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WO2019236639A1 - Méthode de traitement des troubles de l'équilibre acido-basique - Google Patents

Méthode de traitement des troubles de l'équilibre acido-basique Download PDF

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Publication number
WO2019236639A1
WO2019236639A1 PCT/US2019/035470 US2019035470W WO2019236639A1 WO 2019236639 A1 WO2019236639 A1 WO 2019236639A1 US 2019035470 W US2019035470 W US 2019035470W WO 2019236639 A1 WO2019236639 A1 WO 2019236639A1
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patient
meq
composition according
pharmaceutical composition
serum bicarbonate
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Inventor
Gerrit Klaerner
Dawn Parsell OTTO
Yuri STASIV
Vandana Mathur
Claire LOCKEY
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Tricida Inc
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Tricida Inc
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Priority claimed from PCT/US2018/059094 external-priority patent/WO2019236124A1/fr
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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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients

Definitions

  • the present invention generally relates to methods of treating acid- base disorders that may be used, for example, in the treatment of metabolic acidosis.
  • Metabolic acidosis is the result of metabolic and dietary processes that in various disease states create a condition in which non-volatile acids accumulate in the body, causing a net addition of protons (H + ) or the loss of bicarbonate (HCO3 ).
  • Metabolic acidosis occurs when the body accumulates acid from metabolic and dietary processes and the excess acid is not completely removed from the body by the kidneys.
  • Chronic kidney disease is often accompanied by metabolic acidosis due to the reduced capacity of the kidney to excrete hydrogen ions secondary to an inability to reclaim filtered bicarbonate (HCO3 ), synthesize ammonia
  • VBG analysis is a relatively safer procedure as fewer punctures are required thus reducing the risk of needle stick injury to the health care workers. Therefore, as set out below, when the invention requires assessment of metabolic acidosis, it is preferred to complete this assessment using VBG analysis. Any measurements specified herein are preferably achieved by VBG analysis where possible, for example measurements of blood or serum bicarbonate levels.
  • Arterial blood gases are used to identify the type of an acid-base disorder and to determine if there are mixed disturbances.
  • the result of arterial blood gas measures should be coordinated with history, physical exam and the routine laboratory data listed above.
  • An arterial blood gas measures the arterial carbon dioxide tension (P a C02), acidity (pH), and the oxygen tension (P a 02).
  • the HCO3 concentration is calculated from the pH and the P a C02. Hallmarks of metabolic acidosis are a pH ⁇ 7.35, P a C0 2 ⁇ 35 mm Hg and HC0 3 ⁇ 22 mEq/L.
  • Acid-base disturbance are first classified as respiratory or metabolic. Respiratory disturbances are those caused by abnormal pulmonary elimination of C0 2 , producing an excess (acidosis) or deficit (alkalosis) of C0 2 (carbon dioxide) in the extracellular fluid.
  • Respiratory disturbances are those caused by abnormal pulmonary elimination of C0 2 , producing an excess (acidosis) or deficit (alkalosis) of C0 2 (carbon dioxide) in the extracellular fluid.
  • changes in serum bicarbonate (HCO3 ) are initially a direct consequence of the change in PCO2 with a greater increase in PCO2 resulting in an increase in HCO3 .
  • Metabolic disturbances are those caused by excessive intake of, or metabolic production or losses of, nonvolatile acids or bases in the extracellular fluid. These changes are reflected by changes in the concentration of bicarbonate anion (HC0 3 ) in the blood; adaptation in this case involves both buffering (immediate), respiratory (hours to days) and renal (days) mechanisms.
  • HC0 3 bicarbonate anion
  • DuBose TD DaBose TD, MacDonald GA: renal tubular acidosis, 2002, in DuBose TD, Hamm LL (eds): Acid-base and electrolyte disorders: A companion to Brenners and Rector’s the Kidney, Philadelphia, WB Saunders, pp. 189-206).
  • the overall hydrogen ion concentration in the blood is defined by the ratio of two quantities, the serum HCO3 content (regulated by the kidneys) and the PC0 2 content (regulated by the lungs) and is expressed as follows:
  • Acidosis is the process which causes a reduction in blood pH (acidemia) and reflects the accumulation of hydrogen ion (H + ) and its consequent buffering by bicarbonate ion (HCO 3 ) resulting in a decrease in serum bicarbonate.
  • Metabolic acidosis can be represented as follows:
  • nonvolatile acids ⁇ 50-100 mEq/day
  • nonvolatile acids ⁇ 50-100 mEq/day
  • Additional nonvolatile acids lactic acid, butyric acid, acetic acid, other organic acids
  • lactic acid, butyric acid, acetic acid, other organic acids arise from the incomplete oxidation of fats and carbohydrates, and from carbohydrate metabolism in the colon, where bacteria residing in the colon lumen convert the substrates into small organic acids that are then absorbed into the bloodstream.
  • the impact of short chain fatty acids on acidosis is somewhat minimized by anabolism, for example into long-chain fatty acids, or catabolism to water and C0 2.
  • the kidneys maintain pH balance in the blood through two mechanisms: reclaiming filtered HCO 3 to prevent overall bicarbonate depletion and the elimination of nonvolatile acids in the urine. Both mechanisms are necessary to prevent bicarbonate depletion and acidosis.
  • the kidneys In the first mechanism, the kidneys reclaim HC0 3 that is filtered by the glomerulus. This reclamation occurs in the proximal tubule and accounts for ⁇ 4500 mEq/day of reclaimed HCO3 . This mechanism prevents HCO3 from being lost in the urine, thus preventing metabolic acidosis.
  • the kidneys In the second mechanism, the kidneys eliminate enough H + to equal the daily nonvolatile acid production through metabolism and oxidation of protein, fats and carbohydrates. Elimination of this acid load is accomplished by two distinct routes in the kidney, comprising active secretion of H + ion and ammoniagenesis. The net result of these two interconnected processes is the elimination of the 50-100 mEq/day of nonvolatile acid generated by normal metabolism.
  • Citrate is an appropriate alkali therapy to be given orally or IV, either as the potassium or sodium salt, as it is metabolized by the liver and results in the formation of three moles of bicarbonate for each mole of citrate. Potassium citrate administered IV should be used cautiously in the presence of renal
  • Intravenous sodium bicarbonate (NaHC0 3 ) solution can be administered if the metabolic acidosis is severe or if correction is unlikely to occur without exogenous alkali administration.
  • Oral alkali administration is the preferred route of therapy in persons with chronic metabolic acidosis.
  • the most common alkali forms for oral therapy include NaHC0 3 tablets where 1 g of NaHC0 3 is equal to 11.9 mEq of HC0 3 .
  • the oral form of NaHC0 3 is not approved for medical use and the package insert of the intravenous sodium bicarbonate solution includes the following contraindications, warnings and precautions (Hospira label for NDC 0409- 3486-16):
  • Acid-base disorders are common in chronic kidney disease and heart failure patients.
  • Chronic kidney disease CKD
  • CKD progressively impairs renal excretion of the approximately 1 mmol/kg body weight of hydrogen ions generated in healthy adults (Yaqoob, MM. 2010, Acidosis and progression of chronic kidney disease, Curr. Opin. Nephrol. Hyperten. 19:489-492.).
  • Metabolic acidosis resulting from the accumulation of acid (H + ) or depletion of base (HCO3 ) in the body, is a common complication of patients with CKD, particularly when the glomerular filtration rate (GFR, a measure of renal function) falls below 30 ml/min/1 73m 2 .
  • GFR glomerular filtration rate
  • Metabolic acidosis has profound long term effects on protein and muscle metabolism, bone turnover and the development of renal osteodystrophy.
  • metabolic acidosis influences a variety of paracrine and endocrine functions, again with long term consequences such as increased inflammatory mediators, reduced leptin, insulin resistance, and increased corticosteroid and parathyroid hormone production (Mitch WE, 1997, Influence of metabolic acidosis on nutrition, Am. J. Kidney Dis. 29:46-48.).
  • CKD patients of moderate degree first develop hyperchloremic acidosis with a normal anion gap due to the inability to reclaim filtered bicarbonate and excrete proton and ammonium cations. As they progress toward the advanced stages of CKD the anion gap increases, reflective of the continuing degradation of the kidney’s ability to excrete the anions that were associated with the unexcreted protons. Serum bicarbonate in these patients rarely goes below 15 mmol/L with a maximum elevated anion gap of approximately 20 mmol/L.
  • the non-metabolizable anions that accumulate in CKD are buffered by alkaline salts from bone (Lemann J Jr, Bushinsky DA, Hamm LL Bone buffering of acid and base in humans. Am. J. Physiol Renal Physiol. 2003 Nov, 285(5): F811 -32).
  • diabetes diabetes nephropathy
  • hypertension leading to deterioration of renal function.
  • a high sodium intake will worsen the hypertension.
  • hypertensive guidelines strictly limit sodium intake in these patients to less than 1.5 g or 65 mEq per day (HFSA 2010 guidelines, Lindenfeld 2010, J Cardiac Failure V16 No 6 P475).
  • Chronic anti-hypertensive therapies often induce sodium excretion (diuretics) or modify the kidney’s ability to excrete sodium and water (such as, for example, Renin Angiotensin Aldosterone System inhibiting“RAASi” drugs).
  • bicarbonate is also not acceptable as patients with CKD are unable to readily excrete potassium, leading to severe hyperkalemia.
  • Glomerular filtration rate or estimated glomerular filtration rate is typically used to characterize kidney function and the stage of chronic kidney disease.
  • the five stages of chronic kidney disease and the GFR for each stage is as follows:
  • Stage 1 with normal or high GFR (GFR > 90 mL/min/1.73 m 2 )
  • Stage 5 End Stage CKD (GFR ⁇ 15 mL/min/1.73 m 2 ).
  • the average dose of bicarbonate in this study was 1.82 g/day, which provides 22 mEq of bicarbonate per day.
  • the primary end points were rate of CrCI decline, the proportion of patients with rapid decline of CrCI (>3ml/min per 1.73 m 2 /yr), and end-stage renal disease (“ESRD”) (CrCI ⁇ 10 ml/min).
  • ESRD end-stage renal disease
  • Hyperphosphatemia is a common co-morbidity in patients with CKD, particularly in those with advanced or end-stage renal disease.
  • Sevelamer hydrochloride is a commonly used ion-exchange resin that reduces serum
  • a method of treating an individual afflicted with a chronic acid/base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l comprises oral administration of a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system and increase the individual’s serum
  • bicarbonate value to at least 24 mEq/l but less than 30 mEq/l.
  • a method of treating an individual afflicted with a chronic acid/base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l comprises oral administration of a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system and increase the individual’s serum bicarbonate value to at least 24 mEq/l but not greater than 29 mEq/l.
  • Another aspect of the present disclosure is a method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition having the capacity to remove at least 5 meq of a target species as it transits the digestive system to increase the individual’s serum bicarbonate value to at least 24 mEq/l but not greater than 29 mEq/l from baseline within a treatment period not greater than 1 month.
  • the target species is selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein.
  • the orally administered nonabsorbable composition comprises cations (such as Na + , K + , Mg 2+ , Ca 2+ Li + , or a combination thereof) that are exchanged for protons as the nonabsorbable composition transits the digestive system, and the protons are then excreted from the body along with the nonabsorbable composition upon defecation.
  • the net effect is reduction in protons in the body, in exchange for an increase in one or more cations.
  • the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, diluent or excipient, or a combination thereof that does not significantly interfere with the proton-binding characteristics of the nonabsorbable composition in vivo.
  • the pharmaceutical composition may also comprise an additional therapeutic agent.
  • the orally administered nonabsorbable composition comprises anions that are exchanged for chloride ions and if the anion comprised by the orally administered nonabsorbable composition is a stronger base ⁇ e.g., OH ) than the removed base ( e.g ., Cl , HS0 4 , or S0 4 2 ), the net effect is the removal of a strong acid from the body ⁇ e.g., HCI or H 2 S0 4 ) in exchange for a weak acid ⁇ e.g., H 2 0).
  • the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, diluent or excipient, or a combination thereof that does not significantly interfere with the chloride-binding characteristics of the nonabsorbable composition in vivo.
  • a pharmaceutically acceptable carrier diluent or excipient, or a combination thereof that does not significantly interfere with the chloride-binding characteristics of the nonabsorbable composition in vivo.
  • composition may also comprise an additional therapeutic agent.
  • the orally administered nonabsorbable composition is a neutral composition having the capacity to bind and remove a strong acid, such as HCI or H 2 S0 4 , from the body upon oral administration.
  • the nonabsorbable composition may, but does not necessarily, introduce ⁇ i.e., by ion exchange) counterbalancing cations or anions in the process of removing the acid.
  • binding of both ionic species of HCI may be achieved through favorable surface energy of the bulk material, which can include hydrogen bonding and other interactions as well as ionic interactions.
  • Complexation of HCI can occur on functional groups that are dehydrated and upon administration in an acidic aqueous medium, result in the hydrochloride salt of the functional group.
  • a method of treating an individual afflicted with a chronic acid/base disorder comprising oral administration of a pharmaceutical composition containing a nonabsorbable composition having the capacity to bind protons and chloride ions as it transits the digestive system and remove the bound protons and chloride ions from the individual’s digestive system via defecation.
  • the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, diluent or excipient, or a combination thereof that does not significantly interfere with the chloride-binding characteristics of the nonabsorbable composition in vivo.
  • the pharmaceutical composition may also comprise an additional therapeutic agent.
  • any of the methods of treating an individual afflicted with an acid-base disorder disclosed in this application comprise: i) the individual having a diet regimen, or ii) the method including, specifying, prescribing or recommending a diet regimen.
  • said diet regimen is an alkaline diet regimen.
  • said diet regimen is a conventional low- protein diet regimen ( ⁇ 0.6 g/kg per day).
  • said diet regimen is a very low-protein diet regimen (0.3-0.4 g/kg per day).
  • said diet regimen is a vegetarian diet regimen.
  • said diet regimen is a vegetarian diet regimen supplemented with either essential amino acids or a mixture of essential amino acids and nitrogen-free ketoanalogues (keto diet regimen).
  • said diet regimen is ketoanalogue-supplemented vegetarian very low- protein diet.
  • said diet regimen is a vegan diet regimen.
  • said diet regimen is a casein diet regimen.
  • said diet regimen is an adenine-containing diet regimen.
  • said diet regimen comprises one or more base-producing vegetables (e.g. carrots, cauliflower, eggplant, lettuce, potatoes, spinach, tomatoes, or zucchini, or a combination thereof).
  • said diet regimen comprises one or more base- producing fruits (e.g. apple, apricot, oranges, peaches, pears, raisins, or
  • said diet regimen does not comprise acid-producing meat.
  • the diet commences one year before
  • the diet commences six months before administering the nonabsorbable composition. In another embodiment the diet commences one month before administering the nonabsorbable composition. In another embodiment the diet regimen commences when the administering of the nonabsorbable composition commences. In another embodiment the diet commences one month after administering the nonabsorbable composition. In another embodiment the diet commences six months after
  • the diet commences one year after administering the nonabsorbable composition.
  • a method of improving the quality of life of a patient afflicted with chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value of ⁇ 22 mEq/L comprises oral administration of a pharmaceutical composition capable of increasing and maintaining the patient’s serum bicarbonate above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition having the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • a method of treating an individual afflicted with chronic kidney disease comprising administering a composition described herein.
  • the rate of progression of the individual’s chronic kidney disease is decreased.
  • the rate of progression may decrease for at least about 1 month, at least about 4 months, at least about 6 months, or at least about 12 months.
  • the rate of progression of chronic kidney disease is decreased to such an extent that the
  • a method of decreasing the rate of progression of chronic kidney disease in an individual comprising administering a composition described herein.
  • the individual is afflicted with metabolic acidosis.
  • the metabolic acidosis may be eubicarbonatemic metabolic acidosis.
  • the metabolic acidosis may be characterized by a blood serum or blood plasma bicarbonate value not in excess of about 25 mEq/l, 24 mEq/l, or 23 mEq/l.
  • the metabolic acidosis may be characterized by a blood serum or blood plasma bicarbonate value of less than about 22 mEq/l.
  • the rate of decrease in the progression of chronic kidney disease is measurable by a decreased rate of change in eGFR.
  • the decreased rate of change in eGFR occurs to the extent that eGFR stops decreasing.
  • the decreased rate of change in eGFR occurs to the extent that there is an improvement in eGFR.
  • the delay in the progression of chronic kidney disease includes the individual’s stage of chronic kidney disease remaining constant.
  • the patient may remain at stage 1 , 2, 3A, 3B, 4 or 5 of chronic kidney disease.
  • the patient may remain at the claimed stage of chronic kidney disease for at least about 1 month, at least about 4 months, at least about 6 months, or at least about 12 months.
  • the blood pressure of the patient after treatment is unchanged relative to the blood pressure of the patient before treatment.
  • the blood pressure of the patient during treatment is unchanged relative to the blood pressure of the patient before treatment.
  • the method or composition does not adversely affect blood pressure of treated patient or individual.
  • a method of improving the quality of life of a patient afflicted with chronic kidney disease and an acid-base disorder comprises oral administration of a pharmaceutical composition having: (a) the capacity to selectively bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay, wherein the improvement in quality of life is statistically significant compared to a placebo control group for a period of at least twelve weeks as assessed by a Quality of Life (QoL) questionnaire.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Another embodiment provides a method of improving quality of life of a patient afflicted with chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value of ⁇ 22 mEq/L.
  • This method comprises orally administering to the patient an effective amount of TRC101 once daily for a period of time sufficient to statistically significantly increase the patient’s quality of life compared to a placebo control.
  • a further embodiment provides a method of improving quality of life of a patient afflicted with metabolic acidosis disease. This method comprises administering to the patient a daily dose of a nonabsorbed crosslinked amine polymer, which daily dose: (a) is sufficient to increase the patient’s serum
  • bicarbonate concentration by at least 1 mEq/L results in a sustained serum bicarbonate increase of at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to improve the patient’s quality of life compared to a placebo control group over the period, wherein the improvement in quality of life is statistically significant.
  • Another embodiment provides a pharmaceutical composition for improving the quality of life of a human patient afflicted with chronic kidney disease and an acid-base disorder, the patient having a baseline serum bicarbonate level of ⁇ 22 mEq/L prior to treatment.
  • This composition is a nonabsorbable composition having the capacity to: (a) remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) improve the patient’s quality of life compared to a placebo control in a statistically significant manner over at least a twelve-week period.
  • a further embodiment is a pharmaceutical composition for improving the quality of life of a human patient suffering from a disease or disorder by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over at least twelve weeks of treatment.
  • the composition : (a) is a nonabsorbable composition having the capacity to remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) is characterized by a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (c) has the capacity to improve the patient’s quality of life compared to a placebo control in a statistically significant manner over at least the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Another embodiment is a pharmaceutical composition for improving the quality of life of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient per day over at least a twelve-week period; (b) the pharmaceutical composition is nonabsorbable with the capacity to remove from the patient a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (d) the improvement in quality of life compared to a placebo control is statistically significant over the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • a further embodiment is a method of improving the physical function of a patient afflicted with chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value of ⁇ 22 mEq/L.
  • the method comprises oral administration of a pharmaceutical composition capable of increasing and maintaining the patient’s serum bicarbonate above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition having the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • a further embodiment is a method of improving the physical function of a patient afflicted with chronic kidney disease and an acid-base disorder.
  • This method comprises oral administration of a pharmaceutical composition having: (a) the capacity to selectively bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay, wherein the improvement in physical function is statistically significant compared to a placebo control group at least twelve weeks after initiation of treatment as assessed by the patient’s answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF).
  • SIB Simulated Small Intestine Inorganic Buffer
  • Another embodiment is a method of improving the physical function of a patient afflicted with chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value of ⁇ 22 mEq/L.
  • This method comprises orally administering to the patient an effective amount of TRC101 once daily for a period of time sufficient to statistically significantly increase the patient’s physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to the patient’s baseline physical function score.
  • KDQOL-SF Kidney Disease Quality of Life Short Form
  • a further embodiment is a method of improving the physical function of a patient afflicted with metabolic acidosis disease.
  • This method comprises administering to the patient a daily dose of a nonabsorbed crosslinked amine polymer, which daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) results in a sustained serum bicarbonate increase of at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to improve the physical function score of the patient compared to a placebo control group at the end of the period, wherein the improvement in the physical function score is statistically significant.
  • compositions for improving the physical function score of a human patient afflicted with chronic kidney disease and an acid-base disorder, the patient having a baseline serum bicarbonate level of ⁇ 22 mEq/L prior to treatment are a nonabsorbable composition having the capacity to: (a) remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) improve the patient’s physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to a placebo control in a statistically significant manner at the end of at least a twelve-week period.
  • KDQOL-SF Kidney Disease Quality of Life Short Form
  • a further embodiment is a pharmaceutical composition for improving the physical function score of a human patient suffering from a disease or disorder by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over at least twelve weeks of treatment.
  • the composition : (a) is a nonabsorbable composition having the capacity to remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) is characterized by a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (c) has the capacity to improve the patient’s physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to a placebo control in a statistically significant manner at the end of an at least the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Another embodiment is a pharmaceutical composition for improving the physical function score of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient per day over at least a twelve-week period; (b) the pharmaceutical composition is nonabsorbable with the capacity to remove from the patient a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (d) the improvement in physical function score is a statistically significant improvement over a baseline physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to a placebo control at the end of the at least twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • a further embodiment is a method of slowing the progression of kidney disease in a patient afflicted with chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value of ⁇ 22 mEq/L.
  • the method comprises oral administration of a pharmaceutical composition capable of increasing and maintaining the patient’s serum bicarbonate above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical
  • composition having the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Another embodiment is a method of slowing the progression of kidney disease in a patient afflicted with chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value of ⁇ 22 mEq/L.
  • This method comprises orally administering to the patient an effective amount of TRC101 once daily for a period of time sufficient to increase the patient’s serum bicarbonate by at least 1 mEq/L.
  • Another embodiment is a method of slowing the progression of kidney disease in a patient afflicted with chronic kidney disease and metabolic acidosis disease.
  • This method comprises administering to the patient a daily dose of a nonabsorbed crosslinked amine polymer, which daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) results in a sustained serum bicarbonate increase of at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to slow the progression of kidney disease.
  • a further embodiment is a pharmaceutical composition for slowing the progression of kidney disease in a human patient afflicted with chronic kidney disease and an acid-base disorder, the patient having a baseline serum bicarbonate level of ⁇ 22 mEq/L prior to treatment.
  • the composition is a nonabsorbable composition having the capacity to: (a) remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) slow the progression of kidney disease in a human patient over at least a twelve-week period.
  • a further embodiment is a pharmaceutical composition for slowing the progression of kidney disease in a human patient afflicted with chronic kidney disease and an acid-base disorder by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over at least twelve weeks of treatment.
  • the composition (a) is a nonabsorbable composition having the capacity to remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) is characterized by a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (c) has the capacity to slow the progression of kidney disease over at least the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Another embodiment is a pharmaceutical composition for slowing the progression of kidney disease in a human patient also suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical
  • composition is administered to the patient per day over at least a twelve-week period;
  • pharmaceutical composition is nonabsorbable with the capacity to remove from the patient a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids;
  • the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and
  • SIB Simulated Small Intestine Inorganic Buffer
  • Another embodiment is a pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the quality of life of the patient.
  • Yet another embodiment is a pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the physical function of the patient.
  • the present invention is directed to a nonabsorbable composition for use in a method of treating an acid-base disorder, wherein the patient’s physical function increases and the patient’s baseline serum bicarbonate value does not increase, or does not significantly increase or does not increase in proportion to the improvement in the patient’s physical function.
  • the first mechanism proposed is that an increase in blood bicarbonate arising from treatment may be offset by an increased protein intake and consequent increase in acid production.
  • patients with improved physical function may have increased their protein intake in response to increased muscle mass. This hypothesis is supported by the higher excretion of urea nitrogen in a 24 hour urine collection at the end of the study compared to baseline. Any increase in protein intake may have resulted in increased acid production, which would have
  • the second mechanism proposed is that the improvement in physical function occurs due to treatment neutralizing retained acid that was stimulating muscle catabolism.
  • the reduction in muscle catabolism is thought to occur before blood bicarbonate levels increase.
  • the present disclosure sets out a treatment which does not increase serum blood bicarbonate in proportion to the improvement in the patient’s physical function. Therefore, disclosed are methods of treating an acid-base disorder in a patient in need thereof by administering a nonabsorbable composition, wherein the patient’s physical function increases and the patient’s baseline serum bicarbonate value does not increase, or does not significantly increase or does not increase in proportion to the improvement in the patient’s physical function.
  • the physical function of the patient improves and the patient’s baseline serum bicarbonate value does not increase. In one embodiment, the physical function of the patient improves and the patient’s baseline serum bicarbonate value does not significantly increase. In one embodiment, the improvement in physical function of the patient is not proportional to the increase in the patient’s baseline serum bicarbonate value. In one embodiment, the
  • improvement in physical function of the patient is independent of the increase in the patient’s baseline serum bicarbonate value. In one embodiment, the improvement in physical function of the patient occurs before an increase in the patient’s baseline serum bicarbonate value is observed.
  • the quality of life of the patient improves and the patient’s baseline serum bicarbonate value does not increase.
  • the quality of life of the patient improves and the patient’s baseline serum bicarbonate value does not significantly increase. In one embodiment, the improvement in quality of life of the patient is not proportional to the increase in the patient’s baseline serum bicarbonate value. In one embodiment, the improvement in quality of life of the patient is independent of the increase in the patient’s baseline serum bicarbonate value. In one embodiment, the improvement in quality of life of the patient occurs before an increase in the patient’s baseline serum bicarbonate value is observed.
  • Kidney International 86 371 -381 ; Goraya N, Simoni J, Jo C, Wesson D, 2014, Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate, Kidney International 86:
  • the nonabsorbable composition binds chloride ions
  • the nonabsorbable composition selectively bind chloride ions relative to other physiologically significant competing anions such as bicarbonate equivalent anions, phosphate anions, and the conjugate bases of bile and fatty acids that are present in the Gl tract.
  • the nonabsorbable composition remove more chloride ions than any other competing anion in the Gl tract.
  • the nonabsorbable composition binds protons
  • treatment with the nonabsorbable composition will not significantly contribute to edema, hypertension, hyperkalemia, hypercalcemia or a similar disorder associated with an elevated load of sodium, potassium, calcium or other electrolyte.
  • the nonabsorbable composition binds protons
  • treatment with the nonabsorbable composition will not significantly contribute to hypotension, hypokalemia, hypocalcemia or other disorder associated with a depressed serum concentration of sodium, potassium, calcium, magnesium or other electrolyte.
  • the polymers preferably bind and maintain their ability to bind proton and anions at the physiological conditions found along the gastrointestinal (Gl) lumen. These conditions can change according to dietary intake (see, for example, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966; 11 (7):503-21 ) and location along the Gl tract (Binder, H et al. Chapters 41 -45 in“Medical Physiology”, 2nd Edition, Elsevier [2011 ] Boron and Boulpaep [Ed.]). Rapid binding of proton and chloride in the stomach and small intestine is desirable.
  • Gl gastrointestinal
  • the polymers also preferably have a pK a such that the majority of amines are protonated under the various pH and electrolyte conditions encountered along the Gl tract and are thereby capable of removing proton, along with an appropriate counter anion (preferably chloride), from the body into the feces.
  • the stomach is an abundant source of HCI, and the stomach is the first site of potential HCI binding (after the mouth), and since residence time in the stomach is short (gastric residence half-life of approximately 90 minutes), compared to the rest of the Gl tract (small intestine transit time of approximately 4 hours; whole gut transit time of 2-3 days; Read, NW et al. Gastroenterology [1980] 79:1276), it is desirable for the polymer of the present disclosure to demonstrate rapid kinetics of proton and chloride binding in the lumen of this organ, as well as in in vitro conditions designed to mimic the stomach lumen (e.g. SGF).
  • SGF stomach lumen
  • Phosphate is a potential interfering anion for chloride binding in the stomach and small intestine, where phosphate is mostly absorbed (Cross, HS et al Miner Electrolyte Metab [1990] 16:115-24). Therefore rapid and preferential binding of chloride over phosphate is desirable in the small intestine and in in vitro conditions designed to mimic the small intestine lumen (e.g. SIB). Since the transit time of the colon is slow (2-3 days) relative to the small intestine, and since conditions in the colon will not be
  • kinetics of chloride binding by a polymer of the present disclosure do not have to be as rapid in the colon or in in vitro conditions designed to mimic the late small intestine/colon. It is, however, important that chloride binding and selectivity over other interfering anions is high, for example, at 24 and/or 48 hours or longer.
  • Fig. 1A-1 C is a flow chart schematically depicting the mechanism of action of the polymer when passing through the gastrointestinal tract of an individual from oral ingestion/stomach (Fig. 1 A), to the upper Gl tract (FIG. 1 B) to the lower Gl tract/colon (Fig. 1 C).
  • Fig. 2 is a graph of the effect of TRC101 on serum bicarbonate in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 1 of the study described in Example 1.
  • Figs. 3A, 3B and 3C are graphs of the effect of TRC101 on fecal excretion of chloride (Fig. 3A), sulfate (Fig. 3B), and phosphate (Fig. 3C) in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 1 of the study described in Example 1.
  • Fig. 4 is a graph of the effect of TRC101 on serum bicarbonate in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 2 of the study described in Example 1.
  • Figs. 5A, 5B and 5C are graphs of the effect of TRC101 on fecal excretion of chloride (Fig. 5A), sulfate (Fig. 5B), and phosphate (Fig. 5C) in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 2 of the study described in Example 1.
  • Figs. 6A, 6B and 6C are graphs of the in vivo chloride (Fig. 6A), sulfate (Fig. 6B) and phosphate (Fig. 6C) binding capacities of TRC101 and bixalomer in a pig with normal renal function in the study described in Example 2.
  • Fig. 7 is a line graph showing the mean change in serum
  • Fig. 8 is a bar graph showing the least squares mean (LS Mean) change from baseline (CFB) to end of treatment in serum bicarbonate (SBC) by treatment group in a human study as described more fully in Example 3 (Part 1 ).
  • LS Mean least squares mean
  • SBC serum bicarbonate
  • SE standard error
  • Fig. 10 is a line graph showing the mean change in serum bicarbonate (SBC) and standard error (SE) for the four TRC101 active arms and the two placebo arms (pooled) of the study described more fully in Example 3 (Parts 1 and 2).
  • SBC serum bicarbonate
  • SE standard error
  • Fig. 11 is a bar graph showing the least squares mean (LS Mean) change from baseline (CFB) in serum bicarbonate (SBC) by treatment group over time for the four TRC101 active arms and the two placebo arms (pooled) of the study described more fully in Example 3 (Parts 1 and 2).
  • Single asterisk (“ *“) indicates statistically significant difference (p ⁇ 0.5) and double asterisk (“ **“) indicates highly statistically significant difference (p ⁇ 0.0001 ).
  • SBC serum bicarbonate
  • SE standard error
  • Figs. 13A, 13B, 13C and 13D are graphs showing the changes in serum bicarbonate (Fig. 13A), serum chloride (Fig. 13B), serum sodium (Fig. 13C) and serum potassium (Fig. 13D) for the four TRC101 active arms (combined) vs the two placebo arms (pooled) over time for the study described more fully in Example 3 (Parts 1 and 2).
  • Fig. 14 is a graph showing the changes in the calculated anion gap for the four TRC101 active arms (combined) vs the two placebo arms (pooled) over time for the study described more fully in Example 3 (Parts 1 and 2).
  • Fig. 15 is a dataset analysis diagram and timeline, as described in greater detail in Example 4.
  • Fig. 16 is a population analysis flow chart, as described in greater detail in Example 4.
  • FIG. 17 is an illustration of the subpopulation used in the Cox Regression Analysis, as described in greater detail in Example 4.
  • Fig. 18 is an analysis diagram and timeline for the clinical trial as described in more detail in Example 5.
  • Fig. 19A is a graph showing the composite primary endpoint at the end of the treatment period for the clinical study described in more detail in Example 5.
  • Fig. 19B is a graph showing the achievement of serum bicarbonate thresholds at various time points for the clinical study described in more detail in Example 5.
  • Fig. 19C is a graph showing the change from baseline in serum bicarbonate over time at various time points for the clinical study described in more detail in Example 5.
  • Figs. 20A-20B are graphs showing that TRC101 -treated subjects experienced a statistically significant improvement in quality of life, particularly, in physical function, based on results from Question #3 of the KDQOL-SF survey for the clinical study described in more detail in Example 5.
  • Fig. 21 is a copy of Question #3 of the KDQOL-SF survey for the clinical study described in Example 5.
  • Total score sum of all 10, divided by 10.
  • Fig. 22A is a copy of the Single Chair Stand and Repeated Chair Stand protocols, including the scoring criteria (Fig. 22B), as described in more detail in Example 5.
  • Fig. 23 is table showing the analysis from baseline in total score in kidney disease and quality of life (Question 3) at week 12, as described in more detail in Example 5.
  • Fig. 24 is a table showing the analysis from baseline in time
  • Fig. 25 is a diagram showing the overall design of the Retrospective Model, as described in more detail in Example 4.
  • Fig. 26 is a graph showing the time to first occurrence of DD40 endpoint, as described in more detail in Example 4.
  • Fig. 27 is a table showing the differences in outcome of TRC101 treated patients against placebo treated patients in the combined TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • Fig. 28 is a graph showing SBC durability effect for TRC101 -treated patients against placebo treated patients at the end of the TRCA-301 and TRCA- 301 E 52 week study, as described in more detail in Example 6.
  • Fig. 29 is a graph showing the mean change from baseline in serum bicarbonate level for TRC101 treated patients and placebo treated patients at various time points across the combined TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • Fig. 30 is a graph showing the mean change from baseline in KDQOL-Physical Functioning Domain for TRC101 treated patients and placebo treated patients across the TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • the number N at each data point was: Verimer (N) 114, 109 and 113; and Placebo (N) 82, 76 and 78.
  • Fig. 31 is a graph showing the mean change from baseline in time to perform the repeated chair stand test for TRC101 treated patients and placebo treated patients at various time points in the TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • the number N at each data point was: Verimer (N) 114, 106 and 112; and Placebo (N) 81 , 76 and 77.
  • Fig. 31 is a graph showing the mean change from baseline in time to perform the repeated chair stand test for TRC101 treated patients and placebo treated patients at various time points in the TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • the number N at each data point was: Verimer (N) 114, 106 and 112; and Placebo (N) 81 ,
  • Fig. 33 is a table showing the adverse events occurring at >5% of the study populations and the proportions of TRC 101 -treated patients and placebo- treated patients in the TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • Fig. 34 is a table summarizing the number of withdrawals in both TRC101 -treated patients and placebo-treated patients across the TRCA-301 and the TRCA-301 E studies, as described in more detail in Example 6.
  • Fig. 35 is a table showing the incidences of death, dialysis, >50% eGFR decline and DD50 across the TRCA-301 and the TRCA-301 E study for TRC101 -treated patients and placebo-treated patients, without annualising the incidence rate.
  • Fig. 36 is a table showing the annualised incidence rate of death, death/dialysis and DD50 across the TRCA-301 and the TRCA-301 E study for TRC101 -treated patients and placebo-treated patients.
  • Fig. 37 is a plot showing the change in the individual items of the kidney disease and quality of life - physical functioning domain. Patients treated with TRC101 reported greatest improvement in tasks requiring lower body strength.
  • Changes in the limitations related to vigorous activities such as participating in strenuous sports, moderate activities such as moving a table, climbing several flights of stairs, and bathing and dressing did not differ in the two treatment groups.
  • 38A-38B is a table showing that of the 217 patients randomised (124 to veverimer and 93 to placebo) in the TRCA-301 study, 196 (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into the TRCA-301 E study.
  • the groups were well balanced with respect to
  • Fig. 39 is a table showing the adverse events experienced by patients.
  • Fig. 40 is a table showing that the study drug dose was
  • bicarbonate level of 22-29 mmol/L based on the bicarbonate measurement at each visit.
  • Fig. 41 is a table showing the restricted concomitant medications throughout the TRCA-301 and TRCA-301 E studies.
  • Fig. 42 is a table showing the baseline characteristics of patients randomized in the TRCA-301 study who did not enroll in the TRCA-301 E study.
  • Fig. 43 is a table showing the outcome events in the combined TRCA-301 and TRCA-301 E 52 week treatment period.
  • Fig. 44 is a diagram of patient flow through the combined TRCA- 301 and TRCA-301 E studies.
  • Fig. 45 is a Kaplan-Meier plot of time to first occurance of death, renal replacement therapy or >50% decline in eGFR across the TRCA-301 and TRCA-301 E studies.
  • Fig. 46 is a box plot for serum potassium by treatment group across the TRCA-301 and TRCA-301 E studies.
  • Fig. 47 is a box plot for serum chloride by treatment group across the TRCA-301 and TRCA-301 E studies.
  • Fig. 48 is a box plot for serum sodium by treatment group across the TRCA-301 and TRCA-301 E studies.
  • Fig. 49 is a schematic showing the design of the TRCA-301 and TRCA-301 studies.
  • Fig. 50 is a further graph showing SBC durability effect for TRC 101 - treated patients against placebo treated patients at the end of the TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • Fig. 51 is a further graph showing the mean change from baseline in serum bicarbonate level for TRC101 treated patients and placebo treated patients at various time points across the combined TRCA-301 and TRCA-301 E 52 week study, as described in more detail in Example 6.
  • Fig. 52A-52B is a further table showing change from baseline in laboratory parameters and blood pressure after 52 weeks of treatment.
  • Figure 53 is a further copy of Question #3 of the KDQOL-SF survey for the clinical study described in Example 5.
  • the term "absorption capacity" as used herein in connection with a polymer and a swelling agent is the amount of the swelling agent (or such mixture) absorbed during a period of at least 16 hours at room temperature by a given amount of a dry polymer (e.g., in the form of a dry bead) immersed in an excess amount of the swelling agent (or such mixture).
  • the term“adult” refers to an individual over 18 years of age.
  • the term“alicyclic”,“alicyclo” or“alicyclyl” means a saturated monocyclic group of 3 to 8 carbon atoms and includes cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • unsaturated hydrocarbyl moieties having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms, one to about ten carbon atoms, one to about eight carbon atoms, or even one to about four carbon atoms.
  • the aliphatic groups include, for example, alkyl moieties such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso- amyl, hexyl and the like, and alkenyl moieties of comparable chain length.
  • alkanol denotes an alkyl moiety that has been substituted with at least one hydroxyl group.
  • alkanol groups are“lower alkanol” groups comprising one to six carbon atoms, one of which is attached to an oxygen atom.
  • lower alkanol groups comprise one to three carbon atoms.
  • alkenyl group encompasses linear or branched carbon radicals having at least one carbon-carbon double bond.
  • alkenyl group can encompass conjugated and non-conjugated carbon-carbon double bonds or combinations thereof.
  • An alkenyl group for example and without being limited thereto, can encompass two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms.
  • alkenyl groups are "lower alkenyl” groups having two to about four carbon atoms. Examples of alkenyl groups include, but are not limited thereto, ethenyl, propenyl, allyl, vinyl, butenyl and 4-methylbutenyl.
  • alkenyl group and “lower alkenyl group encompass groups having "cis” or "trans” orientations, or alternatively, "E” or "Z” orientations.
  • alkyl group as used, either alone or within other terms such as “haloalkyl group,”“aminoalkyl group” and “alkylamino group”, encompasses saturated linear or branched carbon radicals having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms. In other embodiments, alkyl groups are "lower alkyl” groups having one to about six carbon atoms.
  • lower alkyl groups have one to four carbon atoms.
  • alkylamino group refers to amino groups directly attached to the remainder of the molecule via the nitrogen atom of the amino group and wherein the nitrogen atom of the alkylamino group is substituted by one or two alkyl groups.
  • alkylamino groups are "lower alkylamino" groups having one or two alkyl groups of one to six carbon atoms, attached to a nitrogen atom.
  • lower alkylamino groups have one to three carbon atoms.
  • Suitable "alkylamino" groups may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino,
  • amine or "amino” as used alone or as part of another group, represents a group of formula -N(X 8 )(X 9 ), wherein X 8 and X 9 are
  • aminoalkyl group encompasses linear or branched alkyl groups having one to about ten carbon atoms, any one of which may be substituted with one or more amino groups, directly attached to the remainder of the molecule via an atom other than a nitrogen atom of the amine group(s).
  • the aminoalkyl groups are "lower aminoalkyl” groups having one to six carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • the terms“anion exchange material” and“cation exchange material” take their normal meaning in the art.
  • the terms“anion exchange material” and“cation exchange material” refer to materials that exchange anions and cations, respectively.
  • Anion and cation exchange materials are typically water-insoluble substances which can exchange some of their cations or anions, respectively, for similarly charged anions or cations contained in a medium with which they are in contact.
  • Anion exchange materials may contain positively charged groups, which are fixed to the backbone materials and allow passage of anions but reject cations.
  • a non-exhaustive list of such positively charged groups includes: amino group, alkyl substituted phosphine, and alkyl substituted sulphides.
  • a non- exhaustive list of cation or anion exchange materials includes: clays (e.g., bentonite, kaolinite, and illite), vermiculite, zeolites (e.g., analcite, chabazite, sodalite, and clinoptilolite), synthetic zeolites, polybasic acid salts, hydrous oxides, metal ferrocyanides, and heteropolyacids.
  • Cation exchange materials can contain negatively charged groups fixed to the backbone material, which allow the passage of cations but reject anions.
  • a non-exhaustive list of such negatively charged groups includes: sulphate, carboxylate, phosphate, and benzoate.
  • aromatic group or "aryl group” means an aromatic group having one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
  • an aromatic group is one, two or three rings.
  • Monocyclic aromatic groups may contain 5 to 10 carbon atoms, typically 5 to 7 carbon atoms, and more typically 5 to 6 carbon atoms in the ring.
  • Typical polycyclic aromatic groups have two or three rings.
  • Polycyclic aromatic groups having two rings typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms in the rings.
  • aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • bicarbonate equivalent is used to describe an organic acid or anion that yields bicarbonate when metabolized. Citrate and succinate are exemplary bicarbonate equivalents.
  • a cation e.g.“proton-binding” polymer
  • anion e.g.“proton-binding” polymer
  • the term“ceramic material” takes its normal meaning in the art.
  • the term“ceramic material” refers to an inorganic, nonmetallic, solid material comprising metal, nonmetal or metalloid atoms primarily held in ionic and covalent bonds.
  • a non-exhaustive list of examples of ceramic materials includes: barium titanate, bismuth strontium calcium copper oxide, boron oxide, earthenware, ferrite, lanthanum carbonate, lead zirconate, titanate, magnesium diboride, porcelain, sialon, silicon carbide, silicon nitride, titanium carbide, yttrium barium copper oxide, zinc oxide, zirconium dioxide, and partially stabilised zirconia.
  • the term“clinically significant increase” as used herein in connection with a treatment refers to a treatment that improves or provides a worthwhile change in an individual from a dysfunctional state back to a relatively normal functioning state, or moves the measurement of that state in the direction of normal functioning, or at least a marked improvement to untreated.
  • a number of methods can be used to calculate clinical significance.
  • a non-exhaustive list of methods for calculating clinical significance includes: Jacobson-Truax, Gulliksen- Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and Hierarchical Linear
  • crosslink density denotes the average number of connections of the amine containing repeat unit to the rest of the polymer.
  • the number of connections can be 2, 3, 4 and higher. Repeat units in linear, non- crosslinked polymers are incorporated via 2 connections. To form an insoluble gel, the number of connections should be greater than 2.
  • Low crosslinking density materials such as Sevelamer have on average about 2.1 connections between repeat units. More crosslinked systems such as bixalomer have on average about 4.6 connections between the amine-containing repeat units.“Crosslinking density” represents a semi-quantitative measure based on the ratios of the starting materials used. Limitations include the fact that it does not account for different crosslinking and polymerization methods.
  • small molecule amine systems require higher amounts of crosslinker as the crosslinker also serves as the monomer to form the polymer backbone whereas for radical polymerizations the polymer chain is formed independent from the crosslinking reaction. This can lead to inherently higher crosslinking densities under this definition for the substitution polymerization/small molecule amines as compared to radical polymerization crosslinked materials.
  • crosslinker encompasses hydrocarbyl or substituted hydrocarbyl, linear or branched molecules capable of reacting with any of the described monomers, or the infinite polymer network, as described in Formula 1 , more than one time.
  • the reactive group in the crosslinker can include, but is not limited to alkyl halide, epoxide, phosgene, anhydride, carbamate, carbonate, isocyanate, thioisocyanate, esters, activated esters, carboxylic acids and derivatives, sulfonates and derivatives, acyl halides, aziridines, a,b-unsaturated carbonyls, ketones, aldehydes, pentafluoroaryl groups, vinyl, allyl, acrylate, methacrylate, acrylamide, methacrylamide, styrenic,
  • the crosslinker’s reactive group will include alkyl halide, epoxide, anhydrides,
  • crosslinker isocyanates, allyl, vinyl, acrylamide, and combinations thereof.
  • the crosslinker’s reactive group will be alkyl halide, epoxide, or allyl.
  • diallylamine denotes an amino moiety having two allyl groups.
  • the terms“dry bead” and“dry polymer” refer to beads or polymers that contain no more than 5% by weight of a non-polymer swelling agent or solvent. Often the swelling agent/solvent is water remaining at the end of a purification. This is generally removed by lyophilization or oven drying before storage or further crosslinking of a preformed amine polymer. The amount of swelling agent/solvent can be measured by heating (e.g., heating to 100-200°C) and measuring the resulting change in weight. This is referred to a“loss on drying” or“LOD.”
  • eGFR estimate of the glomerular filtration rate and is estimated from the serum level of an endogenous filtration marker. Creatinine is a commonly used endogenous filtration marker in clinical practice and several equations have been proposed for estimating the glomerular filtration rate. As used herein, all eGFR values may be determined according to the CKD-EPI equation (Levey et al. , A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 2009; 150:604-612):
  • GFR 41 * min(Scr/K, 1 ) a * max(Scr/K, 1 ) 1 209 * 0.993 Age * 1 .018 [if female] * 1 .159 [if black] wherein Scr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is - 0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1 , and max indicates the maximum of Scr/k or 1.
  • the term“ethereal” denotes a moiety having an oxygen bound to two separate carbon atoms as depicted the structural formula *-H x C-0-CH x -*, where * denotes the point of attachment to the remainder of the moiety and x independently equals 0, 1 , 2, or 3.
  • gel is used to describe a crosslinked polymer that has an irregular shape.
  • GFR glomerular filtration rate
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl group encompasses groups wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • monohaloalkyl, dihaloalkyl and polyhaloalkyl groups including perhaloalkyl may have either an iodo, bromo, chloro or fluoro atom within the group.
  • Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups.
  • “Lower haloalkyl group” encompasses groups having 1 -6 carbon atoms. In some embodiments, lower haloalkyl groups have one to three carbon atoms.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • heteroaliphatic describes a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms that can be saturated or unsaturated (but not aromatic), containing one or more
  • heteroatoms such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron.
  • a heteroatom atom may be a part of a pendant (or side) group attached to a chain of atoms (e.g., -CH(OH)- -CH(NH 2 )- where the carbon atom is a member of a chain of atoms) or it may be one of the chain atoms (e.g., -ROR- or -RNHR- where each R is aliphatic).
  • Heteroaliphatic encompasses heteroalkyl and heterocyclo but does not encompass heteroaryl.
  • heteroalkyl describes a fully saturated heteroaliphatic moiety.
  • heteroaryl means a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon.
  • heteroaryl means an atom other than carbon and hydrogen. Typically, but not exclusively, heteroatoms are selected from the group consisting of halogen, sulfur, phosphorous, nitrogen, boron and oxygen atoms.
  • Groups containing more than one heteroatom may contain different heteroatoms.
  • heterocyclo means a saturated or unsaturated group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom such as N, O, B, P and S(0) n , where n is an integer from 0 to 2, the remaining ring atoms being carbon. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -C(O)- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino,
  • heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.
  • hydrocarbon group or “hydrocarbyl group” means a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms.
  • Hydrocarbon groups may have a linear or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Typically, hydrocarbon groups are saturated. Unsaturated hydrocarbon groups may have one or more double bonds, one or more triple bonds, or combinations thereof. Typical unsaturated hydrocarbon groups have one or two double bonds or one triple bond; more typically unsaturated hydrocarbon groups have one double bond .
  • “Initiator” is a term used to describe a reagent that initiates a polymerization.
  • the term“measured glomerular filtration rate” or“mGFR” refers to a measurement of the glomerular filtration rate using any chemical (e.g., inulin, iothalamate, iohexol, etc.) that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted by the kidneys according to standard technique.
  • any chemical e.g., inulin, iothalamate, iohexol, etc.
  • the term“Michael acceptor” takes its normal meaning in the art.
  • the term“Michael acceptor” refers to activated olefins, such as a,b-unsatu rated carbonyl compounds.
  • a Michael acceptor can be a conjugated system with an electron withdrawing group, such as cyano, keto or ester.
  • An electron withdrawing group such as cyano, keto or ester.
  • Michael acceptors includes: vinyl ketones, alkyl acrylates, acrylo nitrile, and fumarates.
  • MW/N molecular weight per nitrogen
  • MW/N the average molecular weight to present one amine function within the crosslinked polymer. It is calculated by dividing the mass of a polymer sample by the moles of nitrogen present in the sample. “MW/N” is the inverse of theoretical capacity, and the calculations are based upon the feed ratio, assuming full reaction of crosslinker and monomer. The lower the molecular weight per nitrogen the higher the theoretical capacity of the crosslinked polymer.
  • nonabsorbable takes its normal meaning in the art. Therefore, if something is nonabsorbable it is not absorbed during its passage through the human Gl tract. This could be measured by any appropriate means.
  • One option known to the skilled person would be to examine faeces to see if the nonabsorbable material is recovered after passing through the Gl tract. As a practical matter, the amount of a nonabsorbable material recovered in this scenario will never be 100% of the material administered. For example, about 90 - 99% of the material might be recovered from the faeces.
  • Nonabsorbable compositions may be particulate compositions that are essentially insoluble in the human Gl tract and have a particle size that is large enough to avoid passive or active absorption through the human Gl tract.
  • nonabsorbable compositions is meant to imply that the substance does not enter the lymph, blood, interstitial fluids or organs through the main entry points of the human Gl tract, namely by paracellular entry between gut epithelial cells, by endocytic uptake through gut epithelial cells, or through entry via M cells comprising the gut epithelial antigen sampling and immune surveillance system (Jung, 2000), either through active or passive transport processes.
  • gut epithelial antigen sampling and immune surveillance system Jung, 2000
  • There is a known size limit for a particulate to be absorbed in the human Gl tract Jung et al.
  • “Optional” or“optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “heterocyclyl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes embodiments in which the heterocyclyl group is substituted with an alkyl group and embodiments in which the heterocyclyl group is not substituted with alkyl.
  • Particle size is measured by wet laser diffraction using Mie theory. Particles are dispersed in an appropriate solvent, such as water or methanol, and added to the sample chamber to achieve red channel obscuration of 10-20%.
  • Sonication may be performed, and a dispersing agent, such as a surfactant (e.g. Tween-80), may be added in order to disrupt weak particle-particle interactions.
  • a dispersing agent such as a surfactant (e.g. Tween-80)
  • Tween-80 a surfactant
  • the refractive index setting of the particles used for size distribution calculation is selected to minimize artifacts in the results and the R parameter value, determined by the laser diffraction software.
  • the D(0.1 ), D(0.5), and D(0.9) values characterizing the particle size distribution by volume-basis are recorded.
  • “Pharmaceutically acceptable” as used in connection with a carrier, diluent or excipient means a carrier, diluent or an excipient, respectively, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable for veterinary use and/or human pharmaceutical use.
  • the term“physical function” as used herein in connection with a patient afflicted with chronic kidney disease and an acid-base disorder may be assessed using (i) the Kidney Disease and Quality of Life (KDQOL) Short Form-36, Question 3 (Physical Functioning Domain) as illustrated in Fig. 22A & 22B and Example 5, or (iii) both the KDQOL Short Form-36 Question 3 and the standardized repeated chair stand test (i.e. ,“i” and“ii” of this paragraph).
  • KDQOL Kidney Disease and Quality of Life
  • post polymerization crosslinking is a term that describes a reaction to an already formed bead or gel, where more crosslinking is introduced to the already formed bead or gel to create a bead or gel that has an increased amount of crosslinking.
  • post polymerization modification is a term that describes a modification to an already formed bead or gel, where a reaction or a treatment introduces an additional functionality. This functionality can be linked either covalently or non-covalently to the already formed bead.
  • the term“quaternized amine assay” (“QAA”) describes a method to estimate the amount of quaternary amines present in a given crosslinked polymer sample. This assay measures chloride binding of a crosslinked polymer at a pH of 11.5. At this pH, primary, secondary and tertiary amines are not substantially protonated and do not substantially contribute to chloride binding. Therefore, any binding observed under these conditions can be attributed to the presence of permanently charged quaternary amines.
  • the test solution used for QAA assay is 100 mM sodium chloride at a pH of 11.5. The concentration of chloride ions is similar to that in the SGF assay which is used to assess total binding capacity of crosslinked polymers. Quaternary amine content as a percentage of total amines present is calculated as follows: constructive Chloride bound (mmol/g) in QAA
  • the free-amine polymer being tested is prepared at a concentration of 2.5 mg/ml (e.g. 25 mg dry mas) in 10 mL of QAA buffer.
  • the mixture is incubated at 37 °C for ⁇ 16 hours with agitation on a rotisserie mixer. After incubation and mixing, 600 microliters of supernatant is removed and filtered using a 800 microliter, 0.45 micrometer pore size, 96-well poly propylene filter plate. With the samples arrayed in the filter plate and the collection plate fitted on the bottom, the unit is centrifuged at 1000Xg for 1 minute to filter the samples. After filtration into the collection plate, the respective filtrates are diluted appropriately before measuring for chloride content.
  • the IC method e.g. ICS-2100 Ion Chromatography, Thermo Fisher Scientific
  • Thermo Fisher Scientific used for the analysis of chloride content in the filtrates consists of a 15 mM KOH mobile phase, an injection volume of 5 microliters, with a run time of three minutes, a washing/rinse volume of 1000 microliters, and flow rate of 1.25 mL /min.
  • Cl start corresponds to the starting concentration of chloride in the QAA buffer
  • Cl eq corresponds to the equilibrium value of chloride in the measured filtrates after exposure to the test polymer
  • 2.5 is the polymer concentration in mg/ml.
  • the terms“short chain carboxylic acid” or“short chain fatty acid” take their normal meaning in the art.
  • the terms“short chain carboxylic acid” or“short chain fatty acid” refer to carboxylic acids having a chain length of 0, 1 , 2, 3, 4, 5 or 6 carbon atoms long.
  • a non-exhaustive list of examples of short chain carboxylic acids includes: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and lactic acid.
  • “Simulated Gastric Fluid” or“SGF” Assay describes a test to determine total chloride binding capacity for a test polymer using a defined buffer that simulates the contents of gastric fluid as follows: Simulated gastric fluid (SGF) consists of 35 mM NaCI, 63 mM HCI, pH 1.2. To perform the assay, the free-amine polymer being tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL of SGF buffer. The mixture is incubated at 37 °C overnight for ⁇ 12-16 hours with agitation on a rotisserie mixer. Unless another time period is otherwise stated, SGF binding data or binding capacities recited herein are determined in a time period of this duration. After incubation and mixing, the tubes containing the polymer are centrifuged for 2 minutes at 500-1 OOOXg to pellet the test samples.
  • SGF Simulated gastric fluid
  • Approximately 750 microliters of supernatant are removed and filtered using an appropriate filter, for example a 0.45 micrometer pore-size syringe filter or an 800 microliter, 1 micrometer pore-size, 96-well, glass filter plate that has been fitted over a 96-well 2 mL collection plate.
  • an appropriate filter for example a 0.45 micrometer pore-size syringe filter or an 800 microliter, 1 micrometer pore-size, 96-well, glass filter plate that has been fitted over a 96-well 2 mL collection plate.
  • a syringe filter may be used in lieu of the filter plate, to retrieve ⁇ 2-4 mL of filtrate into a 15 mL container.
  • the respective filtrates are diluted 4X with water and the chloride content of the filtrate is measured via ion chromatography (IC).
  • IC ion chromatography
  • the IC method e.g. Dionex ICS-2100, Thermo Scientific
  • IC ion chromatography
  • Binding capacity expressed as mmol chloride/g polymer where Cl start corresponds to the starting concentration of chloride in the SGF buffer, Cl eq corresponds to the equilibrium value of chloride in the diluted measured filtrates after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml.
  • “Simulated Small Intestine Inorganic Buffer” or“SIB” is a test to determine the chloride and phosphate binding capacity of free amine test polymers in a selective specific interfering buffer assay (SIB).
  • the buffer used for the SIB assay comprises 36 mM NaCI, 20 mM NaH 2 P0 4 , 50 mM 2- (N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5.
  • MES N-morpholino
  • the SIB buffer contains concentrations of chloride, phosphate and pH that are present in the human duodenum and upper gastrointestinal tract (Stevens T, Conwell DL, Zuccaro G, Van Lente F, Khandwala F, Purich E, et al. Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects. Gastrointestinal endoscopy. 2004;60(3):351 -5, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966; 11 (7):503-21 ) and is an effective measure of the selectivity of chloride binding compared to phosphate binding by a polymer.
  • the free amine polymer being tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL of SIB buffer. The mixture is incubated at 37 °C for 1 hour with agitation on a rotisserie mixer. Unless another time period is otherwise stated, SIB binding data or binding capacities recited herein are
  • the tubes containing the polymer are centrifuged for 2 minutes at 1000Xg to pellet the test samples. 750 microliter of supernatant is removed and filtered using an 800 microliter, 1 micrometer pore-size, 96-well, glass filter plate that has been fitted over a 96-well 2 mL collection plate; with this arrangement multiple samples tested in SIB buffer can be prepared for analysis, including the standard controls of free amine Sevelamer, free amine bixalomer and a control tube containing blank buffer that is processed through all of the assay steps. With the samples arrayed in the filter plate and the collection plate fitted on the bottom, the unit is centrifuged at 1000Xg for 1 minute to filter the samples.
  • a syringe filter (0.45 micrometer) may be used in lieu of the filter plate, to retrieve ⁇ 2-4 mL of filtrate into a 15 mL vial.
  • the respective filtrates are diluted before measuring for chloride or phosphate content.
  • the filtrates under analysis are diluted 4X with water.
  • the chloride and phosphate content of the filtrate is measured via ion chromatography (IC).
  • IC ion chromatography
  • Dionex ICS-2100 Thermo Scientific
  • ICS-2100 Thermo Scientific
  • P stait corresponds to the starting concentration of phosphate in the SIB buffer
  • P final corresponds to the final value of phosphate in the measured diluted filtrates after exposure to the test polymer
  • 4 is the dilution factor
  • 2.5 is the polymer concentration in mg/ml.
  • the term“statistically significant” refers to the likelihood that a relationship between two or more variables is caused by something other than random chance. More precisely, the significance
  • a defined for a study is the probability of the study rejecting the null
  • the p-value, p, of a result is the probability of obtaining a result at least as extreme, given that the null hypothesis were true.
  • the result is statistically significant, by the standards of the study, when p ⁇ a.
  • the significance level for a study is chosen before data collection, and typically set to 5%.
  • substituted hydrocarbyl denotes hydrocarbyl, alkyl, alkenyl, aryl, heterocyclo, or heteroaryl moieties which are substituted with at least one atom other than carbon and hydrogen, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom.
  • substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • “Swelling Ratio” or simply“Swelling” describes the amount of water absorbed by a given amount of polymer divided by the weight of the polymer aliquot.
  • the method used to determine the Swelling Ratio for any given polymer comprised the following:
  • the tube After incubation, the tube is centrifuged at 3000xg for 3 minutes and the supernatant is carefully removed by vacuum suction. For polymers that form a very loose sediment, another step of centrifugation is performed.
  • step (b) the weight of swollen polymer plus tube (Weight B) is recorded.
  • a "target ion” is an ion to which the polymer binds, and usually refers to the major ions bound by the polymer, or the ions whose binding to the polymer is thought to produce the therapeutic effect of the polymer (e.g., proton and chloride binding which leads to net removal of HCI).
  • the term“theoretical capacity” represents the calculated, expected binding of hydrochloric acid in an“SGF” assay, expressed in mmol/g.
  • the theoretical capacity is based on the assumption that 100 % of the amines from the monomer(s) and crosslinker(s) are incorporated in the crosslinked polymer based on their respective feed ratios. Theoretical capacity is thus equal to the concentration of amine functionalities in the polymer (mmol/g).
  • the theoretical capacity assumes that each amine is available to bind the respective anions and cations and is not adjusted for the type of amine formed (e.g. it does not subtract capacity of quaternary amines that are not available to bind proton).
  • “Therapeutically effective amount” means the amount of a proton- binding crosslinked polymer that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The amount
  • a“therapeutically effective amount” will vary depending on the polymer, the severity of the disease and the age, weight, etc., of the mammal to be treated.
  • “Treating” or“treatment” of a disease includes (i) inhibiting the disease, /.e., arresting or reducing the development of the disease or its clinical symptoms; or (ii) relieving the disease, /.e., causing regression of the disease or its clinical symptoms. Inhibiting the disease, for example, would include prophylaxis.
  • the term“triallylamine” denotes an amino moiety having three allyl groups.
  • weight percent crosslinker represents the calculated percentage, by mass, of a polymer sample that is derived from the crosslinker.
  • Weight percent crosslinker is calculated using the feed ratio of the polymerization, and assumes full conversion of the monomer and crosslinker(s).
  • the mass attributed to the crosslinker is equal to the expected increase of molecular weight in the infinite polymer network after reaction (e.g., 1 ,3-dichloropropane is 113 amu, but only 42 amu are added to a polymer network after crosslinking with DCP because the chlorine atoms, as leaving groups, are not incorporated into the polymer network).
  • acid-base disorders may be treated using pharmaceutical compositions comprising a nonabsorbable composition having the capacity to remove clinically significant quantities of protons, the conjugate base of one or more strong acids, and/or one or more strong acids.
  • An individual afflicted with a an acute or chronic acid/base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l may thus be treated by oral administration of a pharmaceutical composition comprising the nonabsorbable composition which then transits the individual’s digestive system, binds a target species (protons, one or more conjugate base(s) of a strong acid and/or one or more strong acid(s)) as it transits the digestive system, and removes the bound target species by normal biological function (defecation).
  • the individual afflicted with an acute or chronic acid/base disorder may be at any stage of chronic kidney disease.
  • the afflicted individual has not yet reached end stage renal disease (“ESRD”) sometimes also referred to as end stage chronic kidney disease and is not yet on dialysis (i.e., the individual has a mGFR (or eGFR) of at least 15
  • ESRD end stage renal disease
  • eGFR mGFR
  • the afflicted individual will be Stage 3B CKD (i.e., the individual has a mGFR (or eGFR) in the range of 30-44
  • the afflicted individual will be Stage 3A CKD (i.e., the individual has a mGFR (or eGFR) in the range of 45-59 mL/min/1.73 m 2 for at least three months).
  • the afflicted individual has a mGFR or an eGFR of less than 60 mL/min/1.73 m 2 for at least three months.
  • the afflicted individual has a mGFR or an eGFR of less than 45 mL/min/1.73 m 2 for at least three months.
  • the afflicted individual has a mGFR or an eGFR of less than 30 mL/min/1.73 m 2 for at least three months.
  • the afflicted individual has a mGFR or an eGFR of 15-30, 15-45, 15- 60, 30-45 or even 30-60 mL/min/1.73 m 2 for at least three months.
  • the baseline serum bicarbonate value may be the serum
  • the baseline serum bicarbonate concentration determined at a single time point may be the mean or median value of two or more serum bicarbonate concentrations determined at two or more time-points.
  • the baseline serum bicarbonate value may be the value of the serum bicarbonate concentration determined at a single time point and the baseline serum bicarbonate value is used as a basis to determine an acute acidic condition requiring immediate treatment.
  • the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn at different time points (e.g., different days).
  • the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn on different days (e.g., at least 2, 3, 4, 5 or more days, that may be consecutive or separated by one or more days or even weeks).
  • the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn on two consecutive days preceding the initiation of treatment.
  • the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 21 , 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 , 10 or 9 mEq/l.
  • the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of at least 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 mEq/l.
  • the acid-base disorder being treated is characterized by a baseline serum bicarbonate value in the range of 9 to 21 mEq/l.
  • oral administration of a pharmaceutical composition containing a nonabsorbable composition increases the individual’s serum bicarbonate value from baseline to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1 , 1.5, 2, 2.5, 3, 3.5 or 4 mEq/l.
  • the treatment increases the individual’s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 5, 6, 7, 8 or 9 mEq/l but does not exceed 29, 28, 27 or 26 mEq/l.
  • the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year.
  • the treatment increases the individual’s serum bicarbonate value from a baseline serum bicarbonate value in the range of 12 to 21 mEq/l to an increased value in the range of 24 mEq/l to 29 mEq/l.
  • the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year.
  • the treatment achieves a clinically significant increase is achieved within a treatment period of less than one month.
  • the treatment achieves a clinically significant increase is achieved without any change in the individual’s diet or dietary habits relative to the period immediately preceding the initiation of treatment.
  • the clinically significant increase is achieved independent of the individual’s diet or dietary habits.
  • the individual’s serum bicarbonate value returns to the baseline value ⁇ 2.5 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value returns to the baseline value ⁇ 2 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value returns to the baseline value ⁇ 1.5 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value returns to the baseline value ⁇ 1 mEq/l within 1 month of the cessation of treatment.
  • the individual upon the cessation of treatment the individual’s serum bicarbonate value decreases by at least 1 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value decreases by at least 1.5 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value decreases by at least 2 mEq/l within 1 month of the cessation of treatment.
  • the individual upon the cessation of treatment the individual’s serum bicarbonate value decreases by at least 2.5 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value decreases by at least 3 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value decreases by at least 3.5 mEq/l within 1 month of the cessation of treatment.
  • the individual upon the cessation of treatment the individual’s serum bicarbonate value decreases by at least 4 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value decreases by at least 4.5 mEq/l within 1 month of the cessation of treatment.
  • the individual’s serum bicarbonate value decreases by at least 5 mEq/l within 1 month of the cessation of treatment.
  • the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point.
  • the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations determined at different time-points.
  • the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on different days.
  • the baseline serum bicarbonate value is the mean or median value of at least two serum bicarbonate concentrations for serum samples drawn on non-consecutive days.
  • the non-consecutive days are separated by at least two days.
  • the non-consecutive days are separated by at least one week.
  • the non- consecutive days are separated by at least two weeks.
  • the non-consecutive days are separated by at least three weeks.
  • the daily dose is no more than 100 g/day of the nonabsorbable composition.
  • the daily dose is no more than 90 g/day of the nonabsorbable composition.
  • the daily dose is no more than 75 g/day of the nonabsorbable composition.
  • the daily dose is no more than 65 g/day of the nonabsorbable composition.
  • the daily dose is no more than 50 g/day of the nonabsorbable composition.
  • the daily dose is no more than 40 g/day of the nonabsorbable
  • the daily dose is no more than 30 g/day of the nonabsorbable composition.
  • the daily dose is no more than 25 g/day of the nonabsorbable composition.
  • the daily dose is no more than 20 g/day of the nonabsorbable composition.
  • the daily dose is no more than 15 g/day of the nonabsorbable composition.
  • the daily dose is no more than 10 g/day of the nonabsorbable
  • the daily dose is no more than 5 g/day of the nonabsorbable composition.
  • the individual is treated with the daily dose for a period of at least one day.
  • the individual is treated with the daily dose for a period of at least one week.
  • the individual is treated with the daily dose for a period of at least one month.
  • the individual is treated with the daily dose for a period of at least two months.
  • the individual is treated with the daily dose for a period of at least three months.
  • the individual is treated with the daily dose for a period of at least several months.
  • the individual is treated with the daily dose for a period of at least six months.
  • the individual is treated with the daily dose for a period of at least one year.
  • the daily dose of the nonabsorbable composition has the capacity to remove at least about 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 mEq/day of the target species.
  • the daily dose of the nonabsorbable composition removes at least about 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49 or 50 mEq/day of the target species.
  • the daily dose of the nonabsorbable composition has insufficient capacity to remove more than 60, 55, 50, 45, 40, 35, 34, 33, 32, 31 , 30, 29, 28, 27, 26, 25, 24, 23, 22,
  • the methods described above refer to daily dose
  • a further aspect of the disclosure include the methods disclosed herein in which the dose is administered less frequently than once per day (while still being administered on a regular basis).
  • the daily dose specified may, instead, be administrated on a less frequent basis.
  • the doses disclosed here may be administered once every two or three days.
  • the doses disclosed here may be administered once, twice or three times a week.
  • biomarkers of acid-base imbalance may be used as a measure of acid-base status.
  • blood serum or plasma
  • pH total C0 2
  • anion gap e.g., the concentration of other electrolytes (e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate) may be used as an indicator of acid-base imbalance.
  • electrolytes e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate
  • net acid excretion (“NAE”)
  • urine pH urine ammonium concentration
  • other electrolytes in the urine e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate
  • concentration of other electrolytes in the urine e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate
  • treatment of an individual as described herein may improve an individuals’ serum anion gap.
  • treating an acid base imbalance with a neutral composition having the capacity to bind both protons and anions can increase serum bicarbonate without an accompanying increase in sodium or potassium (see Example 3 and Figs 13A, 13C and 13D). Consequently, the serum anion gap may be improved (decreased) by at least 1 mEq/l or more (e.g., at least 2 mEq/l) within a period as short as 2 weeks (see Example 3).
  • the various aspects and embodiments may have a range of advantages, such as improved or successful treatment of metabolic acidosis. Such improvements may also include reduced side effects, increased patient compliance, reduced drug loads, increased speed of treatment, increased magnitude of treatment, avoiding unwanted changes to other electrolytes and/or reduced drug- drug interactions. A further improvement may include reducing a patient’s anion gap (as defined above) as part of the methods and other aspects disclosed herein.
  • compositions for use in treatment are provided.
  • one aspect disclosed here is a composition for use in a method of treating metabolic acidosis in an adult human patient wherein in said treatment 0.1 - 12 g of said composition is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic (“SIB”) assay.
  • SIB Simulated Small Intestine Inorganic
  • compositions with this specified level of chloride binding in the“SIB” assay can be used in the specified dose range to successfully treat metabolic acidosis in adult humans.
  • the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein.
  • This aspect is based on the data in the examples showing the absorption and removal of HCI to successfully treat patients using a composition according to this aspect, allowing the amount of the composition to be set based on its capacity to bind chloride in the SIB assay. Surprisingly, the amounts required for successful treatment were relatively low.
  • compositions for use in a method of treating metabolic acidosis in an adult human patient by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment said composition being a nonabsorbable composition having the capacity to remove protons from the patient.
  • the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein.
  • This aspect is based on the data in the examples showing the absorption and removal of HCI to successfully treat patients using a composition according to this aspect which provides new detail regarding the reductions possible using a composition of the disclosure.
  • This aspect includes surprisingly rapid increases in the patient’s serum bicarbonate level, for example in the first few days, as well as surprisingly large increases in serum bicarbonate level.
  • compositions for use in a method of treating metabolic acidosis in an adult human patient said patient having a serum bicarbonate level of less than 20 mEq/L prior to treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient.
  • the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein.
  • This aspect is based on the data in the examples showing, for the first time, the successful treatment of patients with a low serum bicarbonate level, for example levels that have not been shown to be so readily treated previously.
  • the patients with lower serum bicarbonate levels responded particularly well to the treatment and this improvement for this subgroup is one advantage of this aspect.
  • SIB Simulated Small Intestine Inorganic Buffer
  • the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein.
  • SIB Simulated Small Intestine Inorganic Buffer
  • the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein.
  • composition refers to the active pharmaceutical ingredient, including any counter ions, but not to excipients. So, the“amount” of the composition is the amount of active pharmaceutical ingredient without including other parts of any unit dose form.
  • the amount of composition may be any amount disclosed herein in other sections within the range 0.1 g - 12 g.
  • 1 - 11 g, 2 - 10 g, 3 - 9 g, 3 - 8 g, 3 - 7 g, 3 - 6 g, 3.5 - 5.5 g, 4 - 5 g, or 4.5 - 5 g of said polymer is administered to the patient per day, or 0.5 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4.0 g, 4.5 g or 5.0 g of the composition is administered to the patient per day.
  • the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay may be greater than 3, 3.5, 4, or 4.5 mEq/g.
  • SIB Simulated Small Intestine Inorganic Buffer
  • One upper limit for the chloride ion binding capacity in a SIB assay is 10 mEq/g.
  • the upper limits may be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 mEq/g, or there may be no upper limit specified.
  • All combinations of the amount of composition and the chloride ion binding capacity mentioned here are also disclosed. For example, in one
  • the composition has a chloride ion binding capacity in a SIB assay is of at least 4.5 mEq/g and only 0.1 - 6gs of composition is administered in the method of treating metabolic acidosis.
  • composition in these aspects can additionally have any of the properties or features specified elsewhere herein.
  • the composition may be a nonabsorbable composition as described in the following section.
  • the methods of treatment specified in these aspects may include any of the features disclosed in the preceding section regarding certain methods of treatment.
  • the nonabsorbable composition has a preferred particle size range that is (i) large enough to avoid passive or active absorption through the Gl tract and (ii) small enough to not cause grittiness or unpleasant mouth feel when ingested as a powder, sachet and/or chewable tablet/dosage form with a mean particle size of at least 3 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 5 to 1 ,000 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 5 to 500 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 10 to 400 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 10 to 300 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 20 to 250 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 30 to 250 microns.
  • the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 40 to 180 microns.
  • less than 7% of the particles in the population (volume distribution) have a diameter less than 10 microns.
  • less than 5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns.
  • less than 2.5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns.
  • the particle size may be measured using the protocol set out in the abbreviations and definitions section (above).
  • a low Swelling Ratio of the nonabsorbable composition is preferred (0.5 to 10 times its own weight in water).
  • the nonabsorbable composition has a
  • the nonabsorbable composition has a Swelling Ratio of less than 9.
  • the nonabsorbable composition has a Swelling Ratio of less than 8.
  • the nonabsorbable composition has a Swelling Ratio of less than 7.
  • the nonabsorbable composition has a Swelling Ratio of less than 6.
  • the nonabsorbable composition has a Swelling Ratio of less than 5.
  • the nonabsorbable composition has a Swelling Ratio of less than 4.
  • the nonabsorbable composition has a Swelling Ratio of less than 3.
  • the nonabsorbable composition has a Swelling Ratio of less than 2.
  • the amount of the target species (proton, conjugate base of a strong acid and/or strong acid) that is bound as the nonabsorbable composition transits the Gl tract is largely a function of the binding capacity of the composition for the target species (protons, the conjugate base of a strong acid, and/or a strong acid) and the quantity of the nonabsorbable composition administered per day as a daily dose.
  • the theoretical binding capacity for a target species may be determined using a SGF assay and determining the amount of a species that appeared in or disappeared from the SGF buffer during the SGF assay.
  • the theoretical proton binding capacity of a cation exchange resin may be determined by measuring the increase in the amount of cations (other than protons) in the buffer during a SGF assay.
  • the theoretical anion binding capacity of an anion exchange resin in a form other than the chloride form
  • the theoretical anion binding capacity of a neutral composition for protons and the conjugate base of a strong acid may be determined by measuring the decrease in chloride concentration in the buffer during a SGF assay.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 0.5 mEq/g (as determined in an SGF assay).
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 1 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 2 mEq/g.
  • the target species of at least about 0.5 mEq/g (as determined in an SGF assay).
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 1 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 2 mEq/g.
  • nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 3 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 4 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 5 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 7.5 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 10 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 12.5 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 15 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 20 mEq/g.
  • the nonabsorbable composition will typically have a theoretical binding capacity for the target species that is not in excess of about 35 mEq/g.
  • the theoretical binding capacity of the nonabsorbable compositions for the target species may range from 2 to 25 mEq/g, 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to 25 mEq/g, 5 to 20 mEq/g, 6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10 to 20 mEq/g.
  • the binding capacities recited in this paragraph are the theoretical binding capacities for protons and the theoretical binding capacities for the conjugate base(s), independently and individually, and not the sum thereof.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 0.5 mEq/g (as determined in an SGF assay).
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 1 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 2 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 3 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 4 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 5 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 7.5 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 10 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 12.5 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 15 mEq/g.
  • the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 20 mEq/g.
  • the nonabsorbable composition will typically have a theoretical binding capacity for protons that is not in excess of about 35 mEq/g.
  • the theoretical binding capacity of the nonabsorbable compositions for protons that is not be excess of 30 mEq/g.
  • the theoretical binding capacity of the nonabsorbable compositions for protons may range from 2 to 25 mEq/g, 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to 25 mEq/g, 5 to 20 mEq/g, 6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10 to 20 mEq/g.
  • the binding capacities recited in this paragraph are the theoretical binding capacities for protons and the theoretical binding capacities for the conjugate base(s), independently and individually, and not the sum thereof.
  • Phosphate, bicarbonate, bicarbonate equivalents, the conjugate bases of bile and fatty acids are potential interfering anions for chloride or other conjugate bases of strong acids (e.g., HS0 4 and S0 4 2 ) in the stomach and small intestine. Therefore, rapid and preferential binding of chloride over phosphate, bicarbonate equivalents, and the conjugate bases of bile and fatty acids in the small intestine is desirable and the SIB assay may be used to determine kinetics and preferential binding.
  • the nonabsorbable composition is
  • SIB Simulated Small Intestine Inorganic Buffer
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 4.5 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 5 mEq/g in a SIB assay.
  • nonabsorbable composition is characterized by a chloride ion binding capacity of at least 5.5 mEq/g in a SIB assay.
  • the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in a SIB assay.
  • the nonabsorbable composition binds a significant amount of chloride relative to phosphate as exhibited, for example, in a SIB assay.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.1 :1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.2:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.25: 1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.3:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.35:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.4: 1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.45:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.5:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2:3, respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.75:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.9:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1 :1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.25: 1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.5:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.75: 1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2: 1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.25:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.5:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.75:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 3:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 4:1 , respectively.
  • the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 5:1 , respectively.
  • the orally administered nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in Simulated Gastric Fluid of at least 1 mEq/g in a SGF assay.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 2 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 2 mEq/g.
  • nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 3 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 4 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 4 mEq/g.
  • nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 5 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 6 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 6 mEq/g.
  • nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 7 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 8 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 8 mEq/g.
  • nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 9 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 10 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 11 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 12 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 13 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 14 mEq/g.
  • the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 50% of the proton- binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF.
  • the nonabsorbable composition is characterized by a proton- binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 60% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF.
  • the nonabsorbable composition is characterized by a proton- binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 70% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF.
  • the nonabsorbable composition is characterized by a proton- binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 80% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF.
  • the nonabsorbable composition is characterized by a proton- binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 90% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF.
  • the pharmaceutical composition comprises a crosslinked polymer containing the residue of an amine corresponding to Formula 1 :
  • R-i, R 2 and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R-i, R 2 and R 3 is other than hydrogen.
  • the molecular weight per nitrogen of the polymers of the present disclosure may range from about 40 to about 1000 Daltons. In one embodiment, the molecular weight per nitrogen of the polymer is from about 40 to about 500 Daltons. In another embodiment, the molecular weight per nitrogen of the polymer is from about 50 to about 170 Daltons. In another embodiment, the molecular weight per nitrogen of the polymer is from about 60 to about 110 Daltons.
  • an amine-containing monomer is
  • the amine reactant (monomer) in the concurrent polymerization and crosslinking reaction can react more than one time for the substitution polymerization.
  • the amine monomer is a linear amine possessing at least two reactive amine moieties to participate in the substitution polymerization reaction.
  • the amine monomer is a branched amine possessing at least two reactive amine moieties to participate in the substitution polymerization reaction.
  • Crosslinkers for the concurrent substitution polymerization and crosslinking typically have at least two amine-reactive moieties such as alkyl-chlorides, and alkyl-epoxides.
  • primary amines react at least once and potentially may react up to three times with the crosslinker
  • secondary amines can react up to twice with the crosslinkers
  • tertiary amines can only react once with the crosslinker.
  • formation of a significant number of quaternary nitrogens/amines is generally not preferred because quaternary amines cannot bind protons.
  • crosslinking agents that may be used in substitution polymerization reactions and post-polymerization crosslinking reactions include, but are not limited to, one or more multifunctional crosslinking agents such as:
  • dihaloalkanes haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl) amines, diepoxides, triepoxides, tetraepoxides, bis
  • halomethylbenzenes tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-
  • triphenylolmethane triglycidyl ether 3,7,14-tris[[3-(epoxypropoxy
  • the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 2:1 to about 6:1 , respectively.
  • the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 2.5:1 to about 5:1 , respectively.
  • the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 3: 1 to about 4.5:1 , respectively.
  • the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 3.25:1 to about 4.25: 1 , respectively.
  • the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 3.4:1 to about 4:1 , respectively.
  • the molecular weight per nitrogen of the polymer is from about 60 to about 110 Daltons.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b and the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b:
  • n and n are independently non-negative integers
  • each R 1 2 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl;
  • R22 and R 32 are independently hydrogen substituted hydrocarbyl, or hydrocarbyl
  • R 42 is hydrogen, hydrocarbyl or substituted hydrocarbyl
  • X 2 is alkyl, aminoalkyl, or alkanol
  • each X-13 is independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl;
  • z is a non-negative number
  • the amine corresponding to Formula 2b comprises at least one allyl group.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b
  • the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b
  • m and z are independently 0, 1 , 2 or 3
  • n is 0 or 1.
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b
  • the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 1
  • R 12 or R 42 independently comprise at least one allyl or vinyl moiety
  • m is a positive integer and R 2 2 comprises at least one allyl or vinyl moiety
  • n is a positive integer and R 32 comprises at least one allyl moiety.
  • m and z are independently 0, 1 , 2 or 3 and n is 0 or 1.
  • R12 or R 42 in combination comprise at least two allyl or vinyl moieties.
  • m is a positive integer and R12, R22 and R 42 , in combination comprise at least two allyl or vinyl moieties.
  • n is a positive integer and R12, R32 and R 42 , in combination comprise at least two allyl or vinyl moieties.
  • m is a positive integer
  • n is a positive integer
  • the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b
  • the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b
  • each R 12 is independently hydrogen, aminoalkyl, allyl, or vinyl
  • R22 and R 32 are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, alkanol, heteroaryl, alicyclic heterocyclic, or aryl
  • R 42 is hydrogen or substituted hydrocarbyl.
  • each R 12 is aminoalkyl, allyl or vinyl
  • R22 and R 32 are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, or alkanol
  • R 42 is hydrogen or substituted hydrocarbyl.
  • each R 12 and R 42 is independently hydrogen, alkyl, allyl,
  • Exemplary amines and crosslinkers (or the salts thereof, for example the hydrochloric acid, phosphoric acid, sulfuric acid, or hydrobromic acid salts thereof) for the synthesis of polymers described by Formula 2b include but are not limited to the ones in Table C. Table C
  • the post-polymerization crosslinked amine polymer is a crosslinked amine polymer comprising a structure corresponding to Formula 4:
  • nitrogen atoms of the crosslinked amine polymer ( N ⁇ ⁇ ) and a, b, c, and m are integers.
  • m is a large integer indicating an extended polymer network.
  • a ratio of the sum of a and b to c (/. e. , a+b:c) is in the range of about 1 : 1 to 5: 1 .
  • a ratio of the sum of a and b to c is in the range of about 1 .5:1 to 4:1 .
  • a ratio of the sum of a and b to c is in the range of about 1 .75: 1 to 3: 1 .
  • a ratio of the sum of a and b is 57, c is 24 and m is large integer indicating an extended polymer network.
  • a ratio of the sum of a and b to c may be in the range of about 2:1 to 2.5: 1 .
  • the ratio of the sum of a and b to c may be in the range of about 2.1 : 1 to 2.2: 1 .
  • the ratio of the sum of a and b to c may be in the range of about 2.2: 1 to 2.3: 1 .
  • the ratio of the sum of a and b to c may be in the range of about 2.3: 1 to 2.4: 1 .
  • the ratio of the sum of a and b to c may be in the range of about 2.4:1 to 2.5:1.
  • each R may independently be hydrogen or an ethylene crosslink between two nitrogen atoms.
  • 35-95% of the R substituents will be hydrogen and 5-65% will be an ethylene crosslink ( N ⁇ ) .
  • 50-95% of the R substituents will be hydrogen and 5-50% will be an ethylene crosslink (
  • 55-90% of the R substituents are
  • 65-90% of the R substituents are hydrogen and 10-35% are an ethylene crosslink.
  • R substituents are hydrogen and 10-30% are an ethylene crosslink.
  • a, b, c and R are such that the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 2:1 to about 6:1 , respectively.
  • the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 2.5: 1 to about 5: 1 , respectively.
  • the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3:1 to about 4.5:1 , respectively.
  • the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.25: 1 to about 4.25: 1 , respectively.
  • the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.4: 1 to about 4: 1 , respectively.
  • the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.5: 1 to about 3.9:1 , respectively.
  • the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.55:1 to about 3.85:1 , respectively.
  • the polymer of Formula 4 is derived from monomers and crosslinkers, each of which comprise less than 5 wt% oxygen.
  • polymers in which crosslinking and/or entanglement were increased were found to have lower swelling than those with lower crosslinking and/or entanglement, yet also had a binding capacity for target ion (e.g., chloride) that was as great as or greater than the lower crosslinking and/or entanglement polymers while binding of interfering ions such as phosphate were significantly reduced.
  • target ion e.g., chloride
  • the selectivity effect may be introduced in two different manners: 1 ) Overall capacity was sacrificed for chloride specificity.
  • Crosslinkers that don’t include chloride binding sites (e.g., epichlorohydrin) allow for increased crosslinking while overall capacity is decreased proportional to the amount of crosslinker incorporated into the polymer. 2) Overall capacity is preserved for chloride specificity:
  • Crosslinkers that include chloride binding sites e.g., epichlorohydrin
  • diallylamines allow for increased crosslinking while overall capacity is staying the same or is reduced by only a small amount.
  • crosslinked polymers having a high capacity for chloride binding and high selectivity for chloride over other competing anions such as phosphate may be prepared in a two-step process in accordance with one embodiment of the present disclosure.
  • the selectivity of the polymer is a function of its crosslinking density and the capacity of the polymer is a function of the free amine density of the crosslinked polymer.
  • the two-step process disclosed herein provides both, high capacity for chloride binding, and high selectivity for chloride over other competing ions by relying primarily upon carbon- carbon crosslinking in the first step, and nitrogen-nitrogen crosslinking in the second step.
  • the crosslinking is preferably capacity-sparing, i.e., free amine sparing, crosslinking from carbon to carbon.
  • the crosslinking is amine-consuming and is directed towards tuning for selectivity.
  • the C-N ratio is preferably optimized to maximize amine functionalities for HCI binding, while still maintaining a spherical polymer particle of controlled particle size to ensure nonabsorption and acceptable mouth feel that is stable under Gl conditions.
  • the preferred extent of carbon-carbon crosslinking achieved after the first step is sufficient to permit the resulting bead to swell between 4X and 6X in water (i.e. , a Swelling Ratio of 4 to 6).
  • crosslinked polymers having a high capacity for chloride binding and high selectivity for chloride over other competing anions such as phosphate may be prepared in a two-step process, and the product of the first polymerization step is preferably in the form of beads whose diameter is controlled in the 5 to 1000 micrometer range, preferably 10 to 500 micrometers and most preferred 40 - 180 micrometers.
  • the product of the first polymerization step is preferably in the form of beads whose Swelling Ratio in water is between 2 and 10, more preferably about 3 to about 8, and most preferably about 4 to about 6.
  • the preformed amine polymer is at least partially deprotonated by treatment with a base, preferably a strong base such as a hydroxide base.
  • a base preferably a strong base such as a hydroxide base.
  • the base may be NaOH, KOH, NH 4 OH, NaHC0 3 , Na 2 C0 3 , K 2 C0 3 ,
  • LiOH, U 2 C0 3 , CsOH or other metal hydroxides If the charges are removed from the preformed crosslinked amine polymer bead by deprotonation, the bead will tend to collapse and the crosslinking agent used in the second step may not be able to access binding sites on the polymer unless the bead is prevented from collapsing.
  • One means of preventing the crosslinked polymer bead from collapsing is the use of a swelling agent such as water to swell the bead, thereby allowing the second-step crosslinker to access binding sites.
  • the preformed polymer may be crosslinked to form the post- polymerization crosslinked polymer using any of a range of crosslinking compounds containing at least two amine-reactive functional groups.
  • the crosslinker is a compound containing at least two amine-reactive groups selected from the group consisting of halides, epoxides, phosgene, anhydrides, carbamates, carbonates, isocyanates, thioisocyanates, esters, activated esters, carboxylic acids and derivatives thereof, sulfonates and derivatives thereof, acyl halides, aziridines, a,b-unsaturated carbonyls, ketones, aldehydes, and pentafluoroaryl groups.
  • the crosslinker may be, for example, any of the crosslinkers disclosed herein, including a crosslinker selected from Table B.
  • the crosslinker is a dihalide such as a dichloroal
  • a swelling agent for the preformed amine polymer may be included in the reaction mixture for the second polymerization step along with the crosslinking agent.
  • the swelling agent and the crosslinking agent may be miscible or immiscible and the swelling agent may be any composition or combination of compositions that have the capacity to swell the preformed amine polymer.
  • Exemplary swelling agents include polar solvents such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane, propylene carbonate, or a combination thereof.
  • the amount of swelling agent included in the reaction mixture will typically be less than absorption capacity of the preformed amine polymer for the swelling agent.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture be less than 4:1.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 3:1.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 2:1.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 1 :1.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 0.5:1.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 0.4:1.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 0.3:1.
  • the weight ratio of swelling agent to preformed polymer in the reaction mixture will typically be at least 0.05:1 , respectively.
  • crosslinked polymers may be crosslinked
  • the polymers comprise repeat units containing an amine moiety and an intervening linker unit. In other embodiments, multiple amine-containing repeat units are separated by one or more linker units.
  • the polyfunctional crosslinkers may comprise HCI binding functional groups, e.g., amines, (“active crosslinkers”) or may lack HCI binding functional groups such as amines (“passive crosslinkers”).
  • the first polymerization (crosslinking) step yields preformed amine polymer beads having a target size and chloride binding capacity.
  • the beads have a chloride binding capacity of at least 10 mmol/g in Simulated Gastric Fluid (“SGF”) and a Swelling Ratio in the range of 1 to 6.
  • SGF Simulated Gastric Fluid
  • the resulting preformed amine polymer is then preferably (at least partially) deprotonated with a base and combined with a non- protonating swelling agent to swell the free amine polymer without protonating the amine functions.
  • the amount of the non-protonating swelling agent is selected to tune the subsequent degree of crosslinking effectively forming a template that is then locked into place via the amine consuming crosslinking step.
  • the second crosslinking step the swollen, deprotonated preformed amine polymer is crosslinked with a crosslinker containing amine reactive moieties to form a post- polymerization crosslinked polymer.
  • selectivity for chloride over other competing ions is achieved with highly crosslinked polymers.
  • relatively high chloride binding capacity maybe be attained by reacting a preformed amine polymer bead with neat crosslinker in the presence of a swelling agent (water). While this“non- dispersed” reaction provides access to high selectivity for chloride over competing ions in the SIB assay, it also results in macroscopically (and microscopically) aggregated polymer beads.
  • a solvent e.g., heptane
  • DCE 1 ,2-dichloroethane
  • the reaction mixture may contain a wide range of amounts of crosslinking agents.
  • the crosslinker may be used in large excess relative to the amount of preformed amine polymer in the reaction mixtures.
  • the crosslinking agent is a crosslinking solvent, i.e., it is both a solvent for the reaction mixture and a crosslinking agent for the preformed amine polymer.
  • the preformed amine polymer, swelling agent and crosslinker may be dispersed in a solvent that is miscible with the crosslinker and immiscible with the swelling agent.
  • the swelling agent may be a polar solvent; in some such
  • the swelling agent may comprise water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, N,N- dimethylformamide, dimethylsulfoxide, nitromethane, or a combination thereof.
  • the solvent system for the reaction mixture will typically comprise a non-polar solvent such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1 ,4- dioxane, chloroform, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or a combination thereof.
  • the crosslinker and the solvent may be the same; i.e. , the solvent is a crosslinking solvent such as 1 ,2-dichloroethane, 1 ,3-dichloropropane, 1 ,4-dichlorobutane or a combination thereof.
  • crosslinking solvent e.g., a DCE-dispersed reaction
  • there is a large excess of crosslinker regardless of the amount of crosslinking solvent (e.g., DCE) used to disperse the bead (e.g., both 1 g:3 ml_::bead:DCE and 1 g: 10 mL:: bead: DCE are a large excess of crosslinker, most of which is not consumed during the reaction).
  • the relative degree of crosslinking, and the performance in SIB assay are unaffected by changes in the ratio of reactive crosslinker to polymer bead. This is possible because the reaction is limited by the acid-neutralizing capacity of the polymer bead, rather than the amount of crosslinker (e.g., DCE).
  • the amines of the preformed polymer bead preferably have a free electron pair (neutral, deprotonated).
  • the crosslinker e.g., DCE
  • HCI is produced and the amines become protonated, thus limiting the reaction.
  • the preformed amine polymer beads preferably start as the free amine in the second crosslinking step. If the preformed amine polymer bead is protonated after the first step of carbon-carbon crosslinking, amine- consuming crosslinking in the second step will be limited, thus reducing the desired selectivity for chloride over other competing ions.
  • the first reaction step comprises radical polymerization.
  • the amine monomer will typically be a mono-functional vinyl, allyl, or acrylamide (e.g., allylamine) and crosslinkers will have two or more vinyl, allyl or acrylamide functionalities (e.g., diallylamine).
  • Concurrent polymerization and crosslinking occurs through radically initiated polymerization of a mixture of the mono- and multifunctional allylamines.
  • the resulting polymer network is thusly crosslinked through the carbon backbone.
  • Each crosslinking reaction forms a carbon-carbon bond (as opposed to substitution reactions in which a carbon-heteroatom bond is formed during crosslinking).
  • the amine functionalities of the monomers do not undergo crosslinking reactions and are preserved in the final polymer (/. e. , primary amines remain primary, secondary amines remain secondary, and tertiary amines remain tertiary).
  • initiators may be used including cationic and radical initiators.
  • suitable initiators include: the free radical peroxy and azo type compounds, such as azodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2'azo bis(isobutyronitrile), 2,2'- azobis(N,N'-dimethy1 -eneisobutyramidine)dihydrochloride, 2,2'-azobis(2- amidinopropane)dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine ),
  • compositions, nonabsorbable composition, pharmaceutical composition or proton-binding, crosslinked amine polymer of the present invention can comprise or consist essentially of, or be a polymer as defined anywhere herein.
  • the composition, nonabsorbable composition, pharmaceutical composition or crosslinked amine polymer can comprise, consists essentially of, or be the drug substance TRC101 , which has the USAN veverimer. veverimer
  • TRC101 is a non-absorbed free-flowing powder composed of low-swelling, spherical beads, approximately 100 micrometers in diameter; each bead is a single crosslinked, high molecular weight molecule.
  • TRC101 veverimer polymer
  • Veverimer (TRC101 ) has the following structural formula:
  • Veverimer (TRC101 ) has the following molecular formula: , wherein x, y and z are positive integers.
  • Veverimer (TRC101 ) is obtainable by first copolymerizing allylamine hydrochloride and N,N’-diallyl-1 ,3-diaminopropane dihydrochloride, or the salts thereof to form a preformed amine polymer, followed by crosslinking the preformed amine polymer with 1 ,2-dichloroethane.
  • the synthesis of veverimer (TRC101 ) is described in Exemplary Synthesis A and in WO2016/094685 A1.
  • Veverimer (TRC101 ) is the polymer with unique ID 019070-A3 FA in Table S-1 of Exemplary Synthesis A. In the present application, veverimer and TRC101 are used
  • a nonabsorbable free-amine polymer of the present disclosure is orally ingested and used to treat metabolic acidosis (including by increasing serum bicarbonate and normalizing blood pH) in a mammal by binding HCI in the
  • Free-amine polymer is taken orally (Fig. 1A) at compliance enhancing dose targeted to chronically bind sufficient amounts of HCI to enable clinically meaningful increase in serum bicarbonate of 3 mEq/L.
  • Fig. 1 B free amine becomes protonated by binding H + .
  • Positive charge on polymer is then available to bind Cl ; by controlling access of binding sites through crosslinking and hydrophilicity/ hydrophobicity properties, other larger organic anions (e.g., acetate, propionate, butyrate, etc., depicted as X and Y ) are bound to a lesser degree, if at all. The net effect is therefore binding of HCI.
  • the polymer is designed to simultaneously maximize efficacy (net HCI binding and excretion) and minimize Gl side effects (through low swelling particle design and particle size distribution).
  • Optimized HCI binding may be accomplished through a careful balance of capacity (number of amine binding sites), selectivity (preferred binding of chloride versus other anions, in particular organic anions in the colon) and retention (not releasing significant amounts of chloride in the lower Gl tract to avoid the activity of the CI7HC0 3 exchanger [antiporter] in the colon and intestine; if chloride is not tightly bound to the polymer the CI7HC0 3 exchanger can mediate uptake of chloride ion from the intestinal lumen and reciprocal exchange for bicarbonate from the serum, thus effectively decreasing serum bicarbonate.
  • Competing anions that displace chloride lead to a decrease in net bicarbonate through the following mechanisms.
  • displacement of chloride from the polymer in the Gl lumen, particularly the colon lumen provides for a facile exchange with bicarbonate in the serum.
  • the colon has an anion exchanger
  • Short chain fatty acids that reach the colon are absorbed and distributed to various tissues, with the common metabolic fate being the generation of H 2 0 and C0 2 , which is converted to bicarbonate equivalents.
  • binding of SCFA to the polymer to neutralize the proton charge would be detrimental to overall bicarbonate stores and buffering capacity, necessitating the design of chemical and physical features in the polymer that limit SCFA exchange.
  • phosphate binding to the polymer should be limited as well, since phosphate represents an additional source of buffering capacity in the situation where ammoniagenesis and/or hydrogen ion secretion is compromised in chronic renal disease.
  • an anion is preferably bound as the positive charge seeks to leave the human body as a neutral polymer.
  • Binding of an ion, is more than minimal binding, i.e., at least about 0.2 mmol of ion/g of polymer, at least about 1 mmol of ion/g of polymer in some embodiments, at least about 1.5 mmol of ion/g of polymer in some embodiments, at least about 3 mmol of ion/g of polymer in some embodiments, at least about 5 mmol of ion/g of polymer in some embodiments, at least about 10 mmol of ion/g of polymer in some embodiments, at least about 12 mmol of ion/g of polymer in some embodiments, at least about 13 mmol of ion/g of polymer in some embodiments, or even at least about 14 mmol of ion/g of polymer in some embodiments.
  • the polymers are characterized by their high capacity of proton binding while at the same time providing selectivity for anions; selectivity for chloride is accomplished by reducing the binding of interfering anions that include but are not limited to phosphate, citrate, acetate, bile acids and fatty acids.
  • selectivity for chloride is accomplished by reducing the binding of interfering anions that include but are not limited to phosphate, citrate, acetate, bile acids and fatty acids.
  • polymers of the present disclosure bind phosphate with a binding capacity of less than about 5 mmol/g, less than about 4 mmol/g, less than about 3 mmol/g, less than about 2 mmol/g or even less than about 1 mmol/g.
  • polymers of the invention bind bile and fatty acids with a binding capacity of less than about less than about 5 mmol/g, less than about 4 mmol/g, less than about 3 mmol/g, less than about 2 mmol/g, less than about 1 mmol/g in some embodiments, less than about 0.5 mmol/g in some embodiments, less than about 0.3 mmol/g in some
  • the dosage levels of the nonabsorbable compositions for therapeutic and/or prophylactic uses may range from about 0.5 g/day to about 100 g/day. To facilitate patient compliance, it is generally preferred that the dose be in the range of about 1 g/day to about 50 g/day. For example, in one such
  • the dose will be about 2 g/day to about 25 g/day.
  • the dose will be about 3 g/day to about 25 g/day.
  • the dose will be about 4 g/day to about 25 g/day.
  • the dose will be about 5 g/day to about 25 g/day.
  • the dose will be about 2.5 g/day to about 20 g/day.
  • the dose will be about 2.5 g/day to about 15 g/day.
  • the dose will be about 1 g/day to about 10 g/day.
  • the daily dose may be administered as a single dose (/. e. , one time a day), or divided into multiple doses (e.g., two, three or more doses) over the course of a day.
  • the nonabsorbable compositions may be administered as a fixed daily dose or titrated based on the serum bicarbonate values of the patient in need of treatment or other indicators of acidosis. The titration may occur at the onset of treatment or throughout, as required, and starting and maintenance dosage levels may differ from patient to patient based on severity of the underlying disease.
  • the effectiveness of the nonabsorbable composition may be established in animal models, or in human volunteers and patients.
  • in vitro, ex vivo and in vivo approaches are useful to establish HCI binding.
  • In vitro binding solutions can be used to measure the binding capacity for proton, chloride and other ions at different pHs.
  • Ex vivo extracts, such as the gastrointestinal lumen contents from human volunteers or from model animals can be used for similar purposes. The selectivity of binding and/or retaining certain ions preferentially over others can also be demonstrated in such in vitro and ex vivo solutions.
  • In vivo models of metabolic acidosis can be used to test the effectiveness of the
  • nonabsorbable composition in normalizing acid/base balance - for example 5/6 nephrectomized rats fed casein-containing chow (as described in Phisitkul S, hacker C, Simoni J, Tran RM, Wesson DE. Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors. Kidney international. 2008;73(2): 192-9), or adenine-fed rats (Terai K, K Mizukami and M Okada. 2008. Comparison of chronic renal failure rats and modification of the preparation protocol as a hyperphosphatemia model.
  • the nonabsorbable compositions are provided (by oral administration) to an animal, including a human, in a dosing regimen of one, two or even multiple (/.e., at least three) doses per day to treat an acid-base disorder (e.g., metabolic acidosis) and achieve a clinically significant and sustained increase of serum bicarbonate as previously described.
  • an acid-base disorder e.g., metabolic acidosis
  • a daily dose of the nonabsorbable composition (whether orally administered in a single dose or multiple doses over the course of the day) has sufficient capacity to remove at least 5 mmol of protons, chloride ions or each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 10 mmol of protons, chloride ions or each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 20 mmol of protons, the conjugate base of a strong acid (e.g., Cl , HS0 4 and S0 4 2 ) and/or a strong acid (e.g., HCI or H 2 S0 4 ) each per day.
  • a strong acid e.g., Cl , HS0 4 and S0 4 2
  • a strong acid e.g., HCI or H 2 S0 4
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 30 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 30 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 40 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day.
  • a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 50 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day.
  • the dosage unit form of the pharmaceutical comprising the nonabsorbable composition may be any form appropriate for oral administration.
  • Such dosage unit forms include powders, tablets, pills, lozenges, sachets, cachets, elixirs, suspensions, syrups, soft or hard gelatin capsules, and the like.
  • the pharmaceutical composition comprises only the nonabsorbable composition.
  • the pharmaceutical composition may comprise a carrier, a diluent, or excipient in addition to the nonabsorbable composition.
  • Examples of carriers, excipients, and diluents that may be used in these formulations as well as others, include foods, drinks, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl cellulose, methylhydroxybenzoates, propylhydroxybenzoates, propylhydroxybenzoates, and talc.
  • compositions further include a binder, such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providone and xanthan gum; a flavoring agent, such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such as magnesium stearate, stearic acid, sodium stearyl fumurate and vegetable based fatty acids; and, optionally, a disintegrant, such as croscarmellose sodium, gellan gum, low- substituted hydroxypropyl ether of cellulose, sodium starch glycolate.
  • a binder such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providone and xanthan gum
  • a flavoring agent such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol
  • additives may include plasticizers, pigments, talc, and the like.
  • plasticizers pigments, talc, and the like.
  • suitable ingredients are well-known in the art; see, e.g., Gennaro A R (ed), Remington's Pharmaceutical Sciences, 20th Edition.
  • the nonabsorbable composition may be co administered with other active pharmaceutical agents depending on the condition being treated.
  • This co-administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
  • the nonabsorbable composition may be co-administered with common treatments that are required to treat underlying co-morbidities including but not limited to edema, hypertension, diabetes, obesity, heart failure and complications of Chronic Kidney Disease.
  • These medications and the nonabsorbable composition can be formulated together in the same dosage form and administered
  • these treatments and the nonabsorbable composition may be separately and sequentially administered with the administration of one being followed by the administration of the other.
  • the daily dose of the chronic metabolic acidosis treatment is compliance enhancing (approximately 15 g or less per day) and achieves a clinically significant and sustained increase of serum bicarbonate of approximately 3 mEq/L at these daily doses.
  • the non-absorbed nature of the polymer and the lack of sodium load and/or introduction of other deleterious ions for such an oral drug enable for the first time a safe, chronic treatment of metabolic acidosis without worsening blood pressure / hypertension and/or without causing increased fluid retention and fluid overload.
  • Another benefit is further slowing of the progression of kidney disease and time to onset of lifelong renal replacement therapy (End Stage Renal Disease“ESRD” including 3 times a week dialysis) or need for kidney transplants. Both are associated with significant mortality, low quality of life and significant burden to healthcare systems around the world. In the United States alone, approximately 20 % of the 400,000 ESRD patients die and 100,000 new patients start dialysis every year.
  • a further aspect of the present disclosure is a method of slowing the progression to dialysis of a patient afflicted with chronic kidney disease and an acid- base disorder characterized by a baseline serum bicarbonate value of ⁇ 22 mEq/L, the method comprising oral administration of a pharmaceutical composition capable of increasing and maintaining the patient’s serum bicarbonate above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition having the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • a further aspect of the present disclosure is a method of slowing the progression to dialysis of a patient afflicted with chronic kidney disease and an acid- base disorder, wherein the patient has a baseline serum bicarbonate value of ⁇ 22 mEq/L, comprising orally administering to the patient an effective amount of TRC101 once daily for a period of time sufficient to increase the patient’s serum bicarbonate by at least 1 mEq/L.
  • a further aspect of the present disclosure is a method of slowing the progression to dialysis of a patient afflicted with chronic kidney disease and metabolic acidosis disease, the method comprising administering to the patient a daily dose of a nonabsorbed crosslinked amine polymer, which daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) results in a sustained serum bicarbonate increase of at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to slow the progression to dialysis.
  • a further aspect of the present disclosure is a pharmaceutical composition for slowing the progression to dialysis of a human patient afflicted with chronic kidney disease and an acid-base disorder, the patient having a baseline serum bicarbonate level of ⁇ 22 mEq/L prior to treatment, the composition being a nonabsorbable composition having the capacity to: (a) remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) slow the progression to dialysis of the human patient over at least a twelve-week period.
  • a further aspect of the present disclosure is a pharmaceutical composition for slowing the progression to dialysis of a human patient afflicted with chronic kidney disease and an acid-base disorder by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over at least twelve weeks of treatment, the composition: (a) being a nonabsorbable composition having the capacity to remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) characterized by a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (c) having the capacity to slow the progression to dialysis over at least the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • a further aspect of the present disclosure is a pharmaceutical composition for slowing the progression to dialysis of a human patient also suffering from metabolic acidosis disease, wherein: (a) an effective amount of the
  • the pharmaceutical composition is administered to the patient per day over at least a twelve-week period; (b) the pharmaceutical composition is nonabsorbable with the capacity to remove from the patient a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (d) the progression to dialysis of the patient is slowed over the twelve-week period compared to a placebo control group not receiving the pharmaceutical composition.
  • SIB Simulated Small Intestine Inorganic Buffer
  • the rate of progression to dialysis of the individual is decreased. In one embodiment, the rate of progression to dialysis decreases for at least about 1 month. In one embodiment, the rate of progression to dialysis decreases for at least about 4 months. In one embodiment, the rate of progression to dialysis decreases for at least about 6 months. In one embodiment, the rate of progression to dialysis decreases for at least about 12 months.
  • a further aspect of the present disclosure is a method of decreasing the rate of progression to dialysis of an individual, the method comprising
  • the method includes the method of treatment, or part thereof, described anywhere herein.
  • the rate of decrease in the progression to dialysis is measurable by a decreased rate of change in eGFR.
  • the individual or adult human patient has a baseline eGFR value of at least about 15 mL/min/1.73 m 2 In one embodiment, the individual or adult human patient has a baseline eGFR value of at least about 30 mL/min/1.73 m 2 . In one embodiment, the individual or adult human patient has a baseline eGFR value of less than about 45 mL/min/1.73 m 2 for at least three months. In one embodiment, the individual or adult human patient has a baseline eGFR value of less than about 60 mL/min/1.73 m 2 for at least three months.
  • the decreased rate of change in eGFR value is less than about 1 mL/min/1.73 m 2 over a period of about 1 month. In one embodiment, the decreased rate of change in eGFR value is less than about 5 mL/min/1.73 m 2 over a period of about 1 month. In one embodiment, the decreased rate of change in eGFR value is less than about 10 mL/min/1.73 m 2 over a period of about 1 month. In one embodiment, the decreased rate of change in eGFR value is less than about 15 mL/min/1.73 m 2 over a period of about 1 month. In one
  • the decreased rate of change in eGFR value is less than about 20 mL/min/1.73 m 2 over a period of about 1 month. In one embodiment, the decreased rate of change in eGFR value is less than about 25 mL/min/1.73 m 2 over a period of about 1 month. In one embodiment, the decreased rate of change in eGFR occurs to the extent that eGFR stops decreasing. In one embodiment, the decreased rate of change in eGFR occurs to the extent that there is an improvement in eGFR.
  • the delay in the progression to dialysis is measurable by reduced change in mGFR, or a halt in change to mGFR, or improvement in mGFR. In one embodiment, the delay in the progression to dialysis is measurable by reduced change in mGFR, or a halt in change to mGFR, or improvement in mGFR. In one embodiment, the individual or adult human patient has a baseline mGFR value of at least about 15 mL/min/1.73 m 2 . In one
  • the individual or adult human patient has a baseline mGFR value of at least about 30 mL/min/1.73 m 2 . In one embodiment, the individual or adult human patient has a baseline mGFR value of less than about 45 mL/min/1.73 m 2 for at least three months. In one embodiment, the individual or adult human patient has a baseline mGFR value of less than about 60 mL/min/1.73 m 2 for at least three months. In one embodiment, the decreased rate of change in mGFR value is less than about 1 mL/min/1.73 m 2 over a period of about 1 month.
  • the decreased rate of change in mGFR value is less than about 5 mL/min/1.73 m 2 over a period of about 1 month.
  • the delay in the progression to dialysis includes the individual’s stage of chronic kidney disease remaining constant.
  • the decrease in the rate of progression to dialysis may be determined relative to the baseline rate of progression prior to treatment.
  • the decision to dialyse may be as follows.
  • the method comprises a decision to initiate dialysis.
  • the method comprises administering a composition, or part thereof, described anywhere herein.
  • the method includes the method of treatment, or part thereof, described anywhere herein.
  • the decision to initiate dialysis is based on an overall clinical assessment of uremic signs and/or symptoms of the patient.
  • the decision to initiate dialysis is based on physical functioning of the patient, which may act as one indicator of protein-energy wasting.
  • the physical functioning of the patient is determined using any of the methods for assessing physical function described herein.
  • the decision to initiate dialysis is based on evidence of protein wasting.
  • the decision to initiate dialysis is based on the ability to manage complications from the disorder, such as acidosis and volume overload.
  • veverimer TRC101
  • TRC101 veverimer corrects acidosis and improves physical function, possibly by reducing protein catabolism and/or by allowing a higher protein intake to be tolerated. It is therefore plausible that use of veverimer could forestall initiation of dialysis, independent of any effects on kidney function.
  • a further aspect of the present disclosure is a pharmaceutical product comprising a sealed package and the nonabsorbable composition of the present disclosure within the sealed package.
  • the sealed package is preferably substantially impermeable to moisture and oxygen to increase the stability of the pharmaceutical composition.
  • the dosage unit form may comprise a sealed container (e.g ., a sealed sachet) that prevents or reduces ingress of moisture and oxygen upon packaging the nonabsorbable composition in the container.
  • the container size can be optimized to reduce head space in the container after packaging and any head space may be filled with an inert gas such as nitrogen.
  • container material of construction can be chosen to minimize the moisture and oxygen ingress inside the container after packaging.
  • the nonabsorbable composition may be packaged in a multilayer sachet containing at least one or more layer that serves as a barrier layer to moisture and oxygen ingress.
  • the nonabsorbable composition may be packaged in a single layer or multilayer plastic, metal or glass container that has at least one or more barrier layers incorporated in the structure that limits oxygen and/or moisture ingress after packaging.
  • the sachet (or other container or package) may comprise a multi-layer laminate of an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and outer layer.
  • the container includes one or more oxygen- scavenging layers.
  • Embodiment 1 A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a
  • composition having the capacity to bind at least 5 mEq of a target species as it transits the digestive system to increase the serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period not greater than 1 month, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 2 A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a pharmaceutical
  • composition wherein the pharmaceutical composition given orally binds at least 5 mEq per day on average of a target species in the digestive system to maintain the serum bicarbonate value at a value within the range of 24 to 29 mEq/l, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment s The method of embodiment 2 wherein the oral administration is as frequent as at least weekly within the treatment period.
  • Embodiment 4 The method of embodiment 2 pharmaceutical composition wherein the oral administration is as frequent as at least semi-weekly within the treatment period.
  • Embodiment s The method of embodiment 2 pharmaceutical composition wherein the oral administration is as frequent as at least daily within the treatment period.
  • Embodiment s The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 21 mEq/l.
  • Embodiment / The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 20 mEq/l.
  • Embodiment s The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 19 mEq/l.
  • Embodiment 9 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 18 mEq/l.
  • Embodiment 10 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 17 mEq/l.
  • Embodiment 11 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 16 mEq/l.
  • Embodiment 12 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 15 mEq/l.
  • Embodiment 13 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 14 mEq/l.
  • Embodiment 14 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 13 mEq/l.
  • Embodiment 15 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 12 mEq/l.
  • Embodiment 16 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 11 mEq/l.
  • Embodiment 17 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 10 mEq/l.
  • Embodiment 18 The method of any preceding enumerated embodiment wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 9 mEq/l.
  • Embodiment 19 The method of any of embodiments 1 - 16 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 10 mEq/l.
  • Embodiment 20 The method of any of embodiments 1 - 15 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 11 mEq/l.
  • Embodiment 21 The method of any of embodiments 1 - 14 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/l.
  • Embodiment 22 The method of any of embodiments 1 - 13 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 13 mEq/l.
  • Embodiment 23 The method of any of embodiments 1 - 12 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 14 mEq/l.
  • Embodiment 24 The method of any of embodiments 1 - 11 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/l.
  • Embodiment 25 The method of any of embodiments 1 - 10 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 16 mEq/l.
  • Embodiment 26 The method of any of embodiments 1 - 9 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 17 mEq/l.
  • Embodiment 27 The method of any of embodiments 1 - 8 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 18 mEq/l.
  • Embodiment 28 The method of any of embodiments 1 - 7 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 19 mEq/l.
  • Embodiment 29 The method of any of embodiments 1 - 6 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 20 mEq/l.
  • Embodiment 30 The method of embodiment 1 , 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 21 mEq/l.
  • Embodiment 76 The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l without any change in the individual’s diet or dietary habits relative to the period immediately preceding the initiation of treatment.
  • Embodiment 77 The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l independent of the individual’s diet or dietary habits.
  • Embodiment 247 The method of any preceding enumerated embodiment wherein the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point.
  • Embodiment 248 The method of any of embodiments 1 to 246 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations determined at different time-points.
  • Embodiment 249. The method of any of embodiments 1 to 246 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on different days.
  • Embodiment 250 The method of embodiment 249 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on consecutive days.
  • Embodiment 251 The method of embodiment 249 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on two consecutive days and prior to the initiation of the treatment.
  • Embodiment 252 The method of embodiment 249 wherein the baseline serum bicarbonate value is the mean or median value of at least two serum bicarbonate concentrations for serum samples drawn on non-consecutive days.
  • Embodiment 253 The method of embodiment 252 wherein the non-consecutive days are separated by at least two days.
  • Embodiment 254 The method of embodiment 252 wherein the non-consecutive days are separated by at least one week.
  • Embodiment 255 The method of embodiment 252 wherein the non-consecutive days are separated by at least two weeks.
  • Embodiment 256 The method of embodiment 252 wherein the non-consecutive days are separated by at least three weeks.
  • Embodiment 257 The method of any preceding enumerated embodiment wherein the individual is being treated for acute metabolic acidosis.
  • Embodiment 258 The method of any preceding enumerated embodiment wherein the individual is being treated for chronic metabolic acidosis.
  • Embodiment 259. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 7.5 mEq of a target species as it transits the digestive system.
  • Embodiment 260 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 10 mEq of a target species as it transits the digestive system.
  • Embodiment 261. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 15 mEq of a target species as it transits the digestive system.
  • Embodiment 262 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 20 mEq of a target species as it transits the digestive system.
  • Embodiment 263. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 25 mEq of a target species as it transits the digestive system.
  • Embodiment 264 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 30 mEq of a target species as it transits the digestive system.
  • Embodiment 265. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 35 mEq of a target species as it transits the digestive system.
  • Embodiment 266 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 40 mEq of a target species as it transits the digestive system.
  • Embodiment 267 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 45 mEq of a target species as it transits the digestive system.
  • Embodiment 268 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 50 mEq of a target species as it transits the digestive system.
  • Embodiment 269. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 55 mEq of a target species as it transits the digestive system.
  • Embodiment 270 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 60 mEq of a target species as it transits the digestive system.
  • Embodiment 271. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 65 mEq of a target species as it transits the digestive system.
  • Embodiment 272 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 70 mEq of a target species as it transits the digestive system.
  • Embodiment 273. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 75 mEq of a target species as it transits the digestive system.
  • Embodiment 274 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 80 mEq of a target species as it transits the digestive system.
  • Embodiment 275 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 85 mEq of a target species as it transits the digestive system.
  • Embodiment 276 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 90 mEq of a target species as it transits the digestive system.
  • Embodiment 277 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 95 mEq of a target species as it transits the digestive system.
  • Embodiment 278 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 100 mEq of a target species as it transits the digestive system.
  • Embodiment 279. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 105 mEq of a target species as it transits the digestive system.
  • Embodiment 280 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 110 mEq of a target species as it transits the digestive system.
  • Embodiment 281. The method of any preceding enumerated embodiment wherein the daily dose is no more than 100 g/day.
  • Embodiment 282 The method of any preceding enumerated embodiment wherein the daily dose is no more than 90 g/day.
  • Embodiment 283. The method of any preceding enumerated embodiment wherein the daily dose is less than 75 g/day.
  • Embodiment 284 The method of any preceding enumerated embodiment wherein the daily dose is less than 65 g/day.
  • Embodiment 285. The method of any preceding enumerated embodiment wherein the daily dose is less than 50 g/day.
  • Embodiment 286 The method of any preceding enumerated embodiment wherein the daily dose is less than 40 g/day.
  • Embodiment 287 The method of any preceding enumerated embodiment wherein the daily dose is less than 30 g/day.
  • Embodiment 288 The method of any preceding enumerated embodiment wherein the daily dose is less than 25 g/day.
  • Embodiment 289. The method of any preceding enumerated embodiment wherein the daily dose is less than 20 g/day.
  • Embodiment 290 The method of any preceding enumerated embodiment wherein the daily dose is less than 15 g/day.
  • Embodiment 291. The method of any preceding enumerated embodiment wherein the daily dose is less than 10 g/day.
  • Embodiment 292 The method of any preceding enumerated embodiment wherein the daily dose is less than 5 g/day.
  • Embodiment 293. The method of any preceding enumerated embodiment wherein the individual is treated for at least one day.
  • Embodiment 294 The method of any preceding enumerated embodiment wherein the individual is treated for at least one week.
  • Embodiment 295. The method of any preceding enumerated embodiment wherein the individual is treated for at least one month.
  • Embodiment 296 The method of any preceding enumerated embodiment wherein the individual is treated for at least several months.
  • Embodiment 297 The method of any preceding enumerated embodiment wherein the individual is treated for at least six months.
  • Embodiment 298 The method of any preceding enumerated embodiment wherein the individual is treated for at least one year.
  • Embodiment 299. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition as described in [00236]
  • Embodiment 300 The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a Swelling Ratio as described in [00256]
  • Embodiment 320 The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species as described in [00239]
  • Embodiment 343. The method of any preceding enumerated embodiment wherein the target species comprises protons.
  • Embodiment 344 The method of any preceding enumerated embodiment wherein the target species comprises the conjugate base of a strong acid.
  • Embodiment 345 The method of any preceding enumerated embodiment wherein the target species comprises the conjugate base of a strong acid selected from the group consisting of chloride, bisulfate and sulfate ions.
  • Embodiment 346 The method of any preceding enumerated embodiment wherein the target species comprises chloride ions.
  • Embodiment 347 The method of any preceding enumerated embodiment wherein the target species comprises a strong acid.
  • Embodiment 348 The method of any preceding enumerated embodiment wherein the target species comprises hydrochloric acid.
  • Embodiment 349 The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity as described in [00261]
  • Embodiment 360 The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is as described in [00262]
  • Embodiment 389 The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove an amount of the target species as described in [00216]
  • Embodiment 534 The method of any preceding enumerated embodiment wherein the nonabsorbable composition (i) removes more chloride ions than bicarbonate equivalent anions (ii) removes more chloride ions than phosphate anions, and (iii) removes more chloride ions than the conjugate bases of bile and fatty acids.
  • Embodiment 535 The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant species.
  • Embodiment 536 The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant cationic species.
  • Embodiment 537 The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant anionic species.
  • Embodiment 538 The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum potassium levels of a statistically significant number of individuals.
  • Embodiment 539 The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum phosphate levels of a statistically significant number of individuals.
  • Embodiment 540 The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum low density lipoprotein (LDL) levels of a statistically significant number of individuals.
  • LDL serum low density lipoprotein
  • Embodiment 541 The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable
  • composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1 :
  • R-i , R 2 and R 3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R-i , R 2 and R 3 is other than hydrogen.
  • Embodiment 544 The method of any preceding enumerated embodiment wherein the nonabsorbable composition has an equilibrium chloride binding capacity of at least 7.5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 545 The method of any preceding enumerated embodiment wherein the nonabsorbable composition has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 556 The method of any preceding enumerated embodiment wherein the pharmaceutical composition is in a dosage unit form.
  • Embodiment 557 The method of embodiment 556 wherein the dosage unit form is a capsule, tablet or sachet dosage form.
  • Embodiment 558 The method of any preceding enumerated embodiment wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.
  • Embodiment 559 The method of any preceding enumerated embodiment wherein the daily dose is administered once-a-day (QD).
  • Embodiment 560 The method of any preceding enumerated embodiment wherein the daily dose is administered twice-a-day (BID).
  • Embodiment 561 The method of any preceding enumerated embodiment wherein the daily dose is administered three times a day.
  • Embodiment 562 The method of any preceding enumerated embodiments wherein the daily dose is obtained from a pharmaceutical product comprising a sealed container and the nonabsorbable composition within the sealed container.
  • Embodiment 563 The method of embodiment 562 wherein the sealed container comprises a moisture barrier.
  • Embodiment 564 The method of embodiment 562 or 563 wherein the sealed container comprises an oxygen barrier.
  • Embodiment 565 The method of any of embodiments 562 to 564 wherein the sealed container is a sealed sachet.
  • Embodiment 566 The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and outer layer.
  • Embodiment 567 The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and an oxygen-barrier layer disposed between the contact layer and outer layer.
  • Embodiment 568 The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and a moisture-barrier layer disposed between the contact layer and outer layer.
  • Embodiment 569 The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and an oxygen-barrier layer and a moisture-barrier layer disposed between the contact layer and outer layer.
  • Embodiment 570 The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and an oxygen-scavenging layer disposed between the contact layer and the outer layer.
  • Embodiment 821 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has chronic kidney disease.
  • Embodiment 822 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient is not yet in need for kidney replacement therapy (dialysis or transplant).
  • Embodiment 823 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has not yet reached end stage renal disease (“ESRD”).
  • ESRD end stage renal disease
  • Embodiment 824 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of at least 15 mL/min/1.73 m 2 .
  • Embodiment 825 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of at least 15 mL/min/1.73 m 2 .
  • Embodiment 826 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of at least 30 mL/min/1.73 m 2 .
  • Embodiment 827 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of at least 30 mL/min/1.73 m 2 .
  • Embodiment 828 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of less than 45 mL/min/1.73 m 2 for at least three months.
  • Embodiment 829 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of less than 45 mL/min/1.73 m 2 for at least three months.
  • Embodiment 830 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of less than 60 mL/min/1.73 m 2 for at least three months.
  • Embodiment 831 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of less than 60 mL/min/1.73 m 2 for at least three months.
  • Embodiment 832 The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has Stage 3A CKD, Stage 3B CKD, or Stage 4 CKD.
  • Embodiment 833 A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition containing a nonabsorbable composition; wherein said oral administration increases the individual’s serum bicarbonate value from baseline to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1 mEq/l; and
  • the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or at least one year.
  • Embodiment 834 The method or pharmaceutical composition of embodiment 833, wherein the method or pharmaceutical composition is one of any preceding enumerated embodiments.
  • Embodiment 850 A method of improving the quality of life of a patient afflicted with chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value of ⁇ 22 mEq/L, the method comprising oral administration of a pharmaceutical composition capable of increasing and
  • the pharmaceutical composition having the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 85 A method of improving the quality of life of a patient afflicted with chronic kidney disease and an acid-base disorder, the method comprising oral administration of a pharmaceutical composition having: (a) the capacity to selectively bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay, wherein the improvement in quality of life is statistically significant compared to a placebo control group for a period of at least twelve weeks as assessed by a Quality of Life (QoL) questionnaire.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 852 A method of improving quality of life of a patient afflicted with chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value of ⁇ 22 mEq/L, comprising orally
  • Embodiment 853 A method of improving quality of life of a patient afflicted with metabolic acidosis disease, the method comprising administering to the patient a daily dose of a nonabsorbed crosslinked amine polymer, which daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) results in a sustained serum bicarbonate increase of at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to improve the patient’s quality of life compared to a placebo control group over the period, wherein the improvement in quality of life is statistically significant.
  • Embodiment 854 A pharmaceutical composition for improving the quality of life of a human patient afflicted with chronic kidney disease and an acid- base disorder, the patient having a baseline serum bicarbonate level of ⁇ 22 mEq/L prior to treatment, the composition being a nonabsorbable composition having the capacity to: (a) remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) improve the patient’s quality of life compared to a placebo control in a statistically significant manner over at least a twelve-week period.
  • Embodiment 855 A pharmaceutical composition for improving the quality of life of a human patient suffering from a disease or disorder by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over at least twelve weeks of treatment, the composition: (a) being a nonabsorbable composition having the capacity to remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) characterized by a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (c) having the capacity to improve the patient’s quality of life compared to a placebo control in a statistically significant manner over at least the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 856 A pharmaceutical composition for improving the quality of life of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient per day over at least a twelve-week period; (b) the pharmaceutical composition is nonabsorbable with the capacity to remove from the patient a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (d) the improvement in quality of life compared to a placebo control is statistically significant over the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 857 A method of improving the physical function of a patient afflicted with chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value of ⁇ 22 mEq/L, the method comprising oral administration of a pharmaceutical composition capable of increasing and
  • the pharmaceutical composition having the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 858 A method of improving the physical function of a patient afflicted with chronic kidney disease and an acid-base disorder, the method comprising oral administration of a pharmaceutical composition having: (a) the capacity to selectively bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay, wherein the improvement in physical function is statistically significant compared to a placebo control group at least twelve weeks after initiation of treatment as assessed by the patient’s answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF).
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 859 A method of improving the physical function of a patient afflicted with chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value of ⁇ 22 mEq/L, comprising orally administering to the patient an effective amount of TRC101 once daily for a period of time sufficient to statistically significantly increase the patient’s physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to the patient’s baseline physical function score.
  • KDQOL-SF Kidney Disease Quality of Life Short Form
  • Embodiment 860 A method of improving the physical function of a patient afflicted with metabolic acidosis disease, the method comprising
  • a daily dose of a nonabsorbed crosslinked amine polymer which daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) results in a sustained serum bicarbonate increase of at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to improve the physical function score of the patient compared to a placebo control group at the end of the period, wherein the improvement in the physical function score is statistically significant.
  • Embodiment 861 A pharmaceutical composition for improving the physical function score of a human patient afflicted with chronic kidney disease and an acid-base disorder, the patient having a baseline serum bicarbonate level of ⁇ 22 mEq/L prior to treatment, the composition being a nonabsorbable composition having the capacity to: (a) remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) improve the patient’s physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to a placebo control in a statistically significant manner at the end of at least a twelve-week period.
  • KDQOL-SF Kidney Disease Quality of Life Short Form
  • Embodiment 862 A pharmaceutical composition for improving the physical function score of a human patient suffering from a disease or disorder by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over at least twelve weeks of treatment, the composition: (a) being a nonabsorbable composition having the capacity to remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) characterized by a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (c) having the capacity to improve the patient’s physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to a placebo control in a statistically significant manner at the end of an at least the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 863 A pharmaceutical composition for improving the physical function score of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient per day over at least a twelve-week period; (b) the pharmaceutical composition is nonabsorbable with the capacity to remove from the patient a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (d) the improvement in physical function score is a statistically significant improvement over a baseline physical function score based on answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) compared to a placebo control at the end of the at least twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 864 A method of slowing the progression of kidney disease in a patient afflicted with chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value of ⁇ 22 mEq/L, the method comprising oral administration of a pharmaceutical composition capable of increasing and maintaining the patient’s serum bicarbonate above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition having the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 865 A method of slowing the progression of kidney disease in a patient afflicted with chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value of ⁇ 22 mEq/L, comprising orally administering to the patient an effective amount of TRC101 once daily for a period of time sufficient to increase the patient’s serum bicarbonate by at least 1 mEq/L.
  • Embodiment 866 A method of slowing the progression of kidney disease in a patient afflicted with chronic kidney disease and metabolic acidosis disease, the method comprising administering to the patient a daily dose of a nonabsorbed crosslinked amine polymer, which daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) results in a sustained serum bicarbonate increase of at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to slow the progression of kidney disease.
  • Embodiment 867 A pharmaceutical composition for slowing the progression of kidney disease in a human patient afflicted with chronic kidney disease and an acid-base disorder, the patient having a baseline serum bicarbonate level of ⁇ 22 mEq/L prior to treatment, the composition being a nonabsorbable composition having the capacity to: (a) remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) slow the progression of kidney disease in a human patient over at least a twelve-week period.
  • Embodiment 868 A pharmaceutical composition for slowing the progression of kidney disease in a human patient afflicted with chronic kidney disease and an acid-base disorder by increasing that patient’s serum bicarbonate value by at least 1 mEq/L over at least twelve weeks of treatment, the composition: (a) being a nonabsorbable composition having the capacity to remove a target species from the patient selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) characterized by a target species binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and (c) having the capacity to slow the progression of kidney disease over at least the twelve-week period.
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 869 A pharmaceutical composition for slowing the progression of kidney disease in a human patient also suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical
  • composition is administered to the patient per day over at least a twelve-week period;
  • pharmaceutical composition is nonabsorbable with the capacity to remove from the patient a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids;
  • the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a Simulated Small Intestine Inorganic Buffer (SIB) assay; and
  • SIB Simulated Small Intestine Inorganic Buffer
  • Embodiment 870 A pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the quality of life of the patient.
  • Embodiment 871 A pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the physical function of the patient.
  • Embodiment 872 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1 :
  • R-i , R 2 and R 3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R-i, R 2 and R 3 is other than hydrogen.
  • Embodiment 883 The method/composition according to any one of the preceding enumerated embodiments wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2:
  • R 10 , R 20 , R 30 , and R 40 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl;
  • X 2 is hydrocarbyl or substituted hydrocarbyl; each Xu is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, or amino; and z is a non-negative number.
  • Embodiment 887 The method/composition according to embodiment 883, wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2a:
  • Formula 2a wherein m and n are independently non-negative integers; each R1 1 is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl;
  • R21 and R 31 are independently hydrogen or heteroaliphatic
  • R 4 I is hydrogen, substituted hydrocarbyl, or hydrocarbyl
  • X 2 is alkyl or substituted hydrocarbyl; each X 12 is independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halo; and z is a non-negative number.
  • Embodiment 891 The method/composition according to any one of embodiments 887 to 890 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2b:
  • Formula 2b wherein m and n are independently non-negative integers; each R-12 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl;
  • R22 and R 32 are independently hydrogen substituted hydrocarbyl, or hydrocarbyl
  • R 42 is hydrogen, hydrocarbyl or substituted hydrocarbyl
  • X 2 is alkyl, aminoalkyl, or alkanol; each X- I 3 is independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl; z is a non-negative number; and the amine corresponding to Formula 2b comprises at least one allyl group.
  • Embodiment 892 The method/composition according to
  • Embodiment 893 The method/composition according to any one of embodiments 891 to 892 wherein R 12 or R 42 independently comprise at least one allyl or vinyl moiety.
  • Embodiment 894 The method/composition according to any one of embodiments 891 to 893 wherein (i) m is a positive integer and R 12 , R 22 and R 42 , in combination comprise at least two allyl or vinyl moieties or (ii) n is a positive integer and RI 2 , R 32 and R 42 , in combination, comprise at least two allyl or vinyl moieties.
  • Embodiment 896 The method/composition according to any preceding enumerated embodiment wherein the crosslinked amine polymer is crosslinked with a crosslinking agent appearing in Table B.
  • Embodiment 906 The method/composition according to any preceding enumerated embodiment wherein the crosslinking agent is selected from the group consisting of dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl) amines, diepoxides, triepoxides, tetraepoxides, bis (halomethyl)benzenes, tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-
  • triphenylolmethane triglycidyl ether 3,7,14-tris[[3-(epoxypropoxy
  • Embodiment 907 The method/composition according to any preceding enumerated embodiment wherein the preparation of the crosslinked amine polymer comprises radical polymerization of an amine monomer comprising at least one amine moiety or nitrogen containing moiety.
  • Embodiment 908 The method/composition according to any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1.5 or less.
  • Embodiment 909 The method/composition according to any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1 or less.
  • Embodiment 910 The method/composition according to any preceding enumerated embodiment wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 0.5:1 , respectively, in an aqueous simulated small intestine inorganic buffer (“SIB”) containing 36 mM NaCI,
  • SIB aqueous simulated small intestine inorganic buffer
  • Embodiment 911 The method/composition according to any preceding enumerated embodiment wherein the pharmaceutical composition comprises a polymer comprising a structure corresponding to Formula 4:
  • each R is independently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer and a, b, c, and m are integers.
  • Embodiment 912. The method/composition according to
  • Embodiment 913 The method/composition according to
  • embodiment 911 or 912 wherein a ratio of the sum of a and b to c (i.e. , a+b:c) is in the range of about 1 :1 to 5: 1.
  • Embodiment 914 The method/composition according to any one of embodiments 9111 to 913 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.5:1 to 4: 1.
  • Embodiment 915 The method/composition according to any one of embodiments 911 to 914 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75: 1 to 3: 1.
  • Embodiment 916 The method/composition according to any one of embodiments 911 to 915 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 2: 1 to 2.5: 1.
  • Embodiment 917 The method/composition according to any one of embodiments 911 to 916 wherein the sum of a and b is 57 and c is 24.
  • Embodiment 918 The method/composition according to any preceding enumerated embodiment wherein 50-95% of the R substituents are hydrogen and 5-50% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 919 The method/composition according to any preceding enumerated embodiment wherein 55-90% of the R substituents are hydrogen and 10-45% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 920 The method/composition according to any preceding enumerated embodiment wherein 60-90% of the R substituents are hydrogen and 10-40% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 921 The method/composition according to any preceding enumerated embodiment wherein 65-90% of the R substituents are hydrogen and 10-35% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 922 The method/composition according to any one of embodiments 911 to 921 wherein the R substituents are hydrogen and 10-30% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 923 The method/composition according to any preceding enumerated embodiment wherein the composition is the polymer of any of embodiments 768 to 774 wherein 75-85% of the R substituents are hydrogen and 15-25% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 924 The method/composition according to any preceding enumerated embodiment wherein the R substituents are hydrogen and 15-20% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 925 The method/composition according to any preceding enumerated embodiment wherein the R substituents are hydrogen and about 19% are an ethylene crosslink.
  • Embodiment 926 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a SIB assay.
  • Embodiment 927 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay.
  • Embodiment 928 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay.
  • Embodiment 929 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a SIB assay.
  • Embodiment 930 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a SIB assay.
  • Embodiment 931 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in a SIB assay.
  • Embodiment 932 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in a SIB assay.
  • Embodiment 933 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 4.5 mEq/g in a SIB assay.
  • Embodiment 934 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 5 mEq/g in a SIB assay.
  • Embodiment 935 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 5.5 mEq/g in a SIB assay.
  • Embodiment 936 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in a SIB assay.
  • Embodiment 937 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.1 :1 , respectively.
  • Embodiment 938 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.2:1 , respectively.
  • Embodiment 939 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.25:1 , respectively.
  • Embodiment 940 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.3:1 , respectively.
  • Embodiment 941 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.35:1 , respectively.
  • Embodiment 942 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.4:1 , respectively.
  • Embodiment 943 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.45:1 , respectively.
  • Embodiment 944 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.5:1 , respectively.
  • Embodiment 945 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2:3, respectively.
  • Embodiment 946 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.75:1 , respectively.
  • Embodiment 947 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.9:1 , respectively.
  • Embodiment 948 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1 :1 , respectively.
  • Embodiment 949 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1.25:1 , respectively.
  • Embodiment 950 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1.5:1 , respectively.
  • Embodiment 951 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1.75:1 , respectively.
  • Embodiment 952 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2:1 , respectively.
  • Embodiment 953 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2.25:1 , respectively.
  • Embodiment 954. The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2.5:1 , respectively.
  • Embodiment 955 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2.75:1 , respectively.
  • Embodiment 956 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 3:1 , respectively.
  • Embodiment 957 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 4:1 , respectively.
  • Embodiment 958 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 5:1 , respectively.
  • Embodiment 959 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 6:1 , respectively.
  • Embodiment 960 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 7:1 , respectively.
  • Embodiment 961 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 8:1 , respectively.
  • Embodiment 962 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 9:1 , respectively.
  • Embodiment 963 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 10:1 , respectively.
  • Embodiment 964 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 12.5:1 , respectively.
  • Embodiment 965 The method/composition of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 15:1 , respectively.
  • Embodiment 966 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition has an equilibrium chloride binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 967 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition has an
  • Embodiment 968 The method/composition of any preceding enumerated embodiment wherein the pharmaceutical composition has an
  • Embodiment 980 The method/composition of any preceding enumerated embodiment, wherein improvement in quality of life or physical function is assessed by a questionnaire answered by a first cohort at the end of the period, relative to a second cohort who answered the same questionnaire at the end of the period, wherein the first cohort’s subjects receive the pharmaceutical composition and the second cohort’s subjects receive a placebo.
  • Embodiment 981 The method/composition of any preceding enumerated embodiment, wherein improvement in quality of life or physical function is assessed by a questionnaire, which is a clinically validated assessment for evaluating a patient’s physical and mental health.
  • Embodiment 982 The method/composition of any preceding enumerated embodiment, wherein the questionnaire comprises questions
  • Embodiment 983 The method/composition of any preceding enumerated embodiment, wherein the questionnaire comprises questions
  • Embodiment 984 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 10% improvement on the quality of life scale relative to the placebo control.
  • Embodiment 985 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 25% improvement on the quality of life scale relative to the placebo control.
  • Embodiment 986 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 50% improvement on the quality of life scale relative to the placebo control.
  • Embodiment 987 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 75% improvement on the quality of life scale relative to the placebo control.
  • Embodiment 988 The method/composition of any preceding enumerated embodiment, wherein the improvement of the physical function comprises: (a) an improvement in the patient’s baseline physical function score of at least 1.5 points based on the patient’s answers to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF); (b) an improvement in the patient’s baseline repeated chair stand times of at least -1.5 seconds; or (c) an improvement in the patient’s baseline physical function score of at least 1.5 points based on the patient’s answers to question 3 of the KDQOL-SF and an improvement in the patient’s baseline repeated chair stand times of at least -1.5 seconds.
  • KDQOL-SF Kidney Disease Quality of Life Short Form
  • the improvement in the patient’s baseline repeated chair stand times is seen after treatment for a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks. In another aspect of this and other embodiments, the improvement in patient’s baseline repeated chair stand times is seen after treatment for a period of at least about 12 weeks and a period of at least about 40 weeks. In another aspect of this and other embodiments, the improvement in patient’s baseline repeated chair stand times is seen after treatment for a period of at least about 12 weeks and a period of at least about 52 weeks.
  • the improvement in patient’s baseline repeated chair stand times is seen after treatment for a period of at least about 12 weeks, a period of at least about 40 weeks and a period of at least about 52 weeks.
  • improvement in the patient’s baseline repeated chair stand times is at least about 0.5, 0.75, 1.0, 1.1 , 1.2, 1.3, or 1.4 seconds.
  • the improvement in the patient’s baseline physical function score is based on the patient’s performance in the Single Chair Stand and/or Repeated Chair Stand protocols as depicted in Fig.
  • Embodiment 989 The method/composition of any preceding enumerated embodiment, wherein the improvement in the quality of life of the patient comprises a decrease or prevention of further bone loss and/or a decrease or prevention of further muscle loss in the patient.
  • Embodiment 990 The method of any preceding enumerated embodiment, wherein the improvement in physical function score further includes an improvement in the patient’s baseline repeated chair stand times compared to a placebo control of at least -1.5 seconds over the period.
  • the improvement in the patient’s baseline repeated chair stand is seen after treatment for a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks.
  • the improvement in the patient’s baseline repeated chair stand is seen after treatment for a period of at least about 12 weeks and at least about 40 weeks.
  • the improvement in the patient’s baseline repeated chair stand is seen after treatment for a period of at least about 12 weeks and at least about 52 weeks. In another aspect of this and other embodiments, the improvement in the patient’s baseline repeated chair stand is seen after treatment for a period of at least about 12 weeks, at least about 40 weeks and at least about 52 weeks. In another aspect of this and other embodiments, in the Repeated Chair Stand Test, after about twelve weeks of treatment, there is a trend toward significance for the difference between treated and placebo-treated patients. In another aspect of this and other embodiments, in the Repeated Chair Stand Test, after about twelve weeks of treatment, there is a trend toward significance for the difference between treated and placebo-treated patients.
  • improvement in the patient’s baseline repeated chair stand times is at least about 0.5, 0.75, 1.0, 1.1 , 1.2, 1.3, or 1.4 seconds.
  • the improvement in the patient’s baseline physical function score is based on the patient’s performance in the Single Chair Stand and/or Repeated Chair Stand protocols as depicted in Fig. 22.
  • Embodiment 991 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 1.5 point improvement on the KDQOL-SF scale relative to the placebo control.
  • Embodiment 992 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 3.0 point improvement on the KDQOL-SF scale relative to the placebo control.
  • Embodiment 993 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 4.5 point improvement on the KDQOL-SF scale relative to the placebo control.
  • Embodiment 994 The method/composition of any preceding enumerated embodiment, wherein the patient achieves at least about a 6.0 point improvement on the KDQOL-SF scale relative to the placebo control.
  • Embodiment 995 The method/composition of any preceding enumerated embodiment, wherein the disease or disorder is characterized by a baseline serum bicarbonate value of less than 18 mEq/L.
  • Embodiment 996 The method/composition of any preceding enumerated embodiment, wherein the disease or disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/L.
  • Embodiment 997 The method/composition of any preceding enumerated embodiment, wherein the disease or disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/L.
  • Embodiment 998 The method/composition of any preceding enumerated embodiment, wherein the patient’s baseline serum bicarbonate value increases by at least 1 mEq/L during the period.
  • Embodiment 999 The method/composition of any preceding enumerated embodiment, wherein the patient’s baseline serum bicarbonate value increases by at least 2 mEq/L during the period.
  • Embodiment 1000 The method/composition of any preceding enumerated embodiment, wherein the patient’s baseline serum bicarbonate value increases by at least 3 mEq/L during the period.
  • Embodiment 1001 The method/composition of any preceding enumerated embodiment, wherein a daily dose of the pharmaceutical composition is administered to the patient and the daily dose has the capacity to remove at least about 10 mEq/day, at least about 15 mEq/day, at least about 20 mEq/day, at least about 25 mEq/day, or at least about 30 mEq/day of the target species.
  • Embodiment 1002 The method/composition of any preceding enumerated embodiment, wherein a daily dose of the pharmaceutical composition is administered to the patient and the daily dose has the capacity to remove less than 50 mEq/day or less than 35 mEq/day of the target species.
  • Embodiment 1003. The method/composition of any preceding enumerated embodiment, wherein the period is at least three weeks, at least one month, at least two months, at least six months, at least 12 months, at least 18 months, or at least 24 months.
  • Embodiment 1004. The method/composition of any preceding enumerated embodiment, wherein the pharmaceutical composition has the capacity to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
  • Embodiment 1005. The method/composition of any preceding enumerated embodiment, wherein the conjugate base of a strong acid is selected from the group consisting of chloride, bisulfate and sulfate ions.
  • Embodiment 1006 The method/composition of any preceding enumerated embodiment, wherein the target species comprises chloride ions.
  • Embodiment 1007 The method/composition of any preceding enumerated embodiment, wherein the target species comprises hydrochloric acid.
  • Embodiment 62A The method/composition of any preceding enumerated embodiment, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a SIB assay.
  • Embodiment 1008 The method/composition of any preceding enumerated embodiment, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay.
  • Embodiment 1009 The method/composition of any preceding enumerated embodiment, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay.
  • Embodiment 1010 The method/composition of any preceding enumerated embodiment, wherein the pharmaceutical composition has the capacity to bind chloride and phosphate ions in a SIB assay at a ratio that is at least 0.25:1 , respectively.
  • Embodiment 1011 The method/composition of any preceding enumerated embodiment, wherein the pharmaceutical composition has the capacity to bind chloride and phosphate ions in a SIB assay at a ratio that is at least 0.5:1 , respectively.
  • Embodiment 1012 The method/composition of any preceding enumerated embodiment, wherein the pharmaceutical composition has the capacity to bind chloride and phosphate ions in a SIB assay at a ratio that is at least 1 :1 , respectively.
  • Embodiment 1013 The method/composition of any preceding enumerated embodiment, wherein the effective amount of the pharmaceutical composition or TRC101 comprises at least about 1 gm/day.
  • Embodiment 1014 The method/composition of any preceding enumerated embodiment, wherein the effective amount of the pharmaceutical composition or TRC101 comprises from about 1 -9 gm/day.
  • Embodiment 1015 The method/composition of any preceding enumerated embodiment, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 4-6 gm/day.
  • Embodiment 1016 The method/composition of any preceding enumerated embodiment, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 6 gm/day.
  • Embodiment 1017 The method/composition of any preceding enumerated embodiment, wherein the effective amount of the pharmaceutical composition or TRC101 is administered to the patient in an oral dosage form once-a- day.
  • Embodiment 1018 The method/composition of any preceding enumerated embodiment, wherein the effective amount of the pharmaceutical composition or TRC101 is adjusted to maintain the patient’s serum bicarbonate level in a range between 22-29 mEq/L.
  • Embodiment 1019 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline repeated chair stand times represents an improvement for at least one repetition.
  • Embodiment 1020 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline repeated chair stand times represents an improvement for at least two repetitions.
  • Embodiment 1021 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline repeated chair stand times represents an improvement for at least three repetitions.
  • Embodiment 1022 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline repeated chair stand times represents an improvement for at least four repetitions.
  • Embodiment 1023 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline repeated chair stand times represents an improvement for at least five repetitions.
  • Embodiment 1024 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline physical function score is based on the patient’s answers to at least one question to Question 3 the of KDQOL-SF as depicted in Fig. 21.
  • Embodiment 1025 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline physical function score is based on the patient’s answers to at least five questions to
  • Embodiment 1027 The method/composition of any preceding enumerated embodiment, wherein the improvement in the patient’s baseline physical function score is based on the patient’s answers to all questions to Question 3 of the KDQOL-SF as depicted in Fig. 21.
  • Embodiment 1028 A pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the quality of life of the patient.
  • Embodiment 1029 A pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the physical function of the patient.
  • Embodiment 1030 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1 :
  • R-i, R 2 and R 3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R-i, R 2 and R 3 is other than hydrogen.
  • Embodiment 1042 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of the preceding enumerated embodiments wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2:
  • R 20 , R 30 , and R 40 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl;
  • X 2 is hydrocarbyl or substituted hydrocarbyl; each Xu is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, or amino; and z is a non-negative number.
  • Embodiment 1046 The pharmaceutical composition for use in a method of treating an acid-base disorder according to embodiment 1042, wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2a:
  • Formula 2a wherein m and n are independently non-negative integers; each R1 1 is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl;
  • R21 and R 31 are independently hydrogen or heteroaliphatic;
  • R 41 is hydrogen, substituted hydrocarbyl, or hydrocarbyl;
  • X 2 is alkyl or substituted hydrocarbyl; each X12 is independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halo; and z is a non-negative number.
  • Embodiment 1050 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1046 to 1049 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2b:
  • Formula 2b wherein m and n are independently non-negative integers; each R 12 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl;
  • R22 and R 32 are independently hydrogen substituted hydrocarbyl, or hydrocarbyl
  • R 42 is hydrogen, hydrocarbyl or substituted hydrocarbyl
  • X 2 is alkyl, aminoalkyl, or alkanol; each X- I 3 is independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl; z is a non-negative number; and
  • the amine corresponding to Formula 2b comprises at least one allyl group.
  • Embodiment 1051 The pharmaceutical composition for use in a method of treating an acid-base disorder according to embodiment 1050, wherein m and z are independently 0-3 and n is 0 or 1.
  • Embodiment 1052 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1050 to 1051 wherein R12 or R 42 independently comprise at least one allyl or vinyl moiety.
  • Embodiment 1053 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1050 to 1052 wherein (i) m is a positive integer and R I2 , R 22 and R 42 , in combination comprise at least two allyl or vinyl moieties or (ii) n is a positive integer and R I2 , R 32 and R 42 , in combination, comprise at least two allyl or vinyl moieties.
  • Embodiment 1055 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the crosslinked amine polymer is crosslinked with a
  • Embodiment 1065 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the crosslinking agent is selected from the group consisting of dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl) amines, diepoxides, triepoxides, tetraepoxides, bis
  • halomethylbenzenes tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-
  • triphenylolmethane triglycidyl ether 3,7,14-tris[[3-(epoxypropoxy
  • Embodiment 1066 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the preparation of the crosslinked amine polymer comprises radical polymerization of an amine monomer comprising at least one amine moiety or nitrogen containing moiety.
  • Embodiment 1067 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1.5 or less.
  • Embodiment 1068 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1 or less.
  • Embodiment 1069 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 0.5:1 , respectively, in an aqueous simulated small intestine inorganic buffer (“SIB”) containing 36 mM NaCI, 20 mM NaH2P04, and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5 and at 37 °C.
  • SIB aqueous simulated small intestine inorganic buffer
  • MES 2-(N-morpholino)ethanesulfonic acid
  • Embodiment 1070 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the pharmaceutical composition comprises a polymer comprising a structure corresponding to Formula 4:
  • each R is independently hydrogen or an ethylene crosslink between
  • N 3 ⁇ 4 ⁇ ⁇ two nitrogen atoms of the crosslinked amine polymer ( N 3 ⁇ 4 ⁇ ⁇ ) and a, b, c, and m are integers.
  • Embodiment 1071 The pharmaceutical composition for use in a method of treating an acid-base disorder according to embodiment 1070 wherein m is a large integer indicating an extended polymer network.
  • Embodiment 1072 The pharmaceutical composition for use in a method of treating an acid-base disorder according to embodiment 1070 or 1071 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1 : 1 to 5:1.
  • Embodiment 1073 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1072 wherein a ratio of the sum of a and b to c (i.e. , a+b:c) is in the range of about 1.5:1 to 4:1.
  • Embodiment 1074 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1073 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75:1 to 3:1.
  • Embodiment 1075 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1074 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 2:1 to 2.5:1.
  • Embodiment 1076 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1075 wherein the sum of a and b is 57 and c is 24.
  • Embodiment 1077 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein 50-95% of the R substituents are hydrogen and 5-50% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 1078 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein 55-90% of the R substituents are hydrogen and 10-45% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 1079 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein 60-90% of the R substituents are hydrogen and 10-40% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 1080 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein 65-90% of the R substituents are hydrogen and 10-35% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 1081 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1082 wherein the R substituents are hydrogen and 10-30% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 1082 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the composition is the polymer of any of embodiments 768 to 774 wherein 75-85% of the R substituents are hydrogen and 15-25% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 1083 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the R substituents are hydrogen and 15-20% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer.
  • Embodiment 1084 The pharmaceutical composition for use in a method of treating an acid-base disorder according to any preceding enumerated embodiment wherein the R substituents are hydrogen and about 19% are an ethylene crosslink.
  • Embodiment 1085 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a SIB assay.
  • Embodiment 1086 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay.
  • Embodiment 1087 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay.
  • Embodiment 1088 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a SIB assay.
  • Embodiment 1089 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a SIB assay.
  • Embodiment 1090 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in a SIB assay.
  • Embodiment 1091 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in a SIB assay.
  • Embodiment 1092 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 4.5 mEq/g in a SIB assay.
  • Embodiment 1093 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 5 mEq/g in a SIB assay.
  • Embodiment 1094 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 5.5 mEq/g in a SIB assay.
  • Embodiment 1095 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in a SIB assay.
  • Embodiment 1096 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.1 :1 , respectively.
  • Embodiment 1097 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.2:1 , respectively.
  • Embodiment 1098 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.25:1 , respectively.
  • Embodiment 1099 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.3:1 , respectively.
  • Embodiment 1100 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.35:1 , respectively.
  • Embodiment 1101. The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.4:1 , respectively.
  • Embodiment 1102. The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.45:1 , respectively.
  • Embodiment 1103. The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.5:1 , respectively.
  • Embodiment 1104. The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2:3, respectively.
  • Embodiment 1105. The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.75:1 , respectively.
  • Embodiment 1106 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 0.9:1 , respectively.
  • Embodiment 1107 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1 :1 , respectively.
  • Embodiment 1108 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1.25:1 , respectively.
  • Embodiment 1109 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1.5:1 , respectively.
  • Embodiment 1110 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 1.75:1 , respectively.
  • Embodiment 1111 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2:1 , respectively.
  • Embodiment 1112 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2.25:1 , respectively.
  • Embodiment 1113 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2.5:1 , respectively.
  • Embodiment 1114 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 2.75:1 , respectively.
  • Embodiment 1115 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 3:1 , respectively.
  • Embodiment 1116 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 4:1 , respectively.
  • Embodiment 1117 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 5:1 , respectively.
  • Embodiment 1118 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 6:1 , respectively.
  • Embodiment 1119 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 7:1 , respectively.
  • Embodiment 1120 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 8:1 , respectively.
  • Embodiment 1121 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 9:1 , respectively.
  • Embodiment 1122 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 10:1 , respectively.
  • Embodiment 1123 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 12.5:1 , respectively.
  • Embodiment 1124 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the binding capacity of the pharmaceutical composition is characterized by a ratio of the amount of bound chloride to bound phosphate in a SIB assay of at least 15:1 , respectively.
  • Embodiment 1125 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition has an equilibrium chloride binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 1126 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition has an equilibrium chloride binding capacity of at least 7.5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 1127 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment wherein the pharmaceutical composition has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCI and 63 mM HCI at pH 1.2 and 37 °C.
  • SGF aqueous simulated gastric fluid buffer
  • Embodiment 1128 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-base disorder is metabolic acidosis.
  • Embodiment 1129 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the patient is afflicted with chronic kidney disease.
  • Embodiment 1130 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the pharmaceutical composition comprises a polymer as defined anywhere in the description.
  • Embodiment 1131 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 21 mEq/l.
  • Embodiment 1132 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 20 mEq/l.
  • Embodiment 1133 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 19 mEq/l.
  • Embodiment 1134 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 18 mEq/l.
  • Embodiment 1135 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 17 mEq/l.
  • Embodiment 1 136 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 16 mEq/l.
  • Embodiment 1 137 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 15 mEq/l.
  • Embodiment 1 138 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 14 mEq/l.
  • Embodiment 1 139 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 13 mEq/l.
  • Embodiment 1 140 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 12 mEq/l.
  • Embodiment 1 141 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 11 mEq/l.
  • Embodiment 1 142 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of less than about 10 mEq/l.
  • Embodiment 1 143 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 10 mEq/l.
  • Embodiment 1 144 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 11 mEq/l.
  • Embodiment 1 145 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 12 mEq/l.
  • Embodiment 1 146 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 13 mEq/l.
  • Embodiment 1 147.
  • Embodiment 1 148 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 15 mEq/l.
  • Embodiment 1 149 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 16 mEq/l.
  • Embodiment 1 150 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 17 mEq/l.
  • Embodiment 1 151 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 18 mEq/l.
  • Embodiment 1 152 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 19 mEq/l.
  • Embodiment 1 153 The pharmaceutical composition for use in a method of treating an acid-base disorder of any preceding enumerated embodiment, wherein the acid-based disorder is characterized by a baseline serum bicarbonate value of at least about 20 mEq/l.

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Abstract

La présente invention concerne, entre autres, des compositions pharmaceutiques et des méthodes de traitement d'un animal, y compris l'homme, ainsi que des procédés de préparation de telles compositions.<i /> Dans certaines modes de réalisation, les compositions pharmaceutiques contiennent des compositions non absorbables et peuvent être utilisées, par exemple, pour traiter des maladies ou d'autres affections métaboliques dans lesquelles l'élimination des protons, de la base conjuguée d'un acide fort et/ou d'un acide fort du tractus gastro-intestinal apporterait des bienfaits physiologiques, tels qu'une normalisation des concentrations sériques en bicarbonate et du pH sanguin chez l'animal, y compris l'homme. Dans certains modes de réalisation, l'invention concerne également des compositions et des méthodes d'amélioration de la qualité de vie et/ou du score de fonction physique chez de tels patients. Dans certains modes de réalisation, l'invention concerne en outre des compositions et des méthodes de ralentissement de la progression d'une maladie rénale chez de tels patients.
PCT/US2019/035470 2018-06-04 2019-06-04 Méthode de traitement des troubles de l'équilibre acido-basique Ceased WO2019236639A1 (fr)

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USPCT/US2018/059094 2018-11-03
PCT/US2018/059094 WO2019236124A1 (fr) 2018-06-04 2018-11-03 Méthode de traitement de troubles de l'équilibre acido-basique
US201962825006P 2019-03-27 2019-03-27
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