymers may be additionally rinsed with water and then dried in, for example, a vacuum oven or inert atmosphere until, for example, less than 5% moisture remains.
  • Crosslinked cation-binding polymers with calcium and/or magnesium counterions may be produced from the acid form of the polymer through the addition of a calcium and/or magnesium base (e.g, CaC0 3, MgO).
  • the base may be added to the polymer as a solid or solution and the polymer may be hydrated prior to addition of the base.
  • the polymer and base may be stirred and/or heated to facilitate neutralization of the polymer with the base.
  • the calcium and/or magnesium crosslinked cation-binding polymers may be additionally rinsed with water and then dried in, for example, a vacuum oven or inert atmosphere until, for example, less than 5% moisture remains.
  • Exemplary crosslinked cation-binding polymers including for example those prepared according to Examples 1 -4, generally have a pH 7 buffered saline holding capacity of about 20 g/g or greater, including, for example, greater than about 40 g/g; and contain less than about 5,000 ppm of sodium, less than about 20 ppm of heavy metals, less than about 1000 ppm (e.g., less than about 500 ppm) of residual monomer, less than about 2,000 ppm of residual chloride, and less than about 20 wt % of soluble polymer.
  • acidified polymers useful as crosslinked cation-binding polymers prepared according to this disclosure have a saline holding capacity of preferably greater than about 40 g/g, (e.g., 80 g/g) contain less than about 500 ppm of sodium, less than about 20 ppm of heavy metals, less than about 500 ppm of residual monomer, less than about 1 ,500 ppm of residual chloride, and less than about 10 wt.% of soluble polymer.
  • Crosslinked cation-binding polymers prepared, for example, according to the method of Example 1 or 2 using acrylic acid monomers, followed by acidification as described in Example 3, or crosslinked cation-binding polymers prepared, for example, as described in Example 4, are referred to as "H-CLP" or "HCLP" throughout the Examples.
  • the polymer particles may be reduced in size by milling or grinding or other means known to those skilled in the art. Particles of certain size ranges or a particle size distribution may be obtained by means known to those of skill in the art, for example, by sieving through sieves or screens. Seives may be stacked vertically starting with the smallest pore size at the bottom (largest mesh size) to largest pore size at the top (smallest mesh size). The material is placed on top of the screen and the screens are shaken to allow particles to pass through screens until they are caught on a screen with a pore size smaller than the particle diameter. The material on each screen will then be smaller than the screen above, but larger than the screen below.
  • particles that pass through an 18 Mesh screen and are caught on a 20 Mesh screen are between 850 and 1000 microns in diameter.
  • Screen mesh and the corresponding maximum particle size allowed to pass through the mesh include, 18 mesh, 1000 microns; 20 mesh, 850 microns; 25 mesh, 710 microns; 30 mesh, 600 microns; 35 mesh, 500 microns, 40 mesh, 425 microns; 45 mesh, 35 microns; 50 mesh, 300 microns; 60 mesh, 250 microns; 70 mesh, 212 microns; 80 mesh, 180 microns; 100 mesh, 150 microns; 120 mesh, 125 microns; 140 mesh, 106 microns; 170 mesh, 90 microns; 200 mesh, 75 microns; 230 mesh, 63 microns; and 270 mesh, 53 microns.
  • particles of varying sizes may be obtained through the use of one or more screens.
  • the particle size range may be characterized, for example, by sieves or screens, a particle size distribution determined, for example, by laser light diffraction, by an average size, or other measures.
  • a particles size distribution for material passing through a 100 mesh (150 microns) screen but captured on a 200 mesh (75 microns) screen may be characterized as the weight % of the polymer greater than 150 microns, the fraction between 75 to 150 microns, and the fraction below 75 microns. Alternatively, this material could be characterized by the fraction less than 150 micronsand the fraction less than 75 microns. In an exemplary polymer fraction collected using 100 and 200 mesh screens, the fraction between 75-150 microns would preferably be greater than 70%.
  • the particle size distribution can also be characterized by describing particle diameters where 10% (D 0. i), 50% (D0.5), or 90% (D0.9) of the particles are smaller than that particle size.
  • compositions, formulations, and/or dosage forms comprising a cross-linked cation-binding polymer comprising monomers containing carboxylic acid groups ⁇ e.g., a cross-linked polyacrylic acid polymer) and wherein the polymer further comprises calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer (alternately, the polymer comprises calcium counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer).
  • a cross-linked cation-binding polymer comprising monomers containing carboxylic acid groups ⁇ e.g., a cross-linked polyacrylic acid polymer
  • the polymer further comprises calcium cations, wherein the calcium cations are counter
  • the polymer comprises calcium cations that are counterions to about 50%, about 55%, about 60%, about 65%, or about 70% of the carboxylate groups in the polymer.
  • the calcium cations are counterions to about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, or about 70% of the carboxylate groups in the polymer.
  • These polymers, compositions, formulations, and/or dosage forms may be delivered to a subject, including using a wide variety of routes or modes of administration.
  • the compositions, formulations, and/or dosage forms as disclosed herein optionally comprise an added base. Preferred routes for administration are oral or intestinal.
  • compositions, formulations, and/or dosage forms comprising a cross- linked cation-binding polymer comprising monomers containing carboxylic acid groups ⁇ e.g., a cross-linked polyacrylic acid polymer) and wherein the polymer further comprises calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer (alternately, the polymer comprises calcium and magnesium counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer.
  • a cross- linked cation-binding polymer comprising monomers containing carboxylic acid groups ⁇ e.g
  • the polymer comprises calcium and magnesium cations that are counterions to about 50%, about 55%, about 60%, about 65%, or about 70% of the carboxylate groups in the polymer.
  • the calcium and magnesium cations are counterions to about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, or about 70% of the carboxylate groups in the polymer.
  • compositions, formulations, and/or dosage forms may be delivered to a subject, including using a wide variety of routes or modes of administration.
  • the compositions, formulations, and/or dosage forms as disclosed herein optionally comprise an added base.
  • Preferred routes for administration are oral or intestinal.
  • a composition, formulation, or dosage form as disclosed herein comprises a polymer that comprises calcium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer, and sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer.
  • the polymer further comprises hydrogen cations (e.g., protons) as counterions to all or substantially all of the carboxylate groups to which calcium and sodium are not counterions (e.g., "free carboxylates"), for example about 95% of the free carboxylates, about 96% of the free carboxylates, about 97% of the free carboxylates, about 98% of the free carboxylates, about 99% of the free carboxylates, about 99.5% of the free carboxylates, or about 100% of the free carboxylates.
  • hydrogen cations e.g., protons
  • free carboxylates for example about 95% of the free carboxylates, about 96% of the free carboxylates, about 97% of the free carboxylates, about 98% of the free carboxylates, about 99% of the free carboxylates, about 99.5% of the free carboxylates, or about 100% of the free carboxylates.
  • the polymer comprises calcium cations as counterions to about 50% to about 60% of the carboxylate groups on the polymer, sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer, and hydrogen cations (e.g., protons) as counterions to all or substantially all of the free carboxylates.
  • a composition, formulation, or dosage form as disclosed herein comprises a polymer that comprises calcium and magnesium cations as counterions to about 50% to about 70% of the carboxylate groups on the polymer and sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and further comprises hydrogen cations (e.g., protons) as counterions to all or substantially all of the carboxylate groups to which magnesium or sodium are not counterions (e.g., "free carboxylates"), for example about 95% of the free carboxylates, about 96% of the free carboxylates, about 97% of the free carboxylates, about 98% of the free carboxylates, about 99% of the free carboxylates, about 99.5% of the free carboxylates, or about 100% of the free carboxylates.
  • hydrogen cations e.g., protons
  • the polymer comprises calcium and magnesium cations as counterions to about 50% to about 60% of the carboxylate groups on the polymer, sodium cations as counterions to no more than about 5% of the carboxylate groups on the polymer, and hydrogen cations (e.g., protons) as counterions to all or substantially all of the free carboxylates.
  • a composition, formulation, or dosage form as described herein comprises a crosslinked cation-binding polymer comprising repeat units containing carboxylic acid groups, and wherein the polymer further comprises calcium cations that are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer) and further comprises an added base, wherein the base is present in an amount sufficient to provide up to about 0.45 equivalents of base per equivalent of carboxylic acid groups in the polymer.
  • composition, formulation, or dosage form contains about 0.05 equivalents, about 0.1 equivalents, about 0.15 equivalents, about 0.2 equivalents, about 0.25 equivalents, about 0.3 equivalents, about 0.35 equivalents, about 0.4 equivalents, or about 0.45 equivalents of base per equivalent of carboxylic acid groups in the polymer.
  • a composition, formulation, or dosage form as described herein comprises a crosslinked cation-binding polymer comprising repeat units containing carboxylic acid groups, and wherein the polymer further comprises calcium and magnesium cations that are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and further comprises an added base, wherein the base is present in an amount sufficient to provide up to about 0.45 equivalents of base per equivalent of carboxylic acid groups in the polymer.
  • composition, formulation, or dosage form contains about 0.05 equivalents, about 0.1 equivalents, about 0.15 equivalents, about 0.2 equivalents, about 0.25 equivalents, about 0.3 equivalents, about 0.35 equivalents, about 0.4 equivalents, or about 0.45 equivalents of base per equivalent of carboxylic acid groups in the polymer.
  • a composition, formulation, and/or dosage form as described herein comprises a crosslinked cation-binding polymer comprising carboxylic acid-containing monomers and calcium cations, wherein the calcium cations are present in an amount sufficient to act as counterions to about 50% to about 70% of the carboxylate groups in the polymer, and an amount of added base sufficient to provide up to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer (alternatively, about 0.25 to about 0.30, about 0.25 to about 0.35, about 0.25 to about 0.40, about 0.25 to about 0.45, about 0.30 to about 0.35, about 0.30 to about 0.40, about 0.30 to about 0.45, about 0.35 to about 0.40, about 0.35 to about 0.45, or about 0.40 to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer).
  • the calcium cations are present in an amount sufficient to act as counterions to about 50% to about 60% of the carboxylate groups in the polymer, and added base is present in an amount sufficient to provide up to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer (alternatively, about 0.35 to about 0.45, or about 0.35 to about 0.40, equivalents of base per equivalent of carboxylate groups in the polymer).
  • a composition, formulation, and/or dosage form as described herein comprises a crosslinked cation-binding polymer comprising carboxylic acid-containing monomers and calcium and magnesium cations, wherein the calcium and magnesium cations are present in an amount sufficient to act as counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and an amount of added base sufficient to provide up to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer (alternatively, about 0.25 to about 0.30, about 0.25 to about 0.35, about 0.25 to about 0.40, about 0.25 to about 0.45, about 0.30 to about 0.35, about 0.30 to about 0.40, about 0.30 to about 0.45, about 0.35 to about 0.40, about 0.35 to about 0.45, or about 0.40 to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer).
  • the calcium and magnesium cations are present in an amount sufficient to act as counterions to about 50% to about 60% of the carboxylate groups in the polymer, and added base is present in an amount sufficient to provide up to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer (alternatively, about 0.35 to about 0.45, or about 0.35 to about 0.40, equivalents of base per equivalent of carboxylate groups in the polymer).
  • the polymers in any of the compositions, formulations, and/or dosage forms disclosed herein may comprise sodium cations which (if present) are counterions to no more than about 5%, 4%, 3%, 2%, 1 %, or 0.5% of the carboxylate groups in the polymer.
  • the polymers disclosed herein for inclusion in a composition, formulation, or dosage form, e.g., for administration to an individual, e.g., for use in methods of treatment disclosed herein are individual particles or particles agglomerated to form a larger particle (for example, flocculated particles), and have a diameter of about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 20 microns to about 125 microns, about 20 microns to about 150 microns, about 20 microns to about 200 microns, about 35 microns to about 150 microns, about 35 microns to about 125 microns, about 50 microns to about 125 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns,
  • the particles or agglomerated particles have a diameter of about 1 , about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 1 10, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000 , about 1500, about 2000, about 2500, about 3000, about 3500, about 4000, about 4500, about 5000, about 5500, about 6000, about 7000, about 7500, about 8000, about 8500, about 9000, about 9500, or about 10,000 microns.
  • the crosslinked cation-binding polymer disclosed herein for inclusion in a composition, formulation, or dosage form, e.g., for administration to an individual, e.g., for use in methods of treatment disclosed herein is a crosslinked polyacrylate polymer.
  • the polymer may be a polyacrylate polymer crosslinked with about 0.025 mol% to about 3.0 mol%, including from about 0.025 mol% to about 0.3 mol%, from about 0.025 mol% to about 0.17 mol%, from about 0.025 mol% to about 0.34 mol%, or from about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol.% to about 3.0 mol.% including, for example, from about 0.025 mol.% to about 0.3 mol.%., , and for example, may comprise an in vitro saline holding capacity of at least about 20 times its weight (e.g., at least about 20 grams of saline per gram of polymer, or "g/g"), at least about 30 times its weight, at least about 40 times its weight, at least about 50 times its weight, at least about 60 times its weight, at least about 70 times its weight, at least about 80 times its weight, at least about 90 times its weight
  • the crosslinked polyacrylate polymer is in the form of individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the diameter of individual particles or agglomerated particles (e.g., average particle diameter) is about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 20 microns to about 125 microns, about 20 microns to about 150 microns, about 20 microns to about 200 microns, about 35 microns to about 150 microns, about 35 microns to about 125 microns, about 50 microns to about 125 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns, about 500 microns to about 1000 microns, about 1000
  • a polymer including a polyacrylate polymer
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 100 microns.
  • no less than about 70% of the polymer has a particle size of about 212 microns to about 500 microns, a particle size from about 75 microns to about 150 microns, or a particle size of about 75 microns or less.
  • the polyacrylate polymer is in the form of small particles that flocculate to form agglomerated particles with a diameter of about 1 micron to about 10 microns or about 0.1 microns to about 20 microns. In one embodiment, the polyacrylate polymer is in the form of small particles that flocculate to form agglomerated particles with a diameter of about 1 micron to about 10 microns.
  • the optionally added base component is one or more of: an alkali metal hydroxide, an alkali metal acetate, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal oxide, an alkali earth metal hydroxide, an alkali earth metal acetate, an alkali earth metal carbonate, an alkali earth metal bicarbonate, an alkali earth metal oxide, an organic base, choline, lysine, arginine, histidine, an acetate, a butyrate, a propionate, a lactate, a succinate, a citrate, an isocitrate, a fumarate, a malate, a malonate, an oxaloacetate, a pyruvate, a phosphate, a carbonate, a bicarbonate, a lactate, a benzoate, a sulfate,
  • a composition, formulation, or dosage form disclosed herein comprises a polyacrylate polymer that comprises calcium counterions to about 50% to about 70% of the carboxylate groups in the polymer, for example, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, or about 70% of the carboxylate groups in the polymer, and wherein sodium cations (if present) are counterions to no more than about 5% of the carboxylate groups in the polyacrylate polymer.
  • the composition, formulation, or dosage form additionally comprises added base, for example, calcium carbonate base, present in an amount to provide up to about 0.45 equivalents of base per carboxylate group on the polyacrylate polymer, for example, about 0.05 equivalents, 0.1 equivalents, 0.15 equivalents, 0.2 equivalents, 0.25 equivalents, 0.3 equivalents, 0.35 equivalents, 0.4 equivalents, or 0.45 equivalents of base per equivalent of carboxylate groups in the polyacrylate polymer.
  • base for example, calcium carbonate base
  • a composition, formulation, or dosage form disclosed herein comprises a polyacrylate polymer that comprises calcium and magnesium counterions to about 50% to about 70% of the carboxylate groups in the polymer, for example, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, or about 70% of the carboxylate groups in the polymer, wherein magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and wherein sodium cations (if present) are counterions to no more than about 5% of the carboxylate groups in the polyacrylate polymer.
  • the composition, formulation, or dosage form additionally comprises added base, for example, calcium carbonate base, present in an amount to provide up to about 0.45 equivalents of base per carboxylate group on the polyacrylate polymer, for example, about 0.05 equivalents, 0.1 equivalents, 0.15 equivalents, 0.2 equivalents, 0.25 equivalents, 0.3 equivalents, 0.35 equivalents, 0.4 equivalents, or 0.45 equivalents of base per equivalent of carboxylate groups in the polyacrylate polymer.
  • base for example, calcium carbonate base
  • compositions, formulations, and/or dosage forms additionally comprise one or more excipients, carriers, or diluents.
  • Compositions for use in accordance with the present disclosure may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the polymer into preparations which may be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • Such compositions may contain a therapeutically effective amount of polymer and may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include those approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans.
  • Carriers can include an active ingredient in which the disclosed compositions are administered.
  • the dosage form is a capsule, a tablet, a chewable tablet, a suspension, an oral suspension, a powder, a gel block, a gel pack, a confection, a chocolate bar, a pudding, a flavored bar, or a sachet.
  • the dosage form contains about 0.25 g, 0.5 g, or 1 g to about 7.5 g, 15 g, 30 g, or about 100 g of a disclosed cation-binding polymer.
  • the composition, formulation, or dosage form may include about 0.25 g, about 0.5 g, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g, about 1 1 g, about 12 g, about 13 g, about 14 g, about 15 g, about 16 g, about 17 g, about 18 g, about 19 g, about 20 g, about 21 g, about 22 g, about 23 g, about 24 g, about 25 g, about 26 g, about 27 g, about 28 g, about 29 g, about 30 g , about 35 g, about 40 g, about 45 g, about 50 g, about 55
  • the dosage forms of the present disclosure may optionally also include up to about 0.45 equivalents of base, for example, a pharmaceutically and/or physiologically acceptable base, per equivalent of carboxylate groups in the polymer, for example, about 0.05 equivalents, about 0.1 equivalents, about 0.15 equivalents, 0.2 equivalents, about 0.25 equivalents, about 0.3 equivalents, about 0.35 equivalents, about 0.4 equivalents, or about 0.45 equivalents of base per equivalent of carboxylic acid groups in the polymer.
  • base for example, a pharmaceutically and/or physiologically acceptable base, per equivalent of carboxylate groups in the polymer, for example, about 0.05 equivalents, about 0.1 equivalents, about 0.15 equivalents, 0.2 equivalents, about 0.25 equivalents, about 0.3 equivalents, about 0.35 equivalents, about 0.4 equivalents, or about 0.45 equivalents of base per equivalent of carboxylic acid groups in the polymer.
  • the base is present in an amount sufficient to provide from about 0.25 to about 0.30, about 0.25 to about 0.35, about 0.25 to about 0.40, about 0.25 to about 0.45, about 0.30 to about 0.35, about 0.30 to about 0.40, about 0.30 to about 0.45, about 0.35 to about 0.40, about 0.35 to about 0.45, or about 0.40 to about 0.45 equivalents of base per equivalent of carboxylate groups in the polymer.
  • the disclosed polymers and/or compositions may be formulated readily by combining them with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compositions of the disclosure to be formulated, as tablets, chewable tablets, pills, dragees, capsules, liquids, gel packs, gel blocks, syrups, slurries, suspensions, wafers, sachets, powders, dissolving tablets and the like, for oral ingestion by a subject, including a subject to be treated.
  • the compositions have a coating.
  • the compositions or capsules containing the compositions have an enteric coating.
  • the compositions or capsules containing the disclosed polymers do not have an enteric coating.
  • a composition, formulation, and/or dosage form as described herein comprises a base and a crosslinked polycarboxylate polymer as described herein ⁇ e.g., a cross-linked polyacrylic acid polymer), wherein the polymer further comprises calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer (alternately, counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), and is administered in an amount sufficient to provide from about 0.01 moles of carboxylate groups to about 0.5 moles or about 1.4 moles of carboxylate groups to the subject per day, for example, about 0.01 moles, about 0.02 moles, about 0.03 moles, about 0.04 moles
  • the dosage forms are administered in an amount sufficient to provide from about 0.01 to about 0.25 moles of carboxylate groups per day. In a more preferred embodiment, the dosage forms are administered in an amount sufficient to provide from about 0.1 to about 0.25 moles of carboxylate groups per day.
  • a composition, formulation, and/or dosage form as described herein comprises a base and a crosslinked polycarboxylate polymer as described herein ⁇ e.g., a cross-linked polyacrylic acid polymer), wherein the polymer further comprises calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer (alternately, counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and is administered in an amount sufficient to provide from about 0.01 moles of carboxylate groups to about 0.5 moles or about 1 .4 moles of carboxy
  • the dosage forms are administered in an amount sufficient to provide from about 0.01 to about 0.25 moles of carboxylate groups per day. In a more preferred embodiment, the dosage forms are administered in an amount sufficient to provide from about 0.1 to about 0.25 moles of carboxylate groups per day.
  • the dosage form comprises a base and a crosslinked polycarboxylate polymer as described herein, ⁇ e.g., a cross-linked polyacrylic acid polymer), wherein the polymer further comprises calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer (alternately, counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), and is administered in an amount sufficient to provide from about 1 g to about 30 g or about 1 g or up to about 100 g or more of polymer per day, for example, about 1 g per day, about 2 g per day, about 3 g per day, about 4 g per day, about 5 g per day, about 6
  • the dosage form comprises a base and a crosslinked polycarboxylate polymer as described herein, ⁇ e.g., a cross-linked polyacrylic acid polymer), wherein the polymer further comprises calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylic acid groups in the polymer (alternately, counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and is administered in an amount sufficient to provide from about 1 g to about 30 g or about 1 g or up to about 100 g or more of polymer per day, for example, about 1 g per day
  • the dosage form is a sachet and contains a polymer or polymer-containing composition according to the present disclosure in sufficient amount to provide from about 1 g to about 30 g of the polymer.
  • a sachet may contain a composition according to the present disclosure in sufficient amount to provide about 1 g, about 1 .5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 1 1 g, about 1 1 .5 g, about 12 g, about 12.5 g, about 13 g, about 13.5 g, about 14 g, about 14.5 g, about 15 g, about 15.5 g, about 16 g, about 16.5
  • the dosage form is a capsule containing an amount of a polymer or polymer-containing composition according to the present disclosure sufficient to provide from about 0.1 g to about 1 g of the polymer.
  • a capsule may contain an amount of a composition according to the present disclosure that is sufficient to provide about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, or about 1 g of polymer.
  • the dosage form is a tablet that contains an amount of a polymer or polymer-containing composition according to the present disclosure to provide from about 0.3 g to about 1 g or 2 g of the polymer.
  • the tablet may contain about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, or about 1 g or 2 g of polymer.
  • a disclosed composition is formulated as a tablet that is spherical or substantially spherical.
  • the dosage form is a sachet, flavored bar, gel block, gel pack, pudding, or powder that contains an amount of a polymer or polymer-containing composition according to the present disclosure to provide from about 1 g to about 30 g of the polymer.
  • the sachet, flavored bar, gel block, gel pack, pudding, or powder may contain an amount of a composition according to the present disclosure to provide about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 1 1 g, about 12 g, about 13 g, about 14 g, about 15 g, about 16 g, about 17 g, about 18 g, about 19 g, about 20 g, about 21 g, about 22 g, about 23 g, about 24 g, about 25 g, about 26 g, about 27 g, about 28 g, about 29 g, or about 30 g of the polymer.
  • the dosage form is a suspension or an oral suspension that contains an amount of a polymer or polymer-containing composition according to the present disclosure to provide from about 1 g to about 30 g of the polymer.
  • the suspension or oral suspension may contain an amount of a composition according to the present disclosure to provide about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 1 1 g, about 12 g, about 13 g, about 14 g, about 15 g, about 16 g, about 17 g, about 18 g, about 19 g, about 20 g, about 21 g, about 22 g, about 23 g, about 24 g, about 25 g, about 26 g, about 27 g, about 28 g, about 29 g, or about 30 g of the polymer.
  • compositions, formulations, and/or dosage forms according to the present disclosure further include an additional agent.
  • the additional agent is one that causes, routinely causes, typically causes, is known to cause, or is suspected of causing an increase in an ion level or total body fluid (e.g., edema) in at least some subjects upon administration.
  • the additional agent may be an agent known to cause an increase in serum potassium levels in at least some subjects upon administration.
  • the additional agent may be an agent known to cause an increase in serum sodium levels in at least some subjects upon administration.
  • the additional agent may be one or more of: a tertiary amine, spironolactone, fluoxetine, pyridinium and its derivatives, metoprolol, quinine, loperamide, chlorpheniramine, chlorpromazine, ephedrine, amitryptyline, imipramine, loxapine, cinnarizine, amiodarone, nortriptyline, a mineralocorticosteroid, propofol, digitalis, fluoride, succinylcholine, eplerenone, an alpha-adrenergic agonist, a RAAS inhibitor, an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, an aldosterone antagonist, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ram
  • compositions, formulations, and/or dosage forms of the present disclosure may be administered in combination with other therapeutic agents.
  • therapeutic agents that may be co-administered with the compositions of the disclosure will depend, in part, on the condition being treated.
  • Polymers, compositions, formulations, and/or dosage forms of the present disclosure may be administered in combination with a therapeutic agent that causes an increase, or is known to commonly cause an increase, in one or more ions in the subject.
  • a therapeutic agent that causes an increase, or is known to commonly cause an increase, in one or more ions in the subject.
  • the crosslinked cation-binding polymer of the present disclosure may be administered with a therapeutic agent that causes an increase, or is known to commonly cause an increase, in the potassium and/or sodium level of a subject.
  • the disclosed polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may be used to treat a subject with a disease and/or disorder. Additionally or alternatively, the disclosed polymers, compositions comprising the disclosed polymers and/or oral dosage forms comprising the disclosed polymers may be used to prevent a subject from becoming afflicted with a disease and/or disorder.
  • a base may be co-administered along with the polymer, composition comprising a polymer, and/or dosage form comprising a polymer, either simultaneously (e.g., at the same time) or sequentially (e.g., before and/or after administration of the polymer). When administering the polymer in a dosage form, the base may be included in the same dosage form or separate from the dosage form containing the polymer.
  • the disclosed polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may be used in methods for the binding and/or removal of ions (e.g., potassium ions and/or sodium ions) and/or of fluid from a subject.
  • ions e.g., potassium ions and/or sodium ions
  • the disclosed polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may be useful in the treatment or prevention of diseases or disorders in which the removal of ions (e.g., potassium ions and/or sodium ions) and/or fluid from a subject is desired.
  • the disclosed polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may be used to preferentially remove certain ions (e.g., potassium, sodium, or potassium and sodium) and/or fluid depending on the environment to which the disclosed polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers are exposed.
  • certain ions e.g., potassium, sodium, or potassium and sodium
  • Ions bound to the disclosed polymers and fluid binding capacity of the disclosed polymers may vary based on the type of subject to which it is administered (e.g., a healthy subject or a subject having a disease or disorder or at risk of having a disease or disorder).
  • a healthy subject or a subject having a disease or disorder or at risk of having a disease or disorder e.g., the concentration of potassium and sodium in the colon are typically in the range of from about 55 mM to about 75 mM and from about 20 mM to about 30 mM, respectively, for a ratio of K/Na of approximately 2. However, this ratio may be significantly changed in various disease states and/or in response to therapeutic agents.
  • fecal potassium excretion is also known to increase.
  • hypoaldosterone states such as Addison's disease, congenital hypoaldosteronism
  • patients develop hyperkalemia and hyponatremia due to a decrease in colonic and renal potassium excretion and an increase in sodium excretion.
  • Administration of spironolactone may increase urinary and fecal sodium excretion.
  • the fecal sodium may rise to 50 -100 mM and the fecal potassium may decrease to 15 - 20 mM.
  • the ratio of K/Na may be less than 0.3 mM.
  • polymer compositions may primarily bind potassium in healthy subjects or in subjects with certain disease states or disorders, they may bind primarily sodium in subjects with other diseases or disorders, for example, subjects with aldosterone plasma level or with ulcerative colitis.
  • ions bound to disclosed polymers and fluid binding capacity of disclosed polymers may vary as the polymers travel through the digestive tract.
  • compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers reside in the colon for a significant fraction of the total gastrointestinal transit time, the local concentration of cations in the colon will have a significant effect on the concentrations of sodium, potassium and other cations bound to the polymer and excreted in the feces.
  • polymers as disclosed herein, and/or compositions, formulations, and/or dosage forms containing the polymers may be used in methods to treat congestive heart failure (CHF), chronic kidney disease (CKD), end stage renal disease (ESRD), hyperkalemia, hypernatremia, or hypertension.
  • CHF congestive heart failure
  • CKD chronic kidney disease
  • ESRD end stage renal disease
  • hyperkalemia hypernatremia
  • hypertension hypertension
  • polymers as disclosed herein, and/or compositions, formulations, and/or dosage forms containing the polymers may be used in methods for the removal of fluid from a subject.
  • the polymers as disclosed herein, and/or compositions, formulations, and/or dosage forms containing the polymers may be used in methods to treat or prevent fluid accumulation and/or maldistribution, and/or ion (e.g., sodium and/or potassium) accumulation and/or imbalances.
  • ion e.g., sodium and/or potassium
  • polymers as disclosed herein, and/or compositions, formulations, and/or dosage forms containing the polymers may be used in methods for treating diseases or disorders associated with increased retention of fluid and/or ion imbalances.
  • the polymers as disclosed herein, and/or compositions, formulations, and/or dosage forms containing the polymers may be used to remove one or more ions selected from the group consisting of: sodium, potassium, calcium, magnesium, and/or ammonium.
  • the polymers of the present disclosure, and compositions, formulations, and dosage forms of the present disclosure that comprise crosslinked cation- binding polymers comprising monomers containing carboxylic acid groups (e.g., polyacrylate polymers) and wherein the polymer further comprises: i) calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer (alternatively, counterions to about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 60% to about 65%, about 60% to about 70%, or about 65% to about 70% of the carboxylate groups in the polymer), and wherein sodium cations (if present) are counterions to no more than about 5% of the carboxylate groups in the polymer, or ii) calcium and magensium cations, wherein the calcium and magnesium cations are counterions to about 50%
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • the polymers and compositions, formulations, and/or dosage forms containing the polymers as described herein are useful for the treatment of a variety of diseases or disorders, including those involving ion (e.g., potassium and/or sodium) and/or fluid imbalances (e.g., overloads).
  • calcium cations are counterions to about 50% to
  • the polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers as disclosed herein may be substantially coated with a coating, e.g., an enteric coating, that allows it to pass through the gut, e.g., upper gastrointestinal tract, and open in the intestine where the polymer may absorb fluid and/or specific ions that are concentrated in that particular portion of the intestine.
  • a coating e.g., an enteric coating
  • the polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers disclosed herein do not comprise such a coating.
  • the absorbent material, e.g., polymer as disclosed herein may be encapsulated in a capsule.
  • the capsule may be substantially coated with a coating, e.g., an enteric coating, that allows it to pass through the gut and open in the intestine where the capsule may release the polymer to absorb fluid or specific ions that are concentrated in that particular position of the intestine.
  • the capsule does not contain such a coating.
  • Individual particles of polymer or groups of particles may be encapsulated or alternatively, larger quantities of beads or particles may be encapsulated together.
  • polymers as disclosed herein may be milled to give finer particles in order to increase drug loading of capsules, or to provide better palatability for formulations such as gels, bars, puddings, or sachets.
  • milled particles or groups of particles, or unmilled polymeric material ⁇ e.g., beads) may be coated with various common pharmaceutical coatings.
  • These coatings may or may not have enteric properties but will have the common characteristic that they will separate the polymer from the tissues of the mouth and prevent the polymer from adhering to tissue.
  • coatings may include, but are not limited to: a single polymer or mixtures thereof, such as may be selected from polymers of ethyl cellulose, polyvinyl acetate, cellulose acetate, polymers such as cellulose phthalate, acrylic based polymers and copolymers or any combination of soluble, insoluble polymers or polymer systems, waxes and wax based coating systems.
  • the polymers disclosed herein for administration to an individual or inclusion in a composition, formulation, or dosage form for administration to an individual, e.g., for use in a method of treatment as disclosed herein are individual particles or particles agglomerated to form a larger particle (for example, flocculated particles), and have a diameter of about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 20 microns to about 125 microns, about 20 microns to about 150 microns, about 20 microns to about 200 microns, about 35 microns to about 150 microns, about 35 microns to about 125 microns, about 50 microns to about 125 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns
  • the particles or agglomerated particles have a diameter of about 1 , about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 1 10, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000 , about 1500, about 2000, about 2500, about 3000, about 3500, about 4000, about 4500, about 5000, about 5500, about 6000, about 7000, about 7500, about 8000, about 8500, about 9000, about 9500, or about 10,000 microns.
  • the crosslinked cation-binding polymer as described, for example, for administration to an individual or inclusion in a composition, formulation, or dosage form for administration to an individual, e.g., for use in a method of treatment as disclosed herein, is a crosslinked polyacrylate polymer (e.g., derived from acrylic acid monomers or a salt thereof) that comprises calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, and wherein sodium cations (if present) are counterions to no more than about 5% of the carboxylate groups in the polymer.
  • a crosslinked polyacrylate polymer e.g., derived from acrylic acid monomers or a salt thereof
  • the polymer may be a polyacrylate polymer crosslinked with about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol% to about 3.0 mol%, including from about 0.025 mol% to about 0.3 mol%, from about 0.025 mol% to about 0.17 mol%, from about 0.025 mol% to about 0.34 mol%, or from about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol.% to about 3.0 mol.% including, for example, from about 0.025 mol.% to about 0.3 mol.%., and for example, may comprise an in vitro saline holding capacity of at least about 20 times its weight (e.g., at least about 20 grams of saline per gram of polymer, or "g/g"), at least about at least about 30 times its weight, at least about 40 times its weight, at least about 50 times its weight, at least about 60 times its weight, at least
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns, about 500 microns to about 1000 microns, about 1000 to about 5000 microns, or about 5000 microns to about 10,000 microns.
  • the individual or agglomerated particle diameter e.g., average particle diameter
  • administration of such a crosslinked polyacrylate polymer comprises calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer
  • an added base e.g., up to about 0.45 equivalents of added base per equivalents of carboxylate groups in the polymer
  • acid/base status e.g., acid/base balance
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium cations, wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, may be administered, optionally with added base as described herein, to an individual for removal of fluid and/or ions, for example, sodium and/or potassium cations, wherein such administration does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • the crosslinked cation-binding polymer as described, for example, for administration to an individual or inclusion in a composition, formulation, or dosage form for administration to an individual, e.g., for use in a method of treatment as disclosed herein, is a crosslinked polyacrylate polymer (e.g., derived from acrylic acid monomers or a salt thereof) that comprises calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, and wherein sodium cations (if present) are counterions to no more than about 5% of the carboxylate groups in the polymer.
  • a crosslinked polyacrylate polymer e.g., derived from acrylic acid monomers or a salt thereof
  • the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer
  • the magnesium cations are counterions to
  • the polymer may be a polyacrylate polymer crosslinked with about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol% to about 3.0 mol%, including from about 0.025 mol% to about 0.3 mol%, from about 0.025 mol% to about 0.17 mol%, from about 0.025 mol% to about 0.34 mol%, or from about 0.08 mol% to about 0.2 mol% crosslinker or alternatively from about 0.025 mol.% to about 3.0 mol.% including, for example, from about 0.025 mol.% to about 0.3 mol.%., and for example, may comprise an in vitro saline holding capacity of at least about 20 times its weight (e.g., at least about 20 grams of saline per gram of polymer, or "g/g"), at least about at least about 30 times its weight, at least about 40 times its weight, at least about 50 times its weight, at least about 60 times its weight, at least
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 1 to about 10,000 microns (alternatively, about 1 micron to about 10 microns, about 1 micron to about 50 microns, about 10 microns to about 50 microns, about 10 microns to about 200 microns, about 50 microns to about 100 microns, about 20 microns to about 125 microns, about 20 microns to about 150 microns, about 20 microns to about 200 microns, about 35 microns to about 150 microns, about 35 microns to about 125 microns, about 50 microns to about 125 microns, about 50 microns to about 200 microns, about 50 microns to about 1000 microns, about 500 microns to about 1000 microns, about 1000 to about 5000 micron
  • the crosslinked polyacrylate polymer comprises individual particles or particles that are agglomerated (for example, flocculated) to form a larger particle, wherein the individual or agglomerated particle diameter (e.g., average particle diameter) is about 100 microns.
  • administration of such a crosslinked polyacrylate polymer comprising calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, is administered with an added base (e.g., up to about 0.45 equivalents of added base per equivalents of carboxylate groups in the polymer), and such administration of the polymer and base does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • an added base e.g., up to about 0.45 equivalents of added base per equivalents of carboxylate groups in the polymer
  • acid/base status e.g., acid/base balance
  • an acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a crosslinked polyacrylate polymer comprising calcium and magnesium cations, wherein the calcium and magnesium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, wherein the magnesium cations are counterions to no more than about 35% of the carboxylate groups in the polymer, may be administered, optionally with added base as described herein, to an individual for removal of fluid and/or ions, for example, sodium and/or potassium cations, wherein such administration does not change or does not significantly change acid/base status (e.g., acid/base balance) in an individual to whom it is administered, for example, as measured by serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject
  • the polymer may be mixed with one or more base(s) in the same composition, formulation, and/or dosage form and may be in contact with fluid within the dosage from, such as suspensions or gels.
  • pharmaceutical coatings known in the art can be used to coat the polymer, the base, or both to prevent or impede interaction of the polymer and the base.
  • the pharmaceutical coating may have enteric properties.
  • pharmaceutical coatings may include but are not limited to: a single polymeric coating or mixtures of more than one pharmaceutical coating, such as may be selected from polymers of ethyl cellulose, polyvinyl acetate, cellulose acetate; polymers such as cellulose phthalate, acrylic based polymers and copolymers, or any combination of soluble polymers, insoluble polymers and/or polymer systems, waxes and wax based coating systems.
  • the polymer and base are administered in separate dosage forms.
  • pharmaceutical coatings known in the art can be used to coat the particles to reduce bioadhesion, for example during oral administration.
  • a subject ⁇ e.g., an individual or patient), as disclosed herein, includes a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as cats, dogs and horses), primates, and rodents (such as mice and rats).
  • a subject includes any animal such as those classified as a mammal, including humans, domestic and farm animals, and zoo, wild, sports, or pet animals, such as dogs, horses, cats, cows, etc.
  • the subject for treatment, prognosis and/or diagnosis is human.
  • a disease or disorder includes any condition that would benefit from treatment with a composition as disclosed herein. This includes both chronic and acute diseases or disorders, including those pathological conditions which predispose the subject to the disease or disorder in question.
  • treatment or treating refers to clinical intervention in an attempt to alter the natural course of the subject being treated, and can be performed either for prophylaxis ⁇ e.g., prevention) or during the course of clinical pathology ⁇ e.g., after the subject is identified as having a disease or disorder or the symptoms of a disease or disorder).
  • Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, and/or diminishment of any direct or indirect pathological consequences of the disease or disorder, decreasing the rate of disease progression, amelioration or palliation of the disorder, and remission or improved prognosis.
  • Terms such as treating/treatment/to treat or alleviating/to alleviate refer to both 1 ) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed disease or disorder ⁇ e.g., a pathologic condition or disorder) and 2) prophylactic or preventative measures that prevent and/or slow the development of a disease or disorder ⁇ e.g., a targeted pathologic condition or disorder).
  • those in need of treatment may include those already with the disease or disorder; those prone to have the disease or disorder; and those in whom the disease or disorder is to be prevented.
  • An effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • a therapeutically effective amount of a composition disclosed herein may vary according to factors such as the disorder, age, sex, and weight of the subject, and the ability of the composition to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.
  • a prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount may be less than the therapeutically effective amount.
  • a therapeutically effective amount includes administration of about 1 g to about 30 g or up to 100 g or more per day of a disclosed cross-linked polymer to an individual. In some embodiments, a prophylactically effective amount includes administration of about 1 g to about 30 g or up to 100 g or more per day of a disclosed cross-linked polymer to an individual.
  • base is co-administered at up to about 0.9 equivalents, for example, about 0.05 equivalents, about 0.1 equivalents, about 0.15 equivalents, about 0.2 equivalents, about 0.25 equivalents, about 0.3 equivalents, about 0.35 equivalents, about 0.4, equivalents, about 0.45 equivalents, about 0.5 equivalents, about 0.55 equivalents, about 0.6 equivalents, about 0.65 equivalents, about 0.7 equivalents, about 0.75 equivalents, about 0.8 equivalents, about 0.85 equivalents, or about 0.9 equivalents with respect to carboxylic acid groups on the polymer.
  • a therapeutically or prophylactically effective amount of polymer and base may be administered in a single dosage or multiple doses, for example, administered once per day or administered 4 or more times daily, e.g., divided into and administered as 1 , 2, 3, 4, or more doses per day, or administered at intervals of 2, 3, 4, 5, or 6 days, weekly, bi-weekly, etc.
  • Pharmaceutically acceptable includes approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.
  • a pharmaceutically acceptable salt includes a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • a pharmaceutically acceptable excipient, carrier or adjuvant includes an excipient, carrier or adjuvant that can be administered to a subject, together with at least one composition of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic or prophylactic amount of the composition.
  • a pharmaceutically acceptable vehicle includes a diluent, adjuvant, excipient, or carrier with which at least one composition of the present disclosure is administered.
  • Polymers, or compositions, formulations, and/or dosage forms comprising cross- linked cation binding polymers as disclosed herein can be used either alone or in combination with one or more other agents for administration to a subject ⁇ e.g., in a therapy or prophylaxis).
  • combined therapies or prophylaxis include combined administration (where the polymer, composition, formulation, and/or dosage form and one or more agents are included in the same or separate composition, formulation, and/or dosage form) and separate administration, in which case, administration of the polymer, composition, formulation, and/or dosage form disclosed herein can occur prior to, contemporaneous with and/or following, administration of the one or more other agents ⁇ e.g., for adjunct therapy or intervention).
  • co-administered or co-administration includes administration of the polymers, compositions, formulations, and/or dosage forms of the present disclosure before, during and/or after the administration of one or more additional agents or therapies.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers are useful for treating a disease or disorder.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymer, and/or dosage forms comprising the disclosed polymers are co-administered with a base, as described herein.
  • the disease or disorder is one or more of: heart failure, a renal insufficiency disease, end stage renal disease, liver cirrhosis, chronic renal insufficiency, chronic kidney disease, fluid overload, fluid maldistribution, edema, pulmonary edema, peripheral edema, lymphedema, nephrotic edema, idiopathic edema, ascites, cirrhotic ascites, interdialytic weight gain, high blood pressure, hyperkalemia, hypernatremia, abnormally high total body sodium, hypercalcemia, tumor lysis syndrome, head trauma, an adrenal disease, hyporeninemic hypoaldosteronism, hypertension, salt-sensitive hypertension, refractory hypertension, renal tubular disease, rhabdomyolysis, crush injuries, renal failure, acute tubular necrosis, insulin insufficiency, hyperkalemic periodic paralysis, hemolysis, malignant hyperthermia, pulmonary edema secondary to cardiogenic pathophysio
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers are useful for treating: hyperkalemia including, hyperkalemia caused by disease and/or use of certain drugs; patients at risk of developing high serum potassium concentrations through use of agents that cause potassium retention; chronic kidney disease and heart failure patients including, drug induced potassium retention; and/or drugs that interfere with potassium excretion including, for example, K-sparing diuretics, ACEs, ARBs, beta blockers, aldosterone antagonists (AAs), renin inhibitors, aldosterone synthase inhibitors, non-steroidal anti-inflammatory drugs, heparin, or trimethoprim.
  • hyperkalemia including, hyperkalemia caused by disease and/or use of certain drugs
  • patients at risk of developing high serum potassium concentrations through use of agents that cause potassium retention chronic kidney disease and heart failure patients including, drug induced potassium retention
  • drugs that interfere with potassium excretion including, for example, K-sparing di
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers are also useful for removal of potassium from a patient, wherein a patient is in need of such potassium removal.
  • a patient is in need of such potassium removal.
  • patients experiencing hyperkalemia caused by disease and/or use of certain drugs benefit from such potassium removal.
  • patients at risk for developing high serum potassium concentrations through use of agents that cause potassium retention could be in need of potassium removal.
  • the methods described herein are applicable to these patients regardless of the underlying condition that is causing the high serum potassium levels.
  • Dosing regimens for chronic treatment of hyperkalemia can increase compliance by patients, particularly for disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers that are taken in gram quantities.
  • the present disclosure is also directed to methods of chronically removing potassium from an animal subject in need thereof, and in particular chronically treating hyperkalemia with a potassium binder such as a crosslinked cation binding polymer as described herein.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers can be administered on a periodic basis to treat a chronic condition.
  • such treatments may enable patients to continue using drugs that may cause hyperkalemia, such as potassium-sparing diuretics, ACEs, ARBs, aldosterone antagonists, ⁇ -blockers, renin inhibitors, non-steroidal anti-inflammatory drugs, heparin, trimethoprim, or combinations thereof.
  • drugs that may cause hyperkalemia such as potassium-sparing diuretics, ACEs, ARBs, aldosterone antagonists, ⁇ -blockers, renin inhibitors, non-steroidal anti-inflammatory drugs, heparin, trimethoprim, or combinations thereof.
  • use of the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may enable certain patient populations, who were unable to use certain above
  • a buffer uptake can be measured for a crosslinked polycarboxylic acid.
  • the buffer uptake is the amount of buffer taken up by the polymer as the calcium and/or magnesium polycarboxylate (in contrast to the saline holding capacity where the polymer with calcium and/or magnesium counterions is converted first to the acid and then the saline holding capacity determined for the sodium form).
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers have a buffer uptake less than about 20g/g per day, or less than about 10 g/g per day.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers and methods described herein are used in the treatment of hyperkalemia in patients in need thereof, for example, when caused by excessive intake of potassium. Excessive potassium intake alone is an uncommon cause of hyperkalemia. More often, hyperkalemia is caused by indiscriminate potassium consumption in a patient with impaired mechanisms for the intracellular shift of potassium or renal potassium excretion. Polymer compositions for use in various diseases or disorders (e.g.
  • hyperkalemia, fluid overload states, etc. may be selected based on the relative desire to eliminate sodium and/or potassium in the feces for the particular disease or disorder, the population of subjects (e.g., patients), including the additional agents (e.g., concomitant medications) being taken by the population of subjects (e.g., patients).
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers can be co-administered with other active pharmaceutical agents. 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.
  • the crosslinked the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers can be co-administered with drugs that cause the hyperkalemia, such as potassiumsparing diuretics, angiotensin-converting enzyme inhibitors (ACEs), angiotensin receptor blockers (ARBs), aldosterone antagonists (AAs), beta blockers, renin inhibitors, non-steroidal anti-inflammatory drugs, heparin, or trimethoprim.
  • drugs that cause the hyperkalemia such as potassiumsparing diuretics, angiotensin-converting enzyme inhibitors (ACEs), angiotensin receptor blockers (ARBs), aldosterone antagonists (AAs), beta blockers, renin inhibitors, non-steroidal anti-inflammatory drugs, heparin, or trimethoprim.
  • drugs that cause the hyperkalemia such as potassiumsparing diuretics, angiotensin-converting enzyme inhibitors (ACEs
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers can be co- administered with ACEs (e.g., captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazipril, and fosinopril), ARBs (e.g., candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan), AAs (e.g., spironolactone, eplerenone, canrenone), and renin inhibitors (e.g. aliskiren).
  • the agents are simultaneously administered, wherein both the agents are present in separate compositions. In other embodiments, the agents are administered separately in time (e.g., sequentially).
  • Treating or treatment of hyperkalemia includes achieving a therapeutic benefit including, for example, an eradication, amelioration, or prevention of the underlying disorder being treated.
  • a therapeutic benefit includes eradication or amelioration of the underlying hyperkalemia.
  • 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.
  • administration of the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers to a patient experiencing hyperkalemia provides therapeutic benefit not only when the patient's serum potassium level is decreased, but also when an improvement is observed in the patient with respect to other disorders that accompany hyperkalemia, like renal failure.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may be administered to a patient at risk of developing hyperkalemia or to a patient reporting one or more of the physiological symptoms of hyperkalemia, even though a diagnosis of hyperkalemia may not have been made.
  • patients suffering from chronic kidney disease and/or congestive heart failure can be in need of potassium removal because agents used to treat these conditions may cause potassium retention in a significant population of these patients.
  • decreased renal potassium excretion results from renal failure (especially with decreased glomerular filtration rate), often coupled with the ingestion of drugs that interfere with potassium excretion, for example, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACEs), angiotensin receptor blockers (ARBs), beta blockers, aldosterone antagonists (AAs), rennin inhibitors, aldosterone synthase inhibitors, nonsteroidal anti-inflammatory drugs, heparin, or trimethoprim.
  • ACEs angiotensin-converting enzyme inhibitors
  • ARBs angiotensin receptor blockers
  • AAs aldosterone antagonists
  • rennin inhibitors aldosterone synthase inhibitors
  • nonsteroidal anti-inflammatory drugs heparin, or trimethoprim.
  • ACEs angiotensin-convering enzyme inhibitors
  • ARBs angiotensin receptior blockers
  • aldosterone antagonists are commonly prescribed.
  • the angiotensin-converting enzyme inhibitor is captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazipril, fosinopril, or combinations thereof and the angiotensin receptor blocker is candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, or combinations thereof and the renin inhibitor is aliskiren.
  • the aldosterone antagonists spironolactone, eplerenone and canrenone can also cause potassium retention. Thus, it can be advantageous for patients in need of these treatments to also be treated with an agent that removes potassium from the body.
  • the aldosterone antagonists typically prescribed are spironolactone, eplerenone, and the like.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations, comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein are useful for treating a disease or disorder involving an ion imbalance in a subject by administering to the subject an effective amount of the polymer, composition, formulation, and/or a dosage form ⁇ e.g., an effective amount), as disclosed herein.
  • the polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the disease or disorder is or includes hyperkalemia.
  • the disease or disorder is or includes hypernatremia.
  • the disease or disorder is or includes an abnormally high total body sodium level. In some embodiments, the disease or disorder is or includes an abnormally high potassium level. In some embodiments, the disease or disorder is or includes hyponatremia, hypernatremia and hyperkalemia. In some embodiments, the disease or disorder is or includes fluid overload. In some embodiments, the disease or disorder is or includes fluid overload and hyperkalemia. In some embodiments, the disease or disorder is or includes fluid overload and hyperkalemia and abnormally high total body sodium level.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers as disclosed herein are useful for treating a subject with heart failure by administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form as disclosed herein.
  • the polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the subject has both heart failure and chronic kidney disease.
  • the methods further comprise reducing one or more symptoms of a fluid overload state in the subject.
  • Symptoms of a fluid overload state in a subject are known to those skilled in the art, and may include, for example and without limitation, difficulty breathing when lying down, ascites, fatigue, shortness of breath, difficulty breathing on exertion, increased body weight, peripheral edema, and/or pulmonary edema.
  • the subject may be on concomitant dialysis therapy.
  • the dialysis therapy may be reduced or discontinued after administration of a disclosed polymer, a composition comprising the disclosed polymer, a formulation comprising the disclosed polymer, and/or a dosage form comprising the disclosed polymer, as disclosed herein.
  • the method further comprises identifying the subject as having heart failure before administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising the disclosed polymer.
  • administration of the disclosed polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as described herein improves or ameliorates at least one symptom of heart failure, for example, at least one symptom that impacts the subject's quality of life and/or physical function.
  • administration may result in body weight reduction, dyspnea improvement (for example, overall and dyspnea at exertion), six minute walk test improvement, and/or improvement or absence of peripheral edema.
  • administration of the disclosed polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as described herein results in reduction of patient classification by at least one heart failure class, according to the New York Heart Association Class I, II, III, IV functional classification system.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein are useful for treating a subject with end stage renal disease (ESRD) by administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form, as disclosed herein.
  • ESRD end stage renal disease
  • the polymers, compositions, formulations, and/or dosage forms may be coadministered with a base, as described herein.
  • the subject is on concomitant dialysis therapy.
  • the method reduces blood pressure in an ESRD subject on concomitant dialysis therapy, for example, pre-dialysis, post-dialysis, and/or interdialytic systolic and diastolic blood pressure may be reduced.
  • the method reduces interdialytic weight gain in an ESRD subject on concomitant dialysis therapy.
  • the subject also has heart failure.
  • one or more symptoms of intradialytic hypotension are improved after administration of a disclosed polymer, a composition comprising a disclosed polymer, a formulation, comprising a disclosed polymer, and/or a dosage form comprising a disclosed polymer, as disclosed herein.
  • a disclosed polymer a composition comprising a disclosed polymer, a formulation, comprising a disclosed polymer, and/or a dosage form comprising a disclosed polymer, as disclosed herein.
  • incidences of vomiting, fainting and/or drops in blood pressure levels are reduced or eliminated.
  • the subject experiences one or more of: a reduced frequency of emergency dialysis sessions, a reduced frequency of inadequate dialysis sessions, a reduced frequency of dialysis sessions on low-potassium dialysis bath, and/or reduced frequency or reduced severity of EKG signs during dialysis sessions.
  • one or more symptom of intradialytic hypotension are reduced or eliminated after administration of a polymer, a composition comprising a disclosed polymer, a composition comprising a disclosed polymer, a formulation comprising a disclosed polymer, and/or a dosage form comprising a disclosed polymer.
  • Symptoms of intradialytic hypotension are known to those skilled in the art and may include, for example, vomiting, fainting, an abrupt decrease in blood pressure, seizures, dizziness, severe abdominal cramping, severe leg or arm muscular cramping, intermittent blindness, infusion, medication, and dialysis session interruption or discontinuation.
  • ESRD subjects may experience an improvement in physical function as expressed by increase in performance in the 6 Minute Walk Test.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein are useful for treating a subject having chronic kidney disease.
  • the methods comprise administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form.
  • the polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the methods further comprise identifying the subject as having a chronic kidney disease before administration of a disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein.
  • the methods further comprise reducing one or more symptoms of a fluid overload state in the subject.
  • a comorbidity of chronic kidney disease is reduced, alleviated, and/or eliminated after administration of a polymer, a composition comprising a disclosed polymer, a formulation comprising a disclosed polymer, and/or a dosage form comprising a disclosed polymer.
  • Comorbidities of chronic kidney disease are known to those skilled in the art and include, for example, fluid overload, edema, pulmonary edema, hypertension, hyperkalemia, excess total body sodium, heart failure, ascites, and/or uremia.
  • CKD patients may experience prevention of doubling of serum creatinine over the duration of a study (e.g., 1 to 2 years), prevention of disease progression to dialysis, and/or prevention of death and CKD related hospitalizations and/or complications.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the polymers as, disclosed herein are useful for treating a subject having hypertension.
  • the methods comprise administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form.
  • the polymers, compositions, formulations, and/or dosage forms may be coadministered with a base, as described herein.
  • the methods further comprise identifying that the subject has hypertension before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein.
  • hypertension includes the various subtypes of hypertension known to those skilled in the art, for example and without limitation: primary hypertension, secondary hypertension, salt sensitive hypertension, refractory hypertension, and combinations thereof.
  • the method is effective in reducing the subject's blood pressure.
  • the method may further comprise determining a blood pressure level before, after, or both before and after administration of the polymer, composition comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer as disclosed herein.
  • the method may further comprise determining the subject's diastolic blood pressure, systolic blood pressure, and/or mean arterial pressure ("MAP") before, after, or both before and after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • MAP mean arterial pressure
  • one or more symptom of a fluid overload state is reduced, improved, or alleviated by administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein.
  • the method may further comprise determining a fluid overload state symptom before, after, or both before and after administration of a disclosed polymer, composition comprising a disclosed polymer formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer as disclosed herein.
  • the method may further comprise observing an improvement in the subject's breathing while lying down, ascites, fatigue, shortness of breath, body weight, peripheral edema, and/or pulmonary edema.
  • the subject is on concomitant diuretic therapy.
  • diuretic therapy refers to administration of pharmaceutical compositions ⁇ e.g., diuretic agents), and non-chemical intervention, such as dialysis or restriction of fluid intake.
  • Diuretic agents are known to those skilled in the art and include, for example, furosemide, bumetanide, torsemide, hydrochlorthiazide, amiloride and/or spironolactone.
  • the diuretic therapy may be reduced or discontinued following administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein are useful for treating hyperkalemia in a subject.
  • the method comprises administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form as disclosed herein.
  • the polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the method further comprises identifying the subject as having hyperkalemia, or as having a risk of developing hyperkalemia, before administering the disclosed polymer, composition comprising a disclosed polymer, formulation, and/or dosage form comprising a disclosed polymer, as disclosed herein. In some embodiments, the method may further comprise determining a potassium ion level in the subject before administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein.
  • the potassium ion level may be within a normal range, slightly elevated, or elevated before administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the subject has been prescribed or will be administered a drug known to increase potassium levels.
  • the subject has already ingested a drug known to increase potassium levels.
  • the method may further comprise determining a second, reduced potassium ion level in the subject after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • an acid/base status (e.g., acid/base balance) associated with the subject does not change, for example, as measured by, serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap, after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein are useful for treating a high sodium level, e.g., an abnormally high sodium level such as hypernatremia, in a subject.
  • the method comprises administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form as disclosed herein.
  • the disclosed polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the method further comprises identifying the subject as having a high sodium level, or as having a risk of developing a high sodium level, before administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the method may further comprise determining a sodium ion level, e.g., a total body sodium ion level, in the subject before administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the sodium ion level e.g., serum sodium ion level
  • the method may further comprise determining a second, reduced sodium ion level, e.g., a total body sodium ion level, in the subject after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • an acid/base status (e.g., acid/base balance) associated with the subject does not change, for example, as measured by, serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap, after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • the subject has taken or will take a drug known to increase sodium levels, for example and without limitation: estrogen containing compositions, mineralocorticoids, osmotic diuretics ⁇ e.g., glucose or urea), vaptans (e.g., tolvaptan, lixivaptan), lactulose, cathartics (e.g., phenolphthalein), phenytoin, lithium, Amphotericin B, demeclocycline, dopamine, ofloxacin, orlistat, ifosfamide, cyclophosphamide, hyperosmolar radiographic contrast agents (e.g., gastrographin, renographin), cidofovir, ethanol, foscarnet, indinavir, libenzapril, mesalazine, methoxyflurane, pimozide, rifampin, streptozotocin, tenofir, triamterene, and/or cholchicine.
  • administration of the disclosed polymer, compositions comprising the disclosed polymer, formulations comprising the disclosed polymer, and/or dosage forms comprising the disclosed polymer may further comprise increasing a dose of one or more additional agents, for example, an agent known to cause an increase in sodium levels.
  • the method further comprises increasing a dose of one or more of: an aldosterone antagonist, an angiotensin II receptor blocker, and/or an angiotensin-converting enzyme inhibitor before, concomitantly, and/or after administering a disclosed polymer, a composition comprising a disclosed polymer, a formulation comprising a disclosed polymer, and/or a dosage form comprising a disclosed polymer.
  • administration of the disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer may further comprise decreasing a dose or discontinuing administration or co-administration of a diuretic.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers ,as disclosed herein are useful for treating a subject with a disease or disorder involving fluid overload ⁇ e.g., a fluid overload state such as heart failure, end stage renal disease, ascites, renal failure, nephritis, and nephrosis).
  • a fluid overload state such as heart failure, end stage renal disease, ascites, renal failure, nephritis, and nephrosis.
  • the method comprises administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form as disclosed herein.
  • the polymers, compositions, formulations, and/or dosage forms may be coadministered with a base, as described herein.
  • the subject may be on concomitant diuretic therapy.
  • the method may further comprise identifying a fluid overload state in the subject, or identifying a risk that the subject will develop a fluid overload state before administration of a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer.
  • Methods of identifying a fluid overload state or a risk of developing a fluid overload state are known to those skill in the art and may include, for example and without limitation: assessing difficulty breathing when lying down, ascites, fatigue, shortness of breath, increased body weight, peripheral edema, and/or pulmonary edema associated with the subject.
  • an acid/base status (e.g., acid/base balance) associated with the subject, for example, as measured by, serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap, does not change within about one day of administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the polymers, as disclosed herein are useful for treating a subject with a disease or disorder involving fluid maldistribution ⁇ e.g., a fluid maldistribution state such as pulmonary edema, angioneurotic edema, ascites, high altitude sickness, adult respiratory distress syndrome, uticarial edema, papille edema, facial edema, eyelid edema, cerebral edema, and scleral edema).
  • a fluid maldistribution state such as pulmonary edema, angioneurotic edema, ascites, high altitude sickness, adult respiratory distress syndrome, uticarial edema, papille edema, facial edema, eyelid edema, cerebral edema, and scleral edema).
  • the method comprises administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form, as disclosed herein.
  • the polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the method may further comprise identifying a fluid maldistribution state or a risk of developing a fluid maldistribution state in the subject before administering to the subject a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein are useful for treating edema in a subject.
  • the method comprises administering to the subject an effective amount of the polymer, composition, formulation, and/or dosage form, as disclosed herein.
  • the polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the method may further comprise identifying an edematous state or a risk of developing an edematous state in the subject before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed , as disclosed herein.
  • the edematous state is nephritic edema, pulmonary edema, peripheral edema, lymphedema, and/or angioneurotic edema.
  • the subject is on concomitant diuretic therapy.
  • the diuretic therapy may be reduced or discontinued after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the method may further comprise, before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein, determining one or more of: a baseline level of one or more ions ⁇ e.g., sodium, potassium, lithium and/or magnesium) in the subject, a baseline total body weight associated with the subject, a baseline total body water level associated with the subject, a baseline total extracellular water level associated with the subject (e.g., a measure of the degree of edema in a particular site as evidenced by depth of pitting or extent of x-ray changes, and/or a baseline total intracellular water level associated with the subject.
  • a baseline level of one or more ions ⁇ e.g., sodium, potassium
  • the method may further comprise, after administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein, determining one or more of: a second level of one or more ions in the subject, a second total body weight associated with the subject, a second total body water level associated with the subject, a second total extracellular water level associated with the subject, and/or a second total intracellular water level associated with said subject.
  • the second level is lower than the corresponding baseline level.
  • an acid/base status (e.g, acid/base balance) associated with said subject, for example, as measured by, serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap, does not significantly change within about one day of administration of the disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a blood pressure level associated with the subject after administration of the disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer is substantially lower than a baseline blood pressure level associated with the subject determined before administration of the disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer.
  • one or more symptoms of edema are reduced and/or eliminated following administration of a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein. Symptoms of edema are known to those skilled in the art; some non-limiting examples include: difficulty breathing when lying down, shortness of breath, peripheral edema, and leg edema.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers according to the present disclosure are useful for treating ascites in a subject.
  • the method comprises administering to the subject an effective amount of the polymer, composition, formulation, and/or a dosage form, as disclosed herein.
  • the disclosed polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the method may further comprise identifying an ascitic state or a risk of developing an ascitic state in the subject.
  • the subject is on concomitant diuretic therapy.
  • the diuretic therapy may be reduced or discontinued after administration of the disclosed composition.
  • the subject may have taken, or will take, a drug known to increase potassium levels.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein are useful for treating nephrotic syndrome in a subject.
  • the method comprises administering to said subject an effective amount of the polymer, composition, formulation, and/or dosage form, as disclosed herein.
  • the disclosed polymers, compositions, formulations, and/or dosage forms may be co-administered with a base, as described herein.
  • the method further comprises identifying the subject as having nephrotic syndrome, or as having a risk of developing nephrotic syndrome, before administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer.
  • the method may further comprise determining one or more of: a level of one or more ions ⁇ e.g., sodium, potassium calcium, lithium, and/or magnesium) in the subject, a total body weight associated with the subject, a total body water level associated with the subject, a total extracellular water level associated with the subject, and/or a total intracellular water level associated with the subject before administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer.
  • a level of one or more ions e.g., sodium, potassium calcium, lithium, and/or magnesium
  • the method may further comprise determining a second, lower level of one or more of: a level of one or more ions in the subject, a total body weight associated with the subject, a total body water level associated with the subject, a total extracellular water level associated with the subject, and/or a total intracellular water level associated with the subject after administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer.
  • an acid/base status (e.g, acid/base balance) associated with the subject, for example, as measured by, serum total bicarbonate, serum total C0 2 , arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap, does not significantly change within about one day of administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising a disclosed polymer.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • a blood pressure level associated with the subject after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer is substantially lower than a baseline blood pressure level associated with the subject before the administration(s).
  • one or more symptoms of fluid overload is alleviated, reduced, or eliminated after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer.
  • the symptom may be one or more of: difficulty breathing when lying down, shortness of breath, peripheral edema, and/or leg edema.
  • the subject may be on concomitant diuretic therapy.
  • the diuretic therapy may be reduced or eliminated after administration of the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer.
  • methods according to the present disclosure may further comprise administering to the subject an additional agent such as mannitol, sorbitol, calcium acetate, sevelamer carbonate (Renvela®), lanthanum carbonate, and/or sevelamer hydrochloride.
  • an additional agent such as mannitol, sorbitol, calcium acetate, sevelamer carbonate (Renvela®), lanthanum carbonate, and/or sevelamer hydrochloride.
  • methods according to the present disclosure may further comprise administering to the subject an agent known to increase potassium levels.
  • an agent known to increase potassium levels refers to agents that are known to cause an increase, are suspected of causing an increase, or are correlated with an increase in potassium levels, e.g., serum potassium levels, upon administration.
  • agents known to cause an increase in potassium levels may include: a tertiary amine, spironolactone, eplerenone, canrenone, fluoxetine, pyridinium and its derivatives, metoprolol, quinine, loperamide, chlorpheniramine, chlorpromazine, ephedrine, amitryptyline, imipramine, loxapine, cinnarizine, amiodarone, nortriptyline, a mineralocorticosteroid, propofol, digitalis, fluoride, succinylcholine, eplerenone, an alpha-adrenergic agonist, a RAAS inhibitor, an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, an aldosterone antagonist, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, pe
  • administration of the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may further comprise increasing a dose of one or more additional agents, for example, an agent known to cause an increase in potassium levels.
  • administration of the polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may further comprise decreasing a dose or discontinuing administration or co-administration of a diuretic, for example, as a result of having treated fluid overload with a disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, as disclosed herein.
  • methods according to the present disclosure may further comprise administering to the subject an agent known to increase sodium levels.
  • an agent known to increase sodium levels refers to agents that are known to cause an increase, are suspected of causing an increase, or are correlated with an increase in sodium levels upon administration, including agents that increase the sodium content in the gastrointestinal tract, including, for example, sodium reuptake inhibitors, sodium transport inhibitors, or inhibitors of NHE3.
  • agents known to cause an increase in sodium levels may include: estrogen containing compositions, mineralocorticoids, osmotic diuretics ⁇ e.g., glucose or urea), vaptans (e.g., tolvaptan, lixivaptan), lactulose, cathartics ⁇ e.g., phenolphthalein), phenytoin, lithium, Amphotericin B, demeclocycline, dopamine, ofloxacin, orlistat, ifosfamide, cyclophosphamide, hyperosmolar radiographic contrast agents ⁇ e.g., gastrographin, renographin), cidofovir, ethanol, foscarnet, indinavir, libenzapril, mesalazine, methoxyflurane, pimozide, rifampin, streptozotocin, tenofir, triamterene, and/or cholchicine.
  • estrogen containing compositions e.g.,
  • administration of the polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may further comprise increasing a dose of one or more additional agents, for example, an agent known to cause an increase in sodium levels, including agents that increase the sodium content in the gastrointestinal tract, including, for example, sodium reuptake inhibitors, sodium transport inhibitors, or inhibitors of NHE3.
  • administration of the polymers, compositions comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers may further comprise decreasing a dose or discontinuing administration or co-administration of a diuretic.
  • methods according to the present disclosure may further comprise determining a baseline level of one or more ions in a subject before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or the dosage form comprising a disclosed polymer, as disclosed herein, and determining a second level of the one or more ions in the subject after administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • a baseline level of potassium is determined in a subject.
  • a baseline level of sodium is determined in a subject.
  • a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein is administered to the subject, followed by a determination of a second potassium and/or sodium level.
  • the second potassium and/or sodium level is lower than the baseline potassium level.
  • methods according to the present disclosure may further comprise determining a baseline total body weight associated with a subject before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein, and determining a second total body weight associated with the subject after administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the second total body weight is lower than the baseline total body weight. Any suitable method for determining the total body weight associated with a subject may be used.
  • methods according to the present disclosure may further comprise determining a baseline total water level, e.g., total body water level, associated with a subject before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer ,as disclosed herein, and determining a second total water level, e.g., total body water level, associated with the subject after administering the disclosed polymer, composition comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the second total water level e.g., total body water level
  • the baseline total water level e.g., total body water level
  • Any suitable method for determining a total water level associated with a subject may be used, for example, by bioimpedance measurement, or through invasive procedures, such as central vein catheters for measurement of pulmonary wedge pressure.
  • methods according to the present disclosure may further comprise determining a baseline total extracellular water level associated with a subject before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein, and determining a second total extracellular water level associated with the subject after administering the polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the second total extracellular water level is lower than the baseline total extracellular water level.
  • Any suitable method for determining a total extracellular water level associated with a subject may be used, for example, by bioimpedance measurement, or through invasive procedures, such as central vein catheters for measurement of pulmonary wedge pressure.
  • methods according to the present disclosure may further comprise determining a baseline total intracellular water level associated with a subject before administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, as disclosed herein, and determining a second total intracellular water level associated with the subject after administering the disclosed polymer, composition comprising the disclosed polymer, formulation comprising the disclosed polymer, and/or dosage form comprising the disclosed polymer, as disclosed herein.
  • the second total intracellular water level is lower than the baseline total intracellular water level.
  • Any suitable method for determining a total intracellular water level associated with a subject may be used, for example, by bioimpedance measurement, or through invasive procedures, such as central vein catheters for measurement of pulmonary wedge pressure.
  • methods according to the present disclosure may further comprise determining an acid/base status (e.g., acid/base balance) associated with a subject. Any method known in the art for determining an acid/base status (e.g., acid/base balance) may be employed. In some embodiments, methods according to the present disclosure comprise determining an acid/base status (e.g., acid/base balance) associated with a subject after administering a composition according to the present disclosure.
  • an acid/base status e.g., acid/base balance
  • an acid/base status (e.g., acid/base balance) may be measured by serum total bicarbonate, arterial blood pH, urine pH, urine phosphorus, urine ammonium, and/or anion gap.
  • anion gap may be calculated by subtracting the serum concentrations of chloride and bicarbonate (anions) from the concentrations of sodium and potassium (cations) as follows:
  • Anion gap ([Na + ] + [K + ]) - ([Cl ⁇ ] + [HC0 3 ⁇ ])
  • anion gap may be calculated by ignoring potassium concentration as follows:
  • Anion gap [Na + ] - ([CI " ] + [HC0 3 ⁇ ])
  • the acid/base status (e.g., acid/base balance) is within a normal range as set by a clinical laboratory.
  • the acid/base status (e.g., acid/base balance) is within a normal range for the subject, and/or within a clinically acceptable range for the subject.
  • an acid/base status (e.g., acid/base balance) associated with a subject after administering a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, according to the present disclosure, is closer to a normal level for the subject, closer to a clinically acceptable level, etc., than compared to a baseline acid/base status ⁇ e.g., acid/base balance) associated with the subject before administration of the polymer, composition, formulation, and/or dosage form.
  • a baseline acid/base status e.g., acid/base balance
  • an acid/base status ⁇ e.g., acid/base balance) associated with the subject does not change or does not significantly change, for example, at the end of a time interval, or about 1 day, within about 18 hours, within about 12 hours, 10 hours, within about 9 hours, within about 8 hours, within about 7 hours, within about 6 hours, within about 5 hours, within about 4 hours, within about 3 hours, within about 2 hours, or within about 1 hour of administration of the composition.
  • An acid/base status that does not change includes one that does not change outside the normal range or outside the normal range for the subject.
  • Methods for determining an ion level in a subject are known to those skilled in the art. Any suitable method for determining an ion level may be used. However, determination of serum sodium levels should be avoided as such levels tend not to fluctuate, even in hypernatremic subjects. If sodium ion levels are desired, another suitable method for determining such levels should preferably be used, such as determining a subject's total body sodium level.
  • methods according to the present disclosure may further comprise determining a blood pressure level before, after, or both before and after administration of a disclosed polymer, composition comprising a disclosed polymer, formulation comprising a disclosed polymer, and/or dosage form comprising a disclosed polymer, according to the present disclosure.
  • a subject's blood pressure level may be determined using any suitable method known in the art. For example and without limitation, a subject's blood pressure level may be determined by measuring the subject's systolic blood pressure, the subject's diastolic blood pressure, and/or the subject's mean arterial pressure ("MAP"). In some embodiments, the subject's blood pressure is lower after treatment than before treatment.
  • the disclosed polymers, compositions comprising the disclosed polymers, formulations comprising the disclosed polymers, and/or dosage forms comprising the disclosed polymers, according to the present disclosure are administered as needed to reduce an ion level in a subject, and/or to maintain an acceptable level of one or more ions in a subject, and/or to reduce a fluid overload state or fluid maldistribution state in a subject.
  • compositions according to the present disclosure are administered at a frequency from 1 time per every 3 days to about 4 times per day.
  • the compositions according to the present disclosure are administered from about 1 time per day to about 4 times per day; for example, once or twice per day.
  • This example demonstrates the preparation of an exemplary cross-linked polyelectrolyte polymer, such as crosslinked polyacrylic acid partially neutralized with sodium.
  • An inverse suspension process may be used with the following components: a monomer ⁇ e.g., acrylic acid), solvent for the monomer ⁇ e.g., hydrophilic, for example, water), base for neutralization of monomer ⁇ e.g., NaOH), lipophilic (e.g., hydrophobic) solvent ⁇ e.g., IsoparTM L), suspending agent ⁇ e.g., fumed silica such as Aerosil R972), chelating agent ⁇ e.g., VersenexTM-80), polymerization initiator ⁇ e.g., sodium persulfate), and cross-linking agent ⁇ e.g., TMPTA).
  • a monomer ⁇ e.g., acrylic acid
  • solvent for the monomer ⁇ e.g., hydrophilic, for example, water
  • base for neutralization of monomer ⁇ e.g., NaOH
  • lipophilic solvent e.g., hydrophobic solvent
  • suspending agent ⁇ e.g.,
  • a monomer solution is prepared in a vessel as the aqueous phase by dissolving an unsaturated carboxylic acid monomer ⁇ e.g., acrylic acid) in water and neutralizing with an aqueous alkali ⁇ e.g., NaOH) to a desired percentage neutralization ⁇ e.g., 70% to 95% neutralized).
  • an unsaturated carboxylic acid monomer ⁇ e.g., acrylic acid
  • an aqueous alkali e.g., NaOH
  • a desired percentage neutralization e.g., 70% to 95% neutralized
  • one or more polymerization initiators ⁇ e.g., sodium persulfate alone or a redox-couple, such as f-butylhydroperoxide paired with thiosulfate
  • a chelating agent ⁇ e.g., VersenexTM-80
  • a chelating agent ⁇ e.g., VersenexTM-80
  • An organic phase ⁇ e.g., IsoparTM L or toluene or n-heptane or cyclohexane
  • a hydrophobic suspending agent ⁇ e.g., Aerosil R972
  • a crosslinking agent is added.
  • the crosslinking agent is soluble in the organic phase ⁇ e.g., divinylbenzene or 1 , 1 , 1-trimethylolpropane triacrylate—also called TMPTA), it is added to the reactor with the organic phase.
  • the crosslinking agent is water soluble ⁇ e.g., highly- ethoxylated trimethylolpropane triacrylate—also called HE-TMPTA— or diacryl glycerol
  • the crosslinking agent is added to the aqueous phase.
  • the aqueous phase is then added to the organic phase in the reactor, e.g., with mixing, and the reaction mixture is agitated to produce aqueous droplets of the appropriate size in the organic solvent.
  • oxygen is removed from the reaction mixture by bubbling an inert gas ⁇ e.g., nitrogen) through the reaction mixture.
  • an inert gas e.g., nitrogen
  • the reaction will either begin ⁇ e.g., in the case of redox couples) or be started by increasing the temperature ⁇ e.g., in the case of sodium persulfate).
  • a second addition of hydrophobic suspending agent may be added as the polymerization proceeds, e.g., to further stabilize the particles.
  • Reaction is completed by maintaining an elevated temperature ⁇ e.g., 65°C) for a time adequate to allow removal, e.g., reaction of substantially all of the monomer ⁇ e.g., 2 to 4 hours).
  • Water may then be removed by azeotropic distillation and the crosslinked cation-binding polymeric material may be isolated by filtration or centrifugation to remove the remaining organic solvent.
  • the polymeric material may be rinsed with fresh organic solvent and dried to the desired moisture and/or organic solvent content as measured by loss on further drying. In some embodiments, less than 500 ppm of the monomer remains after polymerization. The polymer may be rinsed to remove this residual monomer.
  • acrylic acid 140 g was added dropwise to a solution of 124.35 g of 50% NaOH and 140 g of deionized water while keeping the temperature below 40°C to prevent initiation of polymerization.
  • 3.5 g of VersenexTM 80 and 0.70 g of a 10% solution of sodium persulfate were added.
  • 1200 g of IsoparTM L were charged into the main reactor.
  • 0.80 g Aerosil R972 dissolved in 40 g of IsoparTM L and 0.50 g of TMPTA were added to the main reactor.
  • the aqueous monomer solution was added to the reactor, which was then closed. Agitation was started at 330 RPM and argon was bubbled through the reaction mixture.
  • This example illustrates the preparation of an exemplary crosslinked polyelectrolyte polymer by an aqueous phase reaction of a partially neutralized carboxylic acid monomer.
  • a monomer solution is prepared in a reactor by dissolving an unsaturated carboxylic acid monomer ⁇ e.g., acrylic acid) in water and neutralizing with an aqueous alkali ⁇ e.g., NaOH) to a desired percentage neutralization ⁇ e.g., 70 to 95 percent neutralized).
  • a chelating agent ⁇ e.g., VersenexTM 80
  • a suitable crosslinking agent ⁇ e.g., 1 ,1 , 1-trimethylolpropane triacrylate or diacryl glycerol) is added to the reactor.
  • a polymerization initiator is added to the reactor.
  • the reactor is then closed and the reaction mixture is bubbled with an inert gas ⁇ e.g., nitrogen) and agitated until adequate removal of oxygen is achieved.
  • the reaction is then initiated either by reaching an oxygen concentration where a redox couple produces radicals or by adding heat to cause a temperature dependent initiator (e.g., persulfate salts) to produce radicals.
  • a temperature dependent initiator e.g., persulfate salts
  • a monomer feed mix of approximately 6.0 g TMPTA, 2.2 kg water, 0.4 kg sodium hydroxide, and 3.0 g sodium persulfate per kg of acrylic acid was deoxygenated and polymerization initiated with 0.6 g sodium ascorbate per kg of acrylic acid.
  • the solution was then charged to a curing conveyor belt, where the sodium acrylate solution polymerized to a gel as it traveled on the conveyor belt.
  • the polymer gel was then mechanically cut and granulated to reduce the polymer gel particle size and then the polymer was dried. The dried polymer was then milled and sieved to a desired particle size.
  • This example illustrates the conversion of a partially sodium-substituted crosslinked polycarboxylic polymer prepared, for example, according to Example 1 or 2, to a crosslinked polycarboxylic acid polymer with a reduced degree of sodium substitution ⁇ e.g., an acidified polymer).
  • the polymer is weighed and the relative content of different cations (either from knowledge of the preparation or, more preferably, from elemental analysis of a sample) is used to determine the number of moles of carboxylate present.
  • the polymer is then washed with an excess ⁇ e.g., twice the number of moles of carboxylates, or more) of 1 N acid (preferably HCI), either in batches or by column elution.
  • 1 N acid preferably HCI
  • 89.65 g of a polymer produced by the technique of Example 1 were placed into a beaker and stirred with 667 ml. of 1 N HCI for 2 hours. The liquid was drained and the polymeric particles were returned to the vessel. A second aliquot of 667 ml. of 1 N HCI was added and the mixture was stirred for 1 hour. The liquid was drained and a third rinse with 667 ml. of 1 N HCI was performed for 1 hour. The liquid was drained and the polymeric material was placed into 667 ml. of deionized water and stirred for 1 hour. The liquid was drained and another 667 ml. of deionized water was added. The polymeric material was then stirred for 1 hour before draining the liquid. This water washing was continued until the pH of the rinse water was above 3. The crosslinked cation-binding polymer was then dried in a vacuum at 60°C.
  • a cross-linked polyelectrolyte polymer such as a partially neutralized cross-linked polyacrylate polymer ⁇ e.g., prepared as described in Example 1 above
  • a cross-linked polyelectrolyte polymer such as a partially neutralized cross-linked polyacrylate polymer ⁇ e.g., prepared as described in Example 1 above
  • 750 milliliters were added, stirred with the polymer, and removed followed by two or more separate additions of 750 milliliters.
  • the polymer was then rinsed with 2,250 milliliters of low metal content water to remove excess acid surrounding the polyelectrolyte such as a polyacrylate.
  • the crosslinked cation-binding polymer was then dried.
  • a cross-linked polyelectrolyte polymer such as a cross-linked polyacrylate polymer were placed into a filtration funnel or a column equipped with a bottom filter. The polymer was then rinsed with about 2,250 milliliters of pure ⁇ e.g., trace metal or otherwise certified low metal) 1 M HCI for about an hour or more. Next, the polymer was rinsed with 2,250 milliliters of low metal content water. The crosslinked cation-binding polymer was then dried.
  • Exemplary acidified polymers useful as crosslinked cation-binding polymers prepared according to this Example generally have a saline holding capacity of greater than about 40 g/g; and contain less than about 5,000 ppm of sodium, less than about 20 ppm of heavy metals, less than about 500 ppm of residual monomer, less than about 2,000 ppm of residual chloride, and less than about 20 wt.% of soluble polymer.
  • acidified polymers useful as crosslinked cation-binding polymers prepared according to this Example have a saline holding capacity of greater than about 80 g/g; and contain less than about 500 ppm of sodium, less than about 20 ppm of heavy metals, less than about 50 ppm of residual monomer, less than about 1 ,500 ppm of residual chloride, and less than about 10 wt.% of soluble polymer.
  • Crosslinked cation-binding polymers prepared according to the method of Example 1 (using acrylic acid monomers) and acidified to prepare the exemplary acidified polymers of the present Example may be referred to as "H-CLP" or "HCLP".
  • This example demonstrates the preparation of substantially metal free ⁇ e.g., acid form) cross-linked polyelectrolyte polymers, such as cross-linked polyacrylic acid polymer.
  • substantially metal free ⁇ e.g., acid form) cross-linked polyacrylic acid polymer was prepared by placing 140 g of glacial acrylic acid ⁇ e.g., not neutralized as in Example 1 ) into a three to five liter reactor with 2,200 to 2,500 milliliters of dilute acid, such as 1 M HCI.
  • a water soluble cross linking agent such as 1 ,3-diglycerate diacrylate, in a ratio chosen to produce the desired saline holding capacity ⁇ e.g., 20-fold, 30-fold, 40-fold or more) and an initiator were added to the monomer solution.
  • the reaction was started and allowed to proceed for two to four hours until substantially all of the monomer had reacted.
  • the resultant mass of wet polymer was then cut into smaller pieces ⁇ e.g., 1-2 cm per side), dried in a vacuum or in an inert atmosphere, and then disrupted ⁇ e.g., by milling) to produce particles or powder.
  • polycarbophil a polyacrylic acid crosslinked with divinyl glycol may be used (see, e.g., USP monograph).
  • Free-acid forms of crosslinked cation-binding polymers prepared or described according to the present example represent alternative forms of H-CLP.
  • This example describes the preparation of polymers with calcium or calcium and magnesium counterions.
  • Cross-linked polyacrylate polymers with target levels of 50% magnesium counterions or 50% calcium counterions were prepared from NaCLP manufactured by a process substantially similar to Example 1 followed by enteric coating first with 30 wt% 93F19255 and then 1 wt% YS-1 -19025. 352 g of the enteric coated NaCLP polyacrylate particles were washed with 1 M sodium bicarbonate and five 10L rinses with water to remove the enteric coating. The water swollen beads were then washed three times with 1 N HCI, with a total of approximately 6 equivalents of acid, twice the number of equivalents of carboxyl groups on the polyacrylate polymer, to convert the polymer to the acid form.
  • the acid was then washed from polymer with four water washes raising the pH from pH 1 to above 3.
  • the total weight of the wet beads was 1782 g. 137g of the wet beads were placed into each of 2 beakers.
  • To produce polyacrylate with approximately 50% magnesium counterions 2.1 g of MgO was placed on the polymer in one beaker, followed by 250 ml. deionized water.
  • To produce polyacrylate with approximately 50% calcium counterions 2.9g CaO was used.
  • the polymer and base were stirred and allowed to equilibrate and then the free water was decanted.
  • the polyacrylate beads were then dried in a vacuum oven.
  • the cation content of each of the dried polyacrylates was measured by ICP using the method in Example 7.
  • the counterion content of the polyacrylates was 45.1 % magnesium (target 50% magnesium) and 47.5% calcium (50% calcium target).
  • calcium or magnesium bases for example, CaC0 3
  • CaC0 3 calcium or magnesium bases
  • Ca-CLP may be produced from NaCLP.
  • a NaCLP with 50% neutralization may be manufactured according to methods of Example 1 or 2, adjusting the procedure to neutralize 50% of the acrylic acid carboxyl groups with NaOH or with Example 1 or 2 and Example 3 using only enough acid in Example 3 to bring the sodium counterions down to a level where they are counterions to 50% of the carboxyl groups.
  • the hydrated 50% NaCLP polymer is then equilibrated with a calcium salt (e.g. CaCI 2 ) solution to exchange the sodium with calcium. This equilibration may be repeated with fresh solutions of calcium salt to effect more complete exchange with calcium and to remove sodium prior to drying.
  • a calcium salt e.g. CaCI 2
  • Ca-CLP including, for example, from about 50% to about 70% Ca-CLP may be produced from calcium polycarbophil (see, e.g., USP monograph) by adding an appropriate amount of acid (e.g., hydrochloric acid, acetic acid, and/or phosphoric acid) to bring calcium counterion to the desired level (e.g., from about 50% to about 70% Ca-CLP).
  • acid e.g., hydrochloric acid, acetic acid, and/or phosphoric acid
  • a water wash may then be used to remove free calcium and the material dried.
  • H-CLP was prepared according to Examples 1 and 3, for example, a cross-linked polyacrylic acid polymer with less than 5000 ppm sodium (e.g., 153 ppm sodium), less than 20 ppm heavy metals, less than 1000 ppm residual monomer (e.g., 40 ppm residual monomer), less than 20% insoluble polymer (e.g., 3% insoluble polymer), and with loss on drying of less than 5% of its weight (e.g., loss on drying of 1 % of its weight).
  • the H-CLP polymer was milled to break up the bead structure and reduce the particle size. The milled H-CLP was then filled into capsules with 0.7 g per capsule.
  • the objectives of the clinical trial included (1 ) determination of the safety, tolerability and efficacy of H-CLP to remove, e.g., altered fecal excretion of, sodium, calcium, magnesium, potassium, iron, copper, zinc and/or phosphorous; (2) to determine whether administration of H-CLP altered the amount of fluid absorbed, e.g., altered fecal weight, per gram of H-CLP administered; (3) to determine whether administration of H-CLP altered measures of acid/base balance, including serum total bicarbonate, urine pH, and urine phosphorous; and (4) to determine whether administration of H-CLP altered serum potassium levels. For all outcomes, treated groups were compared to the control group.
  • the primary endpoints included net sodium balance compared among treated and control groups. Secondary endpoints included change in stool weight compared among treated and control groups; net balance of calcium, magnesium, potassium, iron, copper, zinc and phosphorous compared among treated and control groups; fluid consumed and excreted in the treated groups compared with the control group; and safety and tolerability based upon review of vital signs, clinical safety labs and adverse events.
  • H-CLP was administered with water, 4 times a day for a total of 9 days (a total of 36 consecutive doses). For each dose group of five subjects, H-CLP was administered one hour before or just after each of 4 standardized meals or snacks as shown in Table 3. Doses were given at the scheduled time (+/- 10 minutes) for each subject.
  • Diet was controlled with all participants having identical meals. Each day all meals and snacks representing one subject were homogenized and the sodium, potassium, calcium, phosphorus, iron, copper, zinc and magnesium content determined. All meals provided to the subjects were controlled for the number of calories, level of sodium (5000 mg per day +/- 100 mg), fiber content (10-15 g per day), fat content and approximate recommended Dietary Reference Intakes. Subjects were requested to consume all of their meals. Meals that were not fully consumed were collected for an entire twenty-four hour period, weighed and frozen for possible metal analysis.
  • Stool weight, fecal electrolytes and fluid balance were determined daily. Serum samples were collected daily and the concentration of sodium, potassium, magnesium, calcium, phosphorus and carbon dioxide determined. All urine specimens were collected and volume recorded. An aliquot of a daily afternoon urine sample was analyzed for pH and osmolality. Urine samples were pooled for each 24-hour period and an aliquot sampled for sodium, potassium, calcium, phosphorous and magnesium analysis.
  • All feces eliminated after consumption of the first controlled meal were collected as individual samples in tared collection containers. The color and consistency of the stool were noted, the sample weighed, then frozen and stored at or below -20°C. All fecal collections were analyzed for sodium, potassium, magnesium, calcium, phosphorous, iron, zinc and copper content. Fecal weights for all samples eliminated in each 24-hour period were added together to determine the total fecal weight per subject per day.
  • Daily fecal and urine weight, urine osmolality and pH, and daily fecal and urine content and concentrations of sodium, calcium, magnesium, potassium and phosphorus (plus copper, iron and zinc only in the stool) were determined for each subject and each treatment group.
  • Daily fluid balance (fluid intake - output) and daily net balance of sodium, magnesium, calcium, potassium and phosphorus were calculated based on the analysis of diet, urine and stool samples for each patient and each group.
  • Fecal metal excretion ⁇ e.g., sodium, potassium, magnesium and calcium
  • Tables 4 to 7 Daily excretion of sodium, potassium, magnesium and calcium for the control group are shown in Table 4.
  • the average daily value of metal cation excretion on days 1 to 9 for the treatment groups are compared to the average value for the control group and are shown for 7.5 g of H-CLP daily (Group A, Table 5), for 15 g of H-CLP daily taken immediately after meal (Group B, Table 6), and for 25 g of H-CLP daily (Group D, Table 7). Fasting before administration of H-CLP did not significantly affect ion excretion.
  • Table 5 Changes in Fecal Metal Excretion Over Control (mg/day) for Subjects Administered 7.5 grams of H-CLP Daily (Group A)
  • HCLP results in a dose dependent increase in the fecal excretion of sodium and potassium.
  • Serum potassium levels were also evaluated daily. The change in average serum potassium for the treatment groups from the average for the control group on Days 5 to 9 values are shown in Table 9. Serum potassium decreased from control values in all treatment groups.
  • the content (e.g., percentage; %) of certain cations including, for example, calcium, sodium, magnesium, and/or potassium, on a polymer may be determined by ICP- OES, ICP-AES and/or ICP-MS, for example, with a ThermoElectron Finnegan Element 2 or a Perkin Elmer Elan 6000 instrument.
  • the percentage of cations that are counterions to the carboxylate groups in the polymer determined in different ICP measurements may vary by ⁇ 5% or less.
  • the determination of 50% to 70% calcium and/or magnesium cations as counterions to carboxylate groups in the polymer may vary in different measurements by ICP (e.g., 50% ⁇ 5% to 70% ⁇ 5%).
  • the calcium and/or sodium content of a polymer prepared according to Example 5 can be determined by diluting a 250 mg sample of the polymer with 5% nitric acid solution to a total volume of 100 mL. After shaking overnight to extract the calcium and sodium cations from the polymer, an aliquot of the mixture can be diluted with a 1 % nitric acid solution as necessary to bring the concentration of the cation within the range of a suitable calibration curve (e.g., a standard curve with a linear range). An appropriate internal standard (e.g., scandium, yttrium, germanium) is used to correct for matrix effects. Samples are diluted to within the range of the linear standard curve for analysis. Preferably the polymer is completely digested.
  • an exemplary method is to fully digest the sample in nitric acid (e.g., until the solution becomes clear and colorless), for example by application of heat; using microwave digestion; using other acids or mixture of acids, hydrogen peroxide, or other reagents; or by other methods known in the art.
  • the polymer may be placed in a nitric acid, hydrochloric acid, and hydrogen peroxide medium and microwave digesting the sample using any method known to one of skill in the art.
  • a 250 mg sample of a polymer prepared according to Example 5 (e.g., Ca-CLP and/or Mg-CLP) was placed in a 100-mL polypropylene tube and a 5% nitric acid solution was added until the total volume of the sample was 100 mL. The tube was then shaken overnight to produce "Mixed Sample A.”
  • a 127 mg sample of the same polymer used to prepare Mixed Sample A was placed in a 100-mL polypropylene tube and a 5% nitric acid solution was added until the total volume of the sample was 100 mL.
  • [x]%Ca-CLP (72.06)(wt.% Ca)/(20.05 -(0.19)(wt.% Ca))
  • polymers of the present disclosure such as crosslinked polyacrylate polymers may have calcium concentration measurements (e.g., average calcium concentration measurements as determined by ICP-AES analysis) of about 122,821 ⁇ g of calcium to about 164284 ⁇ g of calcium per gram of the polymer. This range approximately corresponds to a polymer in which calcium serves as a counterion to about 50% to about 70% of the carboxylate groups, as shown in Table 1 1 below.
  • polymers of the present disclosure such as crosslinked polyacrylate polymers may have calcium concentration measurements (e.g., average calcium concentration measurements as determined by ICP-AES analysis) of about 122,821 ⁇ g of calcium to about 164,284 ⁇ g of calcium per gram of the polymer. This range approximately corresponds to a polymer in which calcium serves as a counterion to about 50% to about 70% of the carboxylate groups, as shown in Table 1 1 below.
  • Table 1 1 Calcium Content for Various Exemplary Polyacrylate Polymers.
  • polymers of the present disclosure such as crosslinked polyacrylate polymers may have magnesium concentration measurements (e.g., average magnesium concentration measurements as determined by ICP-AES analysis) of about 8,400 ⁇ g of magnesium to about 48,300 ⁇ g of magnesium per gram of the polymer. This range approximately corresponds to a polymer in which magnesium serves as a counterion to about 5% to about 30% of the carboxylate groups, as shown in Table 12 below.
  • polymers of the present disclosure such as crosslinked polyacrylate polymers may have magnesium concentration measurements (e.g., average magnesium concentration measurements as determined by ICP-AES analysis) of about 24,700 ⁇ g of magnesium to about 56,000 ⁇ g of magnesium per gram of the polymer. This range approximately corresponds to a polymer in which magnesium serves as a counterion to about 15% to about 35% of the carboxylate groups, as shown in Table 12 below.
  • Table 12 Magnesium Content for Various Exemplary Polyacrylate Polymers.
  • [x]%Na-CLP (72.06)(wt.% Na)/(23.0 - (0.23)(wt.% Na))
  • Polymers of the present disclosure may have sodium concentration measurements ⁇ e.g., average sodium concentration measurements as determined by ICP- AES analysis) of about 0 ⁇ g of sodium to about 16, 100 ⁇ g of sodium per gram of polyacrylate polymer. This range approximately corresponds to a polymer in which sodium serves as a counterion to about 0% to about 5% of the carboxylate groups.
  • the percentage of carboxylate groups to which magnesium serves as a counterion on a polymer can be determined from the weight percent measurement (wt.% Mg) by the following equation:
  • [x]%Mg-CLP (72.06)(wt.% Mg)/(12.15 - (0.1 1 (wt.% Mg))
  • the content of certain cations ⁇ e.g., calcium, sodium, magnesium, potassium or other cations) on a polyacrylate polymer may be determined by ICP-OES.
  • the calcium content of a polymer prepared according to Example 5 can be determined by diluting a measured mass of polyacrylate polymer with a known volume of a 5% aqueous solution of trace metal grade nitric acid. The sample is then digested by first heating the polyacrylate polymer mixture until gaseous N0 2 is apparent. While continuing to heat, a small measured aliquot of 30-40% hydrogen peroxide is added to the solution. The solution foams and may turn brown.
  • An internal scandium/cesium standard/ionization buffer was prepared from CsN0 3 and a scandium standard and was used in all analyses to normalize results and correct for matrix effects.
  • the internal standard was prepared by adding 50 mg scandium standard (1000 ⁇ g/mL) and 1.48 g anhydrous CsN0 3 to 1 L of 5% trace metal grade nitric acid. The internal standard was mixed with the sample online prior to injection into the ICP instrument. Standard solutions for construction of the standard curve were prepared at 0.2, 1 , 5 and 25 ⁇ g/g calcium in 5% nitric acid. Samples were analyzed by ICP-OES on a Perkin Elmer Optima 5300 DV. Calcium concentrations in ⁇ g/g were determined from the standard curve corrected for dilution, divided by the concentration of the originally prepared polymer sample and converted to weight percent as described above.
  • the content of certain cations (e.g., calcium, sodium, magnesium, potassium or other cations) on a polymer may be determined by ICP- OES using microwave digestion of the sample in a nitric acid, hydrochloric acid, and hydrogen peroxide digestion medium.
  • the calcium content of a polymer prepared according to Example 5 can be determined by placing 50 mg of polymer with 0.800 ml. trace metal grade nitric acid, 0.450 ml. concentrated trace metal grade hydrochloric acid and 0.200 ml. of 30% (w/w) hydrogen peroxide in a digestion vessel.
  • the vessel is then placed in a MARS 5 (CEM Corp) microwave at 100% power for 2 minutes (to a temperature of 165°C) followed by 3 minutes at 100% power (to a temperature of 175°C) and then holding the sample at 175°C for 10 minutes to digest the sample including, for example, to completely digest the sample.
  • the digested polymer sample is then diluted to a final volume of 50 ml. with purified water to bring the concentration of the cation within the range of the standard curve.
  • Standard solutions for construction of the standard curve were prepared at 0 (blank), 100, 500 and 1000 ug/mL Ca in 4% (v/v) nitric acid.
  • An internal standard solution was prepared containing 20 ⁇ g/mL yttrium and 100 ⁇ g/mL germanium in 4% trace metal grade nitric acid. The internal standard was used in all analyses to normalize results and correct for matrix effects. Samples were analyzed on a Thermo Electron iCAP 6000 ICP-OES. Ca concentrations in ⁇ g/g were determined from the standard curve with correction for dilution, and converted to weight percent as described above.
  • sodium content in the same sample was analyzed by placing 50 mg of polymer with 0.800 ml. trace metal grade nitric acid, 0.450 ml. concentrated trace metal grade hydrochloric acid and 0.200 ml. of 30% (w/w) hydrogen peroxide in a digestion vessel.
  • the vessel is then placed in a MARS 5 (CEM Corp) microwave at 100% power for 10 minutes (to a temperature of 185°C) followed by 5 minutes at 100% power (to a temperature of 195°C) and then holding the sample at 195°C for 15 minutes to digest the sample.
  • the digested polymer sample is then diluted to a final volume of 50 ml. with purified water to bring the concentration of the cation within the range of the standard curve.
  • Standard solutions for construction of the standard curve were prepared at 0 (blank), 0.1 , 0.5 and 1 .0 ⁇ g/mL Na in 4% (v/v) nitric acid.
  • the saline holding capacity of a cross-linked polyelectrolyte polymer such as a cross-linked polyacrylate polymer, may be determined by known methods in the art.
  • the saline holding capacity distinguished from the buffer capacity, is determined for the polymer after acid washing to produce the acidic polymer followed by loading the polymer with sodium cations. This procedure allows comparison of the saline holding capacity for different polymers without interference from pH from partially neutralized polymer.
  • the saline holding capacity for the polycarboxylic acid polymer with sodium counterions is then determined in a isotonic saline, isotonic physiologic buffer, 50 mM sodium phosphate buffer, or similar sodium buffer at pH 7.
  • the saline holding capacity for Ca-CLP (e.g., 50- 70%CLP) was determined.
  • An amount of cross-linked cation-binding polyelectrolyte for example, cross-linked Ca-CLP particles ⁇ e.g., Ca-CLP prepared according to Examples 1 , 3, and 5) ⁇ e.g., 0.1 grams), was weighed and transferred to a tared filter tube. The mass of the polymer was recorded as W1 . Next, the tube was returned to the balance to record the weight of the tube plus the Ca-CLP sample as W2. A 5-10 mL aliquot of 0.1 N HCI was added to the tube, the tube shaken for 30 minutes and the liquid drained.
  • This acid was was repeated two times with shaking for 60 minutes for the third wash. A 5-10 mL aliquot of deionized water was then added, the tube shaken, and the free liquid removed by suction. This was repeated two more times. A 50 mM sodium phosphate pH 7 buffer was prepared. A 10 mL aliquot of the sodium phosphate buffer was then transferred to the tube containing the sample. The tube was then shaken for two hours and the free fluid drained. This was repeated two more times. The free fluid was then removed and replaced with fresh buffer and shaken again for 30 minutes. This washing with buffer was repeated for a total of 4 saline washes with shaking for 15 min, 15 min and 3 hours hours.
  • the saline holding capacity can be determined for Ca-CLP particles Ca-CLP with 50%, 61 % and 72% calcium counterions prepared using the methods of Example 1 , 2, and 5
  • the saline holding capacity was determined using the method of Example 8.
  • the buffer uptake and sodium and potassium binding of CaCLP with target levels of 10% to 100% calcium counterions can be determined.
  • the buffer uptake measures the amount of buffer absorbed by the polymer in the calcium form, with no conversion to the acid form.
  • NaCLP was manufactured by a process substantially similar to Example 1 followed by enteric coating first with 30 wt% 93F19255 and then 1 wt% YS-1 -19025. 352 g of the enteric coated NaCLP polyacrylate particles were washed with 1 M sodium bicarbonate and five 10L rinses with water to remove the enteric coating. The water swollen beads were then washed three times with 1 N HCI to convert the polymer to the acid form.
  • the acid was then washed from polymer with three water washes raising the pH from pH 1 to about 3.
  • the total weight of the wet beads was 1782 g. 137g of the wet beads were placed into each of 8 beakers and CaO added to prepare CaCLP with 10 to 100% calcium counterions.
  • CaO added to prepare CaCLP with 10 to 100% calcium counterions.
  • to produce polyacrylate with approximately 50% calcium counterions 2.9 g of CaO was placed on the polymer in one beaker, followed by 250 mL deionized water.
  • the polymer and base were stirred and allowed to equilibrate and any free water was decanted.
  • the polyacrylate beads were then dried in a vacuum oven.
  • the cation content of each of the dried polyacrylates was measured by ICP using the method in Example 7 Ca-CLP with target values of 10 to 100% calcium counterions were similarly prepared using the amounts of CaO listed in Table 13.
  • the buffer uptake, sodium content and potassium content of the H-CLP and Ca- CLP with different amounts of calcium counterions was then determined in three incubation buffers: 0.15 M sodium bicarbonate at pH 7; 90 mM potassium bicarbonate with 40 mM sodium bicarbonate at pH 10; and 28 mM potassium bicarbonate with 18 mM sodium bicarbonate at pH 10.
  • the buffer uptake was measured by placing a known amount of cross-linked cation-binding polyelectrolyte (weight W1 ), for example, cross-linked Ca-CLP particles ⁇ e.g., Ca-CLP prepared according to Examples 1 , 3 and 5) ⁇ e.g., 0.1 grams), into a tube then weighing the tube + sample (W2).
  • the buffer holding capacity and sodium and potassium content are shown in Tables 14-15 as a function of initial calcium counterion content on the CLP particles as measured by ICP.
  • Ca- CLP can bind either sodium or potassium. The level of binding of each cation is dependent on the local concentration of the ions in the incubation solution.
  • Table 14 Sodium Content for H-CLP and Ca-CLP
  • the buffer holding capacity of a cross-linked polyelectrolyte polymer such as a cross-linked polyacrylate polymer, may be determined by known methods in the art.
  • a buffer absorption capacity e.g., buffer holding capacity
  • the polymers further comprise calcium and/or magnesium cations (e.g., calcium cations or magnesium cations or a mixture thereof), wherein the calcium and/or magnesium cations are counterions to the carboxylate groups in the polymer is measured using a centrifugal method.
  • the buffer holding capacity of Ca-CLP particles may be determined.
  • a pH seven 75 mM phosphate uptake buffer is prepared with 10.65 g of sodium phosphate dibasic (anhydrous) in 1 L purified water, with pH adjustment to pH 7.0 with 1 N HCI.
  • the weight of a centrifuge tube is determined (Wtube). 100 ⁇ 10 mg of the Ca-CLP particles are weighed and added to the centrifuge tube and the tube reweighed (Wtube+sample). 10 ml. of uptake buffer is then added to centrifuge tube and the tube capped and shaken. The tube is then shaken on a shaker for at least 8 hours. The tube is then centrifuged for 10 minutes and the supernatant decanted. The tube with the swollen gel particles is reweighed (Wtube+swollen gel) and the saline holding capacity determined as:
  • H-CLP e.g., prepared as described in Examples 1 and 3
  • CaCLP prepared by addition of calcium counterions to CLP during manufacture, e.g., as described in Examples 5 and 7
  • H-CLP prepared as described in Examples 1 and 3
  • CaCLP prepared by addition of calcium counterions to CLP during manufacture, e.g., as described in Examples 5 and 7
  • fecal and urinary ion excretion and fecal mass in rats fecal and urinary ion excretion and fecal mass in rats.
  • Ca-CLP with calcium added as counterions during manufacturing at levels as described in Table 16 were prepared using the methods described in Examples 1 , 3 and 5 including drying in a vacuum oven. Each of these CaCLP polymers were tested in groups of six rats to determine the effect of the percent calcium on the CaCLP on the fecal excretion of Na and K and on the mass of feces excreted.
  • Ca-CLP was prepared as described in Examples 1 , 3 and 5. The CaO, HCLP mixture was stirred and left to react overnight at room temperature. Free liquid was decanted and the CaCLP placed into a vacuum oven at approximately 60°C to dry. The amount of calcium associated with the polymer was determined using ICP as described in Example 7.
  • Ca-CLP or H-CLP was mixed at a level of 5% into pulverized LabDiet 5012 and the mixture was processed through a food blender several times until the food/CLP powder was uniform in color and size.
  • Daily measurements of rat weight and 24-hour food intake, water intake, urine output, and fecal output were recorded. Dosing started on Day 1 .
  • On Days 4, 5 and 6 24-hour feces and urine were collected for ICP-AES analysis of fecal Na, fecal K and urine P. Samples were digested for ICP-AES analysis by placing the urine or feces sample in a flask, adding an aqueous solution of 5% trace metal grade concentrated nitric acid, and heating to boiling.
  • Urinary excretion of phosphorus is a measure of the acid/base status of the rat with an increase from control in urine phosphorus correlating with a shift to a more acidic state and a decrease from control correlating with a shift to a more alkalotic state.
  • Table 17 Change From Control in Daily Fecal Sodium, Fecal Potassium, Urinary
  • the polymer was milled to break up the bead structure and reduce the particle size.
  • the CaCLP powder was mixed into pudding immediately prior to dosing. The subjects were required to eat the entire pudding aliquot.
  • the clinical trial evaluated whether administration of CaCLP when compared to a baseline period (1 ) altered fecal excretion of sodium, potassium, or phosphorous (2) altered measures of acid/base balance including serum total bicarbonate, urine pH and urine phosphorus, (3) altered serum potassium levels and (4) altered fecal weight.
  • CaCLP was administered in pudding, 3 times a day for a total of 7 days (a total of 21 doses).
  • the total daily dose was 16 g (5.33g tid).
  • the total daily dose was 18g (6g tid).
  • a dose of 16g of 25%CaCLP and 18g 60%CaCLP each delivered an equivalent number of moles of cation exchange carboxyl groups as 15g of H-CLP (208 mEq).
  • Average daily parameters for the treatment period were compared to average daily parameters for the baseline period (days 3-6).
  • the average change from baseline in fecal excretion of sodium and potassium are shown in Table 18.
  • An increase in the percent calcium counterion from 25 to 60% resulted in a decrease in fecal sodium and a smaller decrease in fecal potassium excretion.
  • Both Ca-CLP forms caused a decrease in serum potassium compared to baseline.
  • Table 18 Average change from baseline in fecal sodium, fecal potassium and serum
  • Measures of acid/base balance included urine pH, total serum C0 2 , and urine phosphate.
  • the average change from baseline (Days 3-6) in these parameters for the treatment period (Days 7-13) are shown in Table 19.
  • the change from baseline in serum bicarbonate and urine pH were similar for 25%CaCLP and 60%CaCLP.
  • the urinary phosphorus excretion decreased by a factor of 10 with an increase from 25% to 60% calcium counterion. This was paralleled by a decrease in fecal phosphorus excretion by a factor of 10 between 25% and 60% calcium counterion.
  • CaCLP may be evaluated in a clinical trial to determine its effects on elimination of cations, acid/base balance, serum cation levels, and/or fecal weight. For example, fecal excretion of sodium, potassium or phosphorus; measures of acid/base balance including serum total bicarbonate, urine pH and urine phosphorus; serum potassium levels; and/or fecal weight may be determined.
  • 1 25%CaCLP is H-CLP with 25% of the carboxyl groups reacted with calcium base; 50% CaC03 is CaC03 added to the formulation at a mass that will neutralize 50% of the carboxyl groups in an equivalent dose of H-CLP.
  • 25%CaCLP and 50%CaCLP were prepared according to Examples 1 , 3 and 5. After cation exchange to load the polyacrylate with calcium, the polymer was milled to break up the bead structure and reduce the particle size. The CaCLP powder was mixed into pudding immediately prior to dosing. The subjects were required to eat the entire pudding aliquot.
  • the clinical trial evaluated whether administration of CLP when compared to a baseline period (1 ) altered fecal excretion of sodium, potassium or phosphorus (2) altered measures of acid/base balance including serum total bicarbonate, urine pH and urine phosphorus, (3) altered serum potassium levels, and (4) altered fecal weight.
  • CLP was administered in capsules with water or in pudding, twice a day (before breakfast and before dinner) for a total of 7 days (a total of 14 doses) as shown in Table 21.
  • Groups 1 and 3 had the CLP formulation administered in capsules with water and
  • Groups 2 and 4 had the CLP formulation mixed into pudding immediately prior to administration. All groups were administered an equivalent number of moles of cation exchange carboxyl groups as 15 g of H-CLP (208 mEq).
  • CaC03 is CaC03 added to the formulation at a mass that will neutralize 50% of the carboxyl groups in an equivalent dose of H-CLP.
  • Measures of acid/base balance included urine pH, total serum C0 2 and urine phosphate. The average change from baseline in these parameters for Days 7-13 are shown in Table 23.
  • CaC03 is CaC03 added to the formulation at a mass that will neutralize 50% of the carboxyl groups in an equivalent dose of H-CLP.
  • 1 25%CaCLP is H-CLP with 25% of the carboxyl groups reacted with calcium base; 50 CaC03 is CaC03 added to the formulation at a mass that will neutralize 50% of the carboxyl groups in an equivalent dose of H-CLP.
  • Data obtained from the Examples provided herein may be used to predict the amount of sodium and potassium excreted through the feces in a human subject using CaCLP with a range of calcium counterions and further extrapolated to predict the amount of sodium and potassium excreted through the feces above the range.
  • the data from Examples 13 and 14 can be combined to predict the behavior of Ca-CLP in normal human volunteers at levels of calcium between 25 and 60%Ca-CLP and can further be used to extrapolate to levels above 60%Ca-CLP.
  • the combined data from Examples 13 and 14 are shown in Table 25.
  • This table shows fecal cation excretion (meq/d) and the ratio of potassium and sodium content in the feces.
  • a linear fit of the fecal sodium and fecal potassium excretion and fecal weight data were used to generate the linear regression data shown in Table 25, with high correlation coefficients.
  • Table 25 Linear regression of fecal Na, K and weight data from Examples 13 and 14
  • This example demonstrates the treatment of heart failure patients with a cross- linked polyelectrolyte polymer such as a crosslinked cation-binding polymer comprising monomers that comprise carboxylic acid groups (e.g., crosslinked polyacrylic acid polymer such as Ca-CLP).
  • a cross- linked polyelectrolyte polymer such as a crosslinked cation-binding polymer comprising monomers that comprise carboxylic acid groups (e.g., crosslinked polyacrylic acid polymer such as Ca-CLP).
  • patients with heart failure including, for example heart failure associated with chronic kidney disease (e.g., patients classified as class III or IV according to the New York Heart Association Classification scheme shown in Table 27 below) are treated with Ca-CLP (e.g., a cross-linked polyacrylic acid polymer that comprises calcium cations, and wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, including, for example, 50% Ca- CLP.
  • Ca-CLP e.g., a cross-linked polyacrylic acid polymer that comprises calcium cations, and wherein the calcium cations are counterions to about 50% to about 70% of the carboxylate groups in the polymer, including, for example, 50% Ca- CLP.
  • Serum chemistry, clinical signs and symptoms of heart failure, urinary electrolytes, thirst evaluation and other assessments may be evaluated throughout the treatment.
  • Assessments which evaluate signs and symptoms of heart failure include the New York Heart Association Class (as shown in Table 27), changes in dyspnea as assessed by the patient's response to a single question using responses on a Likert scale ranging from "much worse” to "much better,” the six minute walk test and a patient reported outcome instrument (Kansas City Cardiomyopathy Questionnaire).
  • Dyspnea may be evaluated using a quantitative patient self-assessment of breathing status compared to baseline with answers on a 7-point Likert scale ranging from "much worse” to "much better.” Additionally, the six-minute walk test is a well-accepted measure of heart failure status, with patients able to walk shorter and shorter distances as heart failure progresses. Further, the Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific instrument for measuring health related quality of life in patients with congestive heart failure. The scale for each of the quality of life parameters is 0 to 100, with 100 being the best quality of life. Fluid status may also be evaluated by total body weight and extremity edema. Serum potassium levels may be monitored as patients receiving RAAS blocking agents are known to increase serum potassium in some patients. Additionally, mean total serum CQ 2 and serum bicarbonate may be measured as a measure of acid/base status.
  • Treatment with Ca-CLP results in significant and clinically meaningful improvement of signs and symptoms in NYHA class lll/IV heart failure patients including, for example, a reduction in NYHA class (e.g., a reduction in class from IV or III to II or I) a reduction of body weight, improvement in subjective symptoms (dyspnea) and quality of life (Kansas City Cardiomyopathy Questionnaire scores), and improvements in objective measures of physical function (6 Minute Walk Test) and clinical signs and symptoms (NYHA Classification; extremity edema) without resulting in a change in the subject's acid/base status.
  • a reduction in NYHA class e.g., a reduction in class from IV or III to II or I
  • a reduction of body weight improvement in subjective symptoms (dyspnea) and quality of life (Kansas City Cardiomyopathy Questionnaire scores)
  • improvements in objective measures of physical function (6 Minute Walk Test) and clinical signs and symptoms (NYHA Classification; extremity edema) without resulting in a change in the
  • Clinical studies may be conducted to evaluate a crosslinked cation-binding polymer comprising monomers that comprise carboxylic acid groups and pKa-decreasing groups including, for example, an electron-withdrawing substituent such as a halide atom (e.g., fluorine (F)) for the treatment of patients with chronic kidney disease (CKD).
  • a halide atom e.g., fluorine (F)
  • patients with chronic kidney disease e.g., patients classified as CKD stage II, III or IV according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) Guidelines shown in Table 27
  • ACEI Angiotensin-converting Enzyme Inhibitor
  • ARB Angiotensin II Receptor Blocker
  • Ca-CLP CLP e.g., a cross-linked polyacrylic acid polymer that comprises calcium cations, and wherein the calcium cations are counterions to about 50% to about 70% or about 50% to about 80% of the carboxylate groups in the polymer, including, for example, 50% Ca-CLP.
  • Such treated patients may include hypertensive patients with nephropathy due to type 2 diabetes mellitus (T2DM) who develop hyperkalemia on maximized kidney sparing treatment with Angiotensin-converting Enzyme Inhibitor (ACEI) and/or Angiotensin II Receptor Blocker (ARB) drugs, with or without spironolactone.
  • T2DM type 2 diabetes mellitus
  • ACEI Angiotensin-converting Enzyme Inhibitor
  • ARB Angiotensin II Receptor Blocker
  • Chronic kidney disease is defined as either kidney damage or GFR
  • Kidney damage is defined as
  • Blood pressure, serum chemistry, kidney function parameters e.g. glomerular filtration rate, serum concentrations of creatinine and BUN
  • urinary electrolytes e.g. glomerular filtration rate, serum concentrations of creatinine and BUN
  • urinary electrolytes e.g. glomerular filtration rate, serum concentrations of creatinine and BUN
  • urinary electrolytes e.g. glomerular filtration rate, serum concentrations of creatinine and BUN
  • urinary electrolytes e.g. glomerular filtration rate, serum concentrations of creatinine and BUN
  • urinary albumin/creatinine ratio e.g. glomerular filtration rate
  • urinary electrolytes e.g. glomerular filtration rate, serum concentrations of creatinine and BUN
  • urinary albumin/creatinine ratio
  • inclusion criteria includes: patients that are 21 to 80 years old at screening, have Type 2 diabetes mellitus (T2DM) which has been treated with oral medications or insulin for at least one year prior to screening, have chronic kidney disease with an eGFR 15 - ⁇ 60 mL/min/1 .73m2 at screening, have urine albumin/creatinine ratio (ACR) of ⁇ 30 mg/g at screening, have serum potassium values of > 5.1 mEq/L at randomization to Ca-CLP, receive an ACEI and/or ARB for at least 28 days prior to screening, have an average systolic blood pressure ⁇ 140 - ⁇ 180 mmHg OR average diastolic blood pressure ⁇ 90 - ⁇ 1 10 mmHg (sitting) at both screening and randomization.
  • T2DM Type 2 diabetes mellitus
  • ACR urine albumin/creatinine ratio
  • Exclusion criteria includes: patients that do not have type 1 diabetes mellitus, serum hemoglobin A1 c > 12% at S1 , diabetic gastroparesis, non-diabetic chronic kidney disease, history of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery (e.g., colectomy), any of the following events having occurred within 2 months prior to screening: unstable angina as judged by the Investigator, unresolved acute coronary syndrome, cardiac arrest or clinically significant ventricular arrhythmias, transient ischemic attack or stroke, use of any intravenous cardiac medication; prior kidney transplant, or anticipated need for transplant during study participation, use loop and thiazide diuretics or other antihypertensive medications (calcium channel blocker, beta-blocker, alpha-blocker, or centrally acting agent) that have not been stable for at least 28 days prior to screening or not anticipated to remain stable during study participation; use of polymer-based drugs (e.g., sevelamer, sodium polystyrene s
  • Chronic kidney disease patients selected for inclusion in the clinical trial more specifically hypertensive patients with nephropathy due to type 2 diabetes mellitus (T2DM) are treated with maximal doses of Angiotensin- converting Enzyme Inhibitor (ACEI) and/or Angiotensin II Receptor Blocker (ARB) drugs, with or without spironolactone during a four week run in period.
  • ACEI Angiotensin- converting Enzyme Inhibitor
  • ARB Angiotensin II Receptor Blocker
  • Ca-CLP doses can be adjusted up or down based on follow up serum potassium levels.
  • Outcome measures include the mean change in serum potassium from baseline to treatment week 4 and 8, proportion of patients maintaining the starting Ca-CLP dose at week 4 and 8, proportion of patients requiring Ca-CLP titration, proportion of patients who maintain serum potassium (K+) in the range of 3.5 - 5.5 mEq/L by visit and during the entire study treatment period, proportion of patients who maintain serum K+ in the range of 4.0 - 5.0 mEq/L by visit and during the entire study treatment period, proportion of patients who discontinue from the study due to high serum potassium withdrawal criteria, mean change in blood pressure from screening to week 4 and 8, mean change in urine albumin to creatinine ratio (ACR) from screening to week 4 and 8, proportion of patients with ⁇ 35% reduction in urine ACR from screening to week 4 and 8, proportion of patients with urine ACR ⁇ 500 mg/g at screening who achieve ACR ⁇ 500 mg/g at week 4 and 8, physical signs and symptoms of fluid overload, e.g. edema of the extremities or abdomen, blood and urinary laboratory parameters.
  • K+
  • Treatment with Ca-CLP results in significant and clinically meaningful improvement of signs and symptoms in CKD stage II, III or IV patients including, for example, a improvement in CKD stage (e.g., a improvement in class from IV to III, or III to II, or I) a reduction of body weight, improvement in subjective symptoms (edema) and serum and urinary laboratory parameters without resulting in a change in the subject's acid/base status.
  • a improvement in CKD stage e.g., a improvement in class from IV to III, or III to II, or I
  • a reduction of body weight improvement in subjective symptoms (edema) and serum and urinary laboratory parameters without resulting in a change in the subject's acid/base status.

Abstract

La présente invention concerne généralement des polymères réticulés de liaison à des cations comprenant des monomères comprenant des groupes acide carboxylique, le polymère contenant i) des cations calcium qui sont des contre-ions à environ 50 % à environ 70 % des groupes acide carboxylique dans le polymère ; ou ii) des cations calcium et des cations magnésium qui sont des contre-ions à environ 50 % à environ 70 % des groupes acide carboxylique dans le polymère, les cations magnésium étant des contre-ions à pas plus d'environ 35 % des groupes carboxylate dans le polymère. La présente invention concerne en outre des procédés de préparation des polymères, et des compositions, des formulations, et des formes pharmaceutiques contenant les polymères, et des procédés d'utilisation des polymères, des compositions, des formulations, et/ou des formes pharmaceutiques pour traiter différentes maladies ou différents troubles.
PCT/US2012/047486 2012-01-10 2012-07-19 Compositions comprenant des polymères réticulés de liaison à des cations et utilisations associées WO2013106086A1 (fr)

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CA2863240A CA2863240A1 (fr) 2012-01-10 2012-07-19 Compositions comprenant des polymeres reticules de liaison a des cations et utilisations associees
IL233578A IL233578A0 (en) 2012-01-10 2014-07-09 Preparations containing cross-linked cation-binding polymers and their uses

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PCT/US2012/020849 WO2012097017A1 (fr) 2011-01-10 2012-01-10 Compositions comportant des polymères réticulés de liaison à des cations et des cations calcium et/ou magnésium, et leurs utilisations
USPCT/US2012/020849 2012-01-10
USPCT/US2012/038908 2012-05-21
PCT/US2012/038908 WO2013106072A1 (fr) 2012-01-10 2012-05-21 Compositions comprenant des polymères réticulés de liaison à des cations et utilisations associées

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WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
WO2015051214A1 (fr) 2013-10-03 2015-04-09 Moderna Therapeutics, Inc. Polynucléotides codant pour un récepteur de lipoprotéines de faible densité
WO2016014846A1 (fr) 2014-07-23 2016-01-28 Moderna Therapeutics, Inc. Polynucléotides modifiés destinés à la production d'anticorps intracellulaires
WO2018213731A1 (fr) 2017-05-18 2018-11-22 Modernatx, Inc. Polynucléotides codant pour des polypeptides d'interleukine-12 (il12) ancrés et leurs utilisations
WO2018213789A1 (fr) 2017-05-18 2018-11-22 Modernatx, Inc. Arn messager modifié comprenant des éléments d'arn fonctionnels
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WO2019226650A1 (fr) 2018-05-23 2019-11-28 Modernatx, Inc. Administration d'adn
WO2020023390A1 (fr) 2018-07-25 2020-01-30 Modernatx, Inc. Traitement enzymatique substitutif basé sur l'arnm combiné à un chaperon pharmacologique pour le traitement de troubles du stockage lysosomal
WO2020047201A1 (fr) 2018-09-02 2020-03-05 Modernatx, Inc. Polynucléotides codant pour l'acyl-coa déshydrogénase à très longue chaîne pour le traitement de l'insuffisance en acyl-coa déshydrogénase à très longue chaîne
WO2020056239A1 (fr) 2018-09-14 2020-03-19 Modernatx, Inc. Polynucléotides codant pour le polypeptide a1, de la famille de l'uridine diphosphate glycosyltransférase 1, pour le traitement du syndrome de crigler-najjar
WO2020056155A2 (fr) 2018-09-13 2020-03-19 Modernatx, Inc. Polynucléotides codant pour les sous-unités e1-alpha, e1-beta et e2 du complexe alpha-cétoacide déshydrogénase à chaîne ramifiée pour le traitement de la leucinose
WO2020056147A2 (fr) 2018-09-13 2020-03-19 Modernatx, Inc. Polynucléotides codant la glucose-6-phosphatase pour le traitement de la glycogénose
WO2020069169A1 (fr) 2018-09-27 2020-04-02 Modernatx, Inc. Polynucléotides codant pour l'arginase 1 pour le traitement d'une déficience en arginase
WO2020227642A1 (fr) 2019-05-08 2020-11-12 Modernatx, Inc. Compositions pour peau et plaies et leurs méthodes d'utilisation
WO2021247507A1 (fr) 2020-06-01 2021-12-09 Modernatx, Inc. Variants de la phénylalanine hydroxylase et leurs utilisations
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WO2022204369A1 (fr) 2021-03-24 2022-09-29 Modernatx, Inc. Polynucléotides codant pour la méthylmalonyl-coa mutase pour le traitement de l'acidémie méthylmalonique
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EP4159741A1 (fr) 2014-07-16 2023-04-05 ModernaTX, Inc. Procédé de production d'un polynucléotide chimérique pour coder un polypeptide ayant une liaison internucléotidique contenant un triazole
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WO2015034928A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides chimériques
WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
WO2015051214A1 (fr) 2013-10-03 2015-04-09 Moderna Therapeutics, Inc. Polynucléotides codant pour un récepteur de lipoprotéines de faible densité
EP4159741A1 (fr) 2014-07-16 2023-04-05 ModernaTX, Inc. Procédé de production d'un polynucléotide chimérique pour coder un polypeptide ayant une liaison internucléotidique contenant un triazole
WO2016014846A1 (fr) 2014-07-23 2016-01-28 Moderna Therapeutics, Inc. Polynucléotides modifiés destinés à la production d'anticorps intracellulaires
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